Azolo-pyrimidines

ES 2 247 478 T3

DESCRIPTION

Azolo-pyrimidines.

Field of the invention

This invention relates to compounds suitable for a treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorders, supranuclear palsy and eating disorders as well as the treatment of immunological, cardiovascular and related diseases. with the heart and colonic hypersensitivity associated with psychopathological complaints and stress, these compounds being certain [1,5-a] -pyrazolo-pyrimidines.

Background of the invention

Corticotropin releasing factor (hereinafter referred to as CRF), a 41 amino acid peptide, is the main physiological regulator of proopiomelanocortin-derived peptide secretion (POMC) from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (United States) 80: 4851 (1983); W. Vale et al., Science 213: 1394 (1981)]. In addition to this endocrine role in the pituitary gland, the immunohistochemical localization of CRF has shown that the hormone has a wide extra-hypothalamic distribution in the central nervous system and that it produces a wide range of autonomic, electrophysiological and behavioral effects consistent with the neurotransmitter and neurotransmitter role. neuromodulator in the brain [W. Vale et al., Rec. Prog. Horm. Res. 39: 245 (1983); GF Koob, Persp. Behav. Med. 2:39 (1985); EB De Souza et al., J. Neurosci. 5: 3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the immune system response to physiological, psychological and immunological stressors [JE Blalock, Physiological Reviews 69: 1 (1989); JE Morley, Life Sci 41: 527 (1987)].

Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders, and eating disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, and amyotrophic lateral sclerosis as they refer to dysfunction of CRF neurons in the nervous system. central [for an analysis see EB De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder, or major depression, the concentration of CRF increases significantly in the cerebrospinal fluid (CSF) of individuals without medication [CB Nemeroff et al., Science 226: 1342 (1984); CM Banki et al., Am. J. Psychiatry 144: 873 (1987); RD France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25: 355 (1989)]. Furthermore, the density of CRF receptors decreases significantly in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [CB Nemeroff et al., Arch. Gen Psychiatry 45: 577 (1988)]. Furthermore, there is a blunt adrenocorticotropin (ACTH) response to CRF (administered iv) observed in depressed patients (PW Gold et al., Am. J. Psychiatry 141: 619 (1984); F. Holsboer et al, Psychoneuroendocrinology 9: 147 (1984), PW 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 CRF hypersecretion may be involved in the symptoms seen in human depression [RM: Sapolsky, Arch. Gen. Psychiatry 46: 1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus 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 disorders has also been postulated. CRF produces anxiogenic effects in animals and benzodiazepine / non-benzodiazepine anxiolytic interactions and CRF has been demonstrated in a wide variety of behavioral anxiety models [DR Britton et al., Lifer Sci. 31: 363 (1982); CW Berridge and AJ Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist an a-helical ovine CRF (9-41) in various behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to those of benzodiazepines [CW Berridge and AJ Dunn Horm. Behav. 21: 939 (1987), Brain Research Reviews 15:71 (1990)]. All neurochemical, endocrine, and receptor binding studies have demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence of the involvement of CRF in these disorders. Chlorodiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test [KT Britton et al., Psychopharmacology 86: 170 (1985); KT Britton et al., Psychopharmacology 94: 306 (1988)] as in the acoustic startle test [NR Swerdlow et al., Psychopharmacology 88: 147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was alone without behavioral activity in the operant conflict assay, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) improved the CRF stocks [KT Britton et al., Psychopharmacology 94: 306 (1988)].

The mechanisms and sites of action through which conventional anxiolytics and antidepressants produce their therapeutic effects continue to be clarified. However, it has been hypothesized that they are involved in suppressing CRF hypersecretion seen in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (CRF_9-4i α-helical) in various behavioral paradigms have shown that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to benzodiazepines [for a discussion see GF Koob and KT Britton, in: Corticotropin2

ES 2 247 478 T3

Releasing Factor: Basic and Clinical Studies of a Neuropeptide, EB De Souza and CB Nemeroff eds., CRC Press p221 (1990)].

Various publications describe corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT Application US94 / 11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and Pfizer EP 0 778 277 A1.

As far as they are known, [1,5-a] -pyrazolo-1,3,5-triazines, [1,5-a] -1,2,3-triazolo-1,3,5-triazines , [1,5a] -pyrazolo-pyrimidines and [1,5-a] -1,2,3-triazole-pyrimidines have not previously been reported as antagonist compounds of corticotropin releasing factor useful in the treatment of psychiatric disorders and neurological diseases. However, there are publications that show some of these effects for other uses.

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

<img file="ES2247478T3_D0001.tif" />

in which R¹ is OH or alkanoyl, R² is H, OH, or SH, and R³ is an unsaturated heterocyclic group, naphthyl or substituted phenyl, and indicates that the compounds have xanthine oxidase inhibitory activity and are useful for the treatment of gout.

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

<img file="ES2247478T3_D0002.tif" />

where A is CH or N, R⁰ and R³ are H or alkyl, and R¹ and R² they are H, alkyl, alkoxy, alkylthio, nitro, etc., and indicates that the compounds inhibit androgens and are useful in the treatment of benign prostatic hypertrophy and prostatic carcinoma.

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

<img file="ES2247478T3_D0003.tif" />

ES 2 247 478 T3 in which R¹ is CH3, C₂H₅ or CeHj, X is H, CeHj, m-CH₃C6H4, CN, COOEt, Cl, I or Br, Y is H, CeHj, or-CH₃C6H4, or P-CH3C6H4, and Z is OH, H, CH3, C2H5, CeHj, n-C3H₇, i-C3H₇, SH, SCH3, NHC4H9, or N ^ Hj ^, and indicates that the compounds are inhibitors of c-AMP-phosphodiesterase useful as bronchodilators.

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

SR * R '

<img file="ES2247478T3_D0004.tif" />

R where R¹ is H or alkyl, R² is H or alkyl, R³ is H, lower alkyl, alkanoyl, carbamoyl, or alkylcarbamoyl and R is pyridyl, pyrimidinyl, or pyrazinyl, indicating that the compounds are useful as bronchodilators.

US 5,137,887 describes pyrazolotriazines of formula

<img file="ES2247478T3_D0005.tif" />

wherein R is lower alkoxy, and shows that the compounds are xanthine oxidase inhibitors and are useful for the treatment of gout.

US 4,892,576 describes pyrazolotriazines of formula

<img file="ES2247478T3_D0006.tif" />

where X is O or S, Ar is a phenyl, naphthyl, pyridyl, or thienyl group, R₆-R₈ are H, alkyl, etc., and R₉ is H, alkyl, phenyl, etc. The patent indicates that the compounds are useful as herbicides and plant growth regulators.

US 5,484,760 and WO 92/10098 describe herbicidal compositions containing, among other things, a herbicidal compound of the formula ^R1

<img file="ES2247478T3_D0007.tif" />

R

ES 2 247 478 T3 where A can be N, B can be CR₃, R₃ can be phenyl or substituted phenyl, etc., R is -N (R₄) SO2R₅ bear₂N (R₆) R₇ and R₁ and R₂ can be taken together to form

<img file="ES2247478T3_D0008.tif" />

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

US 3,910,907 and Senga et al., J. Med. Chem., 1982, 25, 243-249, describe cAMP phosphodiesterase inhibitory triazolotriazines of the formula

<img file="ES2247478T3_D0009.tif" />

where Z is H, OH, CH₃, C₂H₅, C₆H₅, nC₃H₇, iso-C₃H₇, SH, SCH₃, NH (nC₄H₉) on (C₂H₅)₂, R is H or CH₃, and R₁ is CH₃ or C₂H₅. The reference cites eight therapeutic areas in which cAMP phosphodiesterase inhibitors could be useful: asthma, diabetes mellitus, control of female fertility, male infertility, psoriasis, thrombosis, anxiety and hypertension.

WO95 / 35298 (Otsuka, 1995) describes pyrazolopyrimidines and indicates that they are useful as analgesics. Compounds are represented by the formula

<img file="ES2247478T3_D0010.tif" />

where Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond, alkylene or alkenylene, R¹ is H, alkyl, etc., R² is naphthyl, cycloalkyl, heteroaryl, substituted phenyl, or phenoxy, R³ is H, alkyl or phenyl, R⁴ is H, alkyl, alkoxycarbonyl, phenylalkyl, phenyl optionally substituted with phenylthio or halogen, R⁵ and R⁶ they are H or alkyl.

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

<img file="ES2247478T3_D0011.tif" />

ES 2 247 478 T3 in which R₁, R₂, R₃ and IR are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl, or phenyl, R₅is SR₆ or NR₇R₈, R₆ is pyridyl or optionally substituted phenyl, and R₇ and R₈ they are H or optionally substituted phenyl.

Springer et al, J. Med. Chem., 1976, vol. 19, Nos. 2,291-296 and US Springer Patents 4,021,556 and 3,920,652 describe pyrazolopyrimidines of formula

<img file="ES2247478T3_D0012.tif" />

wherein R can be phenyl, substituted phenyl, or pyridyl, and its use to treat gout, based on its ability to inhibit xanthine oxidase.

Joshi et al., J. Prakt. Chemie, 321, 2, 1979, 341-344, describes compounds of formula

<img file="ES2247478T3_D0013.tif" />

in which R¹ is CF3, C2F5, or C6H4F, and R² is CH3, C₂H₅, CF₃ or C₆H₄F.

Maquestiau et al., Bull. Soc. Belg., Vol. 101, no.2, 1992, pages 131-136 describe a pyrazolo [1,5-a] pyrimidine of formula

<img file="ES2247478T3_D0014.tif" />

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

<img file="ES2247478T3_D0015.tif" />

where R is NH2 or OH and Ar is 4-phenyl-3-cyano-2-aminopyrid-2-yl.

ES 2 247 478 T3

Other references describing azolopyrimidines include EP 0 511 528 (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., 24, 610-613 (1981) and J. Het. Chem., 22, 601 (1985).

WO97 / 29109 (Janssen) describes certain pyrazolopyrimidines as CRF receptor antagonists.

Summary of the invention

According to one aspect, the present invention provides new compounds, pharmaceutical compositions that can be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease. , gastrointestinal disease, anorexia nervosa or other eating disorders, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders the treatment of which can be accomplished or facilitated by antagonizing CRF, including but not limited to CRF-induced or facilitated disorders, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis, and allergies; generalized anxiety disorders; panic, phobias, obsessive compulsive disorder; post-traumatic stress disorders, stress-induced sleep disorders; pain perception such as fibromyalgia; mood disorders, such as depression, including major depression, single episode depression, recurrent depression, child abuse-induced depression, and postpartum depression; dystemia; bipolar disorders; cyclothymia; s índrome fatigue, headache induced by stress; 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 syndrome, Crohn's disease, spastic colon, post-operative diarrhea and ileus, and colonic hypersensitivity associated with psychopathological complaints or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes, euthyroid disease syndrome; syndrome of inappropriate antidiuretic hormone (ADH); obesity, infertility, head trauma, spinal cord trauma; ischemic neurological injury (eg, cerebral ischemia such as cerebral ischemia of the hippocampus); excitotoxic neuronal injury; epilepsy; cardiovascular and heart-related diseases including hypertension, tachycardia, and congestive heart failure; apoplexy; immune dysfunctions including stress-induced immune dysfunctions (e.g., stress-induced fevers, swine stress syndrome, bovine transport fever, equine paraxismal fibrillation and confinement-induced dysfunctions in chickens, shearing stress in sheep, or stress related to interaction human-animal in dogs); muscle spasms; urinary incontinence; senile dementia of the Alzheimer's disease type; multi-infarct dementia; amyotrophic lateral sclerosis, chemical addiction dependencies (for example, dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; Psychosocial dwarfism and hypoglycemia in a mammal.

The present invention provides new compounds that bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion. The compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related diseases, post-traumatic stress disorder, supranuclear palsy and eating disorders as well as treatment of immunological, cardiovascular or related diseases. heart and colonic hypersensitivity associated with psychopathological discomfort and stress in a mammal.

In accordance with another aspect, the present invention provides novel compounds described below that are useful as corticotropin releasing factor antagonists. The compounds of the present invention show activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing such compounds of formulas (1) and (2), and the use of such compounds for the manufacture of a medicament suitable for the suppression of CRF hypersecretion, and / or for the treatment of anxiety disorders.

In accordance with yet another aspect of the invention, the compounds provided by this invention (and specially labeled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical agent to bind to the CRF receptor.

ES 2 247 478 T3

Detailed description of the invention

[1] The present invention provides compounds of formula (70)

<img file="ES2247478T3_D0016.tif" />

and geometric isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof selected from the group:

a compound of formula (70) wherein R is Cl, R³ is -NHCH (n-Pr)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (CH₂OMe)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (CH₂CH₂OMe)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (c-Pr) (CH2XH2CN), R^4th is Me, R^4b is H, R^4c is Me, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (CH₂CH₂OMe)₂, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (CH₂OMe)₂, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (EtR R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is Cl, R³ is -N (Et)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (n-Pr) (CH₂CH₂CN), R^4th is Me, R^4b is H, R^4c is Me, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (n-BU) (CH₂CH₂CN), R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (n-Pr) (CH₂OMe), R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (Et)₂, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (CH2OMe) 2, R^4th is Me, R^4b is H, R^4c is OMe, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is (S) -NH (CH₂CH₂OMe) CH₂OMe, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

ES 2 247 478 T3 a compound of formula (70) wherein R is Cl, R³ is -NH (CH₂CH₂OMe) CH₂OMe, R^4th is Me, R^4b is H, R^4c it is

Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (CH₂CH₂OMe)₂, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NH (Et), R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (n-Pr)₂, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (CH₂OMe)₂, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is (S) -NH (CH2CH2OMe) CH2OMe, R^4th is Me, R^4b is H, R^4cis Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NH (CH2CH2OMe) CH2OMe, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (n-Pr) (CH₂CH₂CN), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (Et)₂, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is (S) -NH (CH2CH2OMe) CH2OMe, R^4th is Cl, R^4b is H, R^4cis Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NH (CH2CH2OMe) CH2OMe, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (Et)₂, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (c-Pr) (CH₂CH₂CN), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (c-Pr) (CH₂CH₂CN), R^4th is Cl, R^4b is H, R^4c is Me, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (n-Pr) (CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (n-Pr) (CH₂OMe), R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (Et)₂, R^4th is Br, R^4b is H, R^4c is OMe, R^4d is OMe and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (Et) 2, R^4th is Br, R^4b is H, R^4c is Me, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is Cl, R³ is -N (CH₂CH₂OMe)₂, R^4th is Br, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (CH2OMe) 2, R^4th is Br, R^4b is H, R^4c is OMe, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (Et)₂, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (Et)₂, R^4th is Cl, R^4b is H, R^4c is OMe, R^4d is OMe and R^4eit's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (Et)₂, R^4th is Cl, R^4b is H, R^4c is OMe, R^4d is OMe and R^4e it's H;

ES 2 247 478 T3 a compound of formula (70) wherein R is Cl, R³ is -N (CH₂CH₂OMe)₂, R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (CH₂OMe)₂, R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (Pr) (CH₂CH₂CN), R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (Bu) (Et), R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (Et) CH OMe, R^4th is Cl, R^4b is H, R^4c is H, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (Et) 2, R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (Et)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (Et)₂, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is Cl, R³ is -NHCH (Et) 2, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is Cl, R³ is -NEt₂, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H; and a compound of formula (70) wherein R is Cl, R³ is -N (Pr) (CH2CH2CN), R^4th is Me, R^4b is H, R^4c is OMe, R^4dis H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (n-Pr)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (CH₂OMe)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4dis H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (CH₂CH₂OMe)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (c-Pr) (CH₂CH₂CN), R^4th is Me, R^4b is H, R^4c is Me, R^4dis H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (CH₂CH₂OMe)₂, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (CH₂ OMe)₂, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (Et)₂, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (Et)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (n-Pr) (CH₂CH₂CN), R^4th is Me, R^4b is H, R^4c is Me, R^4dis H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (n-Bu) (CH₂CH₂CN), R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (n-Pr) (CH₂OMe), R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (Et)₂, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and

R^4e it's H;

ES 2 247 478 T3 a compound of formula (70) wherein R is Me, R³ is -NHCH (CH2OMe) 2, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is (S) -NH (CH₂CH₂OMe) CH₂OMe, R^4th is Me, R^4b is H, R^4cis Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NH (CH₂CH₂OMe) CH₂OMe, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (CH₂CH₂OMe)₂, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NH (Et), R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (n-Pr)₂, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (CH₂OMe)₂, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is (S) -NH (CH₂CH₂OMe) CH₂OMe, R^4th is Me, R^4b is H, R^4cis Cl, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NH (CH₂CH₂OMe) CH₂OMe, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (n-Pr) (CH₂CH₂CN), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (Et)₂, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4eit's H;

a compound of formula (70) in which R is Me, R³ is (S) -NH (CH2CH2OMe) CH2OMe, R^4th is Cl, R^4b is H, R^4cis Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NH (CH2CH2OMe) CH2OMe, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (Et)₂, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (c-Pr) (CH₂CH₂CN), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (c-Pr) (CH2CH2CN), R^4th is Cl, R^4b is H, R^4c is Me, R^4dis H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (n-Pr) (CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (n-Pr) (CH₂OMe), R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (Et)₂, R^4th is Br, R^4b is H, R^4c is OMe, R^4d is OMe and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (Et)₂, R^4th is Br, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (CH₂CH₂OMe)₂, R^4th is Br, R^4b is H, R^4c is OMe, R^4dis H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (CH2OMe) 2, R^4th is Br, R^4b is H, R^4c is OMe, R^4dis H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (Et)₂, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

ES 2 247 478 T3 a compound of formula (70) wherein R is Me, R³ is -N (Et)₂, R^4th is Cl, R^4b is H, R^4c is OMe, R^4d is OMe and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (Et)₂, R^4th is Cl, R^4b is H, R^4c is OMe, R^4d is OMe and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (CH₂CH₂OMe)₂, R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (CH₂OMe)₂, R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (Pr) (CH₂CH₂CN), R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (Bu) (Et), R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4eit's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (Et) CH₂OMe, R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (Et)₂, R^4th is Cl, R^4b is H, R^4c is H, R^4d is H and R^4eit's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (Et)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (Et)₂, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NHCH (Et) 2, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NEt₂, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H; and a compound of formula (70) wherein R is Me, R³ is -N (Pr) (CH₂CH₂CN), R^4th is Me, R^4b is H, R^4c is OMe, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (n-Pr)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (CH₂OMe)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (CH2CH2OMe) 2, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (c-Pr) (CI I_;CI I_;CN), R^4th is Me, R^4b is H, R^4c is Me, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (CH₂CH₂OMe)₂ , R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (CH2OMe) 2, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (Et) 2, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is F, R³ is -N (Et)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (n-Pr) (CH₂CH₂CN), R^4th is Me, R^4b is H, R^4c is Me, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (n-BU) (CH2CH2CN), R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

ES 2 247 478 T3 a compound of formula (70) wherein R is F, R³ is -NHCH (n-Pr) (CH₂OMe), R^4th is Me, R^4b is H, R^4c is me,

R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (Et)₂, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (CH2OMe) 2, R^4th is Me, R^4b is H, R^4c is OMe, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is (S) -NH (CH₂CH₂OMe) CH₂OMe, R^4th is Me, R^4b is H, R^4cis Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NH (CH₂CH₂OMe) CH₂OMe, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (CH2CH2OMe) 2, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NH (Et), R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (n-Pr)₂, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (CH2OMe) 2, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is (S) -NH (CH₂CH₂OMe) CH₂OMe, R^4th is Me, R^4b is H, R^4cis Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ en -NI PCI PCI FOMe) CI FOMe, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (n-Pr) (CH₂CH₂CN), R^4th is Me, R^4b is H, R^4c is OMe, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (Et)₂, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is (S) -NH (CH₂CH₂OMe) CH₂OMe, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ en -NI PCI PCI POMe) CI POMe, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (Et)₂, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (c-Pr) (CH2CH2CN), R^4th is Me, R^4b is H, R^4c is OMe, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (c-Pr) (CH₂CH₂CN), R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (n-Pr) (CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (n-Pr) (CH2OMe), R^4th is Cl, R^4b is H, R^4c is Me, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (Et)₂, R^4th is Br, R^4b is H, R^4c is OMe, R^4d is OMe and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (Et)₂, R^4th is Br, R^4b is H, R^4c is OMe, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is F, R³ is -N (CH₂CH₂OMe)₂, R^4th is Br, R^4b is H, R^4c is OMe, R^4d it is

H and R^4e it's H;

ES 2 247 478 T3 a compound of formula (70) wherein R is F, R³ is -NHCH (CH2OMe) 2, R^4th is Br, R^4b is H, R^4c is OMe, R^4d it is

H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (Et)₂, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (Et)₂, R^4th is Cl, R^4b is H, R^4c is OMe, R^4d is OMe and R^4eit's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (Et)₂, R^4th is Cl, R^4b is H, R^4c is OMe, R^4d is OMe and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (CH₂CH₂OMe)₂, R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (CH2OMe) 2, R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (Pr) (CH₂CH₂CN), R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (Bu) (Et), R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (Et) CH₂OMe, R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (Et) 2, R^4th is Cl, R^4b is H, R^4c is Cl, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (Et)₂, R^4th is Me, R^4b is H, R^4c is Me, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (Et)₂, R^4th is Cl, R^4b is H, R^4c is Me, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is F, R³ is -NHCH (Et) 2, R^4th is Me, R^4b is H, R^4c is Cl, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is F, R³ is -NEt₂, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

^Y a compound of formula (70) wherein R is F, R³ is -N (Pr) (CI I₂CII₂CN), R^4th is Me, R^4b is H, R^4c is OMe, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (Pr) (CH2CH2OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (Et) (CH₂CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (Me) (CH₂CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NMeEt, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is Cl, R³ is -NMePr, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is Cl, R³ is -NMeBu, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4eit's H;

a compound of formula (70) wherein R is Cl, R³ is -NH-2-butyl, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is cyclobutylamino, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

ES 2 247 478 T3 a compound of formula (70) wherein R is Cl, R³ is -N (Pr) (CH₂CH₂OMe), R^4th is Me, R^4b is H, R^4c it's OMe,

R^4d is Me and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (Et) (CH₂CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -N (Me) (CH₂CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is -NMeEt, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4eit's H;

a compound of formula (70) wherein R is Cl, R³ is -NMePr, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4eit's H;

a compound of formula (70) wherein R is Cl, R³ is -NMeBu, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4eit's H;

a compound of formula (70) wherein R is Cl, R³ is -NH-2-butyl, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4e it's H;

a compound of formula (70) wherein R is Cl, R³ is cyclobutylamino, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (Pr) (CH2CH2OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (Et) (CH2CH2OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4dis H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (Me) (CH2CH2OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NMeEt, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NMePr, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NMeBu, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NH-2-butyl, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is cyclobutylamino, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (Pr) (CH2CH2OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4dis Me and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (Et) (CH₂CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4dis Me and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -N (Me) (CH₂CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4e it's H;

a compound of formula (70) wherein R is F, R³ is -NMeEt, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4eit's H;

a compound of formula (70) wherein R is F, R³ is -NMePr, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4eit's H;

a compound of formula (70) wherein R is F, R³ is -NMeBu, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4eit's H;

a compound of formula (70) wherein R is F, R³ is -NH-2-butyl, R^4th is Me, R^4b is H, R^4c is OMe, R^4d it's me and

R^4e it's H;

ES 2 247 478 T3 a compound of formula (70) wherein R is F, R³ is cyclobutylamino, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (Pr) (CH₂CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (Et) (CH₂CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (Me) (CH₂CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NMeEt, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4eit's H;

a compound of formula (70) in which R is Me, R³ is -NMePr, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4eit's H;

a compound of formula (70) in which R is Me, R³ is -NMeBu, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4eit's H;

a compound of formula (70) in which R is Me, R³ is -NH-2-butyl, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is cyclobutylamino, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is H and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (Pr) (CH₂CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (Et) (CH2CH2OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -N (Me) (CH₂CH₂OMe), R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NMeEt, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4eit's H;

a compound of formula (70) in which R is Me, R³ is -NMePr, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4eit's H;

a compound of formula (70) in which R is Me, R³ is -NMeBu, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4e it's H;

a compound of formula (70) in which R is Me, R³ is -NH-2-butyl, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4e it's H; and a compound of formula (70) wherein R is Me, R³ is cyclobutylamino, R^4th is Me, R^4b is H, R^4c is OMe, R^4d is Me and R^4e it's H.

[2] The specifically preferred compounds of the present invention include compounds and geometric isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms, wherein said compound is selected from: 7 - (diethylamino) -2,5-dimethyl-3- (2-methyl-4-methoxyphenyl) - [1,5-a] -pyrazolopyrimidine and 7- (N- (3-cyanopropyl) -N-propylamino) -2 , 5-dimethyl-3- (2,4-dimethylphenyl) - [1,5-a] -pyrazolopyrimidine.

[3] The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of the compounds described above and a pharmaceutically acceptable carrier. ⁴

[4] The present invention also provides the use of the above compounds in the manufacture of a medicament suitable for the treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy , immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorders, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, bleeding stress, obesity, infertility, head and spinal cord trauma, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be accomplished or facilitated by antagonizing CRF, including16

ES 2 247 478 T3 going but not limited to CRF-induced or facilitated disorders in mammals comprising administering to the mammal a therapeutically effective amount of the compounds described above.

Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric olefin isomers, C = N double bonds, and the like are also present in the compounds, and all such stable isomers are contemplated by the present invention. The compounds can be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are included unless the specific stereochemical or isomeric form is specifically indicated.

The term "alkyl" includes both straight and branched chain alkyl having the specified number of carbon atoms. Commonly used abbreviations have the following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl. The prefix "n" means a linear alkyl chain. The prefix "c" means a cycloalkyl. The prefix "(S)" refers to the S enantiomer and the prefix "(R)" refers to the R enantiomer. "Alkenyl" includes hydrocarbon chains of straight or branched configuration and one or more unsaturated carbon-carbon bonds that can 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 that can occur at any stable point along the chain, such as ethynyl, propynyl, and the like. "Haloalkyl" is intended to include both straight and branched chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen atoms. "Alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridging bond; "Cycloalkyl" is intended to include saturated ring groups, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. "Halo" or "halogen" includes fluoro, chloro, bromo, and iodo.

The term "substituted", as used herein, means that one or more hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the normal valence of the designated atom is not exceeded and that the substitution results in a stable compound. When a substitution is keto (i.e. = O), then 2 hydrogens on the atom are replaced.

Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to overcome isolation to a useful degree of purity from a reaction mixture, and formulation into an effective therapeutic agent.

The term "appropriate amino acid protecting group" refers to any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. Such amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Willey &amp; Sons, New York (1991) and "The Peptides: Analysis, Synthesis, Biology, Bol. 3, Academic Press, New York. (1981), the description of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) types of aromatic carbamates such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1- (p-biphenyl) -1-methylethoxycarbonyl and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) types of aliphatic carbamates such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl; 4) types of cyclic alkyl carbamate such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol-containing types such as phenylthiocarbonyl and dithiasuccinoyl.

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

Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. In Remington's Pharmaceutical Sciences, 17^to ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference, are lists of suitable salts.

"Prodrugs" are considered to be any covalently linked carrier that releases the active parent drug of formula (I) or (II) in vivo when such a prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) and (II) are prepared by modifying functional groups present in the compounds such that the modifications are cleaved, by routine manipulation or in vivo, in the parent compounds. Prodrugs include compounds in which hydroxy, amine, or sulfhydryl groups are attached to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group,

ES 2 247 478 T3 respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of formulas (I) and (II); and the like.

The term "therapeutically effective amount" of a compound of this invention refers to an amount effective to antagonize an abnormal level of CRF or to treat symptoms of affective disorder, anxiety, or depression in a host.

Synthesis

Some compounds of Formula (1) can be prepared from intermediates of Formula (7), using the procedures outlined in Scheme 1:

Scheme 1

<img file="ES2247478T3_D0017.tif" />

Compounds of Formula (7) (where 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 reaction temperatures ranging from - 80 ° C to 250 ° C, yielding products of Formula (8) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy, or haloalkanesulfonyloxy. Halogenating agents include, but are not limited to, SOCl2, POCl₃, PCl₃, PCl₅, POr₃, PBr₃ or PBr₅. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride), or haloalkylsulfonyl halides or anhydrides. (preferably trifluoromethanesulfonic anhydride). Bases can 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 di-isopropylamide), alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20 ° C to 100 ° C.

Compounds of Formula (8) can be reacted with compounds of Formula R³H (where R³ is defined as above with the exception of R³ not SH, COR⁷, CO₂R⁷, 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 to 250 ° C, generating compounds of Formula (1). Bases may include, but are not limited to, alkali metal hydrides (preferably18

ES 2 247 478 T3 especially sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), carbonates of alkali metals, alkali metal bicarbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran) or

1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulphoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0 ° C to 140 ° C.

Scheme 2 illustrates procedures for converting intermediates of Formula (7) (where Y is S) to some compounds of Formula (1).

Scheme 2

<img file="ES2247478T3_D0018.tif" />

Compounds of Formula (7) (where Y is S) can be treated with an alkylating agent R¹³X (in which R¹³ is as defined above, with the exception 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 to 250 ° C. Bases can include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or

1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulphoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -80 ° C to 100 ° C.

ES 2 247 478 T3

Then, the compounds of Formula (12) (Formula (1) in which R³ is SR¹³) can be reacted with compounds of Formula R³H, yielding compounds of Formula (1), using the same conditions and reagents as used for the conversion of compounds of Formula (8) to compounds of Formula (1) as indicated above for Scheme 1. Alternatively, the compounds of Formula (12) (Formula (1) wherein R³ is SR¹³) can be oxidized to give compounds of Formula (13) (Formula (1) wherein R³ is S (O) nR¹³, n is 1 or 2) by treatment with an oxidizing agent, in the presence of an inert solvent and at temperatures ranging from -80 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 can include, but are not limited to, alkanones (3 to 10 carbons, preferably acetone), water, alkyl alcohols (1 to 6 carbons), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes of 1 to 10 carbons. and 1 to 10 halogens (preferably dichloromethane) or combinations thereof. The choice of oxidant and solvent is known to those skilled in the art (cf., Uemura, S., Oxidation of Sulfur, Selenium and Tellerium, in Comprehensive Organic Synthesis, Trost, BM ed., (Elmsford, NY, Pergamon Press , 1991), 7, 762-769). Preferred reaction temperatures range from -20 ° C to 100 ° C. Compounds of Formula (13) (Formula (1) in which R³ is S (O) nR¹³, n is 1, 2) can then be reacted with compounds of Formula R³H, giving compounds of Formula (1), using the same conditions and reagents that were used for the conversion of compounds of Formula (8) to compounds of Formula (1) as indicated above for scheme (1).

Compounds of Formula (1), in which R³ can be NR⁸COR⁷, -N (COR⁷) 2, -NR⁸CONR⁶R⁷, -NR⁸CO2R¹³, -NR⁶R⁷, -NR⁸SW₂R⁷, can be prepared from compounds of Formula (7), where Y is NH, by the procedures depicted in Scheme 3.

Scheme 3

<img file="ES2247478T3_D0019.tif" />

The reaction of the compounds of Formula (7), in which 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 ranging from -80 ° C to 250 ° C it can produce compounds of Formula (1), in which R³ can be -NR⁸COR⁷, -N (COR⁷) 2, NR⁸CONR⁶R⁷, -NR⁸CO2R¹³, -NR⁶R⁷, -NR⁸SO2R⁷. Alkylating agents may include, but are not limited to, C1-C alkyl halides, tosylates, mesylates, or triflates.₁₀; C haloalkyl halides, tosylates, mesylates or triflates₁-C₁₀ (1 to 10 halogens); C alkoxyalkyl halides, tosylates, mesylates or triflates₂-C₈; C cycloalkyl halides, tosylates, mesylates or triflates₃-C₆; C cycloalkylalkyl halides, tosylates, mesylates or triflates₄-C₁₂; aryl (C alkyl) halides, tosylates, mesylates or triflates₁-C₄); Heteroaryl (C alkyl) halides, tosylates, mesylates or triflates₁-C₄); or heterocyclyl (C alkyl) halides, tosylates, mesylates or triflates₁-C₄). Acylating agents may include, but are not limited to, C alkanoyl halides or anhydrides.₁C₁₀C haloalkanoyl halides or anhydrides₁-C₁₀ with 1-10 C alkanoalkanoyl halogens, halides or anhydrides₂-C₈, C3-C6 cycloalkanoyl halides or anhydrides, C4-C12 cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, arylalkanoyl halides or anhydrides (C₁-C₄), heteroaroyl halides and anhydrides, heteroaroyl halides or anhydrides (C₁-C₄), heterocyclylcarboxylic acid halides or anhydrides or heterocyclylalkanoyl halides or anhydrides (C₁-C₄). Sulfonylating agents include, but are not limited to, C alkylsulfonyl halides or anhydrides.₁ -C₁₀C haloalkylsulfonyl halides or anhydrides₁-C₁₀ with 1 to 10 C alkoxyalkylsulfonyl halogens, halides or anhydrides₂-C₈C cycloalkylsulfonyl halides or anhydrides₃-C₆C cycloalkylsulfonyl halides or anhydrides₄-C₁₂, arylsulfonyl, aryl (C-alkyl) halides or anhydrides₁-C₄) -, heteroarylsulfonyl halides or anhydrides, heteroaryl (C-alkyl) halides or anhydrides₁ -C₄) sulfonyl, heterocyclylsulfonyl halides or anhydrides or heterocyclyl (C1-C4 alkyl) sulfonyl halides or anhydrides. Bases can include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably di20

ES 2 247 478 T3 lithium isopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0 ° C to 100 ° C.

Scheme 4 represents procedures that may be employed to prepare intermediates of Formula (7), where Y is O, S and Z is CR².

Scheme 4

<img file="ES2247478T3_D0020.tif" />

Compounds of formula ArCH₂CN are reacted with compounds of the formula R²COR^b, in which R²is as defined above and R^b is halogen, cyano, lower alkoxy (1 to 6 carbons) or lower alkanoyloxy (1 to 6 carbons), in the presence of a base, in an inert solvent and at reaction temperatures ranging from -78 ° C to 200 ° C , providing compounds of Formula (3). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis (trimethylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-diisopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamide (preferably dimethylformamide), N, N-dialkylformamide (preferably dimethylformamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0 ° C to 100 ° C.

Compounds of Formula (3) can be treated with hydrazine hydrate in the presence of an inert solvent at temperatures ranging from 0 ° C to 200 ° C, preferably from 70 ° C to 150 ° C, to produce compounds of Formula (4). Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4 -dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or

ES 2 247 478 T3 toluene). Compounds of Formula (4) can be reacted with compounds of Formula (5) (where R^C is alkyl (1 to 6 carbons)) in the presence or absence of an acid, in the presence of an inert solvent at temperatures ranging from 0 ° C to 200 ° C, producing compounds of Formula (6). Acids may include, but are not limited to, 2- to 10-carbon alkanoic acids (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids can be used. Inert solvents may include, but are not limited to, water, alkanonitriles (1 to 6 carbons, preferably acetonitrile), halocarbons of 1 to 6 carbons and 1 to 6 halogens (preferably dichloromethane or chloroform), alkyl alcohols of 1 to 10 carbons (preferably ethanol), dialkyl ethers (4 to 12 carbons, preferably diethyl ether or di-isopropyl ether) or cyclic ethers such as dioxane or tetrahydrofuran. Preferred temperatures range from room temperature to 100 ° C.

Compounds of Formula (6) can be converted to intermediates of Formula (7) by treatment with compounds C = Y (R^d)₂ (where Y is O or S and R^d is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) in the presence or absence of a base, in an inert solvent and at reaction temperatures ranging 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 carbons) (preferably sodium methoxide or sodium ethoxide), alkali metal carbonates, alkali metal hydroxides, trialkyl amines (preferably N, N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or

1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred temperatures are 0 ° C to 150 ° C.

Intermediates of Formula (7), where Z is N, can be synthesized according to the procedures outlined in Scheme 5.

Scheme 5

<img file="ES2247478T3_D0021.tif" />

ES 2 247 478 T3

ArCH compounds₂CN are reacted with compounds of Formula R^whatCH₂N₃ (in which R^what is a phenyl group optionally substituted with H, alkyl (1 to 6 carbons) or alkoxy (1 to 6 carbons) in the presence or absence of a base, in an inert solvent and at temperatures ranging from 0 ° C to 200 ° C , generating compounds of Formula (9). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide, sodium ethoxide or potassium t-butoxide), alkaline earth metal hydrides, dialkylamides alkali metal (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-diisopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from room temperature to 100 ° C. Compounds of Formula (9) can be treated with a reducing agent, in an inert solvent and at a temperature of -100 ° C to 100 ° C, providing the products of Formula (10). Reducing agents include, but are not limited to, (a) hydrogen gas in combination with noble metal catalysts such as Pd on carbon, PtO2, Pt on carbon, Pt on alumina or Raney nickel, (b) alkali metals (preferably sodium) in combination with liquid ammonia or (c) ceric ammonium nitrate. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures are -50 ° C to 60 ° C. The compounds of Formula (9) are then converted to compounds of Formula (7) (where Z is N) by intermediates of Formula (11) using the reagents and reaction conditions indicated in Scheme 4 for compound conversion of Formula (4) into compounds of Formula (7) (where Z is CR²).

Compounds of Formula (1) can also be prepared from compounds of Formula (7) (where Y is O, S and Z is as defined above) as indicated in Scheme 6.

Scheme 6

<img file="ES2247478T3_D0022.tif" />

Compounds of Formula (7) can be reacted with compounds of Formula R³H in the presence of a dehydrating agent, in an inert solvent and at reaction temperatures ranging from 0 ° C to 250 ° C. Dehydrating agents include, but are not limited to, P₂OR₅, molecular sieves or inorganic or organic acids. Acids may include, but are not limited to, 2 to 10 carbon alkanoic acids (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), 1 to 10 carbon alkanesulfonic acids (preferably methanesulfonic acid), hydrochloric acid , sulfuric acid or phosphoric acid. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably glyme or diglyme), cyclic ethers ( preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamide (preferably dimethylacetamide), Cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or halocarbons of 1 to 10 carbons and 1 to 10 halogens (preferably chloroform). Preferred reaction temperatures range from room temperature to 150 ° C.

Some compounds of Formula (1) (where A is N) can also be prepared by the procedures shown in Scheme 7:

ES 2 247 478 T3

Scheme 7

<img file="ES2247478T3_D0023.tif" />

Intermediates of Formula (14), where Z is as defined above, can be reacted with compounds of Formula R³C (OR^and) 3, where R^and it can be alkyl (1 to 6 carbons) in the presence or absence of an acid in an inert solvent at temperatures ranging from 0 ° C to 250 ° C. Acids may include, but are not limited to, 2 to 10 carbon alkanoic acids (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), 1 to 10 carbon alkanesulfonic acids (preferably methanesulfonic acid), hydrochloric acid , sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids can be used. Inert solvents may include, but are not limited to, lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 50 ° C to 150 ° C.

Intermediates of Formula (7) can also be synthesized by the reactions shown in Scheme 8.

Scheme 8

<img file="ES2247478T3_D0024.tif" />

Compounds of Formula (15) (where Y is OH, SH, NR⁶R⁷, Z is as defined above, X is Br, Cl, I, O₃SCF₃ or B (OR "")₂ and R "" is H or alkyl (1 to 6 carbons)) can be reacted with a compound of 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 an organometallic catalyst in the presence or absence of a base, in inert solvents and at temperatures ranging from -100 ° C to 200 ° C. Those skilled in the art will recognize that ArM reagents can be generated in situ. Organometallic catalysts include, but are not limited to, palladiophosphine complexes (such as Pd (PPh₃)₄), palladium halides or alkanoates (such as PdCl (PPh₃)₂ o Pd (OAc)₂) or nickel complexes (such as NiCl₂(PPh₃)₂). Bases can include, but are not limited to, alkali metal carbonates or trialkylamines (preferably N, N-di-isopropyl-N-ethyl amine 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), dialkylsulphoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. Preferred reaction temperatures range from -80 ° C to 100 ° C. The choices of M and X are known to those skilled in the art (cf.

ES 2 247 478 T3

Imamoto, T., Organocerium reagents in Comprehensive Organic Synthesis, Trost, BM ed., (Elmsford, NY. Pergamon Press, 1991), 1, 231-250; Knochel, P., Organozinc, Organocadmium and Organomercury Reagents in Comprehensive Organic Synthesis, Trost, BM ed., (Elmsford, NY: Pergamon Press, 1991), 1, 211-230; Knight, DW, Coupling Reactions between sp² Carbon Centers, in Comprehensive Organic Synthesis, Trost, BM ed., (Elmsford, NY. Pergamon Press, 1991), 3,481-520).

Compounds of Formula (1) can also be prepared using the procedures shown in Scheme 9.

Scheme 9

<img file="ES2247478T3_D0025.tif" />

Compounds of Formula (16), in which A, Z, R¹ and R³ are as defined above and X is Br, Cl, I, O₃SCF₃ or B (OR "")₂ and R is H or alkyl (1 to 6 carbons)) can be reacted with a compound of Formula ArM (where M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl2, 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 and at temperatures ranging from -100 ° C to 200 ° C. Those skilled in the art will recognize that ArM reagents can be generated in situ (see Comprehensive Organic Synthesis references above). Organometallic catalysts include, but are not limited to, complexes of palladium and phosphine (such as Pd (PPh₃)₄), palladium halides or alkanoates (such as PdCl₂(PPh₃)₂ o Pd (OAc)₂) or nickel complexes (such as NiCl₂(PPh₃)₂). Bases can include, but are not limited to, alkali metal carbonates or trialkylamines (preferably N, N-di-isopropyl-N-ethyl amine 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 range from -80 ° C to 100 ° C.

Intermediate compounds of Formula (7) (where Y is O, S, NH, Z is CR² and R¹, R² and Ar are as defined above) can be prepared as illustrated in Scheme 10.

Scheme 10

<img file="ES2247478T3_D0026.tif" />

ES 2 247 478 T3

Compounds of Formula (3) can be reacted with compounds of Formula 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 and at temperatures ranging from 0 ° C to 250 ° C, yielding compounds of Formula (17). Acids may include, but are not limited to, 2 to 10 carbon alkanoic acids (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), 1 to 10 carbon alkanesulfonic acids (preferably methanesulfonic acid), hydrochloric acid , sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids can be used. Bases can include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4 -dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).

Preferred reaction temperatures range from 0 ° C to 150 ° C. Compounds of Formula (17) can then be reacted with compounds of Formula R³C (OR^and) 3, where R^and it can be alkyl (1 to 6 carbon atoms) in the presence or absence of an acid in an inert solvent at temperatures ranging from 0 ° C to 250 ° C. Acids may include, but are not limited to, 2 to 10 carbon alkanoic acids (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), 1 to 10 carbon alkanesulfonic acids (preferably methanesulfonic acid), hydrochloric acid , sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids can be employed. Inert solvents may include, but are not limited to, lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 50 ° C to 150 ° C.

Procedures that can be used to convert compounds of Formula (1), wherein R³ is COR⁷, CO2R⁷, NR⁸COR⁷ and CONR⁶R⁷, in other compounds of Formula (1), in which R³ is CH (OH) R⁷, CH2OH, NR⁸CH2R⁷ and CH2NR⁶R⁷, by treatment with a reducing agent in an inert solvent and at temperatures ranging from -80 ° C to 250 ° C.

Scheme 11

<img file="ES2247478T3_D0027.tif" />

Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably sodium or lithium borohydride), borane, dialkyl boranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride). ), alkali metal (trialkoxy) aluminum hydrides or dialkylaluminum hydrides (such as di-isobutylaluminum hydride). Inert solvents can include, but are not limited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from -80 ° C to 100 ° C.

ES 2 247 478 T3

Procedures that can be used to convert the compounds of Formula (1), wherein R³ is COR⁷ or CO2R⁷, in other compounds of Formula (1), in which R³ is C (OH) (R⁷) 2 by treatment with a reagent of Formula R⁷M in an inert solvent at temperatures ranging from -80 ° C to 250 ° C.

Scheme 12

<img file="ES2247478T3_D0028.tif" />

M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, Mgl, CeCl₂, CeBr₂ or copper halides. Inert solvents can include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran), or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from -80 ° C to 106 ° C.

Compounds of Formula (1), in which R³ can be -NR⁸COR⁷, -N (COR⁷)two; -NR⁸CONR⁶R⁷, -NR⁸CO2R¹³, -NR⁶R⁷, -NR⁸SW₂R⁷, can be synthesized as depicted in Scheme 13.

(Scheme goes to next page)

ES 2 247 478 T3

<img file="ES2247478T3_D0029.tif" />

The reaction of the compounds of Formula (18), in which R and R¹ As defined above, with compounds of Formula (4) or (10) in the presence or absence of a base in an inert solvent can produce compounds of Formula (19) at temperatures ranging from -50 ° C to 250 ° C. Bases can include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkaline earth metal dialkylamines (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal b / s (trialkylsilyl) amides (preferably sodium b / s (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 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0 ° C to 100 ° C.

The compounds of Formula (19) can then be reacted with alkylating agents, sulfonylating agents or acetylating agents or sequential reactions with combinations thereof, in the presence or absence of a base in an inert solvent at reaction temperatures ranging from -80 ° C to 250 ° C, which can provide compounds of Formula (1), where R³ can be -NR⁸COR⁷, -N (COR⁷) 2, -NR⁸CONR⁶R⁷, -NR⁸CO2R¹³, -NR⁶R⁷, -NR⁸SO2R⁷. Alkylating agents may include, but are not limited to, C1-C alkyl halides, tosylates, mesylates, or triflates.₁₀; C haloalkyl halides, tosylates, mesylates or triflates₁-C₁₀ (1-10 halogens); C2-C8 alkoxyalkyl halides, tosylates, mesylates or triflates; C3-C6 cycloalkyl halides, tosylates, mesylates or triflates; C cycloalkylalkyl halides, tosylates, mesylates or triflates₄-C₁₂; aryl (C alkyl) halides, tosylates, mesylates or triflates₁-C₄); Heteroaryl (C alkyl) halides, tosylates, mesylates or triflates₁-C₄); or halides, tosylates, mesylates or triflates of heterocyclyl (al28

ES 2 247 478 T3 chyle C₁-C₄). Acylating agents may include, but are not limited to, C alkanoyl halides or anhydrides.₁-C₁₀C haloalkanoyl halides or anhydrides₁-C₁₀ with 1-10 halogens, halides or anhydrides of C alkoxyalkanoyl₂-C₈, halides or anhydrides of cycloalkanoyl C₃-C₆, halides or anhydrides of cycloalkylalkanoyl C₄-C₁₂, halides or anhydrides of aroyl, halides or anhydrides of aryl-alkanoyl (C₁-C₄), heteroaroyl halides or anhydrides, heteroaryl alkanoyl halides or anhydrides (C₁-C₄), heterocyclylcarboxylic acid halides or anhydrides or heterocyclylalkanoyl halides or anhydrides (C₁-C₄). Sulfonylating agents include, but are not limited to, C alkylsulfonyl halides or anhydrides.₁ -C₁₀C haloalkylsulfonyl halides or anhydrides₁-C₁₀ with 1-10 C alkoxyalkylsulfonyl halogens, halides or anhydrides₂-C₈C cycloalkylsulfonyl halides or anhydrides₃-C₆C cycloalkylalkylsulfonyl halides or anhydrides₄-C₁₂, arylsulfonyl halides or anhydrides, aryl (C alkyl) halides or anhydrides₁ -C₄), heteroarylsulfonyl halides or anhydrides, heteroaryl (C-alkyl) halides or anhydrides₁-C₄), heterocyclylsulfonyl halides or anhydrides or heterocyclyl (C-alkyl) halides or anhydrides₁ -C₄) sulfonyl. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkaline earth metal dialkylamines (preferably lithium di-isopropylamide), 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 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0 ° C to 100 ° C.

Compounds of Formula (1), where A is CR and R is defined above, can be synthesized by the procedures depicted in Scheme 14.

Scheme 14

<img file="ES2247478T3_D0030.tif" />

ES 2 247 478 T3

Compounds of Formula (4) or (10) can be treated with compounds of Formula (20), wherein R¹ and R³ have been defined above in the presence or absence of a base in an inert solvent at temperatures ranging from 0 ° C to 250 ° C to give compounds of Formula (1), where A is CR and R is defined above. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkaline earth metal dialkylamides (preferably lithium di-isopropylamide), 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 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0 ° C to 100 ° C. Alternatively, compounds of Formula (1) where A is CR and R is defined above, can be synthesized via intermediates (22) and (23).

Compounds of Formula (4) or (10) can be treated with compounds of Formula (21), wherein R¹ has been defined above and R^and is alkyl (1-6 carbons), in the presence or absence of a base in an inert solvent at temperatures ranging from 0 ° C to 250 ° C giving compounds of Formula (1), in which A is CR and R has defined above. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal 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 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 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 ranging from -80 ° C to 250 ° C giving products of Formula (23) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkane sulfonyloxy). Halogenating agents include, but are not limited to, SOCl₂, POCl₃, PCl₃, PCl₅, POr₃, PBr₃ or PBr₅.

Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride), or haloalkylsulfonyl halides or anhydrides. (preferably trifluoromethanesulfonic anhydride). Bases can include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20 ° C to 100 ° C.

Compounds of Formula (23) can be reacted with compounds of Formula R³H (where R³ is defined as before with the exception that R³ not SH, COR⁷, CO₂R⁷, 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 to generate compounds of Formula (1). Bases can include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamide (preferably dimethylacetamide), Cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0 ° C to 140 ° C.

Some compounds of Formula (1) can also be prepared using the procedures shown in Scheme 15.

ES 2 247 478 T3

Scheme 15

<img file="ES2247478T3_D0031.tif" />

Ar Ac (27) T - O, S (1) «- CR2

A compound of Formula (24) (R_C is a lower alkyl group and Ar has been defined above) can be reacted with hydrazine in the presence or absence of an inert solvent to provide an intermediate of Formula (25), where Ar is as defined above. The conditions employed are similar to those used for the preparation of the intermediate of Formula (4) from the compound of Formula (3) in Scheme 4. Compounds of Formula (25), where A is N, can be prepared with reagents of formula R¹C (= NH) ORe, where R¹ defined above and Re is a lower alkyl group) in the presence or absence of an acid in an inert solvent, followed by reaction with a compound of formula Y is C (Rd) 2 (where Y is O or S and R^d is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) 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, S). The conditions for these transformations are the same as those employed for the conversions of the compound of Formula (4) to the compound of Formula (7) in Scheme 4.

Alternatively, compounds of Formula (25), where A is CR, can be reacted with compounds of Formula R¹ (C = O) CHR (C = Y) ORc (where R¹ and R are as defined above and RC is a lower alkyl group) giving a compound of Formula (27) (where A is CR) using conditions similar to those employed for the conversion of compounds of Formula (21) into compounds of Formula (22) in Scheme 14. Intermediates of Formula (27) (where Y is O) can be treated with halogenating agents or sulfonylating agents in the presence or absence of a base in an inert solvent, followed by reaction with R³H or R²H in the presence or absence of a base in an inert solvent to give compounds of Formula (1) (where Z is CR²).

It will be recognized by those skilled in the art that various combinations of halogenating agents, sulfonylating agents, R³H or R²H in different orders of the reaction sequences in Scheme 15 to provide compounds of Formula (1). For example, in some cases, it may be desired to react the compounds with stoichiometric amounts of halogenating agents or sulfonylating agents, react them with R²H (or R³H) and then repeating the reaction with halogenating agents or sulfonylating agents and reacting them with R³H (or R²H) to give compounds of Formula (1). The reaction conditions and reagents used for these conversions are similar to those used for the conversion of the intermediates of Formulas (22) to (23) to (1) in Scheme 14 (where A is CR) or the conversion of the intermediates of Formulas (7) to (8) in (I) in Scheme I (where A is N).

ES 2 247 478 T3

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^FX (in which R^F is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent, (they can then optionally be oxidized with an oxidizing agent in an inert solvent) and then reacted with R³H in the presence or absence of a base in an inert solvent to give a compound of Formula (1). The conditions and reagents employed are similar to those used in converting the intermediates of Formulas (7) to (12) (or (13)) to compounds of Formula (1) in Scheme 2.

Compounds of Formula (1) can be prepared from compounds of Formula (24), using an alternative route depicted in Scheme 15. Compounds of Formula (24) can be converted to compounds of Formula (27) by reaction with compounds of NH formula₂NH (C = NH) NH₂ in the presence or absence of an acid in an inert solvent, followed by reaction with R compounds¹C (OR_c)₃ (where R_C is lower alkyl and R¹ is as defined above), using the conditions employed for the conversion of compounds of Formulas (3) to (17) into (7) in Scheme 10.

Some compounds of Formula (2) can be prepared by the procedures illustrated in Scheme 16. Scheme 16

<img file="ES2247478T3_D0032.tif" />

Compounds of Formula (27b) can be treated with various alkylating agents R¹⁴X (where R¹⁴ defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to provide structures of Formula (28). The compounds of Formula (28) (Y is O) can then be converted to compounds of Formula (2) by treatment with halogenating agents or sulfonylating agents in the presence or absence of a base in an inert solvent, followed by reaction with R³H in the presence or absence of a base in an inert solvent to give compounds of Formula (2). The reaction conditions used for these conversions are similar to those used for the conversion of intermediates (22) to (23) to (1) in Scheme 14 (where A is CR) or for the conversion of intermediates from Formulas (7) to (8) in (1) in Scheme 1 (where A is N). Alternatively, compounds of Formula (28) (Y is S) can be alkylated with a compound R^FX (where R^F is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent, (then optionally oxidized with an oxidizing oxidizing agent in an inert solvent) and can then be reacted with R³H in the presence or absence of a base in an inert solvent to give a compound of Formula (1). The conditions and reagents employed are similar to those used in converting the intermediates of Formulas (7) to (12) (or (13)) to compounds of Formula (1) in Scheme 2.

Compounds of Formula (1), where Z is COH, can be converted to compounds of Formula (2) illustrated in Scheme 16. Treat with various R alkylating agents¹⁴X (where R¹⁴ defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to provide structures (2). It will be recognized by one of ordinary skill in the art that the procedures used in Scheme 16 may also be used to prepare compounds of Formula (1) wherein Z is COR⁷.

ES 2 247 478 T3

For Scheme 16, the terms "base" and "inert solvent" can have the meanings given below. Bases can include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-di-isopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanonitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide) ), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20 ° C to 100 ° C.

Examples

Analytical data was recorded for the compounds described below using the following general procedures. Proton NMR spectra were recorded on an IBM-Bruker FT-NMR (300 MHz); chemical shifts were recorded in ppm (δ) from an internal tetramethylsilane standard in deuterochloroform or deuterodimethylsulfoxide as specified below. Mass spectra (MS) or high resolution mass spectra (HRMS) were recorded on a Finnegan MAT 8230 spectrometer (using chemical ionization (CI) with NH₃ as carrier gas or gas chromatography (GC) as specified below) or a Hewlett Packard model 5988A spectrometer. Melting points were recorded on a Buchi Model 510 melting point apparatus and are uncorrected. Boiling points are uncorrected. All pH determinations during the treatment were made with indicator paper.

The reagents were purchased from commercial sources and, where necessary, were purified before use according to the general procedures outlined by D. Perrin and WLF Armarego, Purification of Laboratory Chemicals, 3^to ed., (New York: Pergamon Press, 1988).

Chromatography was performed on silica gel using the solvent systems indicated below. For mixed solvent systems, the volume ratios are given. On the other hand, parts and percentages are by weight.

The following examples are provided to describe the invention in more detail. These examples, which set out the currently contemplated best mode for carrying out the invention, are intended to illustrate and not limit the invention. Example 1

Preparation of 2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] -pyrazolo- [1,3,5] -triazin-4 (3H) -one (Formula 7, wherein Y is O, R1 is CH3, Z is C-CH3, Ar is 2,4-dimethylphenyl)

A. 1-Cyano-1- (2,4-dimethylphenyl) propan-2-one

Sodium granules (9.8 g, 0.43 mol) were added portionwise to a solution of 2,4-dimethylphenylacetonitrile (48 g, 0.33 mol) in ethyl acetate (150 ml) at room 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 until pH = 5-6. The mixture was extracted with ethyl acetate (3 x 200 ml); the combined organic phases were dried over MgSO4 and filtered. The solvent was removed in vacuo, providing a white solid (45.7 g, 74% yield): NMR. (CDCl₃, 300 MHz); 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 toluene (500 ml) was stirred at reflux for 18 hours in an apparatus equipped with a Dean-Stark trap. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. 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 phase until pH = 11. The resulting half-solution was extracted three times with ethyl acetate. The combined organic phases were dried over MgSO4 and filtered. The solvent was removed in vacuo to give a pale brown viscous oil (34.6 g, 75% yield): NMR (CDCl3, 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-Acetamidino-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), dichloromethane (120 ml) and water (350 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 120 ml). The combined organic phases were dried over MgSO₄ and filtered. The

ES 2 247 478 T3 solvent was removed by simple distillation and the residue in the container, 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), acetamidate of ethyl (22 g, 0.25 mol) and acetonitrile (500 ml). The resulting reaction mixture was stirred at room temperature for 3 days; after this, it was concentrated in vacuo to approximately one third of its original volume. The resulting suspension was filtered and the collected solid was washed with copious amounts of ether. The white solid was dried in vacuo (31.4 g, 61% yield): NMR (DMSO-d₆, 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-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] -pyrazolo- [1,3,5] -triazin-4 (3H) -one

Sodium granules (23 g, 1 mol) were added portionwise to ethanol (500 ml) with vigorous stirring. After all the sodium reacted, 5-acetamidino-4- (2,4-dimethylphenyl) -3-methylpyrazole, acetic acid salt (31.2 g, 0.1 mol) and diethyl carbonate (97 ml) were added , 0.8 mol). The resulting reaction mixture was heated to reflux temperature and stirred for 18 hours. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in water and a 1N HCl solution was slowly added until pH = 5-6. The aqueous phase was extracted three times with ethyl acetate; the combined organic phases were dried over MgSO₄ and filtered. The solvent was removed in vacuo, giving a pale brown solid (26 g, 98% yield): NMR (CDCl₃, 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

7-hydroxy-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine (Formula 1 where A is CH, R1 is Me, R3 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 glacial acetic acid (30 ml) with stirring. Then, to the resulting solution, ethyl acetoacetate (1.18 ml, 9.2 mmol) was added dropwise. The reaction mixture was then heated to reflux temperature and stirred for 16 hours, then cooled to room temperature. Ether (100 ml) was added and the resulting precipitate was collected by filtration. Drying in vacuo produced a white solid (1.0 g, 42% yield): NMR (CDCl₃, 300 Hz): 8.70 (bs, 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 3

7-chloro-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine (Formula 1 where A is CH, R1 is Me, R3 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), phosphorous oxychloride (2, 7 g, 1.64 ml, 17.4 mmol), N, N-diethylaniline (0.63 g, 0.7 ml, 4.2 mmol) and toluene (20 ml) were stirred at reflux for 3 hours and then cooled to room temperature. The volatiles were removed in vacuo. Flash chromatography (EtOAc: hexane: 1: 2) on the residue gave 7-chloro-5-methyl-3- (2-chloro-4-methylphenyl) -pyrazolo [1,5-a] pyrimidine (900 mg, yield 84%) as a yellow oil: NMR (CDCl₃, 300 Hz): 7.35 (s, 1H), 7.28-7.26 (m, 1H), 71.6 (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 4

7- (pentyl-3-amino) -5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-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-methylphenyl)

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 dimethylsulfoxide (DMSO, 10 ml) was stirred at 150 ° C for 2 hours; then it was cooled to room temperature. The reaction mixture was then poured into water (100 ml) and mixed. Three extractions with dichloromethane, washing the combined organic phases with brine, drying over MgSO₄, filtration and removal of the solvent in vacuo produced a yellow solid. Flash chromatography (EtOAc: hexanes: 1: 4) provided a white solid (140 mg, 60% yield): mp 139-141 ° C; NMR (CDCl₃, 300 Hz): 7.32 (s, 1H), 7.27 (d, 1H, 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), 1.821.60 (m, 4h ), 1.01 (t, 6H, J = 8); Calc analysis. for C₂₀H₂₅ClN₄: C, 67.31, H, 7.06, N, 15.70, Cl: 9.93; Found: C, 67.32, H, 6.95, N, 1S-50, Cl, 9.93.

Examples listed in TABLE 8 can be prepared by the procedures listed in Examples 1A, 1B, 2, 3, and 4. Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl. , cPr is cyclopropyl, Ex. is example, EtOAc is ethyl acetate.

ES 2 247 478 T3

TABLE 8

<img file="ES2247478T3_D0033.tif" />

Ar

<td>the</td><td>R</td><td>R?</td><td>Δε</td>

<td> 2000</td><td>I</td><td>N (CH₂CH₂OMe) 2</td><td>2,4-ClrPh</td>

<td> 2001</td><td>I</td><td>N (Bu) Et</td><td>2,4-ClrPh</td>

<td> 2002</td><td>I</td><td>NHCH (Et) CH₂OMe</td><td>2,4-Clz-Ph</td>

<td> 2003</td><td>I</td><td>N (Pr) CH₂CH₂N</td><td>2,4-CI₂-Ph</td>

<td> 2004</td><td>I</td><td>ΝΗ-3-pentyl</td><td>2,4-CI₂-Ph</td>

<td> 2005</td><td>I</td><td>NHCH (CH₂OMe)₂</td><td>2,4-CI₂-Ph</td>

<td> 2006</td><td>I</td><td>NHCHCEtk</td><td>2,4-MerPh</td>

<td> 2007</td><td>I</td><td>NHCHíChbOMek</td><td>2,4-MerPh</td>

<td> 2008</td><td>I</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

<td> 2009</td><td>I</td><td>N (c-Pr) CH₂CH₂N</td><td>2,4-Me ^ Ph</td>

<td> 2010</td><td>I</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI, 4-MePh</td>

<td> 2011</td><td>I</td><td>NHCHíCHzOMeh</td><td>2-CI, 4-MePh</td>

<td> 2012</td><td>I</td><td>NHCHCEtk</td><td>2-CI, 4-MePh</td>

<td> 2013</td><td>I</td><td>NEt₂</td><td>2,4-MerPh</td>

<td> 2014</td><td>I</td><td>N (Pr) CH₂CH₂CN</td><td>2,4-Mez-Ph</td>

<td> 2015</td><td>I</td><td>N (Bu) CH₂CH₂CN</td><td>2,4-Me ^ Ph</td>

<td> 2016</td><td>I</td><td>NHCH (Et) CH₂OMe</td><td>2,4-Mez-Ph</td>

<td> 2017</td><td>I</td><td>NHCHÍEth</td><td>2-Me, 4- MeOPh</td>

<td> 2018</td><td>I</td><td>NHCH (CH₂OMe) 2</td><td>2-Me, 4- MeOPh</td>

<td> 2019 116^to</td><td>I</td><td>N (CH₂CH₂OMe} 2</td><td>2-Me, 4- MeOPh115-</td>

<td> 2020 2021</td><td>I</td><td>(S) - NHCH (CH₂CH₂OMe) - (CH₂OMe)</td><td>2-Me, 4- MeOPh</td>

<td> 2022 2023</td><td>I</td><td>(S) - NHCH (CH₂CH₂OMe) - (CH₂OMe&gt;</td><td>2,4-MerPh</td>

<td> 2024</td><td>I</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me, 4-CIPh</td>

<td> 2025</td><td>I</td><td>NHEt</td><td>2,4-MerPh</td>

<td> 2026</td><td>I</td><td>NHCHCEtk</td><td>2-Me, 4-CIPh</td>

<td> 2027</td><td>I</td><td>NHCH (CH₂OMe)₂</td><td>2-Me, 4-CIPh</td>

ES 2 247 478 T3

<td> 2028</td><td>I</td><td>N (Ac) Et</td><td>2,4-Me₂-Ph</td>

<td> 2029</td><td>I</td><td>(S&gt;</td><td>2-Me, 4-OPh</td>

<td> 2030 2031</td><td>I</td><td>NHCH (CH₂CH₂OMe) - (CH₂OMe) N (Pr) CH₂CH₂CN</td><td>2-Me, 4-</td>

<td> 2032</td><td>I</td><td>NEt₂</td><td>MeOPh 2-Me, 4-</td>

<td> 2033</td><td>I</td><td>(S) -</td><td>MeOPh 2-CI, 4-MePh</td>

<td> 2034 2035</td><td>I</td><td>NHCH (CH₂CH₂OMe) - (CH₂OMe) NEt₂</td><td>2-CI, 4-MePh</td>

<td> 2036</td><td>I</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Me, 4-</td>

<td> 2037</td><td>I</td><td>N (c-Pr) CH₂CH₂CN</td><td>MeOPh 2-CI, 4-MePh</td>

<td> 2038</td><td>I</td><td>NHCH (Et) CH₂OMe</td><td>2-Me, 4-</td>

<td> 2039</td><td>I</td><td>NHCH (Et) CH₂OMe</td><td>MeOPh 2-CI, 4-MePh</td>

<td> 2040</td><td>I</td><td>NHCH (CH₂OMe)₂</td><td> 2-0,4-</td>

<td> 2041</td><td>I</td><td>N (CH₂CH₂OMe)₂</td><td>MeOPh 2-0.4-</td>

<td> 2042</td><td>I</td><td>NHCH (Et) CH₂OMe</td><td>MeOPh 2-0.4-</td>

<td> 2043</td><td>I</td><td>N (c-Pr) CH₂CH₂N</td><td>MeOPh 2-0.4-</td>

<td> 2044</td><td>I</td><td>NEt₂</td><td>MeOPh 2-0.4-</td>

<td> 2045</td><td>I</td><td>NH-3-pentlo</td><td>MeOPh 2-0.4-</td>

<td> 2046</td><td>I</td><td>NHCH (Et) CH₂CH₂OMe</td><td>MeOPh 2-0.4-</td>

<td> 2047</td><td>I</td><td>NHCH (Me) CH₂CH₂OMe</td><td>MeOPh 2-0.4-</td>

<td> 2048</td><td>I</td><td>NHCH (Et) CH₂CH₂OMe</td><td>MeOPh 2-Br-4-</td>

ES 2 247 478 T3

MeOPh

<td> 2049</td><td>I</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Br-4- MeOPh</td>

<td> 2050</td><td>I</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4- MeOPh</td>

<td> 2051</td><td>I</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Me-4- MeOPh</td>

<td> 2052</td><td>I</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4.5- (MeOfePh</td>

<td> 2053</td><td>I</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4.5- (MeOfePh</td>

<td> 2054</td><td>I</td><td>NHCH (Et) CH₂OMe</td><td>2-CI-4.5- (MeO ^ Ph</td>

<td> 2055</td><td>I</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI-4.5- (MeOfePh</td>

<td> 2056</td><td>I</td><td>NEt₂</td><td>2-CI-4.5- (MeOfePh</td>

<td> 2057</td><td>I</td><td>ΝΗ-3-pentyl</td><td>2-CI-4.5- (MeOfePh</td>

<td> 2058</td><td>I</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-CI-4.5- (MeOfePh</td>

<td> 2059</td><td>I</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-CI-4.5- (MeOfePh</td>

<td> 2060</td><td>I</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4,5- (MeOfePh</td>

<td> 2061</td><td>I</td><td>NHÍC ^ C ^ OMeh</td><td>2-Br-4,5- (MeO ^ Ph</td>

<td> 2062</td><td>I</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4,5- (MeOfePh</td>

<td> 2063</td><td>I</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Br-4,5- (MeO ^ Ph</td>

<td> 2064</td><td>I</td><td>NEt₂</td><td>2-Br-4,5- (MeOfcPh</td>

<td> 2065</td><td>I</td><td>ΝΗ-3-pentyl</td><td>2-Br-4,5-</td>

(MeO ^ Ph

ES 2 247 478 T3

<td> 2066</td><td>I</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-ΒΓ-4.5- (MeOfePh</td>

<td> 2067</td><td>I</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 2068</td><td>I</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4.6- (MeOfePh</td>

<td> 2069</td><td>I</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4.6- (MeOfePh</td>

<td> 2070</td><td>I</td><td>NHCH (Et) CH₂OMe</td><td>2-CI-4.6- (MeO ^ Ph</td>

<td> 2071</td><td>I</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI-4.6- (MeO)₂Ph</td>

<td> 2072</td><td>I</td><td>NEt₂</td><td>2-CI-4.6- (MeOfePh</td>

<td> 2073</td><td>I</td><td>ΝΗ-3-pentyl</td><td>2-CI-4.6- (MeO)₂Ph</td>

<td> 2074</td><td>I</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-CI-4.6- (MeO)₂Ph</td>

<td> 2075</td><td>I</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-CI-4.6- (MeOfePh</td>

<td> 2076</td><td>I</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4,6- (MeO ^ Ph</td>

<td> 2077</td><td>I</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4,6- (MeO ^ Ph</td>

<td> 2078</td><td>I</td><td>NHCH (Et) CH₂OMe</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 2079</td><td>I</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 2080</td><td>I</td><td>NEt₂</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 2081</td><td>I</td><td>ΝΗ-3-pentyl</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 2082</td><td>I</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4,6- (MeOfePh</td>

<td> 2083</td><td>I</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Me-4,6-</td>

ES 2 247 478 T3 (MeOfcPh

<td> 2084</td><td>I</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Br-4,6- (MeOfePh</td>

<td> 2085</td><td>I</td><td>NEt₂</td><td>2-Br-4,6- (MeOfePh</td>

<td> 2086</td><td>I</td><td>ΝΗ-3-pentyl</td><td>2-Br-4,6- (MeOfePh</td>

<td> 2087</td><td>I</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Br-4,6- (MeO)₂Ph</td>

<td> 2088</td><td>I</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Br-4,6- (MeO)₂Ph</td>

<td> 2089</td><td>I</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4- MeOPh</td>

<td> 2090</td><td>I</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Me-4- MeOPh</td>

<td> 2091</td><td>I</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4- MePh</td>

<td> 2092</td><td>I</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4- MePh</td>

<td> 2093</td><td>I</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2094</td><td>I</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4- MePh</td>

<td> 2095</td><td>I</td><td>NEt₂</td><td>2-MeO-4- MePh</td>

<td> 2096</td><td>I</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4- MePh</td>

<td> 2097</td><td>I</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2098</td><td>I</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2099</td><td>I</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4- MePh</td>

<td> 2100</td><td>I</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-</td>

MePh

ES 2 247 478 T3

<td> 2101</td><td>I</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2102</td><td>I</td><td>N (c-PijCH₂CH₂CN</td><td>2-MeO-4- MePh</td>

<td> 2103</td><td>I</td><td>NEt₂</td><td>2-MeO-4- MePh</td>

<td> 2104</td><td>I</td><td>ΝΗ-3-pentllo</td><td>2-MeO-4- MePh</td>

<td> 2105</td><td>I</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2106</td><td>I</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2107</td><td>I</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4- ClPh</td>

<td> 2108</td><td>I</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4- ClPh</td>

<td> 2109</td><td>I</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4- ClPh</td>

<td> 2110</td><td>I</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4- ClPh</td>

<td> 2111</td><td>I</td><td>NEt₂</td><td>2-MeO-4- ClPh</td>

<td> 2112</td><td>I</td><td>ΝΗ-3-pentllo</td><td>2-MeO-4- ClPh</td>

<td> 2113</td><td>I</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4- ClPh</td>

<td> 2114</td><td>I</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4- ClPh</td>

<td> 2115</td><td>Cl</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-ClrPh</td>

<td> 2116</td><td>Cl</td><td>N (Bu) Et</td><td>2,4-CI₂-Ph</td>

<td> 2117</td><td>Cl</td><td>NHCH (Et) CH₂OMe</td><td>2,4-CI₂-Ph</td>

<td> 2118</td><td>Cl</td><td>N (Pr) CH₂CH₂CN</td><td>2,4-CI₂-Ph</td>

<td> 2119</td><td>Cl</td><td>ΝΗ-3-pentllo</td><td>2,4-CI₂-Ph</td>

<td> 2120</td><td>Cl</td><td>NHCH (CH₂OMe)₂</td><td>2,4-CI₂-Ph</td>

<td> 2121</td><td>Cl</td><td>NHCH (Et)₂</td><td>2,4-Me₂-Ph</td>

ES 2 247 478 T3

<td> 2122</td><td>Cl</td><td>NHCH (CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

<td> 2123</td><td>Cl</td><td>N (CH₂CH₂OMe) 2</td><td>2,4-Me₂-Ph</td>

<td> 2124</td><td>Cl</td><td>N (c-Pr) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td>

<td> 2125</td><td>Cl</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI, 4-MePh</td>

<td> 2126</td><td>Cl</td><td>NHCH (CH₂OMe)₂</td><td>2-CI, 4-MePh</td>

<td> 2127</td><td>Cl</td><td>NHCH (Et)₂</td><td>2-CI, 4-MePh</td>

<td> 2128</td><td>Cl</td><td>NEt₂</td><td>2,4-Me₂-Ph</td>

<td> 2129</td><td>Cl</td><td>N (Pr) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td>

<td> 2130</td><td>Cl</td><td>N (Bu) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td>

<td> 2131</td><td>Cl</td><td>NHCH (Et) CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td> 2132</td><td>Cl</td><td>NHCH (Et)₂</td><td>2-Me, 4- MeOPh</td>

<td> 2133</td><td>Cl</td><td>NHCH (CH₂OMe)₂</td><td>2-Me, 4-74-76 ' MeOPh</td>

<td> 2134</td><td>Cl</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me, 4- MeOPh</td>

<td> 2135 2136</td><td>Cl</td><td>(S) - NHCH (CH₂CH₂OMe) - (CH₂OMe)</td><td>2-Me, 4- MeOPh</td>

<td> 2137 2138</td><td>Cl</td><td>(S&gt; NHCH (CH₂CH₂OMe) - (CH₂OMe)</td><td>2,4-Me₂-Ph</td>

<td> 2139</td><td>Cl</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me, 4-CIPh</td>

<td> 2140</td><td>Cl</td><td>NHEt</td><td>2,4-Me₂-Ph</td>

<td> 2141</td><td>Cl</td><td>NHCHÍEtfe</td><td>2-Me, 4-CIPh</td>

<td> 2142</td><td>Cl</td><td>NHCH (CH₂OMe)₂</td><td>2-Me, 4-CIPh</td>

<td> 2143</td><td>Cl</td><td>N (Ac) Et</td><td>2,4-Me₂-Ph</td>

<td> 2144 2145</td><td>Cl</td><td>(S) - NHCH (CH₂CH₂OMe) - (CH₂OMe)</td><td>2-Me, 4-CIPh</td>

<td> 21,46</td><td>Cl</td><td>N (Pr) CH₂CH₂CN</td><td>2-Me, 4- MeOPh</td>

<td> 2147</td><td>Cl</td><td>NEt₂</td><td>2-Me, 4- MeOPh</td>

<td> 2148</td><td>Cl</td><td>(S) -</td><td>2-CI, 4-MePh</td>

ES 2 247 478 T3

NHCH (CH₂CH₂OMe) -

<td> 2149</td><td colspan="3">(CH₂OMe)</td>

<td> 2150</td><td>Cl</td><td>NEt₂</td><td>2-CI, 4-MePh</td>

<td> 2151</td><td>Cl</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Me, 4- MeOPh</td>

<td> 2152</td><td>Cl</td><td>N (c-Pr) CH₂CH₂CM</td><td>2-CI, 4-MePh</td>

<td> 2153</td><td>Cl</td><td>NHCH (Et) CH₂OMe</td><td>2-Me, 4- MeOPh</td>

<td> 2154</td><td>Cl</td><td>NHCH (Et) CH₂OMe</td><td>2-CI, 4-MePh</td>

<td> 2155</td><td>Cl</td><td>NHCH (CH₂OMe) 2</td><td>2-0-4- MeOPh</td>

<td> 2156</td><td>Cl</td><td>MCCHzCHzOMeh</td><td>2-0-4- MeOPh</td>

<td> 2157</td><td>Cl</td><td>NHCH (Et) CH₂OMe</td><td>2-0-4- MeOPh</td>

<td> 2158</td><td>Cl</td><td>H (c-Pr) CH₂CH₂CN</td><td>2-0-4- MeOPh</td>

<td> 2159</td><td>Cl</td><td>NEt₂</td><td>2-0-4- MeOPh</td>

<td> 2160</td><td>Cl</td><td>ΝΗ-3-pentyl</td><td>2-0-4- MeOPh</td>

<td> 2161</td><td>Cl</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-0-4- MeOPh</td>

<td> 2162</td><td>Cl</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-0-4- MeOPh</td>

<td> 2163</td><td>Cl</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Br-4- MeOPh</td>

<td> 2164</td><td>Cl</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Br-4- MeOPh</td>

<td> 2165</td><td>Cl</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4- MeOPh</td>

<td> 2166</td><td>Cl</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Me-4- MeOPh</td>

<td> 2167</td><td>Cl</td><td>NHCHÍCHzOMeh</td><td> 2-0-4,5-</td>

(MeOfePh

ES 2 247 478 T3

<td> 2168</td><td>Cl</td><td>N (CH₂CH₂OMe) 2</td><td>2-0-4.5 (MeOfePh</td>

<td> 2169</td><td>Cl</td><td>NHCH (Et) CH₂OMe</td><td>2-0-4.5 (MeOhPh</td>

<td> 2170</td><td>Cl</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-0-4.5 (MeOfePh</td>

<td> 2171</td><td>Cl</td><td>NEt₂</td><td>2-04.5- (MeOfePh</td>

<td> 2172</td><td>Cl</td><td>ΝΗ-3-pentllo</td><td>2-0-4.5 (MeOfePh</td>

<td> 2173</td><td>Cl</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-0-4.5 (MeOhPh</td>

<td> 2174</td><td>Cl</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-0-4.5 (MeOfePh</td>

<td> 2175</td><td>Cl</td><td>NHCHCCHzOMeh</td><td>2-Br-4,5- (MeOfePh</td>

<td> 2176</td><td>Cl</td><td>NÍCHzCHzOMek</td><td>2-Br-4,5- (MeOfePh</td>

<td> 2177</td><td>Cl</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4,5- (MeOfePh</td>

<td> 2178</td><td>Cl</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Br-4,5- (MeOfcPh</td>

<td> 2179</td><td>Cl</td><td>NEt₂</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 2180</td><td>Cl</td><td>ΝΗ-3-pentllo</td><td>2-Br-4,5- (MeOfcPh</td>

<td> 2181</td><td>Cl</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Br-4,5- (MeOfePh</td>

<td> 2182</td><td>Cl</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Br-4,5- (MeO ^ Ph</td>

<td> 2183</td><td>Cl</td><td>NHCHíCHzOMeh</td><td>2-0-4.6 (MeOfePh</td>

<td> 2184</td><td>Cl</td><td>NÍCHzCHzOMefe</td><td>2-0-4.6 (MeOfePh</td>

<td> 2185</td><td>Cl</td><td>NHCH (Et) CH₂OMe</td><td> 2-0-4,6-</td>

ES 2 247 478 T3 (MeO)₂Ph

<td> 2186</td><td>Cl</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI-4.6- (MeOfePh</td>

<td> 2187</td><td>Cl</td><td>NEt₂</td><td>2-CI-4.6- (MeOfePh</td>

<td> 2188</td><td>Cl</td><td>NH-3-pentlo</td><td>2-CI-4.6- (MeOhPh</td>

<td> 2189</td><td>Cl</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-CI-4.6- (MeOfePh</td>

<td> 2190</td><td>Cl</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-CI-4.6- (MeO)₂Ph</td>

<td> 2191</td><td>Cl</td><td>NHCHíCHzOMek</td><td>2-Me-4,6- (MeO ^ Ph</td>

<td> 2192</td><td>Cl</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4,6- (MeOfePh</td>

<td> 2193</td><td>Cl</td><td>NHCH (Et) CH₂OMe</td><td>2-Me-4,6- (MeOfePh</td>

<td> 2194</td><td>Cl</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Me-4,6- (MeO ^ Ph</td>

<td> 2195</td><td>Cl</td><td>NEt₂</td><td>2-Me-4,6- (MeOfePh</td>

<td> 2196</td><td>Cl</td><td>ΝΗ-3-pentyl</td><td>2-Me-4,6- (MeOfePh</td>

<td> 2197</td><td>Cl</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4,6- (MeOfePh</td>

<td> 2198</td><td>Cl</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Me-4,6- (MeOfePh</td>

<td> 2199</td><td>Cl</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Br-4,6- (MeOfePh</td>

<td> 2200</td><td>Cl</td><td>NEt₂</td><td>2-Br-4,6- (MeOfePh</td>

<td> 2201</td><td>Cl</td><td>ΝΗ-3-pentyl</td><td>2-Br-4,6- (MeOfePh</td>

<td> 2202</td><td>Cl</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Br-4,6-</td>

(MeOfePh

ES 2 247 478 T3

<td> 2203</td><td>Cl</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Br-4,6- (MeOfePh</td>

<td> 2204</td><td>Cl</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-ΜΘ-4- MeOPh</td>

<td> 2205</td><td>Cl</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Me-4- MeOPh</td>

<td> 2206</td><td>Cl</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4- MePh</td>

<td> 2207</td><td>Cl</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4- MePh</td>

<td> 2208</td><td>Cl</td><td>NHCH (Et) CH₂OMe</td><td>2-ΜΘΟ-4- MePh</td>

<td> 2209</td><td>Cl</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4- MePh</td>

<td> 2210</td><td>Cl</td><td>NEt₂</td><td>2-MeO-4- MePh</td>

<td> 2211</td><td>Cl</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4- MePh</td>

<td> 2212</td><td>Cl</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2213</td><td>Cl</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2214</td><td>Cl</td><td>NHCH (CH₂OMe) 2</td><td>2-MeO-4- MePh</td>

<td> 2215</td><td>Cl</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4- MePh</td>

<td> 2216</td><td>Cl</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2217</td><td>Cl</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4- MePh</td>

<td> 2218</td><td>Cl</td><td>NEt₂</td><td>2-MeO-4- MePh</td>

<td> 2219</td><td>Cl</td><td>ΝΗ-3-pentllo</td><td>2-MeO-4- MePh</td>

<td> 2220</td><td>Cl</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4-</td>

ES 2 247 478 T3

MePh

<td> 2221</td><td>Cl</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2222</td><td>Cl</td><td>NHCH (CH₂OMe) 2</td><td>2-MeO-4- ClPh</td>

<td> 2223</td><td>Cl</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4- ClPh</td>

<td> 2224</td><td>Cl</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4- ClPh</td>

<td> 2225</td><td>Cl</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4- ClPh</td>

<td> 2226</td><td>Cl</td><td>NEt₂</td><td>2-MeO-4- ClPh</td>

<td> 2227</td><td>Cl</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4- ClPh</td>

<td> 2228</td><td>Cl</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4- ClPh</td>

<td> 2229</td><td>Cl</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4- ClPh</td>

<td> 2230</td><td>F</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-CI₂-Ph</td>

<td> 2231</td><td>P</td><td>N (Bu) Et</td><td>2,4-Clz-Ph</td>

<td> 2232</td><td>F</td><td>NHCH (Et) CH₂OMe</td><td>2,4-Clz-Ph</td>

<td> 2233</td><td>F</td><td>N (Pr) CH₂CH₂CN</td><td>2,4-CI₂-Ph</td>

<td> 2234</td><td>F</td><td>NH-3-pentlo</td><td>2,4-CI₂-Ph</td>

<td> 2235</td><td>F</td><td>NHCH (CH₂OMe) 2</td><td>2,4-Clz-Ph</td>

<td> 2236</td><td>F</td><td>NHCH (Et)₂</td><td>2,4-Mez-Ph</td>

<td> 2237</td><td>F</td><td>NHCHÍCHzOMeh</td><td>2,4-Mez-Ph</td>

<td> 2238</td><td>F</td><td>NÍCHzCHzOMeh</td><td>2,4-Mez-Ph</td>

<td> 2239</td><td>F</td><td>N (c-Pr) CH₂CH₂CN</td><td>2,4-Mez-Ph</td>

<td> 2240</td><td>F</td><td>N (CH₂CH₂OMe) 2</td><td>2-CI, 4-MePh</td>

<td> 2241</td><td>F</td><td>NHCH (CH₂OMe)₂</td><td>2-CI, 4-MePh</td>

<td> 2242</td><td>F</td><td>NHCHCEtk</td><td>2-CI, 4-MePh</td>

<td> 2243</td><td>F</td><td>NEt₂</td><td>2,4-Me_rPh</td>

<td> 2244</td><td>F</td><td>N (Pr) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td>

<td> 2245</td><td>F</td><td>N (Bu) CH₂CH₂CN</td><td>2,4-Mez-Ph</td>

ES 2 247 478 T3

<td> 2246</td><td>F</td><td>NHCH (Et) CH₂OMe</td><td>2,4-Mez-Ph</td>

<td> 2247</td><td>F</td><td>NHCH (Et) z</td><td>2-Me-4-</td>

<td> 2248</td><td>F</td><td>NHCH (CH₂OMe) z</td><td>MeOPh 2-Me-4-</td>

<td> 2249</td><td>F</td><td>N (CH₂CH₂OMe) 2</td><td>MeOPh 2-Me-4-</td>

<td> 2250</td><td>F</td><td>(S) -</td><td>MeOPh 2-Me-4-</td>

<td> 2251 2252</td><td>F</td><td>NHCH (CH₂CH₂OMe) - (CH₂OMe) (S) -</td><td>MeOPh 2,4-Mez-Ph</td>

<td> 2253 2254</td><td>F</td><td>NHCH (CH₂CH₂OMe) - (CH₂OMe) N (CH₂CH₂OMe) z</td><td>2-Me, 4-CIPh</td>

<td> 2255</td><td>F</td><td>NHEt</td><td>2,4-Mez-Ph</td>

<td> 2256</td><td>F</td><td>NHCH (Et) z</td><td>2-Me, 4-CIPh</td>

<td> 2257</td><td>P</td><td>NHCH (CH₂OMe) 2</td><td>2-Me, 4-CIPh</td>

<td> 2258</td><td>F</td><td>N (Ac) Et</td><td>2,4-Mez-Ph</td>

<td> 2259</td><td>F</td><td>(S) -</td><td>2-Me, 4-CIPh</td>

<td> 2260 2261</td><td>F</td><td>NHCH (CH₂CH₂OMe) - (CH₂OMe) N (Pr) CH₂CH₂CN</td><td>2-Me, 4-</td>

<td> 2262</td><td>F</td><td>NEt₂</td><td>MeOPh 2-Me, 4-</td>

<td> 2263</td><td>F</td><td>(S) -</td><td>MeOPh 2-CI, 4-MePh</td>

<td> 2264 2265</td><td>F</td><td>NHCH (CH₂CH₂OMe) - (CH₂OMe) NEt₂</td><td>2-CI, 4-MePh</td>

<td> 2266</td><td>F</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Me, 4-</td>

<td> 2267</td><td>F</td><td>N (c-Pr) CH₂CH₂CN</td><td>MeOPh 2-CI, 4-MePh</td>

<td> 2268</td><td>F</td><td>NHCH (Et) CH₂OMe</td><td>2-Me, 4-</td>

<td> 2269</td><td>F</td><td>NHCH (BC) CH₂OMe</td><td>MeOPh 2-CI, 4-MePh</td>

ES 2 247 478 T3

<td> 2270</td><td>F</td><td>NHCH (CH₂OMe)₂</td><td>2-0-4- MeOPh</td>

<td> 2271</td><td>F</td><td>N (CH₂CH₂OMe) 2</td><td>2-0-4- MeOPh</td>

<td> 2272</td><td>F</td><td>NHCH (Et) CH₂OMe</td><td>2-0-4- MeOPh</td>

<td> 2273</td><td>F</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-0-4- MeOPh</td>

<td> 2274</td><td>F</td><td>NEt₂</td><td>2-0-4- MeOPh</td>

<td> 2275</td><td>F</td><td>ΝΗ-3-pentyl</td><td>2-0-4- MeOPh</td>

<td> 2276</td><td>F</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-0-4- MeOPh</td>

<td> 2277</td><td>F</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-0-4- MeOPh</td>

<td> 2278</td><td>F</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-0-4- JVleOPh</td>

<td> 2279</td><td>F</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-0-4- MeOPh</td>

<td> 2280</td><td>F</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4- MeOPh</td>

<td> 2281</td><td>F</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-ΜΘ-4- MeOPh</td>

<td> 2282</td><td>F</td><td>NHCHíCHzOMe ^</td><td>2-0-4.5 (MeOfcPh</td>

<td> 2283</td><td>F</td><td>N (CH₂CH₂OMe)₂</td><td>2-0-4.5 (MeOfePh</td>

<td> 2284</td><td>F</td><td>NHCH (Et) CH₂OMe</td><td>2-0-4.5 (MeO) zPh</td>

<td> 2285</td><td>F</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-0-4.5 (MeOfcPh</td>

<td> 2286</td><td>F</td><td>NEt₂</td><td>2-0-4.5 (MeO)₂Ph</td>

<td> 2287</td><td>F</td><td>ΝΗ-3-pentyl</td><td> 2-0-4,5-</td>

ES 2 247 478 T3

<td> 2288</td><td>F</td><td>NHCH (Et) CH₂CH₂OMe</td><td>(MeOfePh 2-CI-4.5-</td>

<td> 2289</td><td>F</td><td>NHCH (Me) CH₂CH₂OMe</td><td>(MeO)₂Ph 2-0-4.5-</td>

<td> 2290</td><td>F</td><td>NHCH (CH₂OMe)₂</td><td>(MeO)₂Ph 2-Br-4,5-</td>

<td> 2291</td><td></td><td>N (CH₂CH₂OMe) 2</td><td>(MeOfePh 2-Br-4,5-</td>

<td> 2292</td><td>F</td><td>NHCH (Et) CH₂OMe</td><td>(MeOfePh 2-Br-4,5-</td>

<td> 2293</td><td>F</td><td>N (c-Pr) CH₂CH₂CN</td><td>(MeOfePh 2-Br-4,5-</td>

<td> 2294</td><td>F</td><td>NEt₂</td><td>(MeOfePh 2-Br-4,5-</td>

<td> 2295</td><td>F</td><td>ΝΗ-3-pentyl</td><td>(MeOfePh 2-Br-4,5-</td>

<td> 2296</td><td>F</td><td>NHCH (Et) CH₂CH₂OMe</td><td>(MeOfePh 2-Br-4,5-</td>

<td> 2297</td><td>F</td><td>NHCH (Me) CH₂CH₂OMe</td><td>(MeOfePh 2-Br-4,5-</td>

<td> 2298</td><td>F</td><td>NHCH (CH₂OMe)₂</td><td>(MeOfePh 2-0-4,6-</td>

<td> 2299</td><td>F</td><td>N (CH₂CH₂OMe)₂</td><td>(MeOfcPh 2-0-4,6-</td>

<td> 2300</td><td>F</td><td>NHCHfEt) CH₂OMe</td><td>(MeO ^ Ph 2-0-4,6-</td>

<td> 2301</td><td>F</td><td>N (c-Pr) CH₂CH₂CN</td><td>(MeO ^ Ph 2-0-4,6-</td>

<td> 2302</td><td>F</td><td>NEt₂</td><td>(MeOfePh 2-0-4,6-</td>

<td> 2303</td><td>F</td><td>ΝΗ-3-pentyl</td><td>(MeO ^ Ph 2-0-4,6-</td>

<td> 2304</td><td>F</td><td>NHCH (Et) CH₂CH₂OMe</td><td>(MeO)₂Ph 2-0-4,6-</td>

<td></td><td></td><td></td><td>(MeO)₂Ph</td>

ES 2 247 478 T3

<td> 2305</td><td>F</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-CI-4.6- (MeOhPh</td>

<td> 2306</td><td>F</td><td>NHCHCCHzOMek</td><td>2-Me-4,6- (MeOfePh</td>

<td> 2307</td><td>F</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4,6- (MeO ^ Ph</td>

<td> 2308</td><td>F</td><td>NHCH (Et) CH₂OMe</td><td>2-ΜΘ-4.6- (MeOfcPh</td>

<td> 2309</td><td>F</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Me-4,6- (MeOfePh</td>

<td> 2310</td><td>F</td><td>NEt₂</td><td>2-ΜΘ-4.6- (MeOfcPh</td>

<td> 2311</td><td>F</td><td>ΝΗ-3-pentyl</td><td>2-Me-4,6- (MeOfePh</td>

<td> 2312</td><td>F</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4,6- (MeOfePh</td>

<td> 2313</td><td>F</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-ΜΘ-4.6- (MeOhPh</td>

<td> 2314</td><td>F</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Br-4,6- (MeOfePh</td>

<td> 2315</td><td>F</td><td>NEt₂</td><td>2-Br-4,6- (MeO)₂Ph</td>

<td> 2316</td><td>F</td><td>NH-3-pentlo</td><td>2-Br-4,6- (MeO)₂Ph</td>

<td> 2317</td><td>F</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Br-4,6- (MeOfePh</td>

<td> 2318</td><td>F</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Br-4,6- (MeOfePh</td>

<td> 2319</td><td>F</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4- MeOPh</td>

<td> 2320</td><td>F</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-ΜΘ-4- MeOPh</td>

<td> 2321</td><td>F</td><td>NHCH (CH₂OMe) 2</td><td>2-MeO-4- MePh</td>

<td> 2322</td><td>F</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-</td>

ES 2 247 478 T3

<td></td><td colspan="3">MePh</td>

<td> 2323</td><td>F</td><td>NHCH (Et) CH₂OMe</td><td>2-ΜΘΟ-4- MePh</td>

<td> 2324</td><td>F</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4- MePh</td>

<td> 2325</td><td>F</td><td>NEt₂</td><td>2-MeO-4- MePh</td>

<td> 2326</td><td>F</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4- MePh</td>

<td> 2327</td><td>F</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2328</td><td>F</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2329</td><td>F</td><td>NHCHÍCHzOMek</td><td>2-MeO-4- MePh</td>

<td> 2330</td><td>F</td><td>N (CH₂CH₂OMe) 2</td><td>2-MeO-4- MePh</td>

<td> 2331</td><td>F</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2332</td><td>F</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4- MePh</td>

<td> 2333</td><td>F</td><td>NEt₂</td><td>2-MeO-4- MePh</td>

<td> 2334</td><td>F</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4- MePh</td>

<td> 2335</td><td>F</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2336</td><td>F</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4- MePh</td>

<td> 2337</td><td>F</td><td>NHCH (CH₂OMe)₂</td><td>2-ΜΘΟ-4- ClPh</td>

<td> 2338</td><td>F</td><td>N (CH₂CH₂OMe) 2</td><td>2-MeO-4- ClPh</td>

<td> 2339</td><td>F</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4- ClPh</td>

ES 2 247 478 T3

<td> 2340</td><td>F</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4- ClPh</td>

<td> 2341</td><td>F</td><td>NEt₂</td><td>2-MeO-4- ClPh</td>

<td> 2342</td><td>F</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4- ClPh</td>

<td> 2343</td><td>F</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4- ClPh</td>

<td> 2344</td><td>F</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4- ClPh</td>

<td> 2345</td><td>I</td><td>NMe (CH₂CH₂OMe)</td><td>2,4-CI₂-Ph</td>

<td> 2346</td><td>I</td><td>NEt (CH₂CH₂OMe)</td><td>2,4-Clz-Ph</td>

<td> 2347</td><td>I</td><td>NPr (CH₂CH₂OMe)</td><td>2,4-CI₂-Ph</td>

<td> 2348</td><td>I</td><td>ΝΗ-2-butyl</td><td>2,4-CI₂-Ph</td>

<td> 2349</td><td>I</td><td>cyclobutylamino</td><td>2,4-ClrPh</td>

<td> 2350</td><td>I</td><td>2-ethylpiperidinyl</td><td>2,4-CI₂-Ph</td>

<td> 2351</td><td>I</td><td>NMe (propargyl)</td><td>2,4-CI₂-Ph</td>

<td> 2352</td><td>I</td><td>NEt (propargyl)</td><td>2,4-CI₂-Ph</td>

<td> 2353</td><td>I</td><td>NEtMe</td><td>2,4-CI₂-Ph</td>

<td> 2354</td><td>I</td><td>NEtPr</td><td>2,4-CI₂-Ph</td>

<td> 2355</td><td>I</td><td>NMeBu</td><td>2,4-CI₂-Ph</td>

<td> 2356</td><td>I</td><td>NMe (CH₂cPr)</td><td>2,4-CI₂-Ph</td>

<td> 2357</td><td>I</td><td>NEt (CH₂cPr)</td><td>2,4-CI₂-Ph</td>

<td> 2358</td><td>I</td><td>NPr (CH₂cPr)</td><td>2,4-CI₂-Ph</td>

<td> 2359</td><td>I</td><td>NMe (CH₂CH₂OMe)</td><td>2-Me-4- MeOPh</td>

<td> 2360</td><td>I</td><td>NEt (CH₂CH₂OMe)</td><td>2-Me-4- MeOPh</td>

<td> 2361</td><td>I</td><td>NPr (CH₂CH₂OMe)</td><td>2-Me-4- MeOPh</td>

<td> 2362</td><td>I</td><td>ΝΗ-2-butyl</td><td>2-Me-4- MeOPh</td>

<td> 2363</td><td>I</td><td>cyclobutylamino</td><td>2-ΜΘ-4- MeOPh</td>

<td> 2364</td><td>I</td><td>2-ethylpiperidinyl</td><td>2-Me-4-</td>

ES 2 247 478 T3

<td colspan="2"></td><td colspan="2">MeOPh</td>

<td> 2365</td><td>I</td><td>NMe (propargyl)</td><td>2-Me-4- MeOPh</td>

<td> 2366</td><td>I</td><td>NEt (propargyl)</td><td>2-Me-4- MeOPh</td>

<td> 2367</td><td>I</td><td>NEtMe</td><td>2-Me-4- MeOPh</td>

<td> 2368</td><td>I</td><td>NEtPr</td><td>2-Me-4- MeOPh</td>

<td> 2360</td><td>I</td><td>NMeBu</td><td>2-ΜΘ-4- MeOPh</td>

<td> 2370</td><td>I</td><td>NMe (CH₂cPr)</td><td>2-Me-4- MeOPh</td>

<td> 2371</td><td>I</td><td>NEt (CH₂cPr)</td><td>2-Me-4- MeOPh</td>

<td> 2372</td><td>I</td><td>NPr (CH₂cPr)</td><td>2-Me-4- MeOPh</td>

<td> 2373</td><td>I</td><td>NMe (CH₂CH₂OMe)</td><td>2,4-MerPh</td>

<td> 2374</td><td>I</td><td>NEt (CH₂CH₂OMe)</td><td>2,4-MerPh</td>

<td> 2375</td><td>I</td><td>NPr (CH₂CH₂OMe)</td><td>2,4-MerPh</td>

<td> 2376</td><td>I</td><td>ΝΗ-2-butyl</td><td>2,4-Me₂-Ph</td>

<td> 2377</td><td>I</td><td>cyclobutylamino</td><td>2,4-Me₂-Ph</td>

<td> 2378</td><td>I</td><td>2-ethylpiperidinyl</td><td>2,4-Me₂-Ph</td>

<td> 2379</td><td>I</td><td>NMe (propargyl)</td><td>2,4-Me₂-Ph</td>

<td> 2380</td><td>I</td><td>NEt (propargyl)</td><td>2,4-Me₂-Ph</td>

<td> 2381</td><td>I</td><td>NEtMe</td><td>2,4-Me₂-Ph</td>

<td> 2382</td><td>I</td><td>MEtPr</td><td>2,4-Mez-Ph</td>

<td> 2383</td><td>I</td><td>NMeBu</td><td>2,4-MerPh</td>

<td> 2384</td><td>I</td><td>NMe (CH₂cPr)</td><td>2,4-MerPh</td>

<td> 2385</td><td>I</td><td>NEt (CH₂cPr)</td><td>2,4-Me₂-Ph</td>

<td> 2386</td><td>I</td><td>NPr (CH₂cPr)</td><td>2,4-MerPh</td>

<td> 2387</td><td>I</td><td>NMe (CH₂CH₂OMe)</td><td>2-CI-4- MeOPh</td>

<td> 2388</td><td>I</td><td>NEt (CH₂CH₂OMe)</td><td>2-CI-4- MeOPh</td>

ES 2 247 478 T3

<td> 2389</td><td>I</td><td>NPr (CH₂CH₂OMe)</td><td>2-0-4- MeOPh</td>

<td> 2390</td><td>I</td><td>ΝΗ-2-butyl</td><td>2-0-4- MeOPh</td>

<td> 2391</td><td>I</td><td>cyclobutylamino</td><td>2-0-4- MeOPh</td>

<td> 2392</td><td>I</td><td>2-ethylpiperidinyl</td><td>2-0-4- MeOPh</td>

<td> 2393</td><td>I</td><td>NMe (propargyl)</td><td>2-0-4- MeOPh</td>

<td> 2394</td><td>I</td><td>NEt (propargyl)</td><td>2-0-4- MeOPh</td>

<td> 2395</td><td>I</td><td>NEtMe</td><td>2-0-4- MeOPh</td>

<td> 2396</td><td>I</td><td>NEtPr</td><td>2-0-4- MeOPh</td>

<td> 2397</td><td>I</td><td>NMeBu</td><td>2-0-4- MeOPh</td>

<td> 2398</td><td>I</td><td>NMe (CH₂cPr)</td><td>2-0-4- MeOPh</td>

<td> 2399</td><td>I</td><td>NEt (CH₂CPr)</td><td>2-0-4- MeOPh</td>

<td> 2400</td><td>I</td><td>NPr (CH₂cPr)</td><td>2-0-4- MeOPh</td>

<td> 2401</td><td>I</td><td>NMe (CH₂CH₂OMe)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2402</td><td>I</td><td>NEt (CH₂CH₂OMe)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2403</td><td>I</td><td>NPr (CH₂CH₂OMe)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2404</td><td>I</td><td>ΝΗ-2-butyl</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2405</td><td>I</td><td>cyclobutylamino</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2406</td><td>I</td><td>2-ethylpiperidinyl</td><td>2,5-Me₂-4-</td>

ES 2 247 478 T3

<td></td><td colspan="3">MeOPh</td>

<td> 2407</td><td>I</td><td>NMe (propargyl)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2408</td><td>I</td><td>NEt (propargyl)</td><td>2.5-ΜΘΖ-4- MeOPh</td>

<td> 2409</td><td>I</td><td>NEtMe</td><td>2.5-ΜΘΖ-4- MeOPh</td>

<td> 2410</td><td>I</td><td>NEtPr</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2411</td><td>I</td><td>NMeBu</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2412</td><td>I</td><td>NMe (CH₂cPr)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2413</td><td>I</td><td>NEt (CH₂CPr)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2414</td><td>I</td><td>NPr (CH₂CPr)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2415</td><td>Cl</td><td>NMe (CH₂CH₂OMe)</td><td>2,4-CI₂-Ph</td>

<td> 2416</td><td>Cl</td><td>NEt (CH₂CH₂OMe)</td><td>2,4-Clz-Ph</td>

<td> 2417</td><td>Cl</td><td>NPr (CH₂CH₂OMe)</td><td>2,4-Clz-Ph</td>

<td> 2418</td><td>Cl</td><td>ΝΗ-2-butyl</td><td>2,4-Clz-Ph</td>

<td> 2419</td><td>Cl</td><td>cyclobutylamino</td><td>2,4-Clz-Ph</td>

<td> 2420</td><td>Cl</td><td>2-ethylpiperidinyl</td><td>2,4-Clz-Ph</td>

<td> 2421</td><td>Cl</td><td>NMe (propargyl)</td><td>2,4-Clz-Ph</td>

<td> 2422</td><td>Cl</td><td>NEt (propargyl)</td><td>2,4-Clz-Ph</td>

<td> 2423</td><td>Cl</td><td>NEtMe</td><td>2,4-Clz-Ph</td>

<td> 2424</td><td>Cl</td><td>NEtPr</td><td>2,4-Clz-Ph</td>

<td> 2425</td><td>Cl</td><td>NMeBu</td><td>2,4-Clz-Ph</td>

<td> 2426</td><td>Cl</td><td>NMe (CH₂cPr)</td><td>2,4-Clz-Ph</td>

<td> 2427</td><td>Cl</td><td>NEt (CH₂cPr)</td><td>2,4-Clz-Ph</td>

<td> 2428</td><td>Cl</td><td>NPr (CH₂cPr)</td><td>2,4-Clz-Ph</td>

<td> 2429</td><td>Cl</td><td>NMe (CH₂CH₂OMe)</td><td>2-Me-4- MeOPh</td>

<td> 2430</td><td>Cl</td><td>NEt (CH₂CH₂OMe)</td><td>2-Me-4- MeOPh</td>

ES 2 247 478 T3

<td> 2431</td><td>Cl</td><td>NPr (CH₂CH₂OMe)</td><td>2-Me-4- MeOPh</td>

<td> 2432</td><td>Cl</td><td>ΝΗ-2-butyl</td><td>2-Me-4- MeOPh</td>

<td> 2433</td><td>Cl</td><td>cyclobutylamino</td><td>2-Me-4- MeOPh</td>

<td> 2434</td><td>Cl</td><td>2-ethylpiperidinyl</td><td>2-Me-4- MeOPh</td>

<td> 2435</td><td>Cl</td><td>NMe (propagated)</td><td>2-Me-4- MeOPh</td>

<td> 2436</td><td>Cl</td><td>NEt (propargllo)</td><td>2-Me-4- MeOPh</td>

<td> 2437</td><td>Cl</td><td>NEtMe</td><td>2-Me-4- MeOPh</td>

<td> 2438</td><td>Cl</td><td>NEtPr</td><td>2-Me-4- MeOPh</td>

<td> 2439</td><td>Cl</td><td>NMeBu</td><td>2-Me-4- MeOPh</td>

<td> 2440</td><td>Cl</td><td>NMe (CH₂CPr)</td><td>2-Me-4- MeOPh</td>

<td> 2441</td><td>Cl</td><td>NEt (CH₂cPr)</td><td>2-Me-4- MeOPh</td>

<td> 2442</td><td>Cl</td><td>NPr (CH₂cPr)</td><td>2-Me-4- MeOPh</td>

<td> 2443</td><td>Cl</td><td>NMe (CH₂CH₂OMe)</td><td>2,4-MerPh</td>

<td> 2444</td><td>Cl</td><td>NEt (CH₂CH₂OMe)</td><td>2,4-Me₂-Ph</td>

<td> 2445</td><td>Cl</td><td>NPr (CH₂CH₂OMe)</td><td>2,4-MerPh</td>

<td> 2446</td><td>Cl</td><td>ΝΗ-2-butyl</td><td>2,4-Mez-Ph</td>

<td> 2447</td><td>Cl</td><td>cyclobutylamino</td><td>2,4-MerPh</td>

<td> 2448</td><td>Cl</td><td>2-ethylpiperidinyl</td><td>2,4-Me ^ Ph</td>

<td> 2449</td><td>Cl</td><td>NMe (propargyl)</td><td>2,4-ΜβΣ-ΡΙι</td>

<td> 2450</td><td>Cl</td><td>NEt (propargyl)</td><td>2,4-Me₂-Ph</td>

<td> 2451</td><td>Cl</td><td>NEtMe</td><td>2,4-MerPh</td>

<td> 2452</td><td>Cl</td><td>NEtPr</td><td>2,4-Me₂-Ph</td>

<td> 2453</td><td>Cl</td><td>NMeBu</td><td>2,4-MerPh</td>

ES 2 247 478 T3

<td> 2454</td><td>Cl</td><td>NMe (CH₂cPr)</td><td>2,4-MerPh</td>

<td> 2455</td><td>Cl</td><td>NEt (CH₂cPr)</td><td>2,4-Me₂-Ph</td>

<td> 2456</td><td>Cl</td><td>NPr (CH₂cPr)</td><td>2,4-MerPh</td>

<td> 2457</td><td>Cl</td><td>NMe (CH₂CH₂OMe)</td><td>2-CI-4- MeOPh</td>

<td> 2458</td><td>Cl</td><td>NEt (CH₂CH₂OMe)</td><td>2-CI-4- MeOPh</td>

<td> 2459</td><td>Cl</td><td>NPr (CH₂CH₂OMe)</td><td>2-CI-4- MeOPh</td>

<td> 2460</td><td>Cl</td><td>ΝΗ-2-butyl</td><td>2-CI-4- MeOPh</td>

<td> 2461</td><td>Cl</td><td>cyclobutylamine</td><td>2-CI-4- MeOPh</td>

<td> 2462</td><td>Cl</td><td>2-ethylpiperidinyl</td><td>2-CI-4- MeOPh</td>

<td> 2453</td><td>Cl</td><td>NMe (propargyl)</td><td>2-CI-4- MeOPh</td>

<td> 2464</td><td>Cl</td><td>NEt (propargyl)</td><td>2-CI-4- MeOPh</td>

<td> 2465</td><td>Cl</td><td>NEtMe</td><td>2-CI-4- MeOPh</td>

<td> 2466</td><td>Cl</td><td>NEtPr</td><td>2-CI-4- MeOPh</td>

<td> 2467</td><td>Cl</td><td>NMeBu</td><td>2-CI-4- MeOPh</td>

<td> 2468</td><td>Cl</td><td>NMe (CH₂CPr)</td><td>2-CI-4- MeOPh</td>

<td> 2469</td><td>Cl</td><td>NEt (CH₂cPr)</td><td>2-CI-4- MeOPh</td>

<td> 2470</td><td>Cl</td><td>NPrtCHzcPr)</td><td>2-CI-4- MeOPh</td>

<td> 2471</td><td>Cl</td><td>NMe (CH₂CH₂OMe)</td><td>2.5-Μθ₂-4- MeOPh</td>

<td> 2472</td><td>Cl</td><td>NEt (CH₂CH₂OMe)</td><td>2,5-Me₂-4-</td>

MeOPh

ES 2 247 478 T3

<td> 2473</td><td>Cl</td><td>NPr (CH₂CH₂OMe)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2474</td><td>Cl</td><td>ΝΗ-2-butyl</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2475</td><td>Cl</td><td>cyclobutylamino</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2476</td><td>Cl</td><td>2-ethylpiperidinyl</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2477</td><td>Cl</td><td>NMe {propargyl)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2478</td><td>Cl</td><td>NEt (propargyl)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2479</td><td>Cl</td><td>NEtMe</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2480</td><td>Cl</td><td>NEtPr</td><td>2.5-ΜΘΣ-4- MeOPh</td>

<td> 2481</td><td>Cl</td><td>NMeBu</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2482</td><td>Cl</td><td>NMe (CH₂cPr)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2483</td><td>Cl</td><td>NEt (CH₂CPr)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2484</td><td>Cl</td><td>NPr (CH₂cPr)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2485</td><td>F</td><td>NMe (CH₂CH₂OMe)</td><td>2,4-CI₂-Ph</td>

<td> 2486</td><td>F</td><td>NEt (CH₂CH₂OMe)</td><td>2,4-CI₂-Ph</td>

<td> 2487</td><td>F</td><td>NPr (CH₂CH₂I)</td><td>2,4-CI₂-Ph</td>

<td> 2488</td><td>F</td><td>ΝΗ-2-butyl</td><td>2,4-CI ^ Ph</td>

<td> 2489</td><td>F</td><td>cyclobutylamino</td><td>2,4-ClrPh</td>

<td> 2490</td><td>F</td><td>2-ethylpiperidinyl</td><td>2,4-CI₂-Ph</td>

<td> 2491</td><td>F</td><td>NMe (propargyl)</td><td>2,4-CI₂-Ph</td>

<td> 2492</td><td>F</td><td>NEt (propargyl)</td><td>2,4-Ch-Ph</td>

<td> 2493</td><td>F</td><td>NEtMe</td><td>2,4-CI₂-Ph</td>

<td> 2494</td><td>F</td><td>NEtPr</td><td>2,4-CI₂-Ph</td>

<td> 2495</td><td>F</td><td>NMeBu</td><td>2,4-CI ^ Ph</td>

ES 2 247 478 T3

<td> 2496</td><td>F</td><td>NMe (CH₂cPr)</td><td>2,4-ClrPh</td>

<td> 2497</td><td>F</td><td>NEt (CH₂cPr)</td><td>2,4-ClrPh</td>

<td> 2498</td><td>F</td><td>NPr (CH₂cPr)</td><td>2,4-CI₂-Ph</td>

<td> 2499</td><td>F</td><td>NMe (CH₂CH₂OMe)</td><td>2-Me-4- MeOPh</td>

<td> 2500</td><td>F</td><td>NEt (CH₂CH₂OMe)</td><td>2-Me-4- MeOPh</td>

<td> 2501</td><td>F</td><td>NPr (CH₂CH₂OMe)</td><td>2-Me-4- MeOPh</td>

<td> 2502</td><td>F</td><td>ΝΗ-2-butyl</td><td>2-Me-4- MeOPh</td>

<td> 2503</td><td>F</td><td>cyclobutylamino</td><td>2-Me-4- MeOPh</td>

<td> 2504</td><td>F</td><td>2-ethylpiperidinyl</td><td>2-Me-4- MeOPh</td>

<td> 2505</td><td>F</td><td>NMe (propargyl)</td><td>2-Me-4- MeOPh</td>

<td> 2506</td><td>F</td><td>NEt (prapargillus)</td><td>2-Me-4- MeOPh</td>

<td> 2507</td><td>F</td><td>NEtMe</td><td>2-Me-4- MeOPh</td>

<td> 2508</td><td>F</td><td>NEtPr</td><td>2-Me-4- MeOPh</td>

<td> 2509</td><td>F</td><td>NMeBu</td><td>2-Me-4- MeOPh</td>

<td> 2510</td><td>F</td><td>NMe (CH₂cPr)</td><td>2-Me-4- MeOPh</td>

<td> 2511</td><td>F</td><td>NEt (CH₂cPr)</td><td>2-Me-4- MeOPh</td>

<td> 2512</td><td>F</td><td>NPr (CH₂cPr)</td><td>2-Me-4- MeOPh</td>

<td> 2513</td><td>F</td><td>NMe (CH₂CH₂OMe)</td><td>2,4-Mez-Ph</td>

<td> 2514</td><td>F</td><td>NEt (CH₂CH₂OMe)</td><td>2,4-Me₂-Ph</td>

<td> 2515</td><td>F</td><td>NPr (CH₂CH₂OMe)</td><td>2,4-Me₂-Ph</td>

<td> 2516</td><td>F</td><td>ΝΗ-2-butyl</td><td>2,4-Me₂-Ph</td>

ES 2 247 478 T3

<td> 2517</td><td>F</td><td>cyclobutylamino</td><td>2,4-Me₂-Ph</td>

<td> 2518</td><td>F</td><td>2-ethylpiperidinyl</td><td>2,4-Me₂-Ph</td>

<td> 2519</td><td>F</td><td>NMe (propargik&gt;)</td><td>2,4-MerPh</td>

<td> 2520</td><td>F</td><td>NEt (propargyl)</td><td>2,4-MerPh</td>

<td> 2521</td><td>F</td><td>NEtMe</td><td>2,4-Me₂-Ph</td>

<td> 2522</td><td>F</td><td>NEtPr</td><td>2,4-Me₂-Ph</td>

<td> 2523</td><td>F</td><td>NMeBu</td><td>2,4-Me₂-Ph</td>

<td> 2524</td><td>F</td><td>NMe (CH₂cPr)</td><td>2,4-Me₂-Ph</td>

<td> 2525</td><td>F</td><td>NEt (CH₂cPr)</td><td>2,4-Me₂-Ph</td>

<td> 2526</td><td>F</td><td>NPr (CH₂cPt)</td><td>2,4-Me₂-Ph</td>

<td> 2527</td><td>F</td><td>NMe (CH₂CH₂OMe)</td><td>2-0-4- MeOPh</td>

<td> 2528</td><td>F</td><td>NEt (CH₂CH₂OMe)</td><td>2-0-4- MeOPh</td>

<td> 2529</td><td>F</td><td>NPr (CH₂CH₂OMe)</td><td>2-0-4- MeOPh</td>

<td> 2530</td><td>F</td><td>ΝΗ-2-butyl</td><td>2-0-4- MeOPh</td>

<td> 2531</td><td>F</td><td>cyclobutylamino</td><td>2-0-4- MeOPh</td>

<td> 2532</td><td>F</td><td>2-ethylpiperidinyl</td><td>2-0-4- MeOPh</td>

<td> 2533</td><td>F</td><td>NMe (propargyl)</td><td>2-0-4- MeOPh</td>

<td> 2534</td><td>F</td><td>NEt (propargyl)</td><td>2-0-4- MeOPh</td>

<td> 2535</td><td>F</td><td>NEtMe</td><td>2-0-4- MeOPh</td>

<td> 2536</td><td>F</td><td>NEtPr</td><td>2-0-4- MeOPh</td>

<td> 2537</td><td>F</td><td>NMeBu</td><td>2-0-4- MeOPh</td>

<td> 2538</td><td>F</td><td>NMe (CH₂cPr)</td><td>2-0-4- MeOPh</td>

<td> 2539</td><td>F</td><td>NEt (CH₂CPr)</td><td> 2-0-4-</td>

ES 2 247 478 T3

<td colspan="2"></td><td colspan="2">MeOPh</td>

<td> 2540</td><td>F</td><td>NPr (CH₂cPr)</td><td>2-CI-4- MeOPh</td>

<td> 2541</td><td>F</td><td>NMe (CH₂CH₂OMe)</td><td>2.5-ΜΘΤ4- MeOPh</td>

<td> 2542</td><td>F</td><td>NEt (CH₂CH₂OMe)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2543</td><td>F</td><td>NPr (CH₂CH₂OMe)</td><td>2,5-Me ^ MeOPh</td>

<td> 2544</td><td>F</td><td>ΝΗ-2-butllo</td><td>2.5-ΜΘΣ-4- MeOPh</td>

<td> 2545</td><td>F</td><td>cyclobutylamino</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2546</td><td>F</td><td>2-ethylpiperidinyl</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2547</td><td>F</td><td>NMe (propargyl)</td><td>2,5-Μβ2-4- MeOPh</td>

<td> 2548</td><td>F</td><td>NEt (propargyl)</td><td>2,5-Μβ2-4- MeOPh</td>

<td> 2549</td><td>F</td><td>NEtMe</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2550</td><td>F</td><td>NEtPr</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2551</td><td>F</td><td>NMeBu</td><td>2,5-Μθ2-4- MeOPh</td>

<td> 2552</td><td>F</td><td>NMe (CH₂CPr)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2553</td><td>F</td><td>NEt (CH₂cPr)</td><td>2,5-Me₂-4- MeOPh</td>

<td> 2554</td><td>F</td><td>NPr (CH₂cPr)</td><td>2,5-Me₂-4- MeOPh</td>

<td>to)</td><td>IQ-EMAR: Cale.</td><td colspan="2">367.2498; Found: 367.2468 (M</td>

<td>b)</td><td>IQ-EMAR: Cale.</td><td colspan="2">.: 387.1952; Found; 387.1939 (M</td>

ES 2 247 478 T3

Utility

CRF-R1 Receptor Binding Assay for Evaluation of Biological Activity

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

Messenger RNA was isolated from the human hippocampus. The mRNA was reverse transcribed using oligo (dt) 1218 and the coding region was simplified by PCR from the start codon to the stop codon. The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from which the insert was recovered using XhoI + XbaI and cloned into the XhoI + XbaI sites of the pm3ar vector (containing a CMV promoter, the splice site " t ”of SV40 and 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 that retained the episome were selected in the presence of 400 juM hygromycin. Cells that survived 4 weeks of selection on hygromycin were pooled, adapted for suspension culture, and used to generate membranes for the binding assay described below. Then individual aliquots containing approximately 1 x 10⁸ of the suspended cells were centrifuged to form a pellet and frozen.

For the binding assay, a frozen pellet described above containing 293EBNA cells transfected with hCRFR1 receptors is homogenized in 10 ml ice-cold tissue buffer (50 mM HEPES buffer, pH 7.0 containing MgCl₂ 10 mM; 2 mM EGTA, 1 pg / l of aprotinin, 1 jug / ml of leupeptin and 1 jug / ml of pepstatin). The homogenate is centrifuged at 40,000 xg for 12 minutes and the resulting pellet is rehomogenized in 10 ml of tissue buffer. After another centrifugation at 40,000 xg for 12 minutes, the pellet is resuspended at a protein concentration of 360 jug / ml to be used in the assay.

Binding assays are performed in 96-well plates; each well having a capacity of 300 // l. To each well is added 50 μl of test drug dilutions (final concentration of a range of drugs of 10^-10- 10 ⁵ M), Jul 100, ¹²⁵I-sheep-CRF (¹²⁵Io-CRF) (150 pM final concentration) and 150 µl of the cell homogenate described above. The plates are then allowed to incubate at room temperature for 2 hours before filtering the incubated material on GF / F filters (pre-moistened with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed twice with ice cold assay buffer before individual filters are removed and evaluated for radioactivity in a gamma counter.

The inhibition curves of ¹²⁵Io-CRFs that bind to cell membranes at various dilutions of the test drug are analyzed by the iterative curve fitting program LIGAND [PJ. Munson and D. Rodbard, Anal. Biochem. 107: 220 (1980) which provides Ki values ​​for inhibition which are then used to assess biological activity.

A compound is considered active if it has a Ki value of less than about 10,000 nM for the inhibition of CRF.

Inhibition of CRF-Stimulated Adenylate Cyclase Activity

Inhibition of CRF-stimulated adenylate cyclase activity can be performed as described by G. Battaglia et al., Synapse 1: 572 (1987). Briefly, the assays are performed at 37 ° C for 10 minutes in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37 ° C), MgCl₂ 10 mM, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units / ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10 ⁹ to 10 ⁶¹¹¹) and 0.8 mg wet weight parent tissue (approximately 40-60 mg protein). Reactions are initiated by the addition of 1 mM ATP /³²P] ATP (approximately 2-4 mCi / tube) and terminated by the addition of 100 ml of 50 mM TrisHCl, 45 mM ATP and 2% sodium dodecyl sulfate. To monitor cAMP recovery, add 1 µ of [³H] cAMP (approximately 40,000 dpm) to each tube prior to separation. The separation of [³²p] cAMP of [³²p] ATP is made by sequential elution on Dowex and alumina columns.

In vivo Biological Assays

The in vivo activity of the compounds of the present invention can be evaluated using any one of the available and art-accepted biological assays. Illustrations of these trials include the acoustic startle trial, the stair climbing trial, and the chronic administration trial. These and other useful models for treating compounds of the present invention have been summarized in CW Berridge and AJ Dunn Brain Research Reviews 15:71 (1990).

The compounds can be tested in any species of rodent or small mammal.

The compounds of this invention have utility in treating imbalances associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders, and / or anxiety.

ES 2 247 478 T3

The compounds of this invention can be administered to treat these abnormalities by means that result in contact of the active agent with the agent's site of action in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceutical agents as a single therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected based on the chosen route of administration and standard pharmaceutical practice.

The dosage administered will vary depending on use and known factors such as the pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; and the desired effect. For use in treating such diseases or conditions, the compounds of this invention can be administered orally daily at a dosage of the active ingredient of 0.002 to 200 mg / kg of body weight. Typically, a dose of 0.01 to 10 mg / kg in divided doses one to four times a day, or in a sustained released formulation will be effective in obtaining the desired pharmacological effect.

Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will normally be present in an amount of from about 0.5 to 95% by weight based on the total weight of the composition.

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

Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as, but not limited to, lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make tablets that are compressed. Both tablets and capsules can be manufactured as sustained release products to provide continuous release of medication over a period of time. Tablets that are compressed can be coated with sugar or with a film to mask any unpleasant taste, or can be used to protect the active ingredients from the atmosphere or to allow selective disintegration of the tablet in the gastrointestinal tract.

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

In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose) and solutions of related sugars and glycols, such as propylene glycol or polyethylene glycol, are suitable vehicles for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary buffer substances. Antioxidant agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, are suitable stabilizing agents. Citric acid and its salts, and EDTA are also used. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences", A. Osol, a standard reference in the field.

Useful pharmaceutical dosage forms for the administration of the compounds of this invention can be illustrated as shown below.

Capsules

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

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared or injected by a positive displacement pump to form soft gelatin capsules containing 100 mg of active ingredient. . The capsules were washed and dried.

Tablets

A large number of tablets were prepared by conventional procedures so that the dosage unit 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. Appropriate coatings can be applied to increase palatability or delayed absorption.

ES 2 247 478 T3

The compounds of this invention can also be used as reagents or standards in the biochemical study of neurological function, dysfunction and disease.

Although the present invention has been described and illustrated in terms of certain preferred embodiments, other embodiments will be apparent to those skilled in the art. Therefore, the invention does not limit the particular embodiments described and illustrated, although they may be modified or varied without departing from the invention, the full scope of which is described by the appended claims.