SK9799A3 - Azolo triazines and pyrimidines and pharmaceutical preparations containing thereof - Google Patents

Description

Technical field

The invention relates to the treatment of psychiatric and neurological disorders including depression, anxiety-related disorders, post-traumatic stress-related disorders, supranuclear paralysis and eating disorders, as well as the treatment of immunological, cardiovascular or cardiac diseases and intestinal hypersensitivity associated with psychopathological disorders stress, administration of certain [1,5-a] pyrazolo-1,3,5-triazines, [1,5-a] -1,2,3-triazolo-1,3,5-triazines, [1,5-a] pyrazolopyrimidines and [1,5-a] -1,2,3-triazolopyrimidines.

BACKGROUND OF THE INVENTION

The corticotropin releasing factor (referred to herein as the CRF corticotropin releasing factor), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC) secretion derived from the anterior pituitary gland [J. Rivier et al., Proc. Above. ACAT. Sci. (USA) 80: 4851 (1983); W. Vale et al., Science 213: 1394 (1981)]. In addition to its endocrine role as the pituitary gland, immunohistochemical localization of CRF has demonstrated that this hormone has a broad extrahypothalamic distribution in the central nervous system and produces a broad spectrum of autonomous, electrophysiological and behavioral effects consistent with the role of neurodegenerator or neuromuscular neurotransmitter [ Vale et al., Rec. Prog. Horm. Res. 39: 245 (1983); G.F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5: 3189 (1985)]. There is also no evidence that CRF can play an important role in integrating the immune system's response to physiological, psychological and immunological stressors [J.

Blalock, E., Physiological Reviews 69: 1 (1989); Morley, J. E., Life Sci. 41: 527 (1987)].

Clinical data have shown that CRF can also be applied to psychiatric disorders and neurological disorders including depression, anxiety-related disorders and eating-related disorders. The role of CRF in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, suppressive supranuclear paralysis and amyotrophic lateral sclerosis has also been demonstrated, since these pathological conditions relate to dysfunction of CRF neurons in the central nervous system. . Practice 23:59 (1988)].

In affective disorder or severe depression, the concentration of CRF in cerebral spinal fluid (CSF) increases significantly in individuals who do not receive active drugs [C. Nemeroff et al., Science 226: 1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144: 873 (1987); R. D. France et al., Biol. Psychiatrists 28:86 (1988); M. Arato et al., Biol. Psychiatry 25: 355 (1989)]. In addition, CFR density is significantly reduced in the frontal cerebral cortex of suicide subjects, consistent with excessive CRF secretion [C. B. Nemeroff et al., Ar. Gen. Psychiatry 45: 577 (1988)]. In addition, blunted adrenocorticotropin (ACTH) response to CRF (when administered intravenously) is observed in depressed patients (PW Gold et al., Am. J. Psychiatry 141: 619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9: 147 (1984);

W. Gold et al., New Eng. J. Med. 314: 1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that excessive CRF secretion may be included among the symptoms observed in human depression [R.

M. Sapolsky, Ar. Gen. Psychiatry 46: 1047 (1989)]. It has been tentatively shown that tricyclic antidepressants can alter CRF levels and thereby modulate the number of CRF receptors in the brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

It is also believed that CRF is also implicated in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals, showing interactions between benzodiazepine and non-benzodiazepine anxiolytics, and CRF has been demonstrated in many models of anxiety behavior [D. R. Britton et al., Life Sci. 31: 363 (1982); C.W. Berridge and A.J. Dunn, Regul. Peptides 16:83 (1986)]. Preliminary studies using putative CRF receptor antagonists α-helical sheep CRF (9-41) in a number of behavioral models demonstrate that these antagonists produce anxiolytic-like effects that are qualitatively similar to those of benzodiazepines [C. W. Berridge and A.J. Dunn, Horm. Behav. 21: 393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical endocrine and receptor binding studies have shown an interaction between CRF and benzodiazepine anxiolytics, providing further evidence for the use of CRF in these disorders. Chlorodiazepoxide attenuates the anxiogenic effects of CRF in a conflict test [K. T. Britton et al., Psychopharmacology 86: 170 (1985); K. T. Bitton et al., Psychopharmacology 94: 306 (1988)] also in the acoustic alarm test [N. R. Swerdlow et al., Psychopharmacology 88: 147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro 15: 1788), which alone was free from the effects of the conflict test, reverses the effects of CRF in a dose-dependent manner, while the benzodiazepine inverse agonist (FG 7142) improves the effects of CRF [K. T. Britton et al., Psychopharmacology 94: 306 (1988)].

The mechanism and sites of action by which standard anxiolytics and antodepressants produce their therapeutic effects remain to be elucidated. However, they are hypothetically believed to be involved in the suppression of excessive CRF secretion observed in the above disorders. It is particularly interesting that the previous studies examining the effects of antagonizing the CRF receptors (alpha-helical CRF ₃ _ ₄ i) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces effects similar Anxiolytic that are qualitatively identical with those of benzodiazepine [see GF Koob and

K.T. Britton, Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff, CRC Press, p. 221 (1990)].

Some publications disclose corticotropin releasing factor antagonist compounds and their use in the treatment of psychiatric diseases 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 is known, [1,5-a] pyrazolo-1,3,5-triazines, [1,5-a] -1,2,3-triazolo-1,3,5-triazines, [1,5- a] pyrazolopyrimidines and [1,5-a] -1,2,3, -triazolopyrimidines have not been reported as corticotropin releasing factor antagonist compounds useful in the treatment of psychiatric disorders and neurological diseases. However, there are publications which disclose some of these compounds for other uses.

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

R 1 where R ¹ is OH or alkanoyl, R ^{2 is} OH or SH and R ³ is an unsaturated heterocyclic group, naphthyl or substituted phenyl, and states that these compounds have xanthine oxidase inhibitory activity and are useful for the treatment of gout.

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

OH where A is CH or N, R 0 and R ³ are H or alkyl and R ¹ and R ² are H, alkyl, alkoxy, alkylthio, nitro, etc., and states that the compounds inhibit androgen and are useful in the treatment of benign prostatic hypertrophy and prostate cancer.

US 3,910,907 (ICI, 1975) discloses pyrazolotriazines of the general formula

where R ¹ is CH 2, C 2 H ₅ or C 2 H =, X is H, C 1 H 5, m-CH 2 C ₆ H ₅ , CN, COOEt, Cl, I or Br, Y is H, C ₆ H _5, o-CHsCgH.! or p-CHjCeH.- and Z is OH, H, CH ?, C? H _5, ΟςΗ? ,, n-C? H,

1-C3H7, SH, SCH2, NHCl2H2, or N4-H22, and states that the compounds are c-AMP phosphodiesterase inhibitors useful as bronchodilators.

US 3 995 039 discloses pyrazolotriazines of the general formula

wherein R ¹ is H or alkyl, R ² is H or alkyl, R ³ is H, alkyl, alkanoyl, carbamoyl or lower carbamoyl and R is pyridyl, pyrimidinyl or pyrazinyl, and states that the compounds are useful as bronchodilators.

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

wherein R is a lower alkoxy group and states that the compounds are xanthine oxidase inhibitors and are useful for the treatment of gout.

576 describes pyrazolotriazines of the general formula

wherein X is O or S, Ar is phenyl, naphthyl, pyridyl or thienyl, _R? -R 6 denote H, alkyl, etc., and R 6 denote H? represents H, alkyl, phenyl, etc. The patent states that the compounds are useful as herbicides and plant growth regulators.

US 5,484,760 and WO 92/10098 disclose herbicidal compositions comprising, inter alia, herbicides a compound of the general formula

where A can be N, B can be CR ₃ , R ₃ can be phenyl or substituted phenyl, etc., R is -N (R 1) SO ₂ R = or

-SO ₂ N _(R?) R and R and R ₂ may form

or

Wherein 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 disclose triazolotriazine inhibitors of cAMP-phosphodiesterase of the formula

where Z is H, OH, CH ₃ , C ₂ H ₅ , n-C ₆ H, iso-C ₃ H-, SH, SCH ₃ ,

NH (nC ₁ H ₂ ) or N (C ₂ H =) ₂ , R is hydrogen or CH ₃ and R _{2 is} CH ₃ or C ₂ H ₅ . There are eight therapeutic fields where cAMP-phosphodiesterase inhibitors can be used: asthma, diabetes, regulation of female fertility, male infertility, psoriasis, thrombosis, anxiety and hypertension.

WO 95/35298 (Otsuka, 1995) discloses pyrazolopyrimidines and discloses that they are useful as analgesics. The compounds are represented by the general formula

wherein 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, R ³ is H, R ⁴ is H, alkyl, alkoxycarbonyl, phenylalkyl, optionally phenylthio-substituted phenyl or halogen, R ⁵ and R ⁶ are H or alkyl.

EP 0 591 528 (Otsukä, 1991) discloses the anti-inflammatory uses of pyrazolopyrimidines represented by the general formula

where Ri, R ?, R? and R are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl or phenyl, R ₅ is SR? or NR-R ₃ , R? is pyridyl or optionally substituted phenyl; denote H or optionally substituted phenyl.

Springer et al., J. Med. Chem., 1976, vol. 19, no. 2, 291-296 and Springer U.S. Patents 4,021,556 and 3,920,652 disclose pyrazolopyrimidines of the general formula

wherein R may be phenyl, substituted phenyl or pyridyl, and their use in the treatment of gout, based on their ability to inhibit xanthine oxidase.

Joshi et al., J. Prakt. Chem., 321, 2, 1979, 341-344 discloses compounds of the general formula

where R ¹ is CF 2, C 2 F 5 or C ² H ² F and R ² is CH 2, C 2 H 3 _? .

CF ₃ or CrH ₄ F.

Maquestiau et al., Bull. Soc. Belg., Vol. 101, no. 2

1992, p. 131-136 discloses pyrazolo [1,5-a] pyrimidines of general formula

Ibrahim et al., Ar. Pharm. 320, 487-491 (1987) discloses pyrazolo [1,5-a] pyrimidines of the general formula

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

Other references that describe 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., 34, 610-613 (1981) and J. Het. Chem., 22, 601 (1985).

SUMMARY OF THE INVENTION

The present invention relates to novel compounds, pharmaceutical compositions and methods that can be used in the treatment of diseases including emotional disorders, anxiety, depression, irritable bowel syndrome, post-traumatic stress, supranuclear paralysis, immune suppression, Alzheimer's disease, gastrointestinal disease, and anorexic nerve food-related disorders, alcohol or drug withdrawal symptoms, inflammatory diseases, fertility, diseases whose treatment may be effective or facilitated by antagonizing CRF, including, but not limited to, diseases established or facilitated by CRF or diseases selected from inflammatory diseases, such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergy; seizure disorders, obsessive-compulsive disease; post-traumatic stress; stress-related sleep disorders, pain perception such as fibromyalgia, mood disorders such as depression, simple seizure depression, recurrent depression, childhood abuse depression and postpartum depression; dysthemia; bipolar diseases; cyclothymia; fatigue symptom; stress caused by headache; 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, intestinal cramps, diarrhea and post-operative illusion and intestinal hypersensitivity associated with psychopathological disorders or stress; eating disorders such as anorexia and bulimia; bleeding stress; stress caused by psychotic events; eutyroid syndrome; inappropriate antidiaretic hormone (ADH) syndrome; obesity; infertility; head injury; spinal cord injury;

ischemic neuronal damage (e.g., cerebral ischemia such as hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and cardiac diseases including hypertension, tachycardia, congestive heart failure; stroke; immune dysfunctions, including stress caused by immune dysfunctions (e.g., fever stress, swine stress symptom, fever due to cattle transport, equine paroxysmal fibrillation and dysfunction due to reduced poultry movement, sheep shearing stress, or stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer type; multi-infarct dementia; amyotropic lateral sclerosis; chemical dependency and addiction (eg alcohol, cocaine, heroin, benzodiazepine or other drugs); withdrawal symptoms from alcohol or drugs; osteoporosis; psychosocial stunting and hypoglycemia in mammals.

The present invention relates to novel compounds that bind to corticotropin releasing factor receptors, thereby converting the anxiogenic effects of secretinone CRF. The compounds of the present invention are useful for the treatment of psychiatric and neurological diseases, anxiety-dependent diseases, diseases caused by post-traumatic stress, supranuclear paralysis and food-borne diseases, and also for the treatment of immunological, cardiovascular or heart diseases and intestinal hypersensitivity associated with psychopathology in mammals.

In another aspect, the invention relates to novel compounds of general formula 1 and 2 (described below) which are useful as antagonists of corticotropin releasing factor. The compounds of the present invention exhibit effects as corticotropin releasing factor antagonists and suppress CRF hypersecretion. The present invention also encompasses pharmaceutical compositions comprising compounds of formulas 1 and 2 and a method of using them for suppressing CRF hypersecretion and / or treating anxiogenic diseases.

In yet another aspect of the invention, the compounds provided by the invention (and in particular the indicated compounds of the invention) are also useful as standards and reagents for determining the ability of potential pharmaceuticals to bind to the CRF receptor.

The present invention encompasses a method of treating emotional diseases, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear paralysis, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorectic nervosis and other eating disorders associated with eating disorders, alcohol or drugs, inflammatory diseases, cardiovascular or cardiac diseases, fertility, human immunodeficiency virus infections, haemorrhagic stress, obesity, infertility, head and spinal cord injuries, epilepsy, stroke, ulcers, amyotropic lateral sclerosis, hypoglycaemia or diseases whose treatment may be effective or facilitated by antagonizing CRF, including but not limited to diseases caused or facilitated by CRF in a mammal, comprising administering to the mammal an effective amount of a compound of Formula 1 or 2

(1) (2) and their isomers, stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms thereof, wherein:

A is N or CR;

Z is N or CR ² ;

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-

1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R ⁴ groups and each Ar attached to an unsaturated carbon atom;

R is independently selected from H, C 1 -C. _; alkyl, C ₂ -Cialkenyl, C? -C? alkynyl, _C? -C ₄ cycloalkyl, C ₄ -C ₄ cycloalkylalkyl, halogen, CN, C 1 -C ₄ haloalkyl;

R ¹ is independently selected from H, C 1 -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C 4 _; alkynyl, halogen, CN, C1-C _; haloalkyl, C ₂ -C ₁₂ hydroxyalkyl, C _{; 2} -C alkoxyalkyl, C ₂ -C ₁₀ cyanoalkyl, _{C? F-C,} cycloalkyl, _C; -C _i? cycloalkylalkyl, NR ⁹ R ¹⁰ ,

_{C: C:} alkyl-NR ⁹ R ^10, NR ⁹ COR ^10, OR ^11, SH or S (O) _' R ¹² ;

R ² is selected from H, C> C,, alkyl, hydroxy C 2 C _ alkenyl, C2-C4 alkynyl, C -C cycloalkyl, C4-C10 cycloalkylalkyl, C Cihydroxyalkyl, halogen, CN, -NR ⁶ R ⁷ , NR ⁹ COR ¹⁰ , -NR ⁶ S (O) 1 R ⁷ , S (O) r NR ⁶ R ⁷ , C 2 -C ₄ haloalkyl, -OR ⁷ , SH or -S (O) _r R ¹² ;

R ³ is selected from the group consisting of

- H, OR ⁷ , SH, S (O) rR ¹³ , COR ⁷ , CO ² R ⁷ , OC (O) R ¹³ , NR ⁸ COR ⁷ , N (COR ⁷ ) 2, NR ⁸ CONR ⁶ R ⁷ , NR ⁸ CO2R ¹³ , NR ⁶ R ⁷ , NR ^6a R ^7a , N (OR ⁷ ) R ⁶ , CONR ⁶ R ⁷ , aryl, heteroaryl and heterocyclyl or

- Cx-Clo, C ₂ -C ₂ -alkenyl, C ₂ -C ₀ alkynyl, C ₃ -C ₅ cycloalkyl, C Cpcykloalkenyl, C? -C cycloalkylalkyl or _C? -Ciocykloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ci-C? -Alkyl, _C? C _f cycloalkyl, halogen, C ~ C. _; haloalkyl, cyano, OR ^15, SH, S (O) _r; R ¹³ ,

COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹³ , nr ⁸ cor ¹⁵ , N (COR ¹⁵ ) 2, nr ⁸ conr ¹⁶ r ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl , heteroaryl and heterocyclyl;

R ⁴ is independently selected from the group consisting of

C 1 -C 10 alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₂₀ alkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₂₂ cycloalkylalkyl, NO ₂ , halogen, CN, C 1 -C ₄ haloalkyl, NR ⁶ R ⁷ , NR ⁸ COR ⁷ , NR ⁸ CO ₂ R ⁷ , OR ⁷ , CONR ⁸ R ⁷

CO (NOR ⁹⁾ R ^7, CO 2 R ^7, or S (O) LIT ^7, wherein each C Cmalkvl,

Cir-C2, alkenyl, C - _C:, alkynyl, C -C cycloalkyl, C ₄ -C ₂ cycloalkylalkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of Ci-C ₄ alkyl, _N0:, halo, CN , NR ⁶ R ^7, NR ⁸ COR ^7, NR ⁸ CO 2 R ^7, COR ^7, oR ^7, CONR ⁷ R ^8, CO 2 R ^7, CO (NOR ⁹⁾ R ⁷ or S (O) _y R ^7;

R ⁶ and R ⁷ , R ^6a and R ^7a are independently selected from the group consisting of:

- H,

- C 1 -C 10 alkyl, C 3 -C ₂ -alkenyl, C 3 -C ₁₀ alkynyl, C 1 -C 10 haloalkyl of 1 to 10 halogen atoms, C ₀ -C 10 alkoxyalkyl,

C ^ -Cccykloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ or C _{-Cmcykloalkenyl?} -Ci.icykloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of a C -C _alkyl, C ₃ -C ₆ cycloalkyl, halogen, _C, -C ₄ haloalkyl, cyano, OR ^15, SH, S ( O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl;

aryl, aryl (C 1 -C ₄ alkyl), heteroaryl, heteroaryl (C 1 -C ₄ alkyl), heterocyclyl or heterocyclyl (C 1 -C ₄ alkyl);

alternatively NR ⁶ R ⁷ , NR ^{6 and} R ^7a independently are piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1 to 3 C 1 -C ₄ alkyl groups;

R ⁸ is independently selected from H or C 1 -C 6 alkyl;

R ⁹ and R ¹⁰ are independently selected from the group consisting of H,

C 1 -C ₄ alkyl or C 1 -C ₄ cycloalkyl;

R ¹¹ is selected from the group consisting of H, C ₁ -C ₄ alkyl,

C 1 -C 6 haloalkyl or C 1 -C 6 cycloalkyl;

R 2 is C _: -C _; alkyl or C ₁ -C 4 haloalkyl;

R ³ is selected from the group consisting of C ₁ -C 3 _; alkyl, C 1 -C 4 haloalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 5 cycloalkyl, C 1 -C 5 cycloalkylalkyl, aryl, aryl (C 1 -C ₄ alkyl) heteroaryl or heteroaryl (C 1 -C ₄ alkyl) -;

R ¹⁴ is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 6 alkenyl, C 3 -C 6 alkynyl, C 1 -C 4 cycloalkyl or C 1 -C 6 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected from C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, halogen, C 1 -C 6 haloalkyl, cyano, OR ¹⁵ , SH, S (O) -R ¹⁵ , COR ¹⁵ , CO ¹⁵ , R ¹⁵ , OC (O) R ¹⁵ , NR ^{15 S} COR ¹⁵ , N (COR ¹⁵ ) ;, nr ³ conr ¹⁶ r ¹⁵ , nr ⁸ co: r ¹⁵ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , and C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl and C 1 -C 6 alkylsulfonyl;

R ¹⁵ and R ¹⁶ are independently selected from H, O-C 1-6 alkyl, C 1 -C ₄ cycloalkyl, C ₄ -C ₄ cycloalkylalkyl, except that for S (O) _{1 ';} R ¹⁵ cannot R ¹⁵ be H;

aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected from the group consisting of C ₁ -C ₅ alkyl, C 1 -C 6 cycloalkyl, halogen, C 1 -C 6 haloalkyl, cyano, OR ¹⁵ , SH, S (O) R ¹⁵ , COR ¹⁵ , CO: R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) :, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO: R ¹⁵ , NR ¹⁶ R ¹⁵ and CONR ¹⁶ R ¹⁵ ;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furyl, pyranyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, pyrazolyl, 2,3-dihydrobenzothiophenyl, or 2,3-dihydrobenzothiophenyl, each optionally substituted with 1 to 5 substituents independently selected from the group consisting of a C ~ _C? alkyl, C ₃ -C 4 cycloalkyl, halogen, C 1 -C 5 haloalkyl, cyano, OR ¹⁵ , SH, S (O) -R ¹⁵ , COR ¹⁵ , CO _: R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) :, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO: R ¹⁵ , NR ¹⁶ R ¹⁵ and CONR ¹⁶ R ¹⁵ ;

heterocyclyl is saturated or partially saturated heteroaryl optionally substituted with 1 to 5 substituents independently selected from: C _f C alkyl, _C? -C _? cycloalkyl, halogen, _{-C t} haloalkyl, cyano, OR ^15, SH, S (O) ..- R ^15, COR ^15, CO R ^15, OC (O) R ^13, NR ⁸ COR ^15, N ( COR ¹⁵⁾ :, NR ⁸ CONR ¹⁶ R ^15, NR ⁸ CO _R ^15, NR ^s R ¹⁵ and CONR ¹⁶ R ^15;

n is independently 0, 1 or 2.

[2] Preferred embodiments of the present invention are those wherein, in the compound of Formula 1 or 2, Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 substituents R ⁴ .

[3] Other preferred embodiments of the present invention are those wherein, in the compound of Formula 1 or 2, A is N, Z is CR ² , Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl R ¹ and R ² are CH 2 and R ³ is NR ^{6a and} R ^7a .

[4] The present invention includes compounds of formula or 2:

(d) (2) and their isomers, stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms thereof, wherein:

A is N or CR;

Z is N or CR ² ;

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-

1,2-benzopyranyl, tetralinyl, each Ar being optionally substituted with 1 to 5 R ⁴ groups and each Ar being attached to an unsaturated carbon atom;

R is independently selected from H, Ci-C ₄ alkyl, C? -C? Alkenyl, C ^ -C.jalkinyl _C? -C _? cycloalkyl, C 4 -C 7 cycloalkylalkyl, halogen, CN, C 1 -C 7 haloalkyl;

R ¹ is independently selected from H, C 1 -C ₄ alkyl, C ₂ -C 6 alkenyl, C ₂ -C ₆ alkynyl, halogen, CN, C ₁ -C ₁₀ haloalkyl, C ₁ -C ₁₂ hydroxyalkyl, C ₂ -C ₁₂ alkoxyalkyl, C ₂ -C-cyanoalkyl, _C? -C _? cycloalkyl, C _; -C _1; cycloalkylalkyl, NR ⁹ R ¹⁰ ,

C.-C _: alkyl-NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , OR ¹¹ , SH or S (O) _: -R ¹² ;

R ² is selected from H, C, -C, alkyl, C Chalkenyl, C -.- Chalkinyl C? -Cfcykloalkyl, Ci-C 4 - cycloalkylalkyl, C-Cjhydroxyalkyl, halogen, CN, -NR ⁶ R ⁷ , NR ⁹ COR ¹⁰ , -NR ⁶ S (O) r; R ⁷ , S (O) 1; NR ⁶ R ⁷ , C 1 -C 6 haloalkyl, -OR ⁷ , SH or -S (O): -R ¹² ;

R ³ is selected from the group consisting of

- H, OR ⁷ , SH, S (O) R: R ¹³ , COR ⁷ , CO: R ⁷ , OC (O) R ¹³ , NR ⁸ COR ⁷ , N (COR ⁷ ) 2, NR ⁸ CONR ⁶ R ⁷ , NR ⁸ CO ² R ¹³ , NR ⁶ R ⁷ , NR ^6a R ^7a , N (OR ⁷ ) R ⁶ , CONR ⁶ R ⁷ , aryl, heteroaryl and heterocyclyl or

- C Cinalkyl, C ₂ -C _C, alkenyl, C ₂ -C ₀ alkynyl, _C? -CC _; cycloalkyl, C. = - _C cycloalkenyl, Ca-C ^ cycloalkyl-alkyl, or CF cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of C ₂ -C _{alkyl, C?} -C _? cycloalkyl, halogen, C ₂ -C ₄ haloalkyl, cyano, OR ^15, SH, S (O) _r R ^13,

COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) :, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl;

R ⁴ is independently selected from the group consisting of

Cl-Clo, C ₂ -C, alkenyl, C ₂ -C _H alkynyl, C? -C _f cycloalkyl, C ₂ -C * NO- cycloalkylalkyl, halo, CN, C Cihalogénalkyl, NR ⁶ R ^7, NR ⁸ COR ⁷ , NR ⁸ CO ₂ R ⁷ , OR ⁷ , CONR ⁸ R ⁷

CO (NOR ⁹⁾ R ^7, CO 2 R ^7, or S (O) r R ^7, wherein each C ₂ -Cicalkyl, C ₂ Cioalkenyl, C ₂ -C ₂ alkynyl, C -C cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl is cycloalkyl optionally substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 6 alkyl, NO _; , halogen, CN, NR ⁶ R ⁷ , NR ⁸ COR ⁷ , NR ® CO: R ⁷ , COR ⁷ , OR ⁷ , CONR ⁶ R ⁷ , CO; R ⁷ , CO (NOR ⁹ ) R ⁷ or S (O) R ⁷ ;

R ⁶ and R ⁷ , R ^6a and R ^7a are independently selected from the group consisting of:

- H,

- C '.- Clo, _C-C, -alkenyl, C-alkynyl, Ci-Ci ₀ haloalkyl having 1 to 10 halogen atoms, _C -C _? alkoxyalkyl, C Crcykloalkyl, Cd-C - cycloalkylalkyl, C - or C Cmcykloalkenyl? -Cncykloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _-C? alkyl, _C3-C? cycloalkyl, halogen, C1-C4 _; haloalkyl, cyano, OR ¹⁵ , SH, S (O) -R ¹³ , COR ¹⁵ , CO; R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO _R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl,

aryl, aryl (C 1 -C 4 alkyl), heteroaryl, heteroaryl (C 1 -C 4 alkyl), heterocyclyl or heterocyclyl (C 1 -C ₄ alkyl);

alternatively NR ^e R ⁷ and NR ^6a R ^7a independently are piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1 to 3 C 1 -C ₄ alkyl groups;

R ⁸ is independently selected from H or

C -C alkyl;

R ⁹ and R ¹⁰ are independently selected from the group consisting of H,

C 1 -C 6 alkyl or C 1 -C 6 cycloalkyl;

R ¹¹ is independently selected from H, C-alkyl, _C-C; haloalkyl or C 1 -C 6 cycloalkyl;

R ¹² is a _{C_-C;} alkyl or C ₁ -C 4 haloalkyl;

R ¹³ is selected from the group consisting of C 1 -C 6 alkenyl, C 1 -C 10 haloalkyl, C _; -C 1-6 alkoxyalkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 cycloalkylalkyl, aryl, aryl (C 1 -C 6 alkyl) heteroaryl or heteroaryl (C 1 -C 6 alkyl) -;

R ¹⁴ is selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 cycloalkyl or C 1 -C 6 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group including C 1 -C 8 alkyl, C 1 -C 6 cycloalkyl, halogen, C 1 -C 6, haloalkyl, cyano, OR ¹⁵ , SH, S (O) r R ¹³ , COR ¹⁵ , CO: R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO: R ¹⁵ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ and C 1-6 alkylthio, C 1 -C 6 alkylsulfinyl and C 1 -C 6 alkylsulfonyl;

R ¹⁵ and R ¹⁶ are independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 cycloalkylalkyl, except that for S (O) -R ^{15 it} cannot R ¹⁵ is H;

aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected from the group consisting of _Ci-C? alkyl, C _? -C _? cycloalkyl, halogen, C 1 -C 6 haloalkyl, cyano, OR ¹⁵ , SH, S (O) r R ¹⁵ , COR ¹⁵ , CO; R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ): , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO: R ¹⁵ , NR ¹⁶ R ¹⁵ and CONR ¹⁶ R ¹⁵ ;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furyl, pyryl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzothiofenz, each optionally substituted with 1 to 5 substituents independently selected from the group consisting of _Ci-C? alkyl, C 1 -C 6 cycloalkyl, halogen, C 1 -C 6 _; haloalkyl, cyano, OR ¹⁵ , SH, S (O) r R ¹⁵ , COR ¹⁵ , CO; R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ¹⁵ , NR ¹⁶ R ¹⁵ and CONR ¹⁶ R ¹⁵ ;

heterocyclyl is saturated or partially saturated heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of Ci-C? -alkyl, C? -C _f cycloalkyl, halogen, C ₂ -C. _; haloalkyl, cyano, OR ^15, SH, S (O) .- R ^15, COR ^15, _CO; R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ;, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO; R ¹⁵ , NR ¹⁶ R ¹⁵ and CONR ¹⁶ R ¹⁵ ;

n is independently 0, 1 or 2, provided that:

(1) when A is N, Z is CR ² , R ² is H, R ^{3 * *} is -OR ⁷ or -OCOR ¹³ , and R ⁷ is H, then R ¹ is not H, OH or SH;

(2) when A is N, Z is CR ² , R ¹ is CH 2? or C ² H 5, R ² is H and R ³ is OH, H, CH 2, C: H ₅ , C ₅ H ₅ , nC 2 H ₇ , 1-C 3 H 7, SH, SCH 2, NHC 1 H 8, or N (CH =) ₂ then R is not phenyl or m-CH 2 -phenyl;

(3) when A is N, Z is CR ² , R ² is H and Ar is pyridyl, pyrimidinyl or pyrazinyl and R ³ is NR ^{6a and} R ^7a , then R ^6a and R ^7a are not H or alkyl;

(4) when A is N, it is OH or Z is CR ² and R ² is SO ₂ NR ⁶ R ⁷ , then R ³ is not SH; (5) when A is CR -SO ₂ NR ⁶ R ⁷ ; and Z is CR ² , then R ² is not -NR ⁶ SO ₂ R ⁷ or (6) when A is N, then R ³ is not Z is CR ² and R ² is -NR ⁶ SO-R ⁷ or -SO _; NR ⁶ R ⁷ is OH or SH; (7) when A is N, Z is CR ² , R ¹ is CH 2? or C ₂ H ₅ , R ² is H and R ³

is OH, H, CH ₃ , C ₂ H =, C 2 H ₅ , n C ₃ H -7, iso-C ₂ H _? H-, SH, SCH ₃ , NH (nC _; H 2) or N (C ₂ H =) ₂ of then A is not unsubstituted phenyl or m-CH ₃ -phenyl;

(8) when A is CR, Z is CR ² , R ² is H, phenyl or alkyl, R ³ is not NR ⁸ COR ⁷ and Ar is phenyl or phenyl substituted with phenylthio, then R ⁷ is not aryl, aryl (C ₂ -C 1 alkyl), heteroaryl, heteroaryl (C 1 -C ₄ alkyl), heterocyclyl or heterocyclyl (C 1 -C ₄ alkyl);

(9) when A is CR, Z is CR ² , R ² is H or alkyl, Ar is phenyl and R ³ is SR ¹³ or NR ^{6a and} R ^7a then R ¹³ is not aryl or heteroaryl and R ^6a and R ^7a are not are H or aryl; or (10) when A is CH, Z is CR ² , R ¹ is OR ¹¹ , R ² is H, R ³ is OR ⁷ and

R ⁷ and R ¹¹ are both H, then Ar is not phenyl, p-Br-phenyl, p-Cl-phenyl, p-NHCOCH ₃ -phenyl, p-CH ₃ -phenyl, pyridyl or naphthyl;

(11) when A is CH, Z is CR ² , R ² is H, Ar is unsubstituted phenyl and R ³ is CH _? C ₂ H = CF? or CH 2 _; F, then R ¹ is not

CF ₃ or C ₂ F ₅ ;

(12) when A is CR, R is H, Z is CR ² , R ² is OH and R ¹ and R ³ are H, then Ar is not phenyl;

(13) when A is CR, R is H, Z is CR ² , R ² is OH or NH 2, R ¹ and R ³ are CH 3, then Ar is not 4-phenyl-3-cyano-2-aminopyridine;

2-yl.

[5] Preferred compounds of the invention are compounds of formulas 1 and 2 and their isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, provided that: (1) when A is N, R ¹ is H, C ¹ -C 6 alkyl, halogen, CN, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxyalkyl or SO (C 1 -C 6 alkyl), R ³ is NR ^6a, R ^7a and R ^6a is unsubstituted C 1 -C ⁶ alkyl; , alkyl, then R ^7a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C? _-C? cycloalkyl; and (2) 4 is N, R ¹ is H, C ¹ -C 6 alkyl, halogen, CN, C 1 -C 4 hydroxyalkyl, C 1 -C 3 alkoxyalkyl or SO; (C 1 -C 6 alkyl), R ³ is NR ^6a, R ^7a and R ^7a is unsubstituted C 1 -C 6 alkyl, then R ^6a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furyl, benzofuranyl , benzothiazolyl, indolyl or C? -C cycloalkyl _€.

[6] Preferred compounds of the invention are compounds of formulas 1 and 2 and their isomers, stereoisomeric forms or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 substituents. ⁷ [7] Preferred compounds of the invention are compounds of formula 1 and 2, and isomers thereof, stereoisomeric for27 us or mixtures of stereoisomeric forms thereof and the pharmaceutically acceptable salts or prodrug forms thereof, wherein A is N, Z is ^CR2, Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R ¹ and R ³ are NR ^{6a and} R ^7a .

[11] More preferred compounds of the invention are the compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrug forms thereof, wherein A is N.

[12] More preferred compounds of the invention are the compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrug forms thereof.

[13] More preferred compounds of the invention are the compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted 1 to 4 substituents R ^4th

[14] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ³ is NR ^{6a and} R ^7a or OR ⁷ .

[15] More preferred compounds of the invention are the compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 substituents and R ³ is NR ^{6a and} R ^7a or OR ⁷ .

[16] More preferred compounds of the invention are the compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrug forms thereof, wherein Z is CR ² .

[17] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted 1 to 4 substituents R ^4th

[18] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ³ is NR ^{6a and} R ^7a or OR ⁷ .

[19] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a is independently selected from the group consisting of:

- H,

- C Cinalkyl, C _{3 -C:} .alkenyl, C ₃ -Cioalkinyl, Ci-Ci ₀ haloalkyl with 1-10 halogens, _C2 -Crialkoxyalkýl, C ₂ -Cccykloalkyl, C -C - cycloalkyl-alkyl, Cs- Cwcykloalkenyl or C _f -C ₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of a C -C _alkyl, C? -C ₆ cycloalkyl, halogen, C, -C ₄ haloalkyl, cyano, oR ^15, SH, S (O) -R ¹³ , COR ¹⁵ , CO: R ¹⁵ , OC (O) R ¹³ , NR ^8, COR ¹⁵ , N (COR ¹⁵ ) 2, NR ^8, CONR ¹⁶ R ¹⁵ , NR ^8, CO-R ¹³ , NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl,

aryl, aryl (C 1 -C 4 alkyl), heteroaryl, heteroaryl (C 1 -C ₄ alkyl), heterocyclyl or heterocyclyl (C 1 -C ₄ alkyl); and

R ^7a is independently selected from the group consisting of:

- H,

- C ₅ -C _O alkyl, C ₃ -Cioalkenyl, C ₃ -C ₃ alkynyl, C Ciohalogénalkyl having 1 to 10 halogen atoms, C 2 -C ₃ alkoxyalkyl, C 3 Cr.cykloalkyl C '-C, -. Cycloalkylalkyl , C Cmcykloalkenyl or C 6 _-C: .jcykloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of a C -C _alkyl, C? -C _f cycloalkyl, halogen, _Ci-C4 haloalkyl, cyano, oR ¹⁵ , SH, S (O) rR ¹³ , COR ¹⁵ , CO: R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ;, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO: R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl,

aryl, aryl (C 1 -C ₄ alkyl), heteroaryl, heteroaryl (C 1 -C ₄ alkyl), heterocyclyl or heterocyclyl (C 1 -C ₄ alkyl);

alternatively, NR ⁶ R ⁷ and NR ^6a R ^7a each independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1 to 3 Ci-C ^ alkyl.

[20] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a and R ^7a are the same and selected from the group consisting of:

- Ci-C ₄ alkyl or C ₃ -C _f cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of a C -C _alkyl, C ₃ -C? Cycloalkyl, halogen, C, -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) 1; R ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO 2 R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl,

aryl or heteroaryl.

[21] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a is independently selected from the group consisting of:

- H,

C 1 -C 10 alkyl, C ₃ -C 10 alkenyl, C ₃ -C ₁₀ alkynyl, C 1 -C 10 haloalkyl of 1 to 10 halogen atoms, C ₂ -C ₁₀ alkoxyalkyl, C ₃ -C 6 -cycloalkyl, C 1 -C 6 -cycloalkylalkyl, C 8 -Cwcykloalkenyl or a C ₄ -C _e cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of _Ci-6 alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₂ -C ₄ haloalkyl, cyano, oR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO; R ¹⁵ , OC (O) R ¹³ , NR ^8, COR ¹⁵ , N (COR ¹⁵ ) ;, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl,

aryl, aryl (C 1 -C 4 alkyl), heteroaryl, heteroaryl (C 1 -C 4 alkyl), heterocyclyl or heterocyclyl (C 1 -C 4 alkyl); and

R ^7a is independently selected from the group consisting of

- _{C4 C4} alkyl and each such C-C ₄ alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of C _{4 -C?} , alkyl, hydroxy C ₃ -C. ₃ cycloalkyl, halogen, C 1 -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) _r; R ¹³ , COR ¹⁵

CO ₂ R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) :, nr ⁸ conr ¹⁶ r ¹⁵ , nr ⁸ co; r ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl.

[22] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a and R ^7a are the same and selected from the group consisting of:

C-cycloalkyl, each such C-Cecykloalkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C-C _'f alkyl, C Cbcykloalkyl, halogen, C Cihalogénalkyl, CN, OR ^15, SH, S (O) R, R ^13, COR ^15, CO R ^15, OC (O) R ^13, NR ⁸ COR ^15, N (COR ^15)., NR ⁸ CONR ¹⁶ R ^15, NR ⁸ _CO; R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl,

- aryl,

heteroaryl, or

- heterocyclyl.

[23] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a and R ^7a are independently selected from the group consisting of:

- H or Cl-Clo, wherein each such C ~ C ₁₀ alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C Chalkyl, _C? -C ₅ cycloalkyl, halogen, C 1 -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) r; R ¹³ , COR ¹⁵ , CO: R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) :, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO: R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl.

[24] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted The 1-4 substituents R ⁴ and R ³ are NR ^{6a and} R ^7a or OR ⁷ .

[25] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a is independently selected from the group consisting of:

- H,

- Cir.alkyl C, _C? -C _alkenyl, C -C _{3 H} alkynyl, C Ciohalogénalkyl having 1 to 10 halogen atoms, C ₂ -C ₅ alkoxyalkyl, C -.- Crcykloalkyl, C - C ^ cycloalkyl-alkyl, Cs-C ^ -cycloalkenyl or C _? -C ₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of C Cýalkyl, C _{3 -C?} cycloalkyl, halogen, C 1 -C 6 haloalkyl, cyano, OR ¹⁵ , SH, S (O) r; R ¹³ , COR ¹⁵ , CO: R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (C.OR ¹⁵ ) ;, NR ⁸ CONR ¹⁶ R ^15, NR ⁸ CO R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl,

aryl, aryl (C 1 -C 6 alkyl), heteroaryl, heteroaryl (C 1 -C 4 alkyl), heterocyclyl or heterocyclyl (C 1 -C 6 alkyl);

R ^7a is independently selected from the group consisting of

-H.

C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C 1 -C ₁₀ haloalkyl of 1 to 10 halogen atoms, C ₁ -C ₃ alkoxyalkyl, C 1 -C 3 cycloalkyl, C 1 -C 10 cycloalkylalkyl, C. = - Cwcykloalkenyl or C ₄ -C ₆ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of C, -C _f alkyl, C ₃ -C _{II 'cycloalkyl,} halogen, _C, -C .; haloalkyl, cyano, OR ¹⁵ , SH, S (O) -R ¹³ , COR ¹⁵ , CO _: R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) ;, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO; R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl,

aryl, aryl (C 1 -C 6 alkyl), heteroaryl, heteroaryl (C 1 -C 6 alkyl), heterocyclyl or heterocyclyl (O-Chalkyl);

alternatively, NR ⁶ R ⁷ and NR ^6a R ^7a each independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1 to 3 C-C. _} alkyl groups.

[26] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a and R ^7a are the same and selected from the group consisting of:

- Ci-C ₄ alkyl or _C? -C _? cycloalkyl each optionally substituted with 1 to 3 substituents independently selected from the group consisting of _Ci-C? alkyl, _C3-C? cycloalkyl, halogen, C 1 -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O), R ¹³ , COR ¹⁵ , CO; R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵⁾ ); NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO; R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl,

aryl or heteroaryl.

[27] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a and R ^7a are identical and selected from the group consisting of:

C 1 -C 6 alkyl, each such C 1 -C 6 alkyl. _} Alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _{-C, I 'alkyl,} C ₃ -C. _{1 '} cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁰ , SH, S (O) 1 R ¹³ , COR ¹⁵ , CO: R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵⁾ · L, NR ⁸ CONR ¹⁶ R ^15, NR ⁸ CO _R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl.

[28] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a is independently selected from the group consisting of:

- H,

- C haloalkyl, alkyl, C ₃ -C ₀ alkenyl, C ₃ -C _H alkynyl, _Ci-C haloalkyl with 1-10 halogens, _C2-C3 alkoxyalkyl, C ₃ -Crcykloalkyl, C C - cycloalkylalkyl, C ₃ -C cycloalkenyl or C ₄ -C _e cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _f C alkyl, C -C? cycloalkyl, halogen, C Cthalogénalkyl, cyano, oR ¹⁵ , SH, S (O) R; R ¹³ , COR ¹⁵ , CO; R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) :, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ® CO: R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl,

aryl, aryl (C ₇ -C ₆ alkyl), heteroaryl, heteroaryl alkyl), heterocyclyl or heterocyclyl (C 1 -C 6 alkyl);

R ^7a is independently selected from the group consisting of

- C1-C _; alkyl, each such _C-C4 alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Ci-C ₅ alkyl, C _{3 -C?} C 1-4 alkyl, halogen, C 1 -C 6 _; haloalkyl, cyano, OR ¹⁵ , SH, S (O)., R ¹³ , COR ¹⁵ , CO; R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) :, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO; R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl.

[29] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein one of R ^6a and R ^7a is selected from the group consisting of:

C-Cícykloalkyl, each such C ₃ -C? Cycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of _Ci-C? alkyl, _C3-C? cycloalkyl, halogen, C 1 -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O); - R ¹³ , COR ¹⁵ , CO; R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵⁾ ) :, NR ⁸ CONR ¹⁶ R ^15, NR ⁸ CO _R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl,

- aryl

heteroaryl, or

- heterocyclyl and the other R ^{6 a} and R ⁷ represent an unsubstituted _{C: C:} alkyl.

More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein R ^6a and R ^7a are independently selected from the group consisting of:

- H or C-C-alkyl, each such C'-Clo is optionally substituted with 1 to 3 substituents independently selected from the group consisting of a C -C alkyl, _C? -C ₄ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) -R ¹³ , COR ¹⁵ , CO _: R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N ( COR ¹⁵ ) :,

NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO _: R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl.

[31] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein:

- Ar is phenyl / pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 substituents R1;

- R ³ is NR ^6a R ^7, OR ^7, and

R ¹ and R ² are independently selected from the group consisting of

H, O-C 1-6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 4 cycloalkylalkyl.

[32] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a is independently selected from the group consisting of:

- H,

- Ci ~ Ci _? alkyl, _C3-C:? alkenyl, C Ci.-alkynyl, C-C _{To a} haloalkyl having 1 to 10 halogen atoms, _C -C ₃ alkoxyalkyl, C ₃ -C 5 cycloalkyl, C 1 -C ₃ cycloalkylalkyl, C = -C 4 cycloalkenyl or C 1 -C 3 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1 -C ₆ alkyl, C ₁ -C 6 alkyl, Ocycloalkyl, halogen, C 1 -C 6 haloalkyl, yano, OR ¹⁵ , SH, S (O) - R ¹³ , COR ¹⁵ , CO: R ¹⁵ , OC (O) R ¹³ , NR ^S COR ¹⁵ , N (COR ¹⁵ ) :, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO _: R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl,

aryl, aryl (C 1 -C 6 alkyl), heteroaryl, heteroaryl (C 1 -C 6 alkyl), heterocyclyl or heterocyclyl (C 1 -C 6 alkyl);

R ^7a is independently selected from the group consisting of

-H.

- C, -C, _{-alkyl, C? C:?} alkenyl, C _? -C ₁ -alkynyl, C 1 -C _1? haloalkyl with 1-10 halogens, C Ccalkoxyalkyl C - Crcykloalkyl, CH-O-cycloalkyl-alkyl, C ^ C _f or -Cmcykloalkenyl -Ciicykloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of a C ~ C _? alkyl, C _? -C _? cycloalkyl, halogen, Cr-Chhalogénalkyl, CN, OR ^15, SH, S (O) L. R. ^13, COR ^15, CO R ^15, OC (O) R ^13, NR ⁸ COR ^15, N (COR ^15); , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO: R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl,

aryl, aryl (C 1 -C ₄ alkyl), heteroaryl, heteroaryl (OC ₄ alkyl), heterocyclyl or heterocyclyl (C 1 -C ₄ alkyl);

alternatively, NR ⁶ R ⁷ and NR ^6a R ^7b independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1 to 3 _C-C; alkyl groups.

[33] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a and R ^7a are the same and selected from the group consisting of:

- CLalkyl C or _C? -C _? cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 cycloalkyl, halogen, C 1 -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) rR ¹³ , COR ¹⁵ , CO: R ¹⁵ , OC (O) R ¹³ , NR®COR ¹⁵ , N (COR ¹⁵ ) :, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ^with CO: R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl,

aryl or heteroaryl.

[34] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a and R ^7a are the same and selected from the group consisting of:

C Chalkyl, wherein each such _C-C4 alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C'-CValkyl, _C? -C _1-6 cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) :, R ¹³ , COR ¹⁵ , CO: R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ); NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO; R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl.

[35] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a is selected from the group consisting of:

- H,

- C -C - alkyl, _{C? C:} alkenyl, _{C? C:} -alkynyl, C H C ₁₀ haloalkyl with 1-10 halogens, _C -C 1-6 alkoxyalkyl, C 1 -C 6 -cycloalkyl, C 1 -O _; cycloalkylalkyl, C 1 -C 6 cycloalkenyl or OC-cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from C 1 -C 6 alkyl, C _; -C ₆ cycloalkyl, halogen, C 1 -C ₆ haloalkyl, cyano, OR ¹⁵ , SH, S (O), - R ¹³ , COR ¹⁵ , CO; R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N ( COR ¹⁵ ) ;, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO; R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl,

aryl, aryl (C 1 -C 4 alkyl), heteroaryl, heteroaryl (C 1 -C ₄ alkyl), heterocyclyl or heterocyclyl (C 1 -C ₄ alkyl);

R 7 to t

J θ

C 1 -C 6 alkyl, wherein each such C 1 -C 6 alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, halogen, C 1 -C 6 haloalkyl, cyano, OR ¹⁵ , SH, S (O); R ¹³ , COR ¹⁵ , CO: R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) :, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO: R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl.

More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein one of R ^6a and R ^7a is selected from the group consisting of:

- C _? -C? Cycloalkyl, each such _C? -C? Cycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of C - C? Alkyl, _C? -C 6 cycloalkyl, halogen, C 1 -C 6 haloalkyl, cyano, OR ¹⁵ , SH, S (O) r R ¹³ , COR ¹⁵ , CO: R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵⁾ ) :, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO; R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl,

- aryl,

heteroaryl, or

- heterocyclyl and other ^fea R and R ⁷ represent unsubstituted C alkyl.

[37] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a and R ^7a are independently selected from the group consisting of:

- H or Ci-C ^ alkyl, each such OC-alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of CH-Chalkyl, _C? -Cycloalkyl, halogen, C 1 -C 6 haloalkyl, cyano, OR ¹⁵ ,

SH, S (O) -R ¹³ , C.OR ¹⁵ , CO: R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ J :, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO _: R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl.

[38] Particularly preferred compounds of the invention are those of Formula 50

Formula 50 and their isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, selected from the group consisting of:

compound of general formula formula 50, where R ³ is -NHCH (n-Pr) r ⁴ a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H a R ^4e is H; compound of general formula formula 50, where R ³ is -N (Et) (n-Bu), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H a R ^4e j e H;

a compound of formula 50 wherein R ³ is - (n-Pr) _(CH CPR),

R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;

the compound is Cl, R ^4b R ^4c is Cl, R ^4d 50. is a where H a R ³ R ^4e is -N (CH _: CH _: OMe) is H; R ^4a compound of the general formula 50. where R ³ is -NCH (Et) (n-Bu), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is a ' H a R ^4e is H; compound of the general formula 50. where R ³ is -NCH (Et) (CH _: OMe ) R ^4a is Cl, R ^4b is H, R ^4c is Cl, _R 4d is a : H a R ^4e is H; compound of the general formula 50. where R ³ is -NCH (CH _: OMe) _: R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is a H a R ^4e is H; compound of the general formula 50. where R ³ is -N (Et) _: R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^w is H and R ^4e is a R; compound of the general formula 50. where R ³ is -NHCH (CH _: OEt) R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is a H a R ^4e is H; compound of the general formula 50. where R ³ is -NHCH (Et): R ^4a is a Cl, R ^4b is H, R ^4c is Cl, R ^4d is H a . R ^4e is a H; compound of the general formula 50. where R ³ is -N (Me) (Ph), R ^4a is a Cl, R ^4b is H, R ^4c is Cl, R ^4d is H a . R ^4e is a H; compound of the general formula 50. where R ³ is -N (n-Pr): R ^4a j ABOUT Cl, R ^4b is H, R ^4c is Cl, R ^4d is H a l R ^4e is a H; compound of the general formula 50. where R ³ is -NHCH (Et) (n-Pr) F R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is a H a R ^4e is H;

compound of of formula 50. where R ³ is -NHCH (CH 2 OMe) j, R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is a H a _R 4e j e Me; compound of of formula 50. where R ³ is -NHCH (CH _: OMe) R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is a H a R ^4e is H; compound of of formula 50. where R ³ is -NHCH (CH _: CH _: OMe) R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is a H a R ^4e is H; compound of of formula 50. where R ³ is -NHCH (Et) (CH _: OMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is a H a R ^4e is H; compound of of formula 50. where R ³ is -NHCH _(Et), R ^4a is Me, R ^4b is H, R ^4c is Me. R ^4d is H a . R ^4e is a H; compound of of formula 50. where R ³ is OEt, R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is a H; compound of of formula 50. where R ³ is -N _(Et), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d j e H a Γ \ is a H; compound of of formula 50. where R ³ is -N _(CHjCN), R ^4a is Me, R ^4b is H, R ^4c is Me , R is H č LR ^4e is a H; compound of of formula 50. where R ³ is -NHCH (Me) (CH _: OMe), R ^4a is Me, R ^4b is H, R ^4c j e Me, R ^4d is a H a R ^4e is H; compound of of formula 50. where R ³ is -OCH (Et) (CH _: OMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is a H a R ^4e is H; compound of of formula 50. where R ³ is -N (n-Pr) (CH _: cPr), R ^4a is Me, R ^4b is H, R ^4c 'is Me, R ^4d is a H a R ^4e is H;

a compound of formula 50 wherein R ³ is

-NHCH (Me) (CH ₂ N (Me) ₂ ), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and

R ⁴ ® is H;

a compound of formula 50 wherein R ³ is

-N (cPr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

a compound of formula 50 wherein R ³ is

-N (n-Pr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ⁴ ® is H;

the compound of formula 50 wherein R ³ is -N (n-Bu) (CH ₂ CN),

R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

the compound of formula 50 wherein R ³ is -NHCH (Et) (CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is Me;

the compound of formula 50 wherein R ³ is -NHCH (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is Me;

the compound of formula 50 wherein R ³ is -N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is Me;

the compound of formula 50 wherein R ³ is -NHCH (CH ₂ OMe) ₂ , R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;

the compound of formula 50 wherein R ³ is -NHCH (Et) (CH ₂ OMe), R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ⁴ is H;

the compound of formula 50 wherein R ³ is -N (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H, and R ⁴ is Me;

compound of of formula 50. where R ³ is a -NHCH (CH: OEt): ^R4a is Me, R ^4b is H, R ^4c is Me, R ^4d is a H a R ⁴⁹ is a Me; compound of of formula 50. where R ³ is a

-NHCH _{(CH: CH} OMe) (CH ₂ OMe) _2, R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is Me and R ⁴⁹ is Me;

compound of of formula 50. where R ³ is a morpholino, R ^4a is Me, R ^4b is H, R ^4c is Me R ^4d is H a R ⁴⁹ is a H; compound of of formula 50. where R ³ is a N (CH _CH OMe) 2, R ^4a is Br, R ^4b is H, R ^4c is Me, R ^4d is a H a R ⁴⁹ is a H; compound of of formula 50. where R ³ is a -NHCH (Et)., R ^4a is

Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ⁴⁹ is H;

the compound of formula 50 wherein R ³ is -N (Et) ₂ , R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;

the compound of formula 50 wherein R ³ is -NH (c-Pr), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

the compound of formula 50 wherein R ³ is -NHCH (CH: OMe) ₂ , R ^4a is CN, R ^4b is H, R ^4c is OMe, R ^4d is H and R ⁴⁹ is H;

a compound of formula 50 wherein R ³ is

-N (c-Pr) (CH: CH _: CN), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ⁴⁹ is Me;

the compound of formula 50 wherein R ³ is -NCH (CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ⁴⁰ is Br, R ^4d is H and R ^4e is H;

a compound of formula 50 wherein R ³ is

-NHCH (CH; OMe) (CH-CH _; OMe), R ^4a is Me, R ^4b is H, R ^4c is Br, R ^4d is

H and R ^4e is H;

the compound of formula 50 wherein R ³ is -NHCH (CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is Me and R ^4e is H;

the compound of formula 50 wherein R ³ is -N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is Me and R ^4e is H;

a compound of formula 50 wherein R ³ is -NHCH _(Et), R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is Me and R ^4e is H;

a compound of formula 50 wherein R ³ is -N _(Et), R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is Me and R ^4e is H;

compound of of formula 50. where R ³ is -NHCH (CH-OMe) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is a H a R ^4e is H; compound of of formula 50. where R ³ is -NHCH (Et) (CH ₂ OMe), R ^4a is Cl, R ^4b is H, R ^4c is Me, is a H and R ^4e is H; compound of of formula 50. where R ³ is -N (CH ₂ CH ₂ OMe) R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is a H a R ^4e is H; compound of of formula 50. where R ³ is

-NHCH (CH _; OMe) (CH ₂ CH _: OMe), R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

a compound of formula 50 wherein R ³ is

-N (c-Pr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is Me and R ^4e is H;

a compound of formula 50 wherein R ³ is

-N (c-Pr) (CH _; CH; CN), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and

R ^4e is H;

a compound of formula 50 wherein R ³ is

- (S) -NHCH (CH _: OMe) (CH _; CH _: OMe), R ^4a is Cl, R ^4b is H, R ^4c is C 1, R ^4d is H, and R ^4e is H;

a compound of formula 50 wherein R ³ is

-NHCH (CH-OMe) (CH _; CH ₂ OMe), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;

compound of of formula 50. where R ³ is -NHCH (Et) _; R ^4a is Me, R ^4b is H, R ^4c is Br R ^4d is H a R ^4e is a H; compound of of formula 50. where R ³ is -N (CH ₂ CH ₂ OMe) ₂ ·, R ^4a is Me, R ^4b is H, R ^4c is Br, R ^4d is a H a R ^4e is H; compound of of formula 50. where R ³ is a

-NH (CH ₂ OMe) _(CH -iPr), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

the compound of formula 50 wherein R ³ is -N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is H, R ^4d is H and R ^4e is H;

the compound of formula 50 wherein R ³ is -N (CH 2 CH 2 OMe) 2, R ^4a is Me, R ^4b is H, R ^4c is NMe 2, R ^4d is H and R ^4e is H;

a compound of formula 50 wherein R ³ is

-NHCH (CH ₂ OMe) (n-Pr), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

compound of of formula 50. wherein R ³ is -NHCH (CH _: OEt) (Et R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H; compound of of formula 50. where R ³ is

-NHCH (CH _; OMe) (CH ₂ CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is NMe ₂ , R ^4d is H and R ^4e is H;

R ^4b is H, R ^4c is Cl, R ^4d of formula is H and 50, ^R4e where is a : R ³ H; is -N (Et) ₂ , R ^4a is a Me, compound of of formula 50. where R ³ is -NHCH (Et); . R ^4a is Me, R ^4b is H, R ^4c is Cl R ^4d is H a R ^4e is a H; compound of of formula 50. where R ³ is -N (CH ₂ CH _; OMe) r ⁴ a is Me, R ^4b is H, R ^4c is Cl, R ^4d is a H a R ^4e is H; compound of of formula 50. where R ³ is -NHCH (CH _; OMe _R 4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is a H a R ^4e is H; compound of of formula 50. where R ³ is -N (Et) ₂ , R ^4a is a Me, R ^4b is H, R ^4c is Br, R ^4d is H and R ^4e is a H; compound of of formula 50. where R ³ is -N (Et) ₂ , R ^4a is a Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is a H; compound of of formula 50. where R ³ is -NHCH (Et) ₂ , P 4a is a Cl, R ^4b is H, R ^4c is Me R ^4d is H a . R ^4e is a H; compound of of formula 50. where R ³ is -NHCH (Et) ₂ , R ^4a is a

Me, R ^4b is H, R ^4c is NMe ₂ , R ^4d is H and R ^4e is H;

the compound of formula 50 wherein R ³ is (S) -NHCH (CH-OMe) (CH ₂ CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

a compound of formula 50 wherein R ³ is

-NHCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

a compound of formula 50 wherein R ³ is

(S) -NHCH (CH OMe) _{(CH CH} OMe), R ^4a is Me, R ^4b is H, R ^4c is a Cl, R ^4d is H and R ^4e is H; compound of formula 50 wherein R ³ is -NHCH (CH ₂ OMe) (CH _: CH ₂ OMe), R ^4a is Me, R ^4b is H, R ^4c is Cl, . R ^4d is H and R ^4e is H;

the compound of general formula -N (c-Pr) (CH _: CH _: CN), R ^{4 and} R ^4e is H; of formula is Me, 50, R ^4b where R ³ is is H, R ^4c is Cl, R ^4d is H and compound of general formula of formula 50. wherein R ³ is -NH (Et) (CH _: CN), R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is a H and R ^4e is H; compound of general formula of formula 50. where R ³ is -N (Et) ₂ , R ^4a is Me, R ^4b is Me, R ^4c is OMe, R ^4d is H and R ^4e is H; compound of general formula of formula 50. where R ³ is -N (CH _: CH ₂ OMe) (CH ₂ CH ₂ OH) R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H; compound of general formula of formula 50. wherein R ³ is -N (CH ₂ CH ₂ OMe) R ^4a

is Me, R ^4b is Me, R ^4c is OMe, R ^4d is H and R ^4e is H;

the compound of formula 50 wherein R ³ is -NHCH (Et) ₂ , R ^4a is

Me, R ^4b is Me, R ^4c is OMe, R ^4d is H and R ^4e is H;

the compound of formula 50 wherein R ³ is -N (CH-c-Pr) (n-Pr),

R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;

a compound of formula 50 wherein R ³ is

-N (c-Pr) (CH ₂ CH ₂ CN), R ^4a is Me, _R 4b is Me, R ^4c is OMe, R ^4d is a H a R ^4e is H; compound of the general formula 50. where R ³ is -NHCH (Et) ₂ , R ^4a is a Cl, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e j e H; compound of the general formula 50. where R ³ is -N (Et) ₂ , R ^4a is a Cl, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^{4 e} je H; compound of the general formula 50. where R ³ is -N (CH ₂ CH ₂ OMe b. _R 4a

is Cl, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;

the compound of formula 50 wherein R ³ is -NHCH (Et) (CH ₂ OMe), R ^4a is Cl, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;

compound of the general formula 50. where R ³ is -N (Et) ₂ , R ^4a is Cl R ^4b is H, R ^4c is CN, R ^4d is H and R ^4e is a H; compound of the general formula 50. where R ³ is -N (c-Pr) (CH ₂ CH ₂ CN), R ^4a is Cl, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H; compound of the general formula 50. where R ³ is -NHCH (CH ₂ OH) ₂ , R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is a H a R ^4e is H; and

the compound of formula 50 wherein R ³ is -N (CH _: CH _: OMe) R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H.

[39] Particularly preferred is 4- (bis- (2-methoxyethyl) amino) -

2,7-Dimethyl-8- (2-methyl-4-methoxyphenyl) - [1,5-a] pyrazolo-1,3,5-triazine and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salt or its precursor forms of drugs.

[40] Particularly preferred is 4- (bis- (2-methoxyethyl) amino) -

2,7-Dimethyl-8- (2,5-dimethyl-4-methoxyphenyl) - [1,5-a] pyrazolo-

1,3,5-triazine and its isomers, its stereoisomeric forms, or mixtures of its stereoisomeric forms, and its pharmaceutically acceptable salt or prodrug forms thereof.

More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein A is CR.

More preferred compounds of the invention are the compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts thereof, or prodrug forms thereof.

[43] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted 1 to 4 substituents R ^4th

More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ³ is NR ^{6a and} R ^7a or OR ⁷ .

[45] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted The 1-4 substituents R ⁴ and R ³ are NR ^{6a and} R ^7a or OR ⁷ .

More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein Z is CR ² .

More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted 1 to 4 substituents R ^4th

More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ³ is NR ^{6a and} R ^7a or OR ⁷ .

[49] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted The 1-4 substituents R ⁴ and R ³ are NR ^{6a and} R ^7a or OR ⁷ .

[50] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a and R ^7a are independently selected from the group consisting of:

- H or Cl-Clo, wherein each such C ₂ -C ₂₂ alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C Chalkyl, _C? -C _? cycloalkyl, halogen, C 1 -C 6 haloalkyl, cyano, OR ¹⁵ , SH, S (O) r, R ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl.

[51] More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein:

- Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 substituents R1;

- R ³ is NR ^6a R ^7, OR ^7, and

R ¹ and R ² are independently selected from the group consisting of

H, C 1 -C ₄ alkyl, C 1 -C ₄ cycloalkyl, C ₄ -C 1 -cycloalkylalkyl.

More preferred compounds of the invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a and R ^7a are independently selected from the group consisting of:

- H or C Cwalkyl, wherein each such C C _The alkyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C-Chalkyl, _C? C _f cycloalkyl, halogen, C ^ haloalkyl, CN, OR ^15, SH, S (O) n R ^13, COR ^15, CO 2 R ^15, OC (O) R ^13, NR ⁸ COR ^15, N (COR ¹⁵⁾ _; , NR ⁸ CONR ¹⁶ R ¹⁵ , NR ® CO-R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl.

Particularly preferred compounds of the invention are those of Formula 51

Formula 51 and their isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, selected from the group consisting of:

the compound of formula 51 wherein R ³ is -NHCH (n-Pr) R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

the compound of formula 51 is Me, R ^4b is H, R ^4c is Me, R ^4d is a compound of formula 51, is Me, R ^4b is H, R ^4c is Me, R ^4d is a compound of formula 51, -N ( c-Pr) _{(CH 2} CH CN), R ^4a is Me, R ^4b, R ^4e is H;

the compound of formula 51 is Cl, R ^4b is H, R ^4c is Me, R ^4d is a compound of formula 51, is Cl, R ^4b is H, R ^4c is Me, R ^4d is a compound of formula 51, Cl, R ^4b is H, R ^4c is Me, R ^4d is H?

the compound of formula 51, R ^4b is H, R ^4c is Me, R ^4d is H and R ^{4e the} compound of formula 51, -N (n-Pr) (CH 2 CH 2 CN), R ^4a is Me, R ^4b R ^4e is H;

the compound of formula 51, -N (n-Bu) (CH 2 CH 2 CN), R ^4a is Me, R ^4b R ^4e is H;

wherein R ³ is -NHCH (CH _: OMe) R ^4a H and R ^4e is H;

wherein R ³ is -N (CH _: CH _; OMe) R ^4a H and R ⁴ 'is H;

wherein R ³ is H, R ^4c is Me, R ^4d is H and wherein R ³ is -N _{(CH 2} CH _OMe), R ^4a and R H ^4e is H;

wherein R ³ is -NHCH (CH _; OMe) R ^4a H and R ^4e is H;

wherein R ³ is -NHCH _(Et), R ^4a is. R ^4e is H;

wherein R ³ is -N (Et) _; R ^4a is Me, is H;

wherein R ³ is H, R ^4c is Me, R ^4d is H, and wherein R ³ is H, R ^4c is Me, R ^4d is H, and a compound of formula 51 wherein R ³ is

-NHCH (n-Pr) (CH ₂ COMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

the compound of formula 51 wherein R ³ is -NHCH (Et) ₂ , R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;

the compound of Formula 51 wherein R ³ is -NHCH (CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;

the compound of Formula 51 wherein R ³ is (S) -NH (CH ₂ CH ₂ OMe) CH ₂ OMe, R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

the compound of formula 51 wherein R ³ is

-NH (CH ₂ CH ₂ OMe) CH ₂ OMe, R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and

R ^4e is H;

the compound of Formula 51 wherein R ³ is -N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;

the compound of formula 51 wherein R ³ is -NH (Et), R ^4a is

Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

the compound of formula 51 wherein R ³ is -NHCH (n-Pr) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;

the compound of formula 51 wherein R ³ is -NHCH (CH ₂ OMe) ₂ , R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;

a compound of formula 51 wherein R ³ is (S) -N (CH ₂ CH ₂ OMe) CH _£ OMe, R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;

the compound of formula 51 wherein R ³ is -NH (CH _; CH _: OMe) CH _; OMe, R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;

compound of formula 51 where R ³ is -N (n-Pr) (CH _: CH _: CN), R ^4a is Me, R ^4b j e H R ^4c is OMe, R ^4d is H and R ^4e is H; compound of formula 51 where R ³ is -N (Et) R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^{4 e} je H; compound of formula 51 where R ³ is (S) -N (CH, _CH, OMe) CHjOMe, R ⁴ is Cl, R ^4b is H, R ^4c is a Me, R ^4d is H and R ^4e is H; compound of formula 51 where R ³ is -NH (CH _: CH _: OMe) CH _; OMe, R ^4a is C. 1, R ^4b is H, R ^4c e Me R ^4d is H and R ^4e is H;

the compound of formula 51 wherein R ³ is -N (Et) _; R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

the compound of formula 51 wherein R ³ is

-N (c-Pr) (CH _: CH; CN), R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;

the compound of formula 51 wherein R ³ is

-N (c-Pr) (CH; CH; CN), R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

the compound of formula 51 wherein R ³ is

-NHCH (n-Pr) (CH _; OMe), R ^4a is Me, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;

the compound of formula 51 wherein R ³ is

-NHCH (n-Pr) (CH ₂ OMe), R ^4a is Cl, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is H;

the compound of formula 51 wherein R ³ is -NHCH (Et) ₂ , R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is OMe and R ^4e is H;

the compound of formula 51 wherein R ³ is -NHCH (Et); R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;

the compound of Formula 51 wherein R ³ is -N (CH ₂ CH ₂ OMe) ₂ , R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;

the compound of formula 51 wherein R ³ is -NHCH (CH ₂ OMe) ₂ , R ^4a is Br, R ^4b is H, R ^4c is OMe, R ^4d is H and R ^4e is H;

compound 51, where R ³ is -N (Et) _; R ^4a is a Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is a H; compound 51, where R ³ is -N (Et) ₂ , R ^4a is a Cl, R ^4b is H, R ^4c is OMe, R ^4d is OMe and R ^4e is H; compound 51, where R ³ is -NHCH (Et) ₂ , R ^4a is a Cl, R ^4b is H, R ^4c is OMe, R ^4d is OMe and R ^4e is H; compound 51, where R ³ is -N (CH ₂ CH ₂ OMe ) ?, R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H a R ^4e is H;

compound of of formula 51 wherein R ³ is a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is a compound of of formula 51 wherein R ³ is a R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e compound of of formula 51 wherein R ³ is a Cl, R ^4b is H, R ^4c is Cl R ^4d is H and R ^4e is a H; compound of of formula 51 wherein R ³ is a R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e compound of of formula 51 wherein R ³ is a Cl, R ^4b is H, R ^4c is Cl R ^4d is H and R ^4e is a H; compound of of formula 51 wherein R ³ is a Me, R ^4b is H, R ^4c is Me R ^4d is H and R ^4e is a H; compound of of formula 51 wherein R ³ is a Cl, R ^4b is H, R ^4c is Me R ^4d is H and R ^4e is a H; compound of of formula 51 wherein R ³ is a Me, R ^4b is H, R ^4c is Cl R ^4d is H and R ^4e is a H; compound of of formula 51 wherein R ³ is a R ^4b is H ^,: R ^4c is OMe, R 4 ^4d is H and R ^4e is H; compound of of formula 51 wherein R ³ is a R ^4a is Me, R ^4b is H, R ^{4c :} is OMe, ^R4d is H and R '

-NHCH (Et) ₂ ,

-NHCH (Et) ₂ ,

-NHCH (Et) ₂ , ^4e is H.

-NHCH (CH ₂ OMe) R ^4a

Η;

-N (Pr) (CH _; CH _: CN) is Η;

-N (Bu) (Et), R ^4a is

NHCH (Et) CH ₂ OMe, it Η;

_R 4a _R 4a

-NHCH (Et) ₂ , _R 4 and _R 4a is is them

-NEt ₂ , R ^4a is Me,

-N (Pr) (CH ₂ CH ₂ CN), [54] Particularly preferred is 7- (3-pentylamino) -2,5-dimethyl-3- (2-methyl-4-methoxyphenyl) - [1,5-a] pyrazolopyrimidine and its isomers 59, its stereoisomeric forms or mixtures of its stereoisomeric forms, and its pharmaceutically acceptable salts or prodrug forms thereof.

[55] Particular preference is given to 7- (diethylamino) -2,5-dimethyl-3- (2-methyl-4-methoxyphenyl) - [1,5-a] pyrazolopyrimidine and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrug forms thereof.

[56] Particularly preferred is 7- (N- (3-cyanopropyl) -N-propylamino) -

2,5-dimethyl-3- (2,4-dimethylphenyl) - [1,5-a] pyrazolopyrimidine and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms, and its pharmaceutically acceptable salts or prodrug forms thereof.

The present invention further encompasses pharmaceutical compositions comprising compounds of Formulas 1 and 2 and a pharmaceutically acceptable carrier.

Many of the compounds of the present 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. A number of isomers of olefins, C = N double bonds and the like may be present in the compound of the invention. and all such isomers are included in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how optically active forms can be prepared, for example by dissolving racemic forms or by synthesis from optically active starting materials. All chiral (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of the structure are contemplated only if the specific stereochemistry or isomeric form is specifically indicated.

The term "alkyl" includes straight or branched chain alkyl having a specific number of carbon atoms. The abbreviations commonly used have the following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl. The prefix "n" denotes straight-chain alkyl. The prefix "c" denotes cycloalkyl. The prefix "(S) denotes the enantiomer S and the prefix" (R) denotes the enantiomer R. "Alkenyl means a hydrocarbon chain of straight or branched configuration with one or more unsaturated carbon-carbon bonds which may be located at any stable point in the chain, such as is ethenyl, propenyl and the like. "Alkynyl" means a straight or branched chain hydrocarbon chain having one or more triple carbon-carbon bonds that may be located at any stable point in the chain, such as ethynyl, propynyl, and the like. "Haloalkyl" includes straight or branched chain alkyl with a specific number of carbon atoms, substituted with one or more halogens; "Alkoxy" means an alkyl group having a specified number of carbon atoms attached through an oxygen bridge; "Cycloalkyl" means saturated cyclic groups including mono-, bi- or polycyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. "Halogen means fluorine, chlorine, bromine and iodine.

The term "substituted" as used herein means that one or more of the hydrogen atoms of the labeled moiety is replaced by a group selected from the indicated group, provided that no normal valency increases and that substitution results in a stable compound. When the substituent is a keto group on (i.e., = O), then two hydrogen atoms attached to the atom of said group are replaced.

A combination of substituents and / or variables is permissible only if such a combination results in a stable compound. By "stable compound" or "stable structure" is meant herein a compound that is large enough to resist isolation to a usable degree of purity from the reaction mixture and the preparation of an effective therapeutic agent.

The term "suitable amino acid protecting group as used herein" means any group known in the art of organic synthesis for the protection of an amine or carboxylic acid groups. Such amine protecting groups include those described by Green and Wuts in Protective Groups in Organic Synthesis by John Wiley & Sons, New York (1991) and The Peptides: Analysis, Synthesis, Biology, Volume 3, Academic Press, New York (1981). , herein incorporated by reference. Any amine protecting group known in the art may also 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; aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1- (p-biphenyl) -1-methylethoxycarbonyl and 9-fluorenylmethyloxycarbonyl (Fmoc); aliphatic carbamate types such as tert-butoxycarbonyl (Boe), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl; 4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilanes such as trimethylsilane; and 7) thiol-containing types such as phenylthiocarbonyl and dithiasuccinoyl.

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

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 a suitable base or acid in water or an organic solvent or a mixture of the two; generally, anhydrous media such as ether, ethyl acetate, ethanol, isopropyl alcohol or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Companv, Easton, PA, 1985, p. 1418, incorporated herein by reference.

By "prodrugs" are meant any covalently bound carriers that release the active principle active ingredient of the formula I or II in vivo when administered to a mammal. Prodrugs comprising compounds of Formula I or II are prepared by modifying the functional groups present in the compounds by cleaving said modification either by conventional manipulation or in vivo to the parent compounds. Drug prodrugs include compounds wherein hydroxy, amino, or sulfhydryl groups are bonded to a particular group, so that when the prodrug is administered to a mammal, it is cleaved as a free hydroxyl group, an amino group, and an amino group, respectively. sulfhydryl group. Prodrugs include, for example, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I and II, and the like.

The term "therapeutically effective amount of a compound of the invention" means an amount effective to antagonize abnormal levels of CRF or to treat symptoms of emotional disease, anxiety or depression in a host.

synthesis

Certain compounds of Formula 1 may be prepared from intermediates of Formula 7 using the procedures outlined in Scheme 1:

Scheme 1

(1) Y = N

Compounds of formula 7 (where Y is O) may be treated with a halogenating agent or a sulfonylating agent in the presence or absence of a base, in the presence or inert solvent at a reaction temperature ranging from -80 ° C to 250 ° C to give products of formula 8 ( wherein X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkanesulfonyloxy). Halogenating agents include, but are not limited to, SOCl _; , POC1 _3, PCl 3, PCl 5, POBr _3, PBr ₃ or PBr _fifth Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or halenesulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), bis alkali metal (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran, or the like).

1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane). A preferred reaction temperature range is from -20 ° C to 100 ° C.

Compounds of formula 8 may be reacted with a compound of formula R ³ H (wherein R ³ is as defined above except that R ³ is not SH, COR ⁷ , CO _; R ⁷ , aryl or heteroaryl) in the presence or absence of an inert solvent at a reaction temperature in the range of -80 ° C to 250 ° C to give compounds of formula 1. The bases may include, without limitation, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably methoxide or ethoxide). sodium), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl) -N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1, 2). 4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane). The preferred reaction temperature range is from 0 ° C to 140 ° C.

Scheme 2 illustrates the process for converting an intermediate of Formula 7 (where Y is S) to some compounds of Formula 1.

Scheme 2

(1) Y = N

Compounds of formula 7 (where Y is S) may be treated with an alkylating agent R ¹³ X (wherein X is as defined above, with R ¹³ not being aryl or heteroaryl), in the presence or absence of an inert solvent at a reaction temperature in the range pd -80 ° C to 250 ° C. The bases may include, without limitation, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1, 2). 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 having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane). The preferred reaction temperature range is from 0 ° C. to 140 ° C.

Compounds of formula 12 (formula 1 where R ³ is SR ¹³ ) can then be reacted with a compound of formula R ³ H to form compounds of formula 1 using the same conditions and reagents as used to convert compounds of formula 8 to compounds of Formula 1 and as shown in Scheme 1 above. Alternatively, the compound of formula 12 (Formula 1 wherein R ³ is SR ¹³⁾ may be oxidized to a compound of formula 13 (the specimen 1, wherein R ³ is S (O) _when R ^13, n is 1, 2) by treatment with an oxidizing agent, in the presence or absence of an inert solvent at a temperature in the range of pd -80 ° C to 250 ° C. Oxidizing agents include, but are not limited to, hydrogen peroxide, alkane or arylperoxy acids, (preferably peracetic acid or m-chloroperbenzoic acid), dioxirane, oxone, or sodium periodinate. Inert solvents may include, but are not limited to, alkanones (3 to 10 carbon atoms, preferably acetone), water alkyl alcohols (1 to 6 carbon atoms), aromatic hydrocarbons (preferably benzene or toluene), or 1 to 10 carbon atoms of 1 to 10 carbon atoms. up to 10 halogen atoms (preferably dichloromethane) or combinations thereof. The choice of oxidizing agent and solvent is known to those skilled in the art (see Uemura, S., Oxidation of Sulfur, Selenium and Telerium in Comprehensive Organic Synthesis, Trost, BM, editor., (Elmsford, NY: Pergamon Press, 1991), 7, 762-769 ). Preferred reaction temperatures range from -20 ° C to 100 ° C. Compounds of formula 13 (formula 1 wherein R ³ is S (O) _r. R ¹³ , n is 1, 2) can be reacted with compounds of formula R ³ H to form a compound of formula 1 using the same conditions and reagents, as used to convert compounds of formula 8 to compounds of formula 1 as shown in Scheme 1 above.

Compounds of formula 1 wherein R ³ can be -NR ⁸ COR ⁷ , -N (COR ⁷ ) -nr ⁸ conr ⁶ r ⁷ , -nr ⁸ co _: r ¹³ , -nr ⁶ r ⁷ , -nr ⁸ so.r ⁷ , may be prepared from compounds of formula 7 wherein Y is NH by the procedure outlined in Scheme 3.

Scheme 3

r ₃ = NR ⁶ R ⁷ , NR ⁸ COR ⁷ , N (COR ⁷ ) 2, NR ^e CONR ^e R ⁷ , NR ⁸ CO 2 R 13

Reaction of compounds of formula 7 wherein 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 from -80 ° C to 250 ° C may provide compounds of formula I wherein R ³ may be - NR ⁸ COR ⁷ , -N (COR ⁷ ) 2 / -NR ⁸ CONR ⁶ R ⁷ , -NR ⁸ CO 2 R ¹³ , -NR ⁶ R ⁷ , -NR ⁸ SO 2 R ⁷ . Alkylating agents may include, but are not limited to, C 1 -C 18 alkyl halides, -tosylates, -mesylates, or -triflates; C 1 -C 10 haloalkyl (1 to 10 halogen atoms) halides, -tosylates, -mesylates or -triflates; C 2 -C 6 alkoxyalkyl halides, -tosylates, mesylates or -triflates; C ₃ -C _? cycloalkyl halides, tosylates, mesylates or -triflates; C 1 -C ₁₂ cycloalkyl halides, -tosylates, mesylates or -triflates; aryl (C 1 -C 6 -alkyl) halides, -tosylates, mesylates or -triflates; heteroaryl (C 1 -C 6 alkyl) halides, tosylates, mesylates or triflates; or heterocyclyl _(C., alkyl) halide, -tosyláty, mesylates or -trifláty. Acylating agents may include, without limitation, C x-Cioalkanoylhalogenidy or anhydrides, or anhydrides with CiCichalogénalkanoylhalogenidy 1 -C 10 mi halogen, C ₂ -C ₅ alkoxyalkanoylhalogenidy or anhydrides, C _{3 -C?} cykloalkanoylhalogenidy or anhydrides, C-C, cykloalkylalkanoylhalogenidy or anhydrides, aroyl halide or anhydrides, aryl _(Cl-C,) alkanoyl halide or anhydride, heteroaryl halides or anhydrides, heteroaryl (C 1 -C 4) alkanoyl halide or anhydride, halides or anhydrides, heterocyclylcarboxylic acid or heterocyclyl ( C 1 -C 12 alkanoyl halides or anhydrides. Sulfonating agents are not limited to include C -C ₁₂ alkylsulfonyl halides or anhydrides, C Ciohalogénalkylsulfonylhalogenidy or anhydrides with 1-10 halogens, C ₂ -C ₃ alkoxyalkylsulfonylhalogenidy or anhydrides, C ₃ -C _e cykloalkylsulfonylhalogenidy or anhydrides, _C -C ₁₂ cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl (C ₁ -C ₅ alkyl) heteroarylsulfonyl halides or anhydrides, heteroaryl (C ₁ -C ₆ alkyl) sulfonyl halides or anhydrides, heterocyclylsulfonyl halides or anhydrides or heterocyclyl (C 1 -C 6 alkyl or sulfides). The bases may include, without limitation, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1, 2). 4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). The preferred reaction temperature range is from 0 ° C to 140 ° C.

Scheme 4 illustrates procedures that can be used to prepare compounds of Formula 7 wherein Y is O, S and Z is CR ² .

Scheme 4

Compounds of formula ArCH ₂ CN are reacted with compounds of formula R ² COR ^b , wherein R ² is as defined above and R ^b is halogen, cyano, lower alkoxy (1 to 6 carbon atoms) or lower alkanoyloxy (1 to 6 carbon atoms) in the presence of a base in an inert solvent at a reaction temperature in the range of -78 ° C to 200 ° C to give a compound of formula 3. The bases may include, without limitation, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms). ) (preferably sodium methoxide or ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N (diisopropyl-N-ethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1). 4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). A preferred reaction temperature range is from 0 ° C to 100 ° C.

Compounds of formula 3 may be treated with hydrazine hydrate in the presence of an inert solvent at temperatures ranging from 0 ° C to 200 ° C, preferably 70 ° C to 150 ° C, to form a compound of formula 4. Inert solvents may include, but are not limited to, without limitation, water, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Compounds of formula 4 may be reacted with a compound of formula 5 (wherein R ^c is C 1 -C 6 alkyl) in the presence or absence of acid in the presence of an inert solvent at a temperature ranging from 0 ° C to 200 ° C to form compounds of formula 6. Acids which may be used include but are not limited to alkanoic acids of 2 to 10 carbon atoms (preferably acetic acid), haloalkanoic acids (2 to 10 carbon atoms, 1 to 10 halogen atoms such as trifluoroacetic acid), arylsulfonic acids ( preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbon atoms (preferably methanesultonic acid), hydrochloric acid, sulfuric acid and phosphoric acid. A stoichiometric or catalytic amount of such an acid may be used. Inert solvents may include, but are not limited to, water, alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), halogenated hydrocarbons of 1 to 6 carbon atoms and 1 to 6 halogen atoms (preferably dichloromethane or chloroform), alkyl alcohols of 1 to 10 carbon atoms (preferably ethanol), dialkyl ethers (4 to 12 carbon atoms, preferably diethyl ether or diisopropyl ether) or cyclic ethers such as dioxane or tetrahydrofuran. The preferred temperature range is from ambient temperature to 100 ° C.

Compounds of formula 6 can be converted to intermediate compounds of formula 7 by treatment with C = Y (R ^d ) ₂ , wherein Y is O or S and R ^d is halogen (preferably chlorine), alkoxy (1-4 carbon atoms), or alkylthio (1-4 carbon atoms) in the presence or absence of a base in an inert solvent at reaction temperatures from -50 ° C to 200 ° C. The bases may include, without limitation, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or ethoxide), alkali metal carbonates, alkali metal hydroxides, trialkylamines (preferably N, N-diisopropyl-N) -ethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran, or ethanol).

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). A preferred reaction temperature range is from 0 ° C to 150 ° C.

Intermediate compounds of formula 7 wherein Z is N may be prepared by the methods outlined in Scheme 5.

Scheme 5

ArCH ₂ CN

(9)

Ar reducing agent, solvent

(7) Y = O, S; Z = N

Compounds of formula ArCH _; CN are reacted with compounds of formula ^Rq CH _{; N? Z} wherein R ^q is a phenyl group optionally substituted by H, alkyl (1-6 carbons), or alkoxy (1-6 carbon atoms) in the presence or absence of a base in an inert solvent at a temperature between 0 DEG C. and 200 DEG C. to form compounds of formula

9. The bases may include, without limitation, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide, sodium ethoxide or potassium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran) or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons ( preferably benzene or toluene). The preferred reaction temperature range is from ambient temperature to 100 ° C.

Compounds of formula 9 can be treated with a reducing agent in an inert solvent at a temperature of -100 ° C to 100 ° C to give products of formula 10. Reducing agents include, but are not limited to, (a) hydrogen gas in combination with a noble metal catalyst such as Pd on carbon, PtO ₂ , Pt on carbon, Rh on alumina or Raney nickel; (b) alkali metals (preferably sodium) in combination with liquid ammonia; or (c) cerito ammonium nitrate. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). A preferred reaction temperature range is from -50 ° C to 60 ° C. Compounds of formula 9 are then converted to compounds of formula 7 (where Z is N) via intermediates of formula 11 using the reagents and reaction conditions outlined in Scheme 4 to convert compounds of formula 4 to compounds of formula 7 (wherein Z is CR ² ).

Compounds of formula I may also be prepared from compounds of formula 7 (wherein Y is O, Z and S are as defined above) as shown in Scheme 6:

Scheme 6

Compounds of formula 7 may be reacted with compounds of formula R ³ H in the presence of a dehydrating agent in an inert solvent at a temperature in the range of 0 ° C to 250 ° C. Dehydrating agents include, but are not limited to, P ₂ O ₅ , molecular sieves or inorganic or organic acids. The acids may include, but are not limited to, C 2 -C 10 alkanoic acids (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), C 1 -C 10 alkanesulfonic acids (preferably methanesulfonic acid), acid hydrochloric acid, sulfuric acid and phosphoric acid. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably glyme or diglyme), cyclic ethers (preferably tetrahydrofuran or ethanol). 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) or halogenated hydrocarbons having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably chloroform). The preferred reaction temperature range is from ambient temperature to 100 ° C.

Certain compounds of Formula 1 (where A is N) may be prepared by the methods outlined in Scheme 7.

Scheme 7

Intermediate compounds of formula 14 wherein Z is as defined above may be reacted with compounds of formula R ³ C (OR ^e ). ₅ , wherein R ^e can be alkyl (1 to 6 carbon atoms) in the presence or absence of acid in an inert solvent at a temperature in the range of 0 ° C to 250 ° C. Acids which may be used include, but are not limited to, C 2 -C 10 alkanoic acids (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), C 1 -C 10 alkanesulfonic acids (preferably methanesulfonic acid) , hydrochloric acid, sulfuric acid and phosphoric acid. A stoichiometric or catalytic amount of such an acid may be used. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide) , Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidine-

2-one), dialkyl sulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) or halogenated hydrocarbons having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane). A preferred reaction temperature range is from 50 ° C to 150 ° C.

Intermediate compounds of formula 7 can also be prepared by the reactions shown in Scheme 8.

Scheme 8

Y

N

X (15) Y = OH, SH NR ⁶ R ⁷ ;

Z = N, CR ²

X = Br, Cl, I, B (OR) 2

ArM, +/- catalyst, 7 "solvent

Y

Ar = (7) A = N

The compounds of formula 15 (wherein Y is OH, SH, ^{NR6 R7;} Z is as defined above, X is Br, Cl, I, O3SCF3 or B (OR '''), and R' is H or alkyl (1 to 6 carbon atoms) can be reacted with a compound of formula ArM (wherein M is halogen, alkali metal, ZnCl, ZnBr, ZnI, ZnI, MgBr, MgCl, Mgl, CeCl ₂ , CeBr ₂ or copper halides) in the presence or the absence of an organometallic catalyst in the presence or absence of a base in an inert solvent at temperatures ranging from -100 ° C to 200 ° C. One skilled in the art can confirm that ArM reactants can be generated in situ. of palladium (such as Pd _(PPh)?) and halides, alkanoates or palladium (such as _PdCl2 (PPh) ₃ or Pd _(OAc),) or nickel complexes (such as NiCl ₂ (PPh) 3) :) - policy may include, but are not limited to, alkali metal carbonates or trialkylamines (preferably N, N-diisopropyl-N-ethyl) mine 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), dialkyl sulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). A preferred reaction temperature range is from -80 ° C to 100 ° C.

Options M and X are known to those skilled in the art (see Imamoto, T., Organocerium Reagents in Coprehensive Organic Synthesis, Trost,

BM Ed., (Elmsford, NY: Pergamon Press, 1991), 1, 231250; 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 Reaction betveen sp ² Carbon Centers in Comprehensive Organic Synthesis, Trost, BM ed., (Elmsford, NY: Pergamon Press, 1991), 3, 481-520.

Compounds of formula I may also be prepared using the methods outlined in Scheme 9.

Scheme 9

(16) X = Br, Cl, I,

B (OR) 2, O 3 SCF 3

ArM, +/- catalyst, solvent

-

Compounds of Formula 16 (wherein A, Z, R ¹ and R ² are as defined above and X is Br, Cl, I, O ₃ SCF ₃ or B (OR "") ₂ and R """is H or alkyl (1 to 6 carbon atoms) can be reacted with a compound of formula ArM (where M is halogen, alkali metal, ZnCl, ZnBr, ZnI, ZnI, MgBr, MgCl, Mgl, CeCl ₂ , CeBr ₂ or copper halides) in the presence or the absence of an organometallic catalyst in the presence or absence of a base in an inert solvent at temperatures ranging from -100 ° C to 200 ° C. One skilled in the art can confirm that ArM reactants can be generated in situ (see Comprehensive Organic Synthesis above). but not limited to, palladium phosphine complexes (such as Pd (PPh) ₃ ) 4, palladium halides or alkanoates (such as PdCl ₂ (PPh) ₃ or Pd (OAc) ₂ ), or nickel complexes (such as

NiCl ₂ (PPh) ₃ ) 2) The bases may include, without limitation, alkali metal carbonates or trialkylamines (preferably N, N-diisopropyl-N-ethylamine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). A preferred reaction temperature range is from -80 ° C to 100 ° C.

Intermediate compounds of formula 7 wherein Y is O, S, NH, Z is CR ² and R ¹ , R ² and Ar are as defined above) can be prepared as outlined in Scheme 10.

Scheme 10

(3)

NH ₂ NH ₂ (C = Y) NH ₂ +/- base or acid, solvent

------------> -

PIC (OR ^e ) 2, +/- acid, solvent

---'------------------>

(7) Y = O, S, NH; Z = CR ²

Compounds of formula 3 may be reacted with compounds of formula H ₂ NNH (C = Y) NH _; wherein Y is O, S or NH, in the presence or absence of a base or acid in an inert solvent at a temperature in the range of 0 ° C to 250 ° C to give compounds of formula 17. As acids, but not limited to alkanes can be used. acids with 2 to 10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids with 1 to 10 carbon atoms (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid and phosphoric acid. A stoichiometric or catalytic amount of such an acid may be used. The bases may include, without limitation, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), bis (trialkylsilyl) alkali metal amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1, 2). 4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) or halogenated hydrocarbons having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane). A preferred reaction temperature range is from 0 ° C to 150 ° C.

Compounds of formula 17 may then be reacted with compounds of formula R ³ C (OR ^e ) ₃ , wherein R ^e may be alkyl (1 to 6 carbon atoms) in the presence or absence of acid in an inert solvent at a temperature ranging from 0 ° C to 250 C. Acids which may be used include, but are not limited to, C 2 -C 10 alkanoic acids (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), C 1 -C 10 alkanesulfonic acids (preferably methanesulfonic acid) , hydrochloric acid, sulfuric acid and phosphoric acid. A stoichiometric or catalytic amount of such an acid may be used. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran, or the like).

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 halogenated hydrocarbons having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane). A preferred reaction temperature range is from 50 ° C to 150 ° C.

Scheme 11 includes a process that can be used to convert compounds of Formula 1 wherein R ³ is COR ⁷ , CO ² R ⁷ , NR ⁸ COR ^7, and CONR ⁶ R ⁷ to other compounds of Formula 1 wherein R ³ is CH (OH ) R ^7, CH 2 OH, NR ⁸ CH 2 R ⁷ and CH 2 NR ⁶ R ^7, and which comprises treating with a reducing agent in an inert solvent at a temperature of 80 ° C. up to 250 ° C

Scheme 11

ch ₂ oh, ch ₂ nr ⁶ r ⁷

Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably sodium borohydride or lithium borohydride), borane, dialkylboranes (such as diisoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy) aluminum or dialkylaluminium hydrides (such as diisobutylaluminium hydride). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbon atoms), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). from -80 ° C to 100 ° C.

Scheme 12 illustrates a procedure that may be used for the conversion of compounds of formula 1, wherein R ³ is COR ⁷ or CO 2 R ^7, to other compounds of formula 1, wherein R ³ is C (OH) (R ⁷⁾ 2, by treatment with of a reagent of formula R ⁷ M in an inert solvent at temperatures ranging from -80 ° C to 250 ° C.

Scheme 12

M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl _2, Cebra ₂ or copper halides. Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran) or aromatic hydrocarbons (preferably benzene or toluene). A preferred reaction temperature range is from -80 ° C to 100 ° C.

Compounds of formula 1 wherein R ³ can be -NR ⁸ COR ⁷ , -N (COR ⁷ ) 2, -nr ⁸ conr ⁶ r ⁷ , -nr ⁸ co ² r ¹³ , -nr ⁶ r ⁷ , -nr ⁸ r ⁷ , -NR ⁸ SO ₂ R ⁷ may be prepared as shown in Scheme 13.

Scheme 13

ABOUT

+/- base solvent --—-- ►

(10) Z = N alkylating, sulfonylating or acylating agent +/- base, solvent

d)

A = CR

R ₃ = nr ⁶ r ⁷ , nr ⁸ cor ⁷ , N (COR ⁷ ) 2, NR ⁸ CONR ⁶ R ⁷ , NR ₈ CO ₂ Ri3

Reaction of compounds of formula 18 wherein R and R ¹ are as defined above with compounds of formula 4 or 10 in the presence or absence of a base in an inert solvent affords compounds of formula 19. The reaction is carried out at a temperature ranging from -50 ° C to 250 ° C. C. The bases may include, without limitation, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates , alkali metal bis (trialkylsilyl) amides (preferably bis (trimethylsilyl) sodium amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1, 2). 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) . A preferred reaction temperature range is from 0 ° C to 100 ° C.

Compounds of formula 19 may then be reacted with alkylating agents, sulfonylating agents or acylating agents or sequential reactions with combinations thereof in the presence or absence of a base in an inert solvent at reaction temperatures from -80 ° C to 250 ° C to provide compounds of formula I, wherein R ³ can be -NR ⁸ COR ⁷ , -n (COR ⁷ ) ;, -NR ⁸ CONR ⁶ R ⁷ , -NR ⁸ CO; R ¹³ , -nr ⁶ R ⁷ , -NR ⁸ SO; R ⁷ . Alkylating agents may include, but are not limited to, C 1 -C 10 alkyl halides, -tosylates, -methylates, or -triflates; C 1 -C 10 haloalkyl (1 to 10 halogen atoms) halides, -tosylates, -methylates or -triflates; C ₂ -C ₀ alkoxyalkyl halides, -tosylates, -mesylates or -triflates; C ₃ -C ₅ cycloalkyl halides, -tosylates, -mesylates or -triflates; C 1 -C ₁₂ cycloalkyl halides, -tosylates, -mesylates or -triflates; aryl (C 1 -C 6 alkyl) halides, -tosylates, -methylates or -triflates; heteroaryl (C, _-C, alkyl) halide, -tosyláty, -mesyláty or -trifláty; or heterocyclyl _(Ci-C alkyl) halides, -tosyláty, -mesyláty or -trifláty. Acylating agents may include, but are not limited to, C 1 -C 6 alkanoyl halides or anhydrides, C ₁ -C ₁₈ , haloalkanoyl halides or anhydrides with 1 to 10 halogen atoms, C ₂ -C ₀ alkoxyalkanoyl halides or anhydrides, C ₃ -C ₅ cycloalkanoyl halides or anhydrides, C ₄ C ₁₂ cykloalkylalkanoylhalogenidy or anhydrides, aroyl halide or anhydrides, aryl _(C,) alkanoyl halide or anhydride, heteroaryl halides or anhydrides, heteroaryl (C-C) alkanoyl halide or anhydride, halides or anhydrides, heterocyclylcarboxylic acid or heterocyclyl _(Ci-C4) alkanoyl halide or anhydride. Sulfonating agents include, but are not limited to, C ₁ -C ₁₀ alkylsulfonyl halides or anhydrides, C 1 -C 10 haloalkylsulfonyl halides or anhydrides with 1 to 10 halogen atoms, C ₂ -C ₁₀ alkoxyalkylsulfonyl halides or anhydrides, C ₅ -C ₁₀ cycloalkylsulfonyl halides or anhydrides, C ₄ -C ₁₂ cycloalkylalkyls , arylsulfonyl halides or anhydrides, aryl (Cl-C. alkyl) heteroarylsulfonylhalogenidy or anhydrides, heteroaryl (C, _C alkyl) sulfonyl halides or anhydrides, or anhydrides heterocyklylsulfonylhalogenidy or heterocyclyl _(Ci-C4 alkyl) sulfonyl halides or anhydrides.

The bases may include, without limitation, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably diisopropyl ethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1, 2). 4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) . The preferred reaction temperature range is from 0 ° C to 100 ° C.

Compounds of formula I wherein A is CR and R is as defined above may be used to prepare by the methods outlined in Scheme 14.

(10) Ζ =

R ^e 0

R (20) +/- base, solvent

CR ₂ -N

+/- principle

R ³ H, +/- base, +/- solvent solvent

OH

halogenating agent or sulfonylating agent +/- base +/- solvent (22) x

N

Compounds of formula 4 or 10 are treated with compounds of formula 20 wherein R ¹ and R ³ are as defined above in the presence or absence of a base in an inert solvent at a temperature ranging from 0 ° C to 250 ° C to form compounds of formula 1 wherein A is CR and R is as defined above. The bases may include, without limitation, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1, 2). 4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). The preferred reaction temperature range is from 0 ° C to 100 ° C. Alternatively, compounds of Formula 1 wherein A is CR and R is as defined above may be prepared via intermediates 22 and 23.

Compounds of formula 4 or 10 may be reacted with compounds of formula 21 wherein R ¹ is as defined above and R ^e is alkyl (1 to 6 carbon atoms), in the presence or absence of a base, in an inert solvent at a temperature ranging from 0 ° C to 250 ° C to give a compound of formula 1 wherein A is CR and R is as defined above. The bases may include, without limitation, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1, 2). 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). A preferred reaction temperature range is from 0 ° C to 100 ° C. Compounds of formula 22 may be treated with a halogenating agent or a sulfonylating agent in the presence or absence of a base, in the presence or absence of an inert solvent at a reaction temperature ranging from -80 ° C to 250 ° C to give products of formula 23 (wherein X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkanesulfonyloxy). The halogenating agent includes, without limitation, SOC1 _2, POC1 _3, PC1 _3, PC1 _5, POBr _3, PBr ₃ or PBr =. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or halosulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). The bases may include, without limitation, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), bis (trialkylsilyl) alkali metal amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-Nethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide) , N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or halogen atoms having 1 to 10 carbon atoms and 1 to 10 carbon atoms halogen atoms (preferably dichloromethane). The preferred reaction temperature range is from -20 ° C to 100 ° C.

Compounds of formula 23 may be reacted with compounds of formula R ³ H, (wherein R ³ is as defined above except that R ³ is not SH, COR ⁷ , CO ₂ R ⁷ , aryl or heteroaryl) in the presence or absence of an inert The solvents may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium methoxide; sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1, 2). 4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane). The preferred reaction temperature range is from 0 ° C to 140 ° C.

Certain compounds of Formula 1 may also be prepared using the methods outlined in Scheme 15.

Scheme 15 measures ₂ RH ₂ , + / - acid / solvent

KH ₂ NH (C = Y) NH ₂ , + / - acid, solvent

For A =

1) R ¹ C (= NH) OR, + / - acid, solvent

2) Y = C (Rd) 2 +/- IISA / γ-solvent

For A = CR;

1) R ¹ (C = O) CHR (C = Y) OR _C +/- Lying J / or Acid Solvent

A compound of Formula 24 (R _{1 '} is a lower alkyl group and Ar is as defined above) may be reacted with hydrazine hydrate in the presence or absence of an inert solvent to form an intermediate of Formula 35 wherein Ar is as defined above. The conditions are similar to those used to prepare an intermediate of formula 4 from a compound of formula 3 in Scheme 4. Compounds of formula 25 wherein A is N can be reacted with reagents of formula R ¹ C (= NH) OR 4, where R ¹ is as defined above and R is lower alkyl, in the presence or absence of an acid in an inert solvent followed by reaction with a compound of the formula YC (R _^d); (wherein Y is O or S and R ^d is halogen (preferably chlorine), alkoxy (1 to 4 carbon atoms) or alkylthio (1 to 4 carbon atoms) in the presence or absence of a base in an inert solvent to form a compound of formula 27 (wherein A is N and Y is O. The conditions for these transformations are the same as those used to convert the compound of Formula 4 to the compound of Formula 7 in Scheme 4.

Alternatively, the compounds of Formula 25 may be:

A is CR, with compounds of formula R ¹ (C = 0) CHR (C = Y) 0R; (wherein R ¹ and R are as defined above and R is lower alkyl) to a compound of formula 27 (wherein Ar is CR) using conditions similar to those used for the conversion of compounds of formula 21 to compound of formula 22 in Scheme 14. Intermediates of formula 27 (where Y is O) can be treated with halogenating or sulfonylating agents in the presence or absence of a base in an inert solvent and then reaction with R ³ H or R ² H in the presence or absence of a base in an inert solvent to form compounds of formula 1 (wherein Z is CR ² ).

It will be appreciated by those skilled in the art that various combinations of halogenating agents, sulfonylating agents, R ³ H or R ² H, which can be used in different order of Reaction Scheme 15, may be used to obtain compounds of Formula 1. For example, to react the compounds with a stoichiometric amount of halogenating or sulfonylating agents, reacting with R ² H (or R ³ H), then reacting with halogenating or sulfonylating agents and reacting with R ³ H (or R ² H) to obtain compounds of the general formula The reaction conditions and reagents for these conversions are similar to those used to convert the intermediate compounds of formula 22 to 23 and to 1 in Scheme 14 (for A equal to CR) or the intermediate compounds of formula 7 to 8 and to 1. in Scheme 1 (where A is N).

Alternatively, compounds of formula 27 wherein Y is S can be converted to compounds of formula 1 in Scheme 15. Intermediate compounds of formula 27 can be alkylated with compounds of formula R ^f X (where R ^f is lower alkyl and X is halogen, alkanesulfonyloxy) or haloalkanesulfonyloxy) in an inert solvent (then optionally oxidized with an oxidizing agent in an inert solvent) and then reacted with R ³ H in the presence or absence of a base in an inert solvent to form a compound of Formula 1. The conditions and reagents used are similar to those used to convert the intermediate compound of formula 7 to 12 (or 13) and to the compound of formula 1 in Scheme 2.

Compounds of formula 1 may be prepared from compounds of formula 24 using an alternative method as shown in Scheme 15. Compounds of formula 24 may be converted to compounds of formula 27 by reaction with compounds of formula NH ² NH (C = NH) NH ₂ in the presence or absence of an acid in an inert solvent followed by reaction with compounds of formula R for-): (wherein _R is lower alkyl and ^R1 is as defined above) according to the conditions to be used for the conversion of compounds of formula 3 to 17 and 7 in Scheme 10.

Some compounds of formula 2 may be prepared by the methods shown in Scheme 16.

Scheme 16

(2)

100

Compounds of formula 27 may be treated with a variety of R ¹⁴ X alkylating agents (wherein R ¹⁴ is as defined above and X is halogen, alkanesulfonyloxy or halosulfonyloxy) in the presence or absence of a base in an inert solvent to form structures of formula 28. Y is O) can then be converted to compounds of formula 2 by treatment with halogenating agents or sulfonating agents in the presence or absence of a base in an inert solvent. This is followed by reaction with R ³ H 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 to convert intermediate compounds of formula 22 to 23 and 1 in Scheme 14. (for A is CR) or the conversion of the intermediate compounds of formula 7 to 8 and 1 in Scheme 1 (where A is N). Alternatively, compounds of formula 28 (Y is S) can be alkylated with R ^f X (wherein R ^f is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent (then optionally oxidized with an oxidizing agent in an inert solvent) followed by reaction with R ³ H in the presence or absence of a base in an inert solvent to give compounds of formula 1. The conditions and reagents used are similar to those used to convert the intermediate compounds of formula 7 to 12 (or 13) and to compounds of formula 1 in Scheme 2.

Compounds of formula 1 wherein Z is COH can be converted to compounds of formula 2 as illustrated in Scheme 16. Treatment with various alkylating agents R ¹⁴ X (where R ¹⁴ is as defined above and X is halogen,

101 (alkanesulfonyloxy or halosulfonyloxy) in the presence or absence of a base in an inert solvent yields structures 2. It will be appreciated that one skilled in the art can use the procedures used in Scheme 16 to prepare compounds of Formula 1 where Z is COR ⁷ .

In Scheme 16, the terms "base and" inert solvent have the meanings given below. The bases may include, without limitation, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), bis (trialkylsilyl) alkali metal amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N , N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or halogen atoms having 1 to 10 carbon atoms and 1 to 10 halogen atoms (preferably dichloromethane). A preferred reaction temperature range is from -20 ° C to 140 ° C.

102

DETAILED DESCRIPTION OF THE INVENTION

Analytical data was recorded for the compounds listed below using the following general procedures. Proton NMR spectra were recorded on an IBM-Bruker FT-NMR (300 MHz); chemical shifts were measured in ppm (δ) relative to the international tetramethylsilane standard in deuterochloroform or deuterodimethylsulfoxide as described below. Mass spectra (MS) or high resolution mass spectra (HRMS) were recorded on a Finnegan MAT 8230 spectrometer (using chemi-ionization (CI) with NH ₃ as a gas carrier or gas chromatography (GC) as specified below) or a spectrometer Hewlett Packard 5988A Melting points were recorded on a Buchi Model 510 and are not corrected. The boiling point is not corrected. All pH determinations were performed with indicator paper.

The reactants were obtained from commercial sources and, where necessary, purified prior to use according to the general methods described by D. Perrin and W. L. Armarego, Purification of Laboratory Chemicals, 3rd Edition (New York: Pergamon Press, 1988). Chromatography was performed on silica gel using the solvent system below. For mixed solvent systems, volume ratios are given. Parts and percentages are by weight unless otherwise stated.

The following examples further describe the present invention. These examples are given by way of illustration only and are not intended to limit the scope of the invention in any way.

103

Example 1

2,7-Dimethyl-8- (2,4-dimethylphenyl) [1,5-a] pyrazolo [1,3,5] triazin-4 (3H) -one (Formula 7 wherein Y is O, R ¹ is _CH, Z is C-CH., Ar is 2,4-dimethyl-phenyl)

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

Sodium pellets (9.8 g, 0.43 mol) were added portionwise at room temperature to a solution of 2,4-dimethylphenylacetonitrile (48 g, 0.33 mol) in ethyl acetate (150 mL). The reaction mixture was heated to reflux and stirred for 16 hours. The resulting suspension was cooled to room temperature and filtered. The collected precipitate was washed with plenty of ether and then air dried. Dissolve the solid in water and add 1N HCl solution to adjust the pH to 5-5

6. Extract the mixture with ethyl acetate (3 x 200 mL); the combined organic layers were dried over MgSO 4 and filtered. The solvent was removed in vacuo to give a white solid (45.7 g, 75% yield): (CDC1 _3, 300 MHz); CI-MS: 188 (M + H) < + >.

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

A mixture of 1-cyano- (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 temperature in an apparatus equipped with a Dean-Stark collector. The reaction mixture was cooled to ambient 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. Concentrated ammonium hydroxide solution was then added to the aqueous layer to pH 11. The resulting semi-solution was extracted three times with ethylation

104 dad. The combined organic layers were dried over MgSO 4 and filtered. The solvent was removed in vacuo to give a pale brown viscous oil (34.6 g, 75% yield): NMR (CDC1 _3, 300 MHz):

7.10 (s, 1H); 7.05 (d, 2H, J = 1.27, 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 quickly added to a vigorously stirred mixture of potassium carbonate (6.9.5 g, 0.50 mol), dichloromethane (120 mL) and water (350 mL). The layer was separated and the aqueous layer was extracted with dichloromethane (2 x 120 mL). The combined organic layers were dried over MgSO 4 and filtered. The solvent was removed by simple distillation and the residue, a clear pale yellow liquid (35.0 g) was used without further purification.

5-Amino-4- (2,4-dimethylphenyl) -

3-methylpyrazole (34 g, 0.17 mol), ethyl acetamidate (22 g, 0.25 mol) and acetonitrile (500 mL) were added glacial acetic acid (9.7 mL, 0.17 mol). The resulting reaction mixture was stirred at room temperature for 3 days; at the end of this time, concentrate in vacuo to approximately one third of the original volume. The resulting suspension was filtered and the solids collected and washed with sufficient ether. The white solid was dried under vacuum (31.4 g, 61% yield):

NMR (DMSO-d 6, 300 MHz): 7.00 (s, 1H), 6.90 (dd, 2H, J = 7.1), 2.28 (s, 3H), 2.08 (S, 3H) 1.00 (s, 3H), 1.90 (s, 3H), 1.81 (s, 3H); CI-MS: 243 (M + H) < + >.

105

D. 2,7-Dimethyl-8- (2,4-dimethylphenyl) [1,5-a] pyrazolo [1,3,5] triazin-4 (3H) -one

Sodium pellets (23 g, 1 mol) were added portionwise with vigorous stirring to ethanol (500 mL). When all the sodium has reacted, acetic acid salt of 5-acetamidino-4- (2,4-dimethylphenyl) -3-methylpyrazole (31.2 g, 0.1 mol) and diethyl carbonate (97 mL, 0.8 mol) are added. ). The resulting reaction mixture was heated to reflux with stirring 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 added slowly to pH 5-6. The aqueous layer was extracted three times with ethyl acetate; the combined organic layers were dried over MgSO 4, and filtered. The solvent was removed in vacuo to give a light brown solid (26 g, 98% yield): NMR (CDC1 _3, 300

MHz): 7.15 (s, 1H), 7.09 (s, 2H), 2.45 (s, 3H), 2.39 (s, 3H),

2.30 (s, 3H); CI-MS: 269 (M + H) < + >.

Example 2

5-Methyl-3- (2,4,6-trimethylphenyl) [1,5-a] - [1,2,3] triazolo [1,3,5] triazin-7 (6H) -one (Formula 7, wherein Y is O, R ¹ is _CH, Z is N, Ar is 2,4,6-trimethylphenyl)

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

A mixture of 2,4,6-trimethylbenzyl cyanide (1.0 g, 6.3 mmol), benzyl azide (0.92 g, 6.9 mmol) and potassium tert-butoxide (0.78 g, 6.9 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature for 2.5 days. The resulting suspension was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO 4 and filtered. The solvent was removed

106 under vacuum to give a brown oil. Trituration with ether and filtration gave a yellow solid (1.12 g, yield 61%):

NMR (CDC1 _3, 300 MHz): 7.60-7.30 (m, 5H), 7.30-7.20 (m, 2H);

5.50 (s, 2H), 3.18 (br s, 2H), 2.30 (s, 3H), 2.10 (s, 6H); CI-MS: 293 (M + H) < + >.

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

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

NMR (CDC1 _3, 300 MHz): 6.97 (s, 2H), 3.68-3.50 (br s, 2H), 2.32 (s, 3H), 2.10 (s, 6H); CI-MS: 203 (M + H) < + >.

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

A mixture of 4- (2,4,6-trimethylphenyl) -5-aminotriazole (400 mg, 1.98 mmol), ethyl acetamidate (261 mg, 3 mmol) and glacial acetic acid (0.1 mL, 1.98 mmol) in acetonitrile (6 mL) was stirred at ambient temperature for 4 hours. The resulting slurry was stirred

107 was filtered and the collected solid was washed with sufficient ether. Drying in vacuo gave a white solid (490 mg, 82% yield): NMR (DMSO-d6, 300 MHz): 7.90-7.70 (br s, 0.5H), 7.50-7.20 (br, s, 0.5H), 6.90 (s, 2H), 6.90 (s, 2H), 3.50-3.10 (br s, 3H), 2.30-2.20 ( br, s, 3H), 2.05 (d, 1H, J = 7), 1.96 (s, 6H), 1.87 (s, 6H); CI-MS: 244 (M + H) < + >.

D. 5-Methyl-3- (2,4,6-trimethyl-phenyl) [1,5-a] - [1,2,3] triazolo [1,3,5] triazin-7 (4H) -one

Sodium (368 mg, 16.2 mmol) was added to ethanol with stirring at room temperature. When the sodium has reacted, acetic acid salt of 4- (2,4,6-trimethylphenyl) -5-acetamidinotriazole (490 mg, 1.6 mmol) and diethyl carbonate (1.6 mL, 13 mmol) are added. The reaction mixture was stirred at reflux temperature for 5 hours and then cooled to room temperature. The reaction mixture was diluted with water, 1N HCl solution was added to pH 5-6 and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO 4 and filtered. The solvent was removed in vacuo to give a yellow residue. Trituration with ether and filtration gave a yellow solid (300 mg, 69% yield):

NMR (CDC1 _3, 300 MHz): 6.98 (s, 2H), 2.55 (s, 3H);

2.35 (s, 3H); 2.10 (s, 6H); CI-MS: 270 (M + H) < + >.

Example 3

Of 4- (di (carbomethoxy) methyl) -2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] -pyrazolo-l, 3,5-triazine (Formula 1, wherein R ³ is CH (CHCO CH?) :, R ¹ is CH ?, Z is _C-CH, Ar is 2, 4-dimethyl-phenyl)

108

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

A mixture of 2,7-dimethyl-8- (2,4-dimethylphenyl) - [1,5-a] pyrazolo-

1,3,5-triazin-4-one (Example 1, 1.38 g, 4.5 mmol), N, N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) were stirred at reflux temperature 48 hours. Excess phosphorus oxychloride was removed in vacuo. The residue was poured into ice water, stirred briefly and extracted three times with ethyl acetate. The combined organic layers were washed with ice water, then dried over MgSO 4 and filtered. The solvent was removed in vacuo to give a brown oil. Flash column chromatography (ethyl acetate: hexanes = 1: 4) gave one fraction (Rf = 0.5). The solvent was removed in vacuo to give a yellow oil (1.0 g, 68% yield): NMR (CDC1 _3, 300 MHz):

7.55 (d, 1H, J = 1), 7.38 (dd, 1H, J = 7.1), 7.30 (d, 1H, J

7), 2.68 (s, 3H), 2.45 (s, 3H); CI-MS: 327 (M + H) < + >.

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

Sodium hydride (60% in oil, 80 mg, 2 mmol) was washed twice with hexanes, decanted after each wash and taken up with anhydrous tetrahydrofuran (THF, 1 mL). A solution of diethyl malnate (0.32 g, 2 mmol) in THF (2 mL) was then added dropwise over 5 minutes with vigorous gas evolution. Then a solution of 4-chloro-2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] pyrazolotriazine (0.5 g, 1.75 mmol) in THF (2 mL) was added and the reaction the mixture was stirred under nitrogen for 48 hours. The resulting mixture was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed once

109 with brine, dried over MgSO 4 and filtered. The solvent was removed in vacuo to give a brown oil. Column chromatography (ethyl acetate: hexanes = 1: 9) gave a light yellow solid (Rf = 0.2, 250 mg, 35% yield) after removal of the solvent in vacuo: mp 50-52 ° C;

NMR (CDC1 _3, 300 MHz): 12.35 br s, 1H, 7.15-7.00 (m, 3H), 4.40 (q, 2H, J = 7), 4.30 (q, 2H J = 7), 2.4, 2.35, 2.3, 2.2, 2.1 (5S, 12H), 1.4 (t, 3H, J = 7), 1.35-1 25 (m, 3H); CI-HRMS: Calcd .: 441.2032, Found: 411.2023.

Example 6

4- (1,3-Dimethoxy-2-propylamino) -2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] pyrazolo-1,3,5-triazine (Formula 1, wherein R ³ is -NHCH (CH 2 OCH?) 2, R ¹ is CH ?, Z is _C-CH, Ar is 2,4-dichlorophenyl)

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

A mixture of 2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] pyrazolo-

1,3,5-triazin-4-one (Example 1, 1.38 g, 4.5 mmol), N, N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) were stirred at reflux temperature 48 hours. Excess phosphorus oxychloride was removed in vacuo. The residue was poured into ice water, stirred briefly and extracted three times with ethyl acetate. The combined organic layers were washed with ice water, then dried over MgSO 4. and filtered. The solvent was removed in vacuo to give a brown oil. Flash column chromatography (ethyl acetate: hexanes = 1: 4) yielded one fraction (Rf = 0.5). The solvent was removed in vacuo to give a yellow oil (1.0 g, 68% yield):

7.55 (d, 1H, J = 1);

J = 7), 2.68 (S, 3H), 2.45 (s,

NMR (CDC1 _3, 300 MHz):

1H, J = 7.1), 7.30 (d, 1H, 3H); CI-MS: 327 (M + H) + 110

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

A mixture of 4-chloro-2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] pyrazolo-1,3,5-triazine (Part A, 570 mg, 1.74 mmol), 1 3-dimethoxypropyl-2-aminopropane (25 mg, 2.08 mmol) and ethanol (10 mL) were stirred at ambient temperature for 18 hours. The reaction mixture was poured into water (25 mL) and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO 4 and filtered. The solvent was removed in vacuo. Column chromatography (CH ₂ C1, _CH? OH = 50: 1) afforded one fraction. Removal of the solvent in vacuo gave a solid (250 mg, 35% yield): mp 118-120 ° C; NMR (CDCl 3, 300 MHz)?

MHz): 7.50 (s, 1 H), 7.28 (dd, 2 H, J = 8.1), 6.75 (d, 1 H, J =

8), 4.70-4.58 (m, 1H), 3.70-3.55 (m, 4H), 3.43 (s, 6H),

2.50 (s, 3H); 2.35 (s, 3H); CI-HRMS: Calcd .: 409.1072, Found: 409, 1085; Analysis calculated for C19H21Cl2N5O2: C,

52.69, H, 5.17, N, 17.07, Cl 17.28; Found: C, 52.82, H, 5.06, N, 16.77, Cl, 17.50.

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

The examples given in Table 1 can be prepared according to the procedures of Examples 1, 2, 3 or 6. The commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Pr is an example.

111

Table 1

Ρι. FROM tt. f ° H 6 ^a C-Me NHCH (CH 2 OMe) 2 2 4-C12-Ph 118-120 ₇ b C-Me NHCHPr2 2 4-C12-Ph 114-116 8 ^C c —ye NetBt 2 4-Cl ₂ -Ph oil ₉ d C-Me NPr (CH2-C-C3H5) 2 4-C12-Ph oil 10 ^e C-Me N (CH ₂ CH ₂ OMe) 2 2 4-C 12 ~ Ph oil n ' C-Me ΝΗ-3-heptyl 2 4-C 12 ~ Ph 90-92 129 C-Me NHCH (Et) -CH2OMe · 2 4-C 12 ~ Ph 179-181 12 ^h C-Me NEt 2 2 4-C12-Ph 133-134 14 ¹ C-Me NHCH (CH2 OEO 2 2 4-C 12 ~ Ph oil 153 C-Me ΝΗ-3-pentyl 2 4-C 12 ~ Ph 139-140 16 ^k C-Me NMePhe 2 4-C 12 ~ Ph 60-62 171 C-Me NPr2 2 4-C 12 ~ Ph oil 18 ⁿ C-Me ΝΗ-3-hexyl 2 4-C 12 ~ Ph 130-132 19 C-Me morpholino 2 4-C 12 ~ Ph 20 C-Me N (CH 2 Ph) CH2CH2OMe 2 4-C 12 ~ Ph 21 C-Me NHCH (CH 2 Ph) CH 2 OMe 2 4-C 12 ~ Ph 22 C-Me ΝΗ-4-tetrahydropyranyl 2 4-C 12 ~ Ph 23 C-Me NH-cytlopentyl 2 4-C12Ph 24 C-Me 1,2,3,4-tetrahydro- isoquinolyl 2 4-C12-Ph 25 C-Me CH2- (1,2,3,4-tetrahydro- isoquinolyl 2 4-C 12 ~ Ph 26 ⁿ C-Me OEt 2 4-C 12 ~ Ph 141-143 27 C-Me OCH (Et) CH 2 OMe 2 4-C 12 ~ Ph

Ή 2.

28 C-Me OCH ₂ Ph 2,4-Cl ₂ -Ph 29 C-Me Ο-3-pentyl 2,4-Cl ₂ -Ph 30 C-Me Set 2,4-Cl ₂ -Ph 31 C-Me S (O) Et, 2,4-Cl ₂ -Ph 32 C-Me SO ₂ Et 2,4-Cl ₂ -Ph 33 C-Me CH (CO ₂ Et) 2 2,4-Cl ₂ -Ph 34 C-Me C (Et) (CO ₂ Et) 2 2,4-Cl ₂ -Ph 35 C-Me CH (EC) CH 2 OH 2,4-Cl ₂ -Ph 36 C-Me CH (Et) CH ₂ OMe 2,4-Cl ₂ -Ph 37 C-Me CONMe ₂ 2,4-Cl ₂ -Ph 38 C-Me COCH3 2,4-Cl ₂ -Ph 39 C-Me CH (OH) CH 3 2,4-Cl ₂ -Ph 40 C-Me C (OH) Ph-3-pyridyl 2,4-Cl ₂ -Ph 41 C-Me ph 2,4-Cl ₂ -Ph 42 C-Me 2-CF3-Ph 2,4-Cl ₂ -Ph 43 C-Me 2-Ph-Ph 2,4-Cl ₂ -Ph 44 C-Me 3-pentyl 2,4-Cl ₂ -Ph 45 C-Me cy ki obutý1 2,4-Cl ₂ -Ph 46 C-Me 3-pyridyl 2,4-Cl ₂ -Ph 47 C-Me CH (Et) CH2CONMe2 2,4-Cl ₂ -Ph 48 C-Me CH (Et) CH ₂ CH ₂ NMe ₂ 2,4-Cl ₂ -Ph 49 ° C-Me NHCH (CH 2 OMe) 2 2,4,6-Me3 ~ Ph 125-127 50 C-Me NHCHPr ₂ 2,4,6-Me3 "Ph 51 C-Me NetBt 2,4,6-Me3 ~ Ph 52 C-Me NPr (CH2-C-C3H5) 2,4,6-Me3-Ph 53 ^ae C-Me N (CH2CH2OMe) 2 2,4,6-Me3 ~ Ph 123-124 54 C-Me ΝΗ-3-heptyl 2,4,6-Me3-Ph 55 ^ac C-Me NHCH (Et) CH ₂ OMe 2,4,6-Me3 ~ Ph 145-146 56 ^ah C-Me NEt 2 2,4,6-Me3 ~ Ph 88-90 57 ^ai C-Me -NHCH (CH 2 OEt) 2 2,4,6-Me3-Ph 132-134 58 ^ad C-Me ΝΗ-3-pentyl 2,4,6-Me3-Ph 134-135 59 C-Me NMePhe 2,4,6-Me3-Ph 60 C-Me NPr ₂ 2,4,6-Me3 ~ Ph 61 C-Me ΝΗ-3-hexyl 2,4,6-Me3 ~ Ph 62 C-Me morpholino 2,4,6-Me3-Ph 63 C-Me N (CH ₂ Ph) CH ₂ CH ₂ OMe 2,4,6-Me3-Ph

Ί13

64 C-Me NHCH (CH 2 Ph) CH 2 OMe 2,4,6-Me3-Ph 65 C-Me ΝΗ-4-Tetahydropyranyl 2,4,6-Me3 ~ Ph 66 C-Me NH-cyclopentyl 2,4,6-Me3 ~ Ph 67 C-Me 1,2,3,4-tetrahydro- isoquinolyl 2,4,6-Me3 ~ Ph 68 C-Me CH2 ~ d, 2,3,4-tetrahydroisoquinolinyl) 2,4,6-Me3 ~ Ph 69 C-Me OEt 2,4,6-Me3 ~ Ph 70 C-Me OCH (Et) CH 2 OMe 2,4,6-Me3 ~ Ph 71 C-Me OCH2Ph 2,4,6-Me3 ~ Ph 72 C-Me Ο-3-pentyl 2,4,6-Me3-Ph 73 C-Me Set 2,4,6-Me3 ~ Ph 74 C-Me S (0) Et 2,4,6-Me3 ~ Ph 75 C-Me SO2E 2,4,6-Me3 ~ Ph 76 C-Me CH (CO2EC) 2 2,4,6-Me3 ~ Ph 77 C-Me C (Et) (CO ₂ Et) 2 2,4,6-Me3 ~ Ph 78 C-Me CH (Et) CH 2 OH 2,4,6-Me3 ~ Ph 79 C-Me CH (Et) GH2OMe 2,4,6-Me3-Ph 80 C-Me CONMe2 2,4,6-Me3 ~ Ph 81 C-Me COCH3 2,4,6-Me3 ~ Ph 82 C-Me CH (OH) CH 3 2,4,6-Me3 ~ Ph 83 C-Me C (OH) Ph-3-pyridyl 2,4,6-Me3-Ph 84 C-Me ph 2,4,6-Me3-Ph 85 C-Me 2-CF3-Ph 2,4,6-Me3 ~ Ph 86 C-Me 2-Ph-Ph 2,4,6-Me3 ~ Ph 87 C-Me 3-pentyl 2,4,6-Me3-Ph 88 C-Me cyclobutyl 2,4,6-Me3-Ph 89 C-Me 3-pyridyl 2,4,6-Me3 ~ Ph 90 C-Me CH (Et) CH 2 CONMe 2 2,4, delta-may-Ph 91 C-Me CH (Et) CH2CH2NMe2 2,4,6-Me3-Ph 92Ρ C-Me NHCH (CH20Me) 2 2,4-Me 2 Ph ~ 44-45 939 C-Me N (CH2CH2OMe) 2 2,4-Me2-Ph oil 94 ^r C-Me NHCH (Et) CH 2 OMe 2,4-Me 2 ^- Ph 102-104 95 ^p C-Me ΝΗ-3-pentyl 2,4-Me 2 Ph ~ 102-104 96 ^c C-Me NEt ₂ 2,4-Me 2 Ph ~ oil g ₇ U C-Me N (CH 2 CN) 2 2,4-Me 2 Ph ~ 148-150

ΜΗ-

98 ^v C-Me NHCH (Me) CH 2 OMe 2,4-Me2-Ph 102-104 99 ^w C-Me OCH (Et) CH 2 OMe 2,4-Me2-Ph oil 100 * C-Me NPr-c-C3H5 2,4-Me 2 Ph ~ oil 1017 C-Me NHCH (Me) CH2NMe2 2,4-Me 2 Ph ~ 47-48 102 ^z C-Me N (c-C3H5) CH2CH2CN 2,4-Me 2 Ph ~ 117-118 103 ^aa C-Me N (Pr) CH2CH2CN 2,4-Me 2 Ph ~ oil 104 ^ab C-Me N (Bu) CH 2 CH 2 CN 2,4-Me 2 Ph ~ oil 105 C-Me NHCHPT2 2,4-Me 2 Ph ~ 100 · C-Me NetBt 2,4-Me 2 Ph ~ 107 C-Me NPr (CH2-C-C3H5) 2,4-Me2-Ph 108 C-Me ΝΗ-3-heptyl 2,4-Me 2 "Ph 109 C-Me NEt ₂ 2,4-Me 2 Ph ~ 110 C-Me -NHCH (CH 2 OEt) 2 2,4-Me 2 Ph ~ 111 C-Me ΝΗ-3-pentyl 2,4-Me2-Ph 112 C-Me NMePhe 2,4-Me2-Ph 113 C-Me NPr2 2,4-Me2-Ph 114 C-Me ΝΗ-3-hexyl 2,4-Me 2 Ph ^_ 115 C-Me morpholino 2,4-Me 2 Ph ~ 116 C-Me N (CH 2 Ph) CH2CH2OMe 2,4-Me 2 Ph ~ 117 C-Me NHCH (CH 2 Ph) CH 2 OMe 2,4-Me 2 Ph ~ 118 C-Me ΝΗ-4-Tetahydropyranyl 2,4-Me 2 "Ph 119 C-Me NH-cyklopencyl 2,4-Me 2 Ph ~ 120 C-Me 1,2,3,4-tetrahydro- isoquinolyl 2,4-Me 2 Ph ~ 121 C-Me CH2 ~ d from 2,3,4-tetrahydro- isoquinolyl 2,4-Me 2 Ph ~ 122 C-Me OEt 2,4-Me2-Ph 123 C-Me OCH (Et) CH 2 OMe 2,4-Me 2 Ph ~ 124 C-Me OCH2Ph 2,4-Me 2 "Ph 125 C-Me Ο-3-pentyl 2,4-Me2-Ph 126 C-Me Set 2,4-Me2 ~ Ph- 127 C-Me S (O) Et 2,4-Me 2 Ph ~ 128 C-Me SO2E 2,4-Me 2 "Ph 3 C-Me CH (CO 2 e) 2 2,4-Me 2 Ph ~ 50-52 129 C-Me C (Et) (CO 2 e) 2 2,4-Me 2 Ph ~

115 -

130 C-Me CH (Et) CH 2 OH 2,4-Me 2 Ph ~ 131 C-Me CH (Et) CH 2 OMe 2,4-Me2-Ph 132 C-Me CH (Et) CH 2 OEt 2,4-Me 2 Ph ^_ 133 C-Me CONMe2 2,4-Me 2 Ph ~ 134 C-Me COCH3 2,4-Me 2 Ph ~ 135 C-Me CH (OH) CH 3 2,4-Me 2 Ph ~ 136 C-Me C (OH) Ph-3-pyridyl 2,4-Me 2 Ph ~ 137 C-Me ph 2,4-Me 2 Ph ~ 135 C-Me 2-CF3-Ph 2,4-Me 2 Ph ~ 139 C-Me 2-Ph-Ph 2,4-Me2-Ph 140 C-Me 3-pentyl 2,4-Me 2 Ph ~ 141 C-Me cy clututyl 2,4-Me 2 Ph ~ 142 C-Me 3-pyridyl 2,4-Me 2 Ph ~ 143 C-Me CH (Et) CH2CONMe2 2,4-Me 2 Ph ~ 144 C-Me CH (Et) CH2CH2NMe2 2,4-Me 2 Ph ~ 14 5 ^bc C-Me NHCH (CH 2 OMe) 2 2-Me-4-MeO-Ph 45-46 14 6 ^bd C-Me N (CH2CH2OMe) 2 2-Me-4-MeO-Ph oil 147 ^be C-Me NHCH (Et) CH 2 OMe 2-Me-4-MeO-Ph 86-88 14S ^b ^ C-Me N (Pr) CH2CH2CN 2-Me-4-MeO-Ph oil 149 C-Me OCH (Et) CH 2 OMe 2-Me-4-MeO-Ph 150 ^af C-Me NHCH (CH 2 OMe) 2 2-Br-4-MeO-Ph 88-90 151 ^al C-Me N (CH2CH2OMe) 2 2-Br-4-MeO-Ph oil 152 ^and 9 C-Me NHCH (Et) CH 2 OMe 2-Br-4-MeO-PH 95-97 153 C-Me N (Pt) CH 2 CH 2 CN 2-Br-4-MeO-Ph 154 C-Me OCH (Et) CH 2 OMe 2-Br-4-MeO-Ph 155 C-Me NHCH (CH 2 OMe) 2 2-Me-4-NMe 2 ^- Ph 156 C-Me N (CH 2 CH 2 OMe) 2 2-Me-4-NMe 2 "Ph oil 157 C-Me NHCH (Et) CH 2 OMe 2-Me-4-NMe 2 ^- Ph 158 C-Me N (Pr) CH2CH2CN 2-Me-4-NMe2 ~ Ph 159 C-Me OCH (Et) CH 2 OMe 2-Me-4-NMe2 ~ Ph 160 C-Me NHCH (CH 2 OMe) 2 2-Br-4-NMe2 ~ Ph 161 C-Me N (CH2CH2OMe) 2 2-Br-4-NMe2 ~ Ph 162 C-Me NHCH (Et) CH 2 OMe 2-Br-4-NMe 2 "Ph 163 C-Me N (Pr) CH2CH2CN 2-Br-4-NMe 2 "Ph 164 C-Me OCH (Et) CH 2 OMe 2-Br-4-NMe2Ph 165 C-Me NHCH (CH 2 OMe) 2 2-Br-4-iPr-Ph

166 C-Me N (CHjCHjOMe) 2 2-Br-4-iPr-Ph 167 C-Me NHCH (Et) CH 2 OMe 2-Br-4-iPr-Ph 168 C-Me N (Pr) CH2CH2CN 2-Br-4-iPr-Ph 169 C-Me OCH (Et) CH 2 OMe 2-Br-4-iPr-Ph 170 C-Me NHCH (CH 2 OMe) 2 2-Br-4-Me-Ph 171 C-Me N (CH2CH2OMe) 2 2-Br-4-Me-Ph 172 C-Me NHCH (Et) CH 2 OMe 2-Br-4-Me-Ph 173 C-Me N (Pr) CH2CH2CN 2-Br-4-Me-Ph · 17? C-Me OCH (Et) CH 2 OMe 2-Br-4-Me-Ph 175 ^ar C-Me NHCH (CH 2 OMe) 2 2-Me-4-Br-Ph 176 C-Me N (CH ₂ CH ₂ OMe) 2 2-Me-4-Br-Ph 177 C-Me NHCH (Et) CH 2 OMe 2-Me-4-Br-Ph 178 C-Me N (Pr) CH2CH2CN 2-Me-4-Br-Ph 179 C-Me OCH (Et) CH 2 OMe 2-Me-4-Br-Ph 180 C-Me NHCH (CH 2 OMe) 2 2-C1-4,6-Me2 "Ph 181 C-Me N (CH2CH2OMe) 2 2-C1-4, 6-Me2-Ph 182 C-Me NHCH (CH 2 OMe) 2 4-Br-2,6- (Me) 2-Ph 183 C-Me N (CH 2 CH-2OMe) 2 4-Br-2,6- (Me) 2 "Ph 184 C-Me NHCH (CH 2 OMe) 2 4-i-Pr-2-SMe-Ph 185 C-Me N (CH2CH2OMe) 2 4-i-Pr-2-SMe-Ph 186 C-Me NHCH (CH 2 OMe) 2 2-Br-4-CF3-Ph 187 C-Me N (CH 2 CH 2 OMe) 2 2-Br-4-CF3-Ph 188 C-Me NHCH (CH 2 OMe) 2 2-Br-4,6- (MeO) 2 Ph 189 C-Me N (CH2CH2OMe) 2 2-Br-4,6- (MeO) -Ph 190 C-Me NHCH (CH 2 OMe) 2 2-C1-4,6- (MeO) 2 ^- Ph 191 C-Me N (CH2CH2OMe) 2 2-C1-4,6- (MeO) 2-Ph 192 C-Me NHCH (CH 2 OMe) 2 2,6- (Me) 2-4-SMe-Ph 193 C-Me N (CH2CH2OMe) 2 2,6- (Me) 2-4-SMe-Ph 194 C-Me NHCH (CH 2 OMe) 2 4- (COMe) -2-Br-Ph 195 C-Me N (CH2CH2OMe) 2 4- (COMe) -2-Br-Ph 196 C-Me NHCH (CH 2 OMe) 2 2,4,6-Me3-pyrid-3-yl 197 C-Me N (CH2CH2OMe) 2 2,4,6-Me3 ~ pyridin-3-yl 198 C-Me NHCH (CH 2 OMe) 2 2,4 (Br) 2-Ph 199 C-Me N (CH 2 CH 2 OMe) 2 2,4 (Br) 2-Ph 200 · C-Me NHCH (CH 2 OMe) 2 4-i-Pr-2-SMe-Ph 201 C-Me N (CH 2 CH 2 OMe) 2 4-i-Pr-2-SMe-Ph

417

202 C-Me NHCH (CH ₂ OMe) 2 4-i-Pr-2-SO ₂ Me-Ph 203 C-Me N (CH ₂ CH ₂ OMe) 2 4-i-Pr-2-SO ₂ Me-Ph 204 C-Me NHCH (CH ₂ OMe) 2 2,6- (Me) ^_2-4-SMe-Ph 205 C-Me N (CH ₂ CH ₂ OMe) 2 2,6- (Me) 2-4-SMe-Ph 206 C-Me NHCH (CH ₂ OMe) 2 2,6- (Me) 2-4-SO ₂ Me-Ph 207 C-Me N (CH2CH2OMe) 2 2,6- (Me) 2-4-SO ₂ Me-Ph 208 C-Me NHCH (CH ₂ OMe) 2 2-I-4-i-Pr-Ph 209 C-Me N (CH ₂ CH ₂ OMe) 2 2-I-4-i-Pr-Ph 21C C-Me NHCH (CH ₂ OMe) ₂ 2-Br-4-N (Me) 2-6-MeO-Ph 211 C-Me N (CH ₂ CH ₂ OMe) ₂ 2-Br-4-N (Me) ₂ 6-MeO-Ph 212 C-Me NHCH (CH ₂ OMe) 2 2,4- (SMe) 2-Ph 213 C-Me N (CH ₂ CH ₂ OMe) 2 2,4- [SMe] 2-Ph 214 C-Me NHCH (CH ₂ OMe) 2 2,4- [SO ₂ Me] 2-Ph 215 C-Me N (CH ₂ CH ₂ OMe) ₂ 2,4- (SO ₂ Me) 2 -Ph 216 C-Me NHCH (CH ₂ OMe) 2 4-i-P-2-SMe-Ph 217 C-Me N (CH ₂ CH ₂ OMe) ₂ 4-i-Px-2-SMe-Ph 218 C-Me NHCH (CH ₂ OMe) ₂ 4-i-Pr-2-SO ₂ Me-Ph 219 C-Me N (CH ₂ CH ₂ OMe) ₂ 4-i-Px-2-SO ₂ Me-Ph 220 C-Me NHCH (CH ₂ OMe) ₂ 2-N (Me) 2-4-Me-Ph 221 C-Me N (CH ₂ CH ₂ OMe) ₂ 2-N (Me) 2-4-Me-Ph 222 C-Me NHCH (CH ₂ OMe) 2 2-MeS-4,6- (Me) ₂ -Ph 223 C-Me N (CH ₂ CH ₂ OMe) ₂ 2-MeS-4,6- (Me) ₂ -Ph 224 C-Me NHCH (CH ₂ OMe) ₂ 2- (CH 3 CO) -4,6- (Me) 2-Ph 225 C-Me N (CH ₂ CH ₂ OMe) 2 2- (CH 3 CO) -4,6- (Me) ₂ -Ph 226 H NHCH (CH ₂ OMe) 2 2,4-Me ₂ -Ph 227 H NHCH (CH ₂ OMe) 2 2,4-Ph _2-Me 228 CF3 N (CH ₂ CH ₂ OMe) ₂ 2,4-Me ₂ “Ph 229 CF3 N (CH ₂ CH ₂ OMe) 2 2,4-Me ₂ -Ph 230 N NHCH (CH ₂ OMe) ₂ . 2,6-Me3-Ph 231 N NHCHPr ₂ 2,4,6-Me3-Ph 232 N NetBt 2,4,6-Me3-Ph 233 N NPr _(CH2-c-C3H5) 2,6-Me3-Ph 234 N N (CH ₂ CH ₂ OMe) 2 2,4,6-Me3 ~ Ph 235 N ΝΗ-3-heptyl 2,4,6-Me3-Ph 236 N NHCH (Et) CH ₂ OMe 2,4,6-Me3-Ph 237 N NEt ₂ 2,4,6-Me3-Ph

118

238 N -NHCH (CH 2 OEt) 2 2.4. 6-Me ₃ -Ph 239 N ΝΗ-3-penty1 2.4. 6-Me ₃ -Ph 240 N NMePhe 2.4. 6-Me ₃ -Ph 241 N NPr ₂ 2.4. 6-Me ₃ - Ph 242 N ΝΗ-3-hexyl 2.4. 6-Me 3 Ph ~ 243 N morpholino 2.4. 6-Me ₃ -Ph 244 N N (CH ₂ Ph) CH ₂ CH ₂ OMe 2.4. 6-Me ₃ -Ph 245 N NHCH (CH 2 Ph) CH 2 OMe 2.4. 6-Me ₃ -Ph 24I N NH-4-tetrahydrcpyranyl 2.4. 6-Me ₃ - Ph 247 N NH-cyclopentyl 2.4. 6-Me ₃ -Ph 248 N 1,2,3,4-tet rahydro- isoquinolyl 2.4. 6-Me ₃ -Ph 249 N _CH2 - D, 2,3,4-isoquinolyl tetrahyaro- 2.4. 6-Me ₃ -Ph 250 N OEt 2.4. 6-Me ₃ -Ph 251 N OCH (Et) CH 2 OMe 2.4. 6-Me ₃ -Ph 252 N OCH ₂ Ph 2.4. 6-Me ₃ -Ph 253 N Ο-3-pentyl 2.4. 6-Me ₃ -Ph 254 N Set 2.4. 6-Me ₃ -Ph 255 N S (0) Et 2.4. 6-White ₃ -Ph 256 N SO ₂ Et 2.4. 6-Me ₃ -Ph 257 N CH (CO 2 e) 2 2.4. 6-Me ₃ -Ph 258 N C (Et) (CO ₂ Et) 2 2.4. 6-Me ₃ -Ph 259 N CH (Et) CH ₂ OH 2.4. 6-Me ₃ -Ph 260 N CH (Et) CH ₂ OMe 2.4. 6-Me ₃ -Ph 261 N CONMe ₂ 2.4. 6-Me 3 Ph ~ 262 N COCH3 2.4. 6-Me ₃ -Ph 263 N CH (OH) CH ₃ 2.4. 6-Me ₃ -Ph 264 N C (OH) Ph-3-pyridyl 2.4. 6-Me ₃ -Ph 265 N ph 2.4. 6-Me ₃ -Ph 266 N 2-CF ₃ -Ph 2.4. 6-Me ₃ -Ph 267 N 2-Ph-Ph 2.4. 6-Me ₃ -Ph 268 N 3-pentyl 2.4. 6-Me ₃ -Ph 269 N cyclobutyl 2.4. 6-Me ₃ -Ph 270 N 3-pyridyl 2.4. 6-Me ₃ -Ph 271 N CH (Et) CH ₂ CONMe ₂ 2.4. 6-Me ₃ -Ph

272 N CH (Et) CH ₂ CH ₂ NMe ₂ 2,4,6-Me3 ~ Ph 273 N NHCH (CH ₂ OMe) 2 2 4-Me ₂ -Ph 274 N NHCHPr ₂ 2 4-Me ₂ -Ph 275 N NetBt 2 4-Me ₂ -Ph 276 N NPr (CH2-C-C3H5) 2 4-Me ₂ ^- Ph 277 N N (CH ₂ CH ₂ OMe) 2 . 2 4-Me ₂ -Ph 278 N ΝΗ-3-heptyl 2 4-Me ₂ -Ph 27 9 N NHCH (Et) CH ₂ OMe 2 4-Me ₂ - Ph 28 ύ ' N NEt ₂ 2 4-Me ₂ -Ph 281 N -NHCH (CH ₂ OEt) ₂ 2 4-Me ₂ -Ph 282 N ΝΗ-3-pentyl 2 4-Me ₂ -Ph 283 N NMePhe 2 4-Me ₂ - Ph 284 N NPr ₂ 2 4-Me ₂ -Ph 285 N ΝΗ-3-hexyl 2 4-Me ₂ -Ph 286 M morpholino: 2 4-Me ₂ -Ph 287 N N (CH ₂ Ph) CH ₂ CH ₂ OMe 2 4-Me ₂ -Ph 288 N NHCH (CH ₂ Ph) CH ₂ OMe 2 4-Me ₂ -Ph 289 N NH-4-tecrahydropyranyl 2 4-Me ₂ -Ph 290 N NH-cyclopentyl 2 4-Me ₂ -Ph 291 N 1,2,3,4-tetrahydroisoquinolinyl 2 4-Me ₂ -Ph 292 N CH ₂ - (1,2,3,4-tetrahydro-isoquinolinyl 2 4-Me ₂ -Ph 293 N OEt 2 4-Me ₂ -Ph 294 N OCH (Et) CH ₂ OMe 2 4-Me ₂ -Ph 295 N OCH ₂ Ph 2 4-Me ₂ -Ph 296 N Ο-3-pentyl 2 4-Me ₂ - Ph 297 N Set 2 4-Me ₂ -Ph 298 N S (O) Et, 2 4-Me ₂ -Ph 299 N SO ₂ Et 2 4-Me ₂ - Ph 300 N CH (CO ₂ Et) 2 2 4-Me ₂ ^- Ph 301 N C (Et) (CO ₂ Et) 2 2 4-Me ₂ -Ph 302 N CH (Et) CH ₂ OH 2 4-Me ₂ - Ph 303 N CH (Et) CH ₂ OMe 2 4-Me ₂ ^- Ph 304 N CONMe ₂ 2 4-Me ₂ - Ph 305 N COCH3 2 4-Me ₂ -Ph

120

306 N CH (OH) CH ₃ 2,4-Me ₂ -Ph 307 N C (OH) Ph-3-pyridyl 2,4-Me ₂ -Ph 308 N ph 2,4-Ph _2-Me 309 N 2-CF ₃ -Ph 2,4-Me ₂ -Ph 310 N 2-Ph-Ph 2,4-Me ₂ -Ph 311 N 3-pentyl 2,4-Me ₂ -Ph 312 N cyclobutyl 2,4-Me ₂ -Ph 313 N 3-pyridyl 2,4-Me ₂ -Ph 31; N CH (Ec) CH ₂ CONMe ₂ 2,4-Me ₂ -Ph 315 N CH (Et) CH ₂ CH ₂ NMe ₂ 2,4-Me ₂ -Ph 316 ^an C-Me NEt 2 2-Br-4-MeO-Ph oil 317 ^am C-Me NH-3-pentyl 2-Br-4-MeO-Ph oil 31 8 ^and 3 C-Me NHCH (CH ₂ CH ₂ OMe) CH ₂ OMe 2,4,6-Me ₃ -Ph 101-103 319 ^ao C-Me NH (cC ₃ H5) 2,4-Me ₂ -Ph oil 320 ^ak C-Me morpholino 2,4,6-Me ₃ -Ph 139-141 321 ^and P C-Me NHCH (CH ₂ OMe) ₂ 2-CN-4-Me-Ph 152-153 322 ^ac I C-Me N (C-C ₃ H ₅ ) CH ₂ CH ₂ CN 2,4,6-Me ₃ -Ph 149-151 324 ^as C-Me NHCH (CH ₂ CH ₂ OMe) CH ₂ OMe 2-Me-4-Br-Ph 115-117 325 ^at C-Me NHCH (CH ₂ OMe) ₂ 2,5-Me ₂ -4-MeO-Ph 55-57 326 ^au C-Me N (CH ₂ CH ₂ OMe) 2 2,5-Me ₂ -4-MeO-Ph 72 327 ^av C-Me ΝΗ-3-pentyl 2,5-Me ₂ -4-MeO-Ph 45-47 328 ^aw C-Me NEt ₂ 2,5-Me ₂ -4-MeO-Ph oil 329 ^ax C-Me NHCH (CH ₂ OMe) 2 2-Cl-4-MePh 80-81 330 ^and Y C-Me CH (Et) CH ₂ OMe 2-Cl-4-MePh 77-79 331 ^az C-Me N (CH ₂ CH ₂ OMe) ₂ 2-Cl-4-MePh oil 332 ^ba C-Me (S) -NHCH (CH ₂ CH ₂ OMe) CH ₂ OMe 2-Cl-4-MePh 139-140 333 ^bb C-Me N (C-C ₃ H ₅ ) CH ₂ CH ₂ CN 2,5-Me ₂ -4-MeOPh 120-122 334 ^B 9 C-Me NEt ₂ 2-Me-4-MeOPh oil 335 ^bh C-TMe OEt 2-Me-4-MeOPh oil 336 ^bi C-Me (S) -NHCH (CH ₂ CH ₂ OMe) CH ₂ OMe 2-Me-4-MeOPh oil 337 3 ^b C-Me N (C-C ₃ H ₅ ) CH ₂ CH ₂ CN 2-Me-4-MeOPh 129 338 ^bk C-Me NHCH (CH ₂ CH ₂ OEt) ₂ 2-Me-4-MeOPh amorphous. 339 C-Me N ( _{c 3} H 5) CH ₂ CH ₂ CN 2,4-Cl ₂ -Ph 109-110 340 C-Me (S) -NHCH (CH ₂ CH ₂ OMe) CH ₂ OMe 2,4-Cl ₂ -Ph 93-94 341 C-Me ΝΗ-3-pentyl 2-Me-4-BrPh 118-119 342 C-Me N (CH ₂ CH ₂ OMe) 2 2-Me-4-BrPh oil

C-Me C-Me C-Me C-Me-Me

C-Me C-Me C-Me-C-Me My C-C-C Me Me Me-C-Me C C ^- N 'Me ³ C-C-C-Me Me Me C-C-C-Me C Me Me C Me Me C Me Me C Me Me C Me Me Me C Me Me Me C Me Me Me Me C Me Me Me Me C Me Me Me Me C Me Me Me Me

NHCH (CH ₂ -Pr) CH ₂ O Me 2,4-Me ₂ -Ph oil NHCH (Pr) CH ₂ O Me 2,4-Me ₂ -Ph 94-95 NHCH (Et) CH ₂ Et 2,4-Me ₂ -Ph 76-77 NHCH (CH ₂ 0me) CH ₂ CH ₂ OMe 2-Me-4-Me ₂ NPh oil NEt ₂ 2-Me-4-ClPh oil ΝΗ-3-pencyl 2-Me-4-ClPh 122-124 N (CH ₂ CH ₂ OMe) 2 2-Me-4-ClPh oil NHCH (CH ₂ 0me) ₂ 2-Me-4-ClPft 122-123 NEt ₂ 2-Me-4-ClPh oil NEt ₂ 2-Cl-4-MePh oil ΝΗ-3-pentyl 2-Cl-4-MePh 120-121 NHCH (CH ₂ 0me) ₂ 2-Cl-4-MeOPh N (CH ₂ CH ₂ OMe) ₂ 2-Cl-4-MeOPh oil NHCH (Ec) CH ₂ Me 2-Cl-4-MeOPh 108-110 N (c-Pr) CH ₂ CH ₂ CN 2-Cl-4-MeOPh 127-129 NEC ₂ 2-Cl-4-MeOPh oil ΝΗ-3-pentyl 2-Cl-4-MeOPh 77-79 NHCH (Ec) CH ² CH ² OMe 2-Cl-4-MeOPh NHCH (Me) CH ₂ CH ₂ OMe 2-Cl-4-MeOPh NHCH (Et) CH ₂ CH ₂ OMe 2-Br-4-MeOPh NHCH (Me) CH ₂ CH ₂ OMe 2-Br-4-MeOPh NHCH (Et) CH ₂ CH ₂ OMe 2-Me-4-MeOPh NHCH (Me) CH ₂ CH ₂ OMe 2-Me-4-MeOPh NHCH (CH ₂ 0me) ₂ 2-C1-4,5- (MeO) ₂ Ph N (CH ₂ CH ₂ OMe) ₂ 2-C1-4,5- (MeO) ₂ Ph NHCH (Et) CH ₂ Me 2-C1-4,5- (MeO) ₂ Ph N (c-Pr) CH ₂ CH ₂ CN 2-C1-4,5- (MeO) ₂ Ph NEt 2 2-C1-4,5- (MeO) ₂ Ph ΝΗ-3-pentyl 2-C1-4,5- (MeO) ₂ Ph NHCH (Et) CH ₂ CH ₂ OMe 2-C1-4,5- (MeO) 2Ph NHCH (Me) CH2CH2OMe 2-C1-4,5- (MeO) ₂ Ph NHCH (CH ₂ 0me) ₂ 2-Br-4,5- (MeO) ₂ Ph 137-138 N (CH2CH2OMe) 2 2-Br-4,5- (MeO) ₂ Ph NHCH (Et) CH ₂ Me 2-Br-4,5- (MeO) ₂ Ph 147-148 N (c-Pr) CH ₂ CH ₂ CN 2-Br-4,5- (MeO) ₂ Ph NEt ₂ 2-Br-4,5- (MeO) ₂ Ph 52-58

• Ίλ2. 379 C-Me ΝΗ-3-pentyl 2-Br-4,5- (MeO) 2? H 380 C-Me NHCH (Et) CH2CH2OMe 2-Br-4,5- (MeO) 2 Ph 381 C-Me NHCH (Me) CH2CH2OMe 2-Br-4,5- (MeO) 2 Ph 382 C-Me NHCH (CH 2 OMe) 2 2-C1-4,6- (MeO) 2 Ph 383 C-Me N (CH ₂ CH ₂ OMe) 2 2-C1-4,6- (MeO) 2 Ph 384 C-Me NHCH (Et) CH 2 OMe 2-C1-4,6- (MeO) 2 Ph 385 C-Me N (c-Pr) CH2CH2CN 2-C1-4,6- (MeO) 2? H 386 C-Me NEt 2 2-C1-4,6- (MeO) 2 Ph 387 C-Me ΝΗ-3-pentyl 2-C1-4,6- (MeO) 2? H 388 C-Me NHCH (Et) CH2CH2OMe 2-C1-4,6- (MeO) 2? H 389 C-Me NHCH (Me) CH2CH2OMe 2-C1-4,6- (MeO) 2 Ph 390 C-Me NHCH (CH ₂ OMe) 2 2-Me-4,6- (MeO) 2 Ph 391 C-Me N (CH 2 CH 2 OMe) 2 2-Me-4,6- (MeO) 2 Ph 392 C-Me NHCH (Et) CH 2 OMe 2-Me-4,6- (MeO) 2 Ph 393 C-Me N (c-Pr) CH 2 CH 2 CN 2-Me-4,6- (MeO) 2 Ph 395 C-Me NEt 2 2-Me-4,6- (MeO) 2 Ph 396 C-Me ΝΗ-3-pentyl 2-Me-4,6- (MeO) 2? H 397 C-Me NHCH (Et) CH2CH2OMe 2-Me-4,6- (MeO) 2 Ph 398 C-Me NHCH (Me) CH2CH2OMe 2-Me-4,6- (MeO) 2? H 399 C-Me N (c-Pr) CH 2 CH 2 CN 2-Br-4,6- (MeO) 2 Ph 400 C-Me NEt 2 2-Br-4, 6- (MeO) 2Ph 401 C-Me ΝΗ-3-pentyl 2-Br-4,6- (MeO) 2 Ph 402 C-Me NHCH (Et) CH2CH2OMe 2-Br-4,6- (MeO) 2 Ph 403 C-Me NHCH (Me) CH2CH2OMe 2-Br-4,6- (MeO) ₂ Ph 404 C-Me NHCH (Et) CH2CH2OMe 2-Me-4-MeOPh 405 C-Me NHCH (Me) CH2CH2OMe 2-Me-4-MeOPh 406 C-Me NHCH (CH ₂ OMe) 2 2-Me0-4-MePh 407 C-Me N (CH2CH2OMe) 2 2-MeO-4-MePh 408 C _' Me NHCH (Et) CH 2 OMe 2-Me0-4-MePh 409 C-Me N (c-Pr) CH 2 CH 2 CN 2-MeO-4-MePh 410 C-Me NEt 2 2-MeO-4-MePh 411 C-Me ΝΗ-3-pentyl 2-MeO-4-MePh 412 C-Me NHCH (Et) CH2CH2OMe 2-MeO-4-MePh 413 C-Me NHCH (Me) CH2CH2OMe 2-MeO-4-MePh 414 C-Me NHCH (CH 2 OMe) 2 2-MeO-4-MePh 415 C-Me N (CH2CH2OMe) 2 2-MeO-4-MePh

416 C-Me NHCH (Et) CH 2 OMe 2-MeO-4-MePh 417 C-Me N (c-Pr) CH 2 CH 2 CN 2-Me0-4-MePh 41Θ C-Me NEt ₂ 2-MeO-4-MePh 419 C-Me ΝΗ-3-pentyl 2-MeO-4-MePh 420 C-Me NHCH (Et) CH2CH2OMe 2-MeO-4-MePh 421 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-MeO-4-MePh 423 ^bt C-Me NHCH (CC ₂ OMe) ₂ 2-Meu-4-ClPh 424 C-Me N (CH ₂ CH ₂ OMe) 2 2-MeO-4-ClPh 425 C-Me NHCH (Et) CH ₂ OMe 2-Me0-4-ClPh 426 C-Me N (c-Pr) CH2CH2CN 2-MeO-4-Cl? H 427 C-Me NEt? 2-MeO-4-ClPh 428 C-Me ΝΗ-3-pentyl 2-MeO-4-ClPh 429 C-Me NHCH (EC) _CH2 CH7OMe 2-MeO-4-ClPh 430 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-MeO-4-ClPh

Notes on Table 1:

a) Analysis: calculated: C: 52.69, H: 5.17, N: 17.07, C1: 17.28; found: C, 52:82, H: 5.06, N: 16.77, C1:

17.50.

b) CI-HRMS: calcd. 406.1565, found ^: 405.1573 (M + H);

Analysis: Calculated: C: 59.11; H, 6.20; N: 17.23; Cl: 17.45; found :; C: 59.93; H, 6.34; N: 16.50; Cl: 16.95;

NMR (CDC1 _3, 300 MHz): 0.95 (t, J = 8, 4H), 1.30-1.40 (m, 4H), 1.50-1.75 (m, 4H), 2, 35 (s, 3H), 2.48 (s, 3H), 4.30-4.45 (m, 1H), 6.15 (d, J = 8, 1H), 7.30 (s, 2H) 7.50 (s, 1H).

c) CI-HRMS: Calcd: 392.1409, _n Unity: 392.1388 (M + H);

NMR (CDC1 _3, 300 MHz): 1.00 (t, J = 8, 3H), 1.35 (t, J = 8, 3H), 1.41 (q, J = 8, 2H), 1, 65-1.85 (m. 2H),

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

d) CI-HRMS: calcd. 404.1409, found: 404.1408 (M + H);

NMR (CDCl3 ₎ , 300 MHz): 0.35-0 45 (m, 2H), 0.52-0.62 (m 2H), 0.98 (T, J = 8, 3H), 1 70 to 1.90 (m, 2H), 2.30 (s, 3H), 2.40 (with, 3H), 3.85-4.02 (m, 2H) , 4.02-4.20 (m, 2H), 7.30 (with, 2H), 7.50 (s, 1H).

e) Cl-HRMS: calcd: 424.1307, found: 424.1307

f) (M + H); NMR (CDCl 3, 300 MHz): 2.28 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.75 (t, J = 8, 4H), 4.20-4.45 (m, 4H), 7.30 (S, 2H), 7.50 (s, 1H).

Cl-HRMS: calcd. 406.1565, found: 406.1578 (M + H);

NMR (CDC1 _3, 300 MHz): 0.90 (t, J = 8, 3H), 1.00 (t,

J = 8, 3H), 1.28-1.45 (m, 4H), 1.50-1.80 (m, 4H),

2.35 (s, 3H), 2.50 (s, 3H), 4.20-4.35 (m, 1H),

6.10-6.23 (m, 1H); 7.30 (s, 2H); 7.50 (s, 1H).

g) Cl-HRMS calculated: 394.1201, found: 394.1209 (M + H);

NMR (CDC1 _3, 300 MHz): 1.02 (t, J = 8, 3H), 1.65-1.90 (m, 2H), 2.35 (s, 3H), 2.48 (s, 3H), 3.40 (s, 3H),

3.50-3.60 (m, 2H), 4.35-4.45 (broad singlet, 1H),

6.50-6.60 (m, 1H); 7.30 (s, 2H); 7.50 (s, 1H).

CI-HRMS: calcd. ³⁶⁴ ' ¹⁰⁹⁶ ' found: 364.1093 (M + H);

Analysis: Calculated: C: 56.05; H: 5.27; N: 19.23; Cl: 19.46; found: C: 55.96; H, 5.24; N: 18.93; Cl:

19.25;

NMR (CDC1 _3, 300 MHz): 1.35 (t, J = 8, 6H), 2.30 (3,

3H), 2.40 (s, 3H), 3.95-4.15 (m, 4H), 7.30 (s, 2H),

7.50 (d, J = 1.1, 1H).

CI-HRMS: calcd: 438.1464, found: 438.1454 (M + H);

NMR (CDC1 _3, 300 MHz): 1.22 (t, J = 8 6H), 2.35 (s, 3H), 2.47 (s, 3H), 3.39 (q, J = 8 4H) , 3.65 (dd, J = 8, 1, 2H), 3.73 (dd, J = 8.1, 2H) , 4.55 - 4.65 (M, 1H), 6.75 (d, J = 8) 1H), 7.30 (D, J = 1, 2H)

7.50 (s, 1 H).

CI-HRMS: Calcd: 378.1252, Found: 378.1249

i)

2.5 (+);

Analysis: Calculated: C: 57.15; H: 5.61; N: 18.51; Cl: 18.74; Found: C: 57.56; H, 5.65; N: 18.35; Cl: 18.45;

NMR (CDC1 _3, 300 MHz): 1.00 (t, J = 8, 6H), 1.55-1.70 (m, 2H), 1.70-1.85 (m, 2H), 2, 35 (s, 3H), 2.50 (s, 3H), 4.15-4.25 (m, 1H), 6.18 (d, J = 8, 1H), 7.30 (s, 2H) 7.50 (s, 1 H).

k) CI-HRMS calcd: 398.0939, found: 398.0922 (M + H);

Analysis: Calculated: C: 60.31; H, 4.30; N: 17.58; Cl: 17.80; found: C: 60.29; H, 4.59; N: 17.09; Cl: 17.57;

NMR (CDC1 _3, 300 MHz): 2.05 (s, 3H), 2.50 (s, 3H), 3.78 (s, 3H), 7.20-7.45 (m, 7 H), 7 50 (d, J = 1, 1 H).

l) CI-HRMS: calc .: 392.1409, found: 392.1391 (M + H); NMR (CDC1 _3, 300 MHz): 0.98 (t, J = 8, 6H),

1.70-1.85 (m, 4H), 2.30 (s, 3H), 2.40 (s, 3H), 3.80-4.10 (m, 4H), 7.30 (s, 2H), 7.50 (d, J = 1, 1H).

m) CI-HRMS: calcd: 392.1409, found: 392.1415 (M + H);

Analysis: Calculated: C: 58.17; H: 5.92; N: 17.85; Cl: 18.07; found: ^C: 58.41; H: 5.85; N: 18.10; Cl: 17.75;

NMR (CDC1 _3, 300 MHz): 0.90-1.05 (m, 6H), 1.35-1.55 (m, 2H), 1.55-1.85 (m, 4H), 2.35 (s, 3H), 2.48 (s, 3H),

4.20-4.35 (m, 1 H), 6.15 (d, J = 8, 1 H), 7.30 (s, 2 H),

7.50 (d, J = 1.1, 1H).

n) CI-HRMS: calcd: 337.0623, found: 337.0689 (M + H);

Analysis: Calculated: C: 53.43; H, 4.18; N: 16.62; Cl: 21.03, found: C: 53.56; H, 4.33; N: 16.56; Cl: 20.75;

NMR (CDC1 _3, 300 MHz): 1.60 (t, J = 8, 3H), 2.40 (s, 3H), 2.55 (s, 3H), 4.80 (q, J = 8, 2H), 7.30 (d, J = 8, 1H), 7.35 (dd, J = 8.1H), 7.55 (d, J = 1, 1H).

o) CI-HRMS: calcd. ₃₈₂ , 2321, found: 383.2309 (M + H);

NMR (CDC1 _3, 300 MHz): 2.00 (s, 6H), 2.20 (s, 3H), 2.30 (s, 3H), 2.45 (s, 3H), 3.45 (s (6H), 3.61 (dd, J = 8.8, 2H), 3.70 (dd, J = 8.8, 2H), 4.60-4.70 (m, 1H), 6.70 (d, J = 8, 1 H), 6.94 (s, 2 H).

p) CI-HRMS: calcd: 370.2243, found: 370.2246 (M + H);

Analysis calculated: C, 65.02; H, 7.38; N: 18.96; found: C: 65.22; H, 7.39; N: 18.71;

NMR (CDC1 _3, 300 MHz): 2.18 (s, 3H), 2.30 (s, 3H), 2.45 (s, 3H), 3.45 (s, 6H), 3.60 (dd J = 8, 8, 2H), 3.69 (dd, J = 8, 8, 2H), 4.60-4.70 (m, 1H), 6.70 (d, J = 8,

1H), 7.05 (d, J = 8, 1H), 7.07 (d, J = 8, 1H), 7.10 (S, 1H).

q) CI-HRMS: calcd: 384.2400, found: 384.2393 (M + H);

NMR (CDC1 _3, 300 MHz): 2.16 (s, 3H), 2.25 (s, 3H), 2.35 (s, 3H), 2.39 (s, 3H), 3.40 (s 6H) 3.77 (t, J = 8)

4H), 4.20-4.45 (m, 4H), 7.02 (d, J = 8, 1 H), 7.05 (s, 1H), 7.10 (d, J = 7, 1 H) .

r) CI-HRMS: calcd: 354.2294, found: 354.2271 (M + H);

Analysis: Calculated: _C: 67.96; H, 7.71; N: 9.81; found: C: 67.56; H: 7.37; N: 19.60;

NMR (CDCl ₃ , 300 MHz): 1.03 (t, J = 8, 3H), 1.65-1.88 (m, 2H), 2.17 (s, 3H), 2.30 (s, 3H), 2.35 (s, 3H),

2.45 (s, 3H), 3.40 (s, 3H), 3.50-3.62 (m, 2H),

4.30-4.45 (m, 1H), 6.51 (d, J = 8, 1H), 7.04 (d, J = 8, 1H), 7.10 (d, J = 8, 1H) 7.12 (s, 1H).

s) CI-HRMS: calcd: 338.2345, found: 338.2332 (M + H);

Analysis: Calculated: _C: 71.18; H, 8.06; N: 20.75; found: C: 71.43; H: 7.80; N: 20.70;

NMR (CDC1 _3, 300 MHz): 1.00 (t, J = 8, 6H), 1.55-1.70 (m, 2H), 1.70-1.85 (m, 2H), 2, 19 (s, 3H), 2.30 (s, 3H), 2.35 (S, 3H), 2.46 (s, 3H), 4.15-4.26 (m, 1H), 6.17 (d, J = 8, 1 H), 7.06 (d, J = 8, 1 H), 7.10 (d, J = 1, 1)

1, 1H), 7.13 (s, 1 H).

t)

CI-HRMS: calcd. 324.2188, found. 324.2188 (M + H);

NMR (CDC1 _3, 300 MHz): 1.25 (t, J = 8.6 H), 2.16 (s, 3H), 2.28 (s, 3H), 2.35 (s, 3H); 2.40 (s, 3H);

4H)

/ (dd,

1H)

1H)

1H)

CI-HRMS: Calcd .: 346.1780, Found: 346.1785 (M + H);

Analysis: Calculated: C: 66.07; H: 5.54; N: 28.39;

Found: C: 66.07; H: 5.60; N: 27.81;

NMR (CDC1 _3, 300 MHz): 2.15 (s, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 2.52 (s, 3H), 5.25 to 5 35 (m, 4H), 7.08 (s,

2H), 7.15 (s, 1H).

(v) CI-HRMS: calcd: 340.2137, found:. 340.2137 (M + H);

Analysis: Calculated: C: 67.23; H, 7.42; N: 20.63; Found: C. 67.11; H, 7.39; N: 20.26;

NMR (CDC1 _3, 300 MHz): 1.40 (d, J = 8, 3H), 2.16 (s,

3H), 2.32 (s, 3H), 2.35 (s, 3H), 2.47 (s, 3H), 3.42 (S, 3H), 3.50-3.60 (m, 2H) 4.50-4.15 (m, 1H), 6.56 (d, J = 8, 1H), 7.00-7.15 (m, 3H).

w) CI-HRMS: calcd: 355.2134, found: 355.2134 (M + H);

NMR (CDC1 _3, 300 MHz): 1.05 (t, J = 8, 3H), 1.85-2.00 (m, 2H), 2.17 (s, 3H), 2.36 (s, 6H), 2.50 (s, 3H), 3.41 (s, 3H), 3.45 (dd, J = 8, 3, 1H), 3.82 (dd, J = 8, 1, 1H) 5.70-5.80 (m, 1H); 7.00-7.20 (m, 3H).

x) CI-HRMS: calcd: 364.2501, found: 364.2501 (M + H);

NMR (CDC1 _3, 300 MHz): 0.35 to 0.43 (m, 2H), 0.50-0.60 (m, 2H), 0.98 (t, J = 8, 3H), 1, 20-1.30 (m, 1H), 1.72-1.90 (m, 2H), 2.18 (s, 3H), 2.28 (s, 3H), 2.35 (s, 3H) 2.40 (s, 3H), 3.88-4.03 (m, 2H), 4.03-4.20 (m, 2H),

7.00-7.15 (m, 3H).

y) CI-HRMS: calcd: 353.2454, found: 353.2454

428 (+ +);

Analysis: calculated: C: 68.15; H: 8, 02; N: 23.84; found: C: 67.43; H: 7.81; N: 23, 45; NMR (CDC1 _3, 300 MHz): 1.38 (d, J = 8 3H), 2.18 (s, 3H), 2.30-2.40 (m, 12H), 2.60-2.75 (M, 2H) , 4.30-4.50 (m, 1H); 6.60-6.70 (m, 1H), 7.00-7. 15 (M, 3H).

z) CI-HRMS: Calcd .: 361.2140, Found: 361.2128 (Μ + Η);

NMR (CDC1 _3, 300 MHz): 0.75-0.83 (m, 2Η), 1.00-1.10 (m,

2Η), 2.17 (s, 3Η), 2.30 (s, 3Η), 2.36 (s, 3Η), 2.47 (S, 3Η), 2.85 (t, J = 8.2, 2Η) ), 3.30-3.40 (m, 1,), 4.40-4.55 (m, 2,), 7.00-7.18 (m, 3Η).

aa) CI-HRMS: Calcd: ^{363 '2297' Dené Li:} 363.2311 (M + H);

NMR (CDC1 _3, 300 MHz): 1.01 (t, 3H, J = 8), 1.75-1.90 (m, 2H), 2.15 (s, 3H), 2.19 (s, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 2.40 (s, 3H), 2.98 (t, 2H, J = 8), 3.97-4.15 (m, 2H), 4.15-4.30 (m, 2H), 7.03 (d, 1H,

1H), 7.08 (d, 1H, J = 8), 7.10 (s, 1H).

ab) CI-HRMS: Calcd .: 363.2297, Found: 363.2295 (M + H);

NMR (CDC1 _3, 300 MHz): 1.01 (t, 3H, J = 8), 1.35-1.55 (m, 2H), 1.75-1.90 (m, 2H), 2, 15 (s, 3H), 2.30 (s, 3H), 2.36 (s, 3H), 2.46 (s, 3H), 4.10-4.30 (m, 2H), 4.95 -5.10 (broad singlet, 2H), 7.05 (d, 1H, J = 8),

7.10 (d, 1H, J = 8); 7.15 (s, 1H).

ac) CI-HRMS: calcd: 368.2450, found. 368.2436; Analysis: calculated: _c . 68.62; H: 7.95; N: 19.06; found: C: 68.73; H, 7.97; N: 19.09;

NMR (CDC1 _3, 300 MHz): 1.05 (t, J = 8, 3H), 1.70-1.90 (m, 2H), 2.01 (d, J = 3, 6H), 2, 20 (s, 3H), 2.30 (s, 3H), 2.46, 2.465 (s, S, 3H), 3.42, 3.48 (s, S, 3H),

3.53-3.63 (m, 2H), 4.35-4.45 (m, 1H), 6.73 (d, J = 8, 1H), 6.97 (s, 2H).

ad) CI-HRMS: calcd: 352.2501, found: 352.2500 (M + H);

Analysis: calculated: 71.76; H: 8.33; N: 19.92;

found: C: 71.55; H: 8.15; N: 19.28;

NMR (CDC1 _3, 300 MHz): 1.01 (t, J = 8, 6H), 1.58-1.70 (m, 2H), 1.70-1.85 (m, 2H), 2, O 2 (s, 6H), 2.19 (s, 3H), 2.45 (s, 3H), 4.12-4.28 (m, 1H), 6.18 (d, J = 8, 1H) 6.95 (s, 2H).

ae) CI-HRMS: calcd: 398.2556, found: 398.2551 (M + H);

Analysis: Calculated: C: 66.47; H, 7.86; N: 17.62; found: C: 66.74; H, 7.79; N: 17.70;

NMR (CDC1 _3, 300 MHz): 2.00 (s, 6H), 2.12 (s, 3H), 2.30 (s, 3H), 2.37 (s, 3H), 3.40 (s 6H), 3.78 (t, J = 8, 4H), 4.25-4.40 (m, 4H), 6.93 (s, 2H).

af) CI-HRMS: Calc'd: 450.1141, Found: 450.1133 (M + H);

Analysis: Calculated: C: 50.67; H: 5.37; N: 15.55; Br: 17.74; found: C: 52.36; H: 5.84; N: 14.90; Br: 17.44;

NMR (CDC1 _3, 300 MHz): 2.32 (s, 3H), 2.57 (s, 3H), 3.42 (s, 6H), 3.60 (q, J = 8, 2H), 3 69 (q, J = 8, 2H), 3.82 (s, 3H), 4.60-4.70 (m, 1H), 6.73 (d, J = 8, 1), 6.93 (dd, J = 8.1, 1H), 7.22 (d, J = 8, 1H).

g) CI-HRMS: calcd: 434.1192, found: 434.1169 (M + H);

Analysis: Calculated: C: 52.54; H: 5.58; N: 16.12; Br: 18.40; Found: C: 52.57; H: 5.60; N: 15.98; Br: 18.22;

NMR (CDC1 _3, 300 MHz): 1.00-1.07 (m, 3H), 1.65-1.85 (m, 2H), 2.35 (s, 3H), 2.46, 2, 47 (s, 3H), 3.40,

3.45 (s, s, 3H), 3.83 (s, 3H), 4.35-4.45 (m, 1H), 6.55 (d, J = 8, 1H), 6.92 ( dd, J = 8.1, 1H), 7.20-7.30 (m, 2H).

ah) Cl-HRMS: calcd: 337.2266, found: 337.2251 (M + H);

Analysis: Calculated: C: 70.18; H, 8.06; N: 20.75; found: ^{1 C:} 70.69; H, 7.66; N: 20.34;

NMR (CDC1 _3, 300 MHz): 1.35 (t, J = 8, 6H), 2.01 (s, 6H), 2.15 (s, 3H), 2.30 (s, 3H), 2 38 (s, 3H) 4.07

130 (q, J = 8.4, 4H), 6.93 (s, 2H).

ai) CI-HRMS: calcd: 412.2713, found: 412.2687 (M + H);

Analysis: Calculated: C: 67.13; H: 8.08; N: 17.02;

Found: C: 67.22; H, 7.85; N: 17.13;

NMR (CDC1 _3, 300 MHz): 1.24 (t, J = 8, 6H), 2.00 (s, 6H), 2.20 (s, 3H), 2.30 (s, 3H), 2 Δ3 (s, 3H), 3.60 (q, J = 8, 4H), 3.66 (dd, J = 8, 3, 2H), 3.75 (dd, J =

8, 3, 2H), 4.55-4.65 (m, 1H), 6.75 (d, J = 8, 1H), 6.95 (S, 2H).

i) CI-HRMS: Calcd .: 398.2556, Found: 398.2545 (M + H);

Analysis: Calculated: C: 66.47; H, 7.86; N: 17.62; found: C: 66.87; H, 7.62; N: 17.75;

NMR (CDC1 _3, 300 MHz): 1.95-2.10 (m, 8 H), 2.20 (s, 3H);

2.32 (s, 3H) , 2.44 (s, 3H) 3.38 (WITH, 3H), 3.42 (with, 3H), 3.50 to 3, 70 (m, 4H), 4.58-4.70 (M, 1H), 6.87 (d, J = 8, 1H), 6 95 (5. 2H).

ak) CI-HRMS: Calc'd: 338.1981, Found: 338.1971 (M + H);

Analysis: Calculated: C: 67.63; H, 6.87; N: 20.06; found: C: 67.67; H, 6.82; N: 20.31;

NMR (CDC1 _3, 300 MHz): 2.15 (s, 3H), 2.29 (s, 3H), 2.35 (s, 3H), 2.43 (s, 3H), 3.90 (t J = 8, 4H), 4.35-4.45 (m, 4H), 7.00-7.15 (m, 3H).

al) CI-HRMS: calcd: 464.1297, found: 464.1297 (M + H);

NMR (CDC1 _3, 300 MHz): 2.28 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.75 (t, J = 8, 4H), 3 83 (s, 3H), 4.20-4.50 (m, 4H), 6.93 (dd, J = 8.1, 1H), 7.20 (s, 1H), 7.24 (d , J = 1, 1H).

am) CI-HRMS: Calc'd: 418.1242, Found: 418.1223 (M + H)

NMR (CDC1 _3, 300 MHz): 1.00 (t, d, J = 8, 1, 6H), 1.55-1.75 (m, 4H), 2.34 (s, 3H), 2, 49 (s, 3H), 2.84 (s, 3H), 4.15-4.27 (m, 1H), 6.19 (d, J = 8, 1H), 6.93

131 (dd, J = 8.1, 1H), 7.21-7.30 (m, 2H).

an) CI-HRMS: calcd: 404.1086, found: 404.1079 (M + H);

NMR (CDC1 _3, 300 MHz): 1.35 (t, J = 8, 6H), 2.28 (s, 3H), 2.40 (s, 3H), 3.83 (s, 3H), 3 90-4.08 (m, 2H), 4.08-4.20 (m, 2H), 6.92 (dd, J = 8.1, 1H), 7.20-7.25 (m, 2H).

ao) CI-HRMS: calcd: 308.1875, found: 308.1872 (M + H);

NMR (CDC1 _3, 300 MHz): 0.75 to 0.80 (m, 2H), 0.93-1.00 (m, 2H), 2.16 (s, 3H), 2.28 (s, 3H), 2.35 (s, 3H), 2.53 (s, 3H), 3.00-3.10 (m, 1H), 6.50-6.55 (m, 1H), 7.00 -7.15 (m, 3H).

ap) CI-HRMS: Calcd: _397, l988, _n Unity: 397.1984 (M + H);

NMR (CDC1 _3, 300 MHz): 2.43 (s, 3H), 2.50 (s, 3H), 3.43

(with, 3H), 3.61 (dd, J = 8.8, 2H), 3.69 (dd, J = 8) 8 2H), 3.88 (s, 3H), 4.58-4.70 (m, 1 H), 6.75 (d, J = 8 1H), 7.20 (dd, J = 8.1, 1H), 7.25 (d, J = 1, 1H) 7.40 (with, 1H). C H RMS: · calculated: 375.2297, found: 375.2286 (M + H) anal ysis: calculated: _C; 70.56; H: 7.01; N, 22.44; found: C: 70.49; H, 6.99; N: 22.45; NMR (CDC1 _3, 300 MHz): 0.79 to 0, 85 (m. 2H.) ), 1.00-1.05 (M, 1H), 2.00 (S, 6H), 2.19 (S, 3H) H, 2.32 (S, 3H), 2.44

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

r) CI-HRMS: Calcd: _434/119 2, Found: 434.1189 (M + H)

Analysis calculated: C: 52.54; H: 5.58; N: 16.12; Br: 18.40; found: ^C: 52.75; H: 5.59; N: 16.09; Br: 18.67;

NMR (CDC1 _3, 300 MHz): 2.19 (s, 3H), 2.30 (s, 3H), 2.47 (s, 3H), 3.43 (s, 6H), 3.60 (dd J = 8, 8, 2H), 3.70 (dd, J = 8, 8, 2H), 4.58-4.70 (m, 1H), 6.71 (d, J = 8,

432

1Η), 7.08 (d, J = 8, 1 H), 7.37 (dd, J = 8, 1, 1 H), and so on)

7.45 (d, J = 1, 1H).

CI-HRMS: Calcd .: 448.1348, Found: 448.1332 (M + H);

Analysis: Calculated: C: 53.58; H: 5.85; N: 16.62; br:

17.82; found: C: 53.68; H, 5.74; N: 15.52; br:

13.03;

NMR (CDC1 _3, 300 MHz): 1.95-2.10 (m, 2H), 2.20 (s, 3H);

2.30 (with, 3H), 2.47 (s, 3H) 3.38 (s, 3H), 3.41 (with, 3H), 3.50 -3.67 (m, 4H), 4, 55-4.70 (m, 1H), 6.89 (d, J = 8, 1H), 7.05 (d, J = 8, 1H), 7.35 (dd, J = 8) 1 1H), 7.47 (d, J = 1, 1H).

Cl-HRMS: calcd: 400.2349, found: 400.2348 (M + H);

Analysis: Calculated: C: 63.14; H, 7.32; N: 17.53; found: C: 63.40; H, 7.08; N: 17.14;

au)

NMR (CDC1 _3, 300 MHz): 2.16 (s, 3H), 2.20 (s, 3H). 2.30 (with, 3H), 2.46 (S, 3H), 3.42 (s , 6H) 3.60 (q, J = 8 2H) 3.70 (q, J = 8, 2H). 3.85 (WITH, 3H), 4.59-4.70 (M, 1H) 6.70 (d, J = 8, 1H); 6.76 (WITH, 1H), 6.96 (s, 1H). Cl HRMS: Calcd .: 414.2505, found: 414.2493 (M + H); NMR (CDC1 _3, 300 MHz): 2.15 (s, 3H), 2.19 (s, 3H), 2.25 (with, 3H), 2.40 (s, 3H), 3.40 (s , 6H) 3.76 (t, J = 8

and in)

4H), 3.84 (s, 3H), 4.20-4.45 (m, 4H), 6.77 (s, 1H),

6.93 (s, 1 H).

CI-HRMS: Calcd .: 368.2450, Found: 368.2447 (M + H);

NMR (CDC1 _3, 300 MHz): 1.00 (t, J = 8, 6H), 1.55-1.85 (m, 4H), 2.19 (s, 3H), 2.20 (s, 3H), 2.30 (s, 3H), 2.47 (s, 3H), 3.88 (s, 3H), 4.10-4.30 (m, 1H), 6.15 (d, J) = 8, 1H), 6.78 (s, 1H), 6.98 (s, 1H).

aw) CI-HRMS: Calcd: 353.2216, _{n Unity:;} 353.2197 (M + H);

NMR (CDC1 _3, 300 MHz): 1.35 (t, J = 8, 6H), 2.17 (s, 3H), 2.19 (s, 3H), 2.28 (s, 3H), 2 40 (s, 3H), 3.85

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

ax) CI-HRMS calcd. 390.1697, found: 390.1688 (M + H);

Analysis: calculated; C: 58.53; H, 6.20; N: 17.96; Cl: 9.09; Found: C: 58.95; H, 6.28; N: 17.73; Cl: 9.15;

NMR (CDC1 _3, 300 MHz): 2.35 (s, 3H), 2.37 (s, 3H), 2.48 (s, 3H), 3.42 (s, 6H), 3.60 (dd J = 8, 8, 2H), 3.68 (dd, J = 8, 2H), 4.59-4.72 (m, 1H), 6.72 (d, J = 8, 1H) 7.12 (d, J = 8, 1H); 7.23 (d, J = 8, 1H); 7.32 (s, 1H).

ay) CI-HRMS: calcd: 374.1748, found: 374.1735 (M + H);

Analysis: Calculated: C: 61.04; H, 6.47; N: 18.73; Cl: 9.48; Found: C: 61.47; H, 6.54; N: 18.23; Cl: 9.61;

NMR (CDC1 _3, 300 MHz): 1.01 (t, J = 8, 3H), 1.62 to 1.88 (m, 4 H), 2.35 (s, 3H), 2.37 (s, 3H), 2.48 (d, J = 1, 3H), 3.40, 3.45 (s, s, 3H), 3.50-3.64 (m, 2H), 4.38-4, 47 (m, 1 H), 6.53 (d, J = 8, 1 H), 7.12 (d, J =

Δ, 1H), 7.07 (d, J = 8, 1H), 7.12 (s, 1H).

az) CI-HRMS: calcd. 404.1853, found: 404.1839 (M + H);

NMR (CDC1 _3, 300 MHz): 2.29 (s, 3H), 2.38 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.76 (t J = 8, 4H), 4.20-4.45 (m, 4H), 7.11 (d, J = 8, 1H), 7.22 (d, J = 8, 1H),

7.31 (s, 1 H).

ba) CI-HRMS: calcd. 404.1853, found: 404.1859 (M + H);

Analysis: C: 59.47; H, 6.50; N: 17.34; Cl: 8.79; Found: C: 59.73; H, 6.46; N: 17.10; Cl: 8.73;

NMR (CDC1 _3, 300 MHz): 1.95-2.08 (m, 2H), 2.35 (s, 3H);

2.38 (with, 3H), 2.46 (with, 3H) , 3.38 (S, 3H), 3.41 (s, 3H), 3.50 -3.65 (m, 4H), 4. 56 to 4.70 (m, 1H), 6.85 (d, J) = 8, 1H), 7.12 (d, J = 8 1H), 7 45 (d, J = 8, 1 H), 7.32 (with, 1H).

bb) CI-HRMS: Calcd .: 391.2246, found 5 391.2258 (M + H);

Analysis: C: 67.67; H, 6.71; N: 21.52; found: _C: 67.93; H, 6.70; N: 21.48;

NMR (CDC1 _3, 300 MHz): from 0.76 to 0.84 (m, 2H), 0.84-0.91 (m, 2H), 1.00-1.08 (m, 2H), 2, 15 (s, 3H), 2.20 (s, 3H),

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

bc) CI-HRMS: calculated; 386.2192, found; 386.2181 (M + H);

Analysis: C: 62.32; H, 7.06; N: 18.17; Found: C, 62.48; H, 6.83; N: 18.15;

NMR (CDC1 _3, 300 MHz): 7.1 (d, 1 H, J = 8), 6.9 (d, 1H, J = 1), 6.8 (dd, 1 H, J = 8.1), 6.7 (broad doublet, 1H, J = 8), 4.7-4.6 (m, 1H), 3.85 (s, 3H), 3.70-3.55 (m, 4H), 3 45 (S, 6H), 2.5 (s, 3H), 2.3 (s, 3H), 2.15 (s,

3H).

bd) CI-HRMS: calcd: 400.2349, found: 400.2336 (M + H);

NMR (CDC1 _3, 300 MHz): 7.1 (d, 1 H, J = 7), 6.85 (d, 1 H, J = 1), 6.75 (dd, 1 H, J = 7.1), 4.45-4.25 (broad singlet, 4H), 3.75 (t, 4H, J = 7), 3.4 (s, 6H), 2.4 (s, 3H), 2.25 (S) 3H), 2.15 (s, 3H).

be) CI-HRMS: calcd: 370.2243, found: 370.2247 (M + H);

Analysis: C: 65.02; H, 7.38; N: 18.96; found; C: 65.28; H, 7.27; N: 18.71;

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

J = 1), 6.8 (dd, 1H, J = 8.1), 6.5 (broad doublet, 1H, J = 1), 4.5-4.3 (m, 1H), 3.85 (s, 3H), 3.65-3.5 (m, 2H), 3.4 (S, 2H), 2.5 (s, 3H), 2.3 (s, 3H), 2.2 ( s, 3H), 1.9-1.7 (m, 2H), 1.05 (t, 3H, J = 7).

bf) CI-HRMS: calculated; 379.2246, found; 379.2248 (M + H);

NMR (CDC1 _3, 300 MHz): 7.1 (d, 1 H, J = 8), 6.85 (d, 1 H, J = 1), 6.8 (dd, 1 H, J = 8.1), 4.3-4.0 (m, 4H), 3.85 (s, 3H), 3.0 (t, 2H, J = 7), 2.45 (s, 3H), 2.3 (s, bg) bh) bi) bj) bk) b1) bm) bn) phases

3H), 2.2 (s, 3H), 1.9-1.8 (m, CI-HRMS: calcd: 340.2137, H);

NMR (CDCl3)

J = 1), multiplet,

3H), 2.2

CI-HRMS:

2H), 1.0 (t, 3H, J = 7). found: 340.2122 (M + (M + H)).

CI-HRMS:

(M +

NMR ₃ , 300 MHz): 7.1 (d,

6.75 (dd, 1H, J = 8.1),

4H), 3.85 (s, 3H), (s, 3H), 1.35 (t, 6H, calcd. 313.1665, v / v)

H);

(CDCl ₃ , 300 MHz):

4.7-4.55 (m, 1H), (S, 3H), 3.35 (s, (s, 3H), 2.1-1.95) at 4.

1H, J = 8), 6.85 (d, 4.2-4.0 (broad

2.4 (s, 3H); 2.3 (S, J = 7).

found: 313.664 found: 400.2346

1H, J = 7), 6.9-6.75

3H), 3.7-3.5 (m, 4H)

3H), 2.3 (s,

7.1 (d,

3.8 (s,

3H), 2.5 (s, (m, 2H)).

found: 377.2092

3H),

3.45

2.2

CI-HRMS: Calcd .: 377.2090, (M + H);

Analysis: C: 67.00; H, 6.44; N: 22.32; found: C: 67.35; H, 6.44; N: 22.23;

NMR (CDC1 _3,

J = 1), 6.8 (dd, (s, 3H), 3.4-3.3)

3H), 2.3 (s, 3H)

H, 6.44; N:

300 MHz)

1H (m,

7.1 (d,

J = 8.1 (1H), 2.85

2.2 (s. 3H)

I

0.85-0.75 (m. 2H)

CI-HRMS: Calcd. 413.2427, (M + H);

NMR (CDCl ₃ , 300 MHz): 7.1 (d,

1H, J = 8.1)

4H), 3.6 (q,

2.2 (s. 3H)

1), 6.75 (dd,

3.75 - 3.6 (m,

2.3 (s, 3H).

----- --- 3H)

3H),

CI-HRMS: Calcd; 420.1802, (M + H);

CI-HRMS: Calcd; 390.1697, (M + H);

CI-HRMS: Calcd .: 397.1465, (M + H);

1 H, (m, t

3H),

1 H, J = 8, 6.9 (d, 1H,

4.55-4.4 (m, 2H), 3.85 (t, 2H, J = 7), 2.5 1.1-1.0 (m, 2H), found: 413.2416

1H, J = 8, 6.85 (d, 4.6, m, 1H), 3.85

4H, J =

1.25 (t,

found:

found:

(with,

1H, (s,

2.5 (S,

J = 7)

7),

6H,

420.1825

390.1707

397.1462

136

bo) CI-HRMS: Calcd .: 3 60.1513, found:: 360.1514 (M + H); bp) CI-HRMS: Calcd .: 374.1748, (M + H); found ^:: 374.1737 bq) CI-HRMS: Calcd .: 479.1155, (M + H); found; 479.1154 br) CI-HRMS: Calcd .: 463.1219, (M + H); found: 463.1211 Analysis: Calculated: C: 51.96; H, 5.23; N: 15.15, Br 17.28; found: C: 52.29; H: 17.47; 5.62; N: 14.79; br: bs) CI-HRMS: Calcd .: 433.1113, (M, ⁷⁹ Br); found: 433.1114 bt) NH ₃ -CI MS: calcd; 406, ná found: 406 (M + H) ^< ^{+ &gt};; NMR (CDCl ₃ , 300 MHz): δ 7.28 (d, J = 10 Hz) (1H), 7.03 J = 8 Hz, 1H), 6.96 (s, 1H), 6.7 (d, J = 9) 1H), 4.63 (m 1H), 3.79 (s, 3H), 3.6 (m, 4H), 3.42 (s 3H), 2.32 (s, 3H). (6H), 2.47

Example 431

2,4,7-Dimethyl-8- (4-methoxy-2-methylphenyl) [1,5-a] pyrazolo-

1,3,5-triazine (Formula 1, wherein R ³ is CH. R ¹ is _referred CH., Z is C-CH ,, Ar is 2,4-dimethyl-phenyl)

Acetic acid 5-Acetamidino-4- (4-methoxy-2-methylphenyl) -3-methylpyrazole (602 mg, 2 mmol) was treated with saturated NaHCO 3 solution. (10 mL). The aqueous mixture was extracted three times with EtOAc. The combined organic layers were dried over MgSO 4 _; , filtered and concentrated in vacuo. The residue was taken up in toluene (10 mL) and trimethyl orthoacetate (0.36 g, 3 mmol) was added to the suspension. The reaction mixture was heated to reflux under a nitrogen atmosphere with stirring for 16 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo to give an oily solid. Column chromatography _(CHC1:.:

137

MeOH = 9: 1) a yellow, viscous oil was obtained after removal of the solvent in vacuo (Rf = 0.6, 210 mg, 37% yield).

NMR (CDC1 _3, 300 MHz): 7.15 (d, 1 H, J = 8), 6.9 (d, 1H, J = 1), 6.85 (dd, 1 H, J = 8.1), 3.85 (s, 3H), 2.95 (s, 3H), 2.65 (s, 3H), 2.4 (s, 3H), 2.15 (s, 3H);

CI-HRMS: calcd; 283.1559, found: 283.1554 (M + H).

Example 432

7-Hydroxy-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine (Formula 1 wherein A is CH, R ¹ is Me, R ³ is OH, Z is C -Me, Ar is 2-chloro-4-methylphenyl)

5-Amino-4- (2-chloro-4-methylphenyl) -3-methylpyrazole (1.86 g, 8.4 mmol) was dissolved in glacial acetic acid (30 mL) with stirring. Ethyl acetate (1.18 mL, 9.2 mmol) was then added dropwise to the resulting solution. The reaction mixture is heated at reflux temperature and stirred for 16 hours and then cooled to room temperature. Ether (100 mL) was added and the resulting precipitate was collected by filtration. Drying in vacuo gave a white solid (1.0 g, 42% yield).

NMR (CDC1 _3, 300 Hz): 8.70 (br, 1H), 7.29 (s, 1H), 7.21-7.09 (m, 2H), 5.62 (s, 1 H), 2. 35 (s, 6H); 2.29 (s, 3H); CI-MS: 288 (M + H) < + >.

Example 433

7-Chloro-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine (Formula 1 wherein A is CH, R ¹ is Me, R ³ is Cl, Z is C -Me, Ar is 2-chloro-4-methylphenyl)

138

A mixture of 7-hydroxy-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine (1.0 g, 3.5 mmol), phosphorus oxychloride (2.7 g, 1 , 64 mL, 17.4 mmol), N, N-diethylaniline (0.63 g, 0.7 mL, 4.2 mmol) and toluene (20 mL) were stirred at reflux temperature for 3 hours and then cooled to ambient temperature. temperature. The volatiles were removed in vacuo. Flash chromatography (EtOH / hexane = 1: 2) of the residue gave 7-chloro-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine (900 mg, 84% yield) as a yellow oil. NMR (CDC1 _3, 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, 1H); 3H), 2.45 (s, 3H), 2.40 (s, 3H); CI-MS: 306 (M + H) < + >.

Example 434

7- (pentyl-3-amino) -5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-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 and then cooled to ambient temperature. The reaction mixture was poured into water (100 mL) and stirred. Extract three times with dichloromethane, wash the combined organic layers with brine, dry over MgSO ₄ , filter, and remove the solvent in vacuo to give a yellow solid. Flash chromatography (EtOAc: hexanes - 1: 4) of the residue gave a white solid (140 mg, 60% yield), mp 139-141 ° ^C - NMR (CDCl ₃ , 300 MHz): 7.32 (s, 1H 7.27 (d, 1 H,

J = 8), 7.12 (d, 1 H, J = 7), 6.02 (d, 1 H, J = 9), 5.78 (s, 1 H), 3.50-3.39 (m, 1H), 2.45 (s, 3H), 2.36 (s, 6H), 1.82-1.60 (m, 4H), 1.01 (t, 6H, J = 8); Calc pr © ^C 2 O 4 ^H 25 ^{C1N: C 67 '31'} · ^{H 7 '06 "N} · ^{15" 70} "· ^{le 9' 93"} · ^with J <3ené :: C 67, 32; H, 6.95; N: 15.50; Cl: 9.93.

139

The examples given in Table 2 can be prepared according to the procedures given in Examples ΙΑ, 1B, 432, 433, 434. Generally used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Pr is for example, EtOAc is ethyl acetate.

1-w

Table 2

Pr. FROM £ 1 Aľ ‘ tt. (° C) 435 ^pts C-Me N (CH2CH2OMe) 2 2,4-C 12 ~ Ph 71-73 4 36 ^c C-Me N (Bu) Et 2,4-C12- ^p h 86-87 437 ^d C-Me Let (Et) CH 2 OMe 2,4-C 12 ~? H 110-111 438 ^e C-Me N (? R) CH2CH2CN 2,4-C12-Ph 83-85 4 39 ^f C-Me ΝΗ-3-pentyl 2,4-C12-PH 175-176 4409 C-Me NHCH (CH 2 OMe) 2 2,4-C 12 ~ Ph 107 441h C-Me NHCH (Et) 2 2,4-Me2-Ph oil 442 ¹ C-Me NHCH (CH 2 OMe) 2 2,4-Me 2 "Ph 103-105 4433 C-Me N (CH 2 CH 2 OMe) 2 2,4-Me2-Ph 87-89 444 ^k C-Me N (c-Pr) CH 2 CH 2 CN 2,4-Me 2 ^- Ph 133 (rozkl) 445 ¹ C-Me N (CH 2 CH 2 OMe) 2 2-C1,4-MePh 77-78 4 4 6 ^m C-Me NHCH (CH 2 OMe) 2 2-C1,4-MePh 131-133 447 ⁿ C-Me NHCH (Et) 2 2-C1,4-MePh 139-141 448 ° C-Me SU 12 2,4-Me 2 "Ph 92-94 449P C-Me N (Pr) CH 2 CH 2 CN 2,4-Me 2 "Ph 143-144 4509 C-Me N (Bu) CH 2 CH 2 CN 2,4-Me 2 "Ph 115-117 451 ^r C-Me NHCH (Et) CH 2 OMe 2,4-Me 2 Ph ~ oil 452 ³ C-Me NHCH (Et) 2 2-Me, 4-MeOPh 104-106 453 ^pts C-Me NHCH (CH 2 OMe) 2 2-Me, 4-MeOPh 115-116 454 ^u C-Me N (CH2CH2OMe) 2 2-Me, 4-MeOPh oil 455 ^v C-Me (S) -NHCH (CH2CH2OMe) - (CH 2 OMe) 2-Me, 4-MeOPh oil 456 ^w C-Me (S) -NHCH (CH2CH2OMe) - 2,4-Me 2 "Ph oil

(CH 2 OMe)

Ί <γ4

457 ^χ C-Me N (CH ₂ CH ₂ OMe) ₂ 2-Me, 4-ClPh oil 458 * C-Me NHeT 2,4-Me ₂ -Ph oil 459 ^ζ C-Me NHCH (Et) ₂ 2-Me, 4-ClPh 94-96 4 60 ^aa C-Me NHCH (CH ₂ OMe) ₂ 2-Me, 4-ClPh 113-114 461 ^ab C-Me N (Ac) Et 2,4-Me ₂ -Ph oil 462 ^ac C-Me (S) -NHCH (CH ₂ CH ₂ OMe) - 2-Me, 4-clPh oil • (CH ₂ OMe) 463 ^ad C-Me N (Pr) CH ₂ CH ₂ CN 2-Me, 4-MeOPh 118-119 464 ^ae C-Me NEt ₂ 2-Me, 4-MeOPh 97-99 465 ^af C-Me (S) -NHCH (CH ₂ CH ₂ OMe) - 2-Cl, 4-MePh 101-103 (CH ₂ OMe) 466 ^and 9 C-Me NEt ₂ 2-Cl, 4-MePh 129-130 467 ^ah C-Me N (c-Pr) CH ₂ CH ₂ CN 2-Me, 4-MeOPh 177-178 468 ^{et al} C-Me N (c-Pr) CH ₂ CH ₂ CN 2-Cl, 4-MePh 162-163 469 ^a ) C-Me NHCH (Et) CH ₂ OMe 2-Me, 4-MeOPh oil 470 ^ak C-Me NHCH (Et) CH ₂ OMe 2-Cl, 4-MePh 111-113 471 C-Me NHCH (CH ₂ OMe) ₂ 2-Cl-4-MeOPh 472 C-Me N (CH ₂ CH ₂ OMe) ₂ 2-Cl-4-MeOPh 473 C-Me NHCH (Et) CH ₂ OMe 2-Cl-4-MeOPh 474 C-Me N (c-Pr) CH ₂ CH ₂ CN 2-Cl-4-MeOPh 475 C-Me NEt ₂ 2-Cl-4-MeOPh 476 C-Me ΝΗ-3-pentyl 2-Cl-4-MeOPh 477 C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-Cl-4-MeOPh 478 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-Cl-4-MeOPh 479 C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-Br-4-MeOPh 480 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-Br-4-MeOPh 481 C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-Me-4-MeOPh 482 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-Me-4-MeOPh 483 C-Me NHCH (CH ₂ OMe) ₂ 2-C1-4,5- (MeO) ₂ Ph 484 C-Me N (CH ₂ CH ₂ OMe) ₂ 2-01-4,5- (MeO) ₂ Ph 485 C-Me NHCH (Et) CH ₂ OMe 2-C1-4,5- (MeO) ₂ Ph 486 C-Me N (c-Pr) CH ₂ CH ₂ CN 2-C1-4,5- (MeO) ₂ Ph 487 C-Me NEt ₂ 2-C 1-4 -4- (MeO) ₂ Ph 99-101 488 C-Me ΝΗ-3-pentyl 2-C 1-4 -4- (MeO) ₂ Ph 169-170 489 C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-C1-4,5- (MeO) ₂ Ph

4V2.

490 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-C1-4,5- (MeO) ₂ Ph 491 C-Me NHCH (CH ₂ OMe) 2 2-Br-4 _of 5- (MeO) ₂ Ph 492 C-Me N (CH ₂ CH ₂ OMe) 2 2-Br-4,5- (MeO) 2 Ph 493 C-Me NHCH (Et) CH ₂ OMe 2-Br-4,5- (MeO) 2 Ph 494 C-Me N (c-Pr) CH ₂ CH ₂ CN 2-ΒΓ-4,5- (MeO) ₂ Ph 495 C-Me NEt ₂ 2-Br-4,5- (MeO) ₂ Ph 496 C-Me ΝΗ-3-pentyl 2-Br-4,5- (MeO) ₂ Ph 497 C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-Br-4,5- (MeO) ₂ Ph 49J C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-Br-4,5- (MeO) 2 Ph 499 C-Me NHCH (CH ₂ OMe) 2 2-C1-4,6- (MeO) ₂ Ph 500 C-Me N (CH ₂ CH ₂ OMe) 2 2-C1-4,6- (MeO) ₂ Ph 501 C-Me NHCH (Et) CH ₂ OMe 2-C1-4,6- (MeO) ₂ Ph 502 C-Me N (c-Pr) CH 2 CH 2 CN 2-C1-4,6- (MeO) 2 Ph 503 C-Me NEt ₂ 2-C1-4,6- (MeO) ₂ Ph 504 C-Me ΝΗ-3-pentyl 2-C1-4,6- (MeO) ₂ Ph 505 C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-C1-4,6- (MeO) ₂ Ph 506 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-C1-4,6- (MeO) ₂ Ph 507 C-Me NHCH (CH ₂ OMe) 2 2-Me-4,6- (MeO) 2 Ph 508 C-Me, N (CH ₂ CH ₂ OMe) 2 2-Me-4,6- (MeO) ₂ Ph 509 C-Me NHCH (Et) CH ₂ OMe 2-Me-4,6- (MeO) ₂ Ph 510 C-Me N (c-Pr) CH ₂ CH ₂ CN 2-Me-4,6- (MeO) ₂ Ph 511 C-Me NEt ₂ 2-Me-4,6- (MeO) 2 Ph ⁵¹² C-Me ΝΗ-3-pentyl 2-Me-4,6- (MeO) ₂ Ph 513 C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-Me-4,6- (MeO) ₂ Ph 514 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-Me-4,6- (MeO) ₂ Ph 515 C-Me N (c-Pr) CH ₂ CH ₂ CN 2-Br-4,6- (MeO) ₂ Ph 516 C-Me NEt ₂ 2-Br-4,6- (MeO) 2 Ph 517 C-Me ΝΗ-3-pentyl 2-Br-4,6- (MeO) ₂ Ph 518 crme NHCH (Et) CH ₂ CH ₂ OMe 2-Br-4,6- (MeO) ₂ Ph 519 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-Br-4,6- (MeO) ₂ Ph 520 C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-Me-4-MeOPh 521 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-Me-4-MeOPh 522 C-Me NHCH (CH ₂ OMe) ₂ 2-MeO-4-MePh 523 C-Me N (CH ₂ CH ₂ OMe) 2 2-MeO-4-MePh 524 C-Me NHCH (Et) CH 2 OMe 2-MeO-4-MePh 525 C-Me N (c-Pr) CH ₂ CH ₂ CN 2-MeO-4-MePh

526 C-Me NEt ₂ 2-MeO-4-MePh 527 C-Me ΝΗ-3-pentyl 2-MeO-4-MePh 528 C-Me NHCH (Et) CH2CH2OMe 2-Me0-4-MePh 529 C-Me NHCH (Me) CH2CH2OMe 2-MeO-4-MePh 530 C-Me NHCH (CH ₂ OMe) 2 2-MeO-4-MePh 531 C-Me N (CH2CH2OMe) 2 2-MeO-4-MePh 532 C-Me NHCH (Et) CH 2 OMe 2-MeO-4-MePh 533 C-Me N (c-Pr) CH2CH2CN 2-MeO-4-MePh 534 C-Me NEt 2 2-MeO-4-MePh 535 C-Me ΝΗ-3-pentyl 2-Me0-4-MePh 536 C-Me NHCH (Et) CH2CH2OMe 2-MeO-4-MePh 537 C-Me NHCH (Me) CH2CH2OMe 2-MeO-4-MePh 538 C-Me NHCH (CH 2 OMe) 2 2-MeO-4-ClPh 539 C-Me N (CH2CH2OMe) 2 2-MeO-4-ClPh 540 C-Me NHCH (Et) CH 2 OMe 2-MeO-4-ClPh 541 C-Me N (c-Pr) CH2CH2CN 2-MeO-4-ClPh 542 C-Me NEt 2 2-Me0-4-ClPh 543 C-Me ΝΗ-3-pentyl 2-MeO-4-ClPh 544 C-Me NHCH (Et) CH2CH2OMe 2-MeO-4-ClPh 545 C-Me NHCH (Me) CH2CH2OMe 2-MeO-4-ClPh

Notes for Table 2:

b) CI-HRMS: Calcd .: 423.1355; found: 423.1337 (M + H).

C) Analysis: C 61.38, H, 6.18. N, 14.32; found: C, 61.54, H, 6.12, N, 14.37. d) Analysis: c. 58.02, H, 5.65. N, 14.24; found; ^c > 58.11, H, 5.52, N, 14.26. e) Analysis: calculated: c. 59.71, H, 5.26. N, 14.85; found: C, 59.94, H, 5,09, N, 17.23. f) Analysis: c. 60.48, H, 5.89. N, 14.85; found: c, 60.62, H, 5.88, N, 14.82.

h) CI-HRMS: Calcd .: 337.2388; found: 337.2392 (M + H).

i)

j)

k)

D

m)

n)

about)

P)

q)

r)

with)

t)

u)

in)

w)

x)

y)

from)

Analysis: calculated: C, 68.45. H, 7.669, N, 15.21; found: C, 68.35, H, 7.49. N, 14.91. Analysis: calculated: C, 69.08. H, 7.915, N, 14.65; found: C, 68.85, H, 7.83. N, 14.54. Analysis: Calculated: C, 73.51. H, 7.01, N, 19.48; found: C, 71.57, H, 7.15. N, 19.12. CI-HRMS: Calcd .: 40 3.1899; found: 40 > 3.1901 (M + H) +. Analysis: Calculated: C, 61.77. H, 6.49, N, 14.41. Cl, 9.13; found: C, 61, 90, H, 6.66, N, 1 .3,6 12, Cl, 9.25 Analysis: Calculated: C, 67.31. H, 7.06, N, 15.70. Cl, 9.93; found: C, 67, 32, H, 6.95, N, 1 .5,5 0, Cl, 9.93 Analysis: calculated; 74.50. H, 8.14, N, 17.38; Found: C, 74.43, H, 7.59. N, 17.16. Analysis: calculated: C, 73.10. H, 7.54, N, 19.37; Found: C, 73.18, H, 7.59. N, 18.81. Analysis: Calculated: C, 73.57. H, 7.78, N, 18.65; Found: C, 73.55, H, 7.79. N, 18.64. CI-HRMS: Calcd .: 35 3.2333; found ;; 3Ξ > 3.2341 (M + H) +. Analysis: calculated: c, 71.56. H, 8.02, N, 15.90; Found: C, 71.45, H, 7.99. N, 15.88. Analysis: Calculated: C, 65.60. H, 7.34, N, 14.57; Found: C, 65.42, H, 7.24. N, 14.37.

CI-HRMS: Calcd .: 399.2398; ^Found: 399.2396 (M + H).

CI-HRMS: Calcd .: 399.2398; found :; 399.2396 (M + H).

CI-HRMS: Calcd .: 383.2450; found :; 383.2447 (M + H).

CI-HRMS: calcd: 403.1887, found: j: 403.1901 (M + H).

CI-HRMS: Calcd .: 295.1919; found: 295.1923 (M + H).

Analysis calculated: c, 67.31, H, 7.06, N, 15.70; Found: C, 67.12, H, 6.86, N, 15.53.

aa) Analysis. calculated: c, 61.77. H, 6.49, N, 14.41. Cl, 9.13; Found: C, 62, 06, H, 6.37, N, 14.25, Cl, 9.12 ab) CI-HRMS: Calcd .: 337.2017; found: : 337,2088 (M + H) +. and c) CI-HRMS: Calcd .: 403.1893; found : 403.1901 (M + H) +. and d) Analysis: calculated: C, 70.00. H, 7.22, N, 18.55; found; C, 70.05, H, 7.22. N, 18.36. ae) Analysis: calculated: C, 70,98, H, 7.74, N, 16.55; found; C, 71.15, H, 7.46. N, 16.56. ag) Analysis: calculated: C, 66.59. H, 6.76, N, 16.34; found ;; C, 66.69, H, 6.82. N, 16.20. ah) Analysis: calculated: C, 70.38. H, 6.71, N, 18.65; found: C, 70.35, H, 6.82. N, 18.83. ai) Analysis: calculated: C, 66.39. H, 5.85, N, 18.44. Cl, 9.33; Found: C, 66, 29, H, 5.51, N, 18.36, Cl, 9.31 aj) CI-HRMS: Calcd .: 369.2278; found : 369,2291 (M + H) +. if) Analysis: calculated: C, 64.42. H, 6.77, N, 15.03; found: c, 64.59, H, 6.51. N, 14.81.

The examples given in Table 3 can be prepared according to the procedures outlined in Examples 1, 2, 3 or 6. Generally used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Pr is example.

Table 3

P r. FROM bi 546 ^a C-Me NHCH (Et) 2 2-Me-4-Me 2 N-Ph 547 ^pts C-Me S-NHCH (CH2CH2OMe) 2,4-Me2-Ph -CH2OMe 548 ^c C-Me S-NHCH (CH2CH2OMe) 2-Me-4-Cl-Ph -CH20Me 549 ^d C-Me N (c-Pr) CH 2 CH 2 CN 2-Me-4-Cl-Ph

tt. (° q

164-166 oil oil

115-116

550 ^e C-Me NHCH (Et) CH ₂ CN 2-Me-4-Cl-Ph 131-132 551 ^f C-Me N (Et) ₂ 2,3-Me ₂ -4-OMe-Ph oil 5529 C-Me N (CH ₂ CH ₂ OMe) CH ₂ CH ₂ OH 2,4-Cl ₂ -Ph oil 553 ^h C-Me N (CH ₂ CH ₂ OMe) ₂ 2,3-Me ₂ -4-OMe-Ph oil 554 ¹ C-Me NHCH (Et) ₂ 2,3-Me ₂ -4-OMePh 123-124 555 j C-Me N _(CH2-c-Pr) Pr 2-Me-4-Cl-Ph oil 556 ^k C-Me N (c-Pr) CH ₂ CH ₂ CN 2,3-Me ₂ -4-OMePh 158-160 557 C-Me N (c-Pr) Et 2-Cl-4-OMePh 558 C-Me N (c-Pr) Me 2-Cl-4-OMePh 559 C-Me N (c-Pr) Pr 2-Cl-4-OMePh 560 C-Me N (c-Pr) Bu 2-Cl-4-OMePh 561 ¹ C-Me N (Et) 2 2-Cl-4-CN-Ph 115-117 562 C-Me N (c-Pr) 2 2-Cl-4-OMe 127-129 563 ^m C-Me NHCH (CH 2 OH) 2 2,4-Cl ₂ -Ph 128-129 564 C-Me N (c-Pr) Et 2-Br ~ 4,5- (MeO) 2 Ph 565 C-Me N (c-Pr) Me 2-Br-4,5- (MeO) 2 Ph 566 C-Me NH-c-Pr 2-Me-4-MeOPh 126-128 567 C-Me NHCH (E e) CH 2 OH 2-Me-4-MeOPh 60-62 568 C-Me NMe ₂ 2-Br-4,5- (MeO) 2 Ph 569 C-Me NHCH (Et) 2 2-Me-4-MeOPh 103-105 570 C-Me N (c-Pr) Et 2-Me-4-MeOPh 173-174 571 C-Me ΝΗ-2-pentyl 2,4-Cl ₂ -Ph 118-120 572 C-Me NHCH (Et) CH 2 CN 2,4-Cl ₂ -Ph 141-1'42 573 C-Me NHCH (Pr) CH 2 OMe 2,4-Cl ₂ -Ph 87-88 574 C-Me NHCH (CH2-iPr) 2 OMe 2,4-Cl ₂ -h amorphous. 575 C-Me ΝΗ-2-butyl 2,4-Me ₂ -Ph oil 576 C-Me ΝΗ-2-pentyl 2,4-Me ₂ -Ph oil 577 C-Me ΝΗ-2-hexyl 2,4-Me ₂ -Ph oil 578 C _r Me NHCH (i-Pr) Me 2,4-Me ₂ -Ph oil 579 C-Me NHCH (Me) CH2-iPr 2,4-Me ₂ -Ph oil 580 C-Me NHCH (Me) -C-C6H11 2,4-Me ₂ -Ph > oil 581 C-Me ΝΗ-2-indanyl 2,4-Me ₂ -Ph oil> 582 C-Me NH-l-indanyl 2,4-Me ₂ -Ph oil 583 C-Me NHCH (Me) Ph 2,4-Me ₂ -Ph oil 584 C-Me NHCH (Me) CH ₂ - (4-ClPh) 2,4-Me ₂ -Ph oil

585 C-Me NHCH (Me) CH 2 CO ₃ 2,4-Me ₂ -Ph oil 586 C-Me NHCH (Ph) CH ₂ Ph 2,4-Me ₂ -Ph oil 587 C-Me NHCH (Me) (CH ₂ ) 3 NEt ₂ 2,4-Me ₂ -Ph oil 588 C-Me NH- (2-Ph-c-C 3 H 4) 2,4-Me ₂ -Ph oil 589 C-Me NHCH (Et) CH ₂ CN 2,4-Me ₂ -Ph 119-120 590 C-Me ΝΗ-3-hexyl 2,4-Me ₂ -Ph oil 591 ⁿ C-Me NEt ₂ 2-MeO-4-CLPR oil 592 ° C-Me NHCH (Et) 2 2-MeO-4-ClPh oil 59; P C-Me NHCH (Et) CH ₂ OMe 2-MeO-4-ClPh oil 594 C-Me NMe ₂ 2-MeO-4-ClPh oil 5959 C-Me NHCH (Et) 2 2-OMe-4-MePh oil 596 ^r C-Me NEt ₂ 2-OMe-4-MePh oil 597S C-c-Pr NHCH (CH ₂ OMe) ₂ 2,4-Cl ₂ -Ph oil 598 C-Me N (c-Pr) Et 2,4-Me ₂ -Ph 599 C-Me N (c-Pr) Et 2,4-Cl ₂ -Ph 600 C-Me N (c-Pr) Et 2,4,6-Me3 ~ Ph 601 C-Me N (c-Pr) Et 2-Me-4-Cl-Ph 602 C-Me N (c-Pr) Et 2-Cl-4-Me-Ph 603 C-Me NHCH (c-Pr) 2 2,4-Cl ₂ -Ph 604 C-Me NHCH (c-Pr) ₂ 2,4-Me ₂ -Ph 605 C-Me NHCH (c-Pr) 2 2-Me-4-Cl-Ph 606 C-Me NHCH (c-Pr) ₂ 2-Cl-4-Me-Ph 607 C-Me NHCH (c-Pr) 2 2-Me-4-OMe-Ph 608 C-Me NHCH (c-Pr) ₂ 2-Cl-4-OMe-Ph 609 C-Me NHCH (CH ₂ OMe) ₂ 2-Cl-5-F-OMePh 610 C-Me NEt ₂ 2-Cl-5-F-OMePh 611 C-Me N (c-Pr) CH ₂ CH ₂ CN 2-Cl-5-F-OMePh 612 C-Me NHCH (Et) ₂ 2-Cl-5-F-OMePh 613 C-Me N (CH ₂ CH ₂ OMe) ₂ 2-Cl-5-F-OMePh 614 C-Me NEt ₂ 2,6-Me ₂ -pyrid-3-yl 615 C-Me N (c-Pr) CH ₂ CH ₂ CN 2,6-Me ₂ -pyrid-3-yl 616 C-Me NHCH (Et) ₂ 2,6-Me ₂ ^- pyrid-3-yl 617 C-Me N (CH ₂ CH ₂ OMe) ₂ 2,6-Me ₂ -pyrid-3-yl 618 C-OH NHCH (CH ₂ OMe) ₂ 2,4-Me ₂ -Ph 619 C-OH NEt ₂ 2,4-Me ₂ -Ph 620 C-OH N (c-Pr) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph ·

621 C-OH NHCH (Et) ₂ 2,4-Ph _2-Me 623 C-OH N (CH ₂ CH ₂ OMe) 2 2,4-Me ₂ -Ph 624 C-NEt ₂ NHCH (CH ₂ OMe) ₂ 2,4-Me ₂ -Ph 625 C-NEt ₂ NEt ₂ 2,4-Me ₂ -Ph 626 C-NEt ₂ N (c-Pr) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph 627 C-NEt ₂ NHCH (Et) 2 2,4-Ph _2-Me 628 C-NEt ₂ N (CH ₂ CH ₂ OMe) 2 2,4-Me ₂ -Ph 629 C-Me NHCH (Et) 2 2-Me-4-CN-Ph 63J C-Me N (CH ₂ CH ₂ OMe) ₂ 2-Me-4-CN-Ph

Notes on Table 3 ·

a) CI-HRMS: Calcd .: 367.2610, Found: (M + H); 367.2607 b) CI-HRMS: Calcd: ^{384 "Highlights 2400} J ^The tried :: (M + H); 384.2393 c) CI-HRMS: Calcd: ^{404 "in 1853,} found: ^(M + H); 404.1844 d) CI-HRMS: Calcd .: 381.1594, Found: (M + H); : 381.1596 Analysis: Calculated: C, 63.07, H, 5.57, N, 22.07, Cl, 9.32; Found: C, 63.40, H, 5.55, N, 21.96, Cl, 9.15 e) CI-HRMS: Calcd .: 369.1594, found: (M + H); : 369.1576 f) CI-HRMS: Calcd .: 354.2216, found; (M + H); : 354,2211 g) CI-HRMS: Calcd .: 410.1072, found (M + H); ; 410.1075 h) CI-HRMS: Calcd .: 414.2427, Found (M + H); : 414,2427 i) CI-HRMS: Calcd .: 368.2372, found: (M + H); : 368,2372 j) CI-HRMS: Calcd .: 384.1955, found (M + H); _; 384.1947 k) CI-HRMS: Calcd .: 391.2168, found (M + H); : 391,2160

1oo

l) CI-HRMS: calcd: 335.1984, found: 335.1961 '(M + H);

m) CI-HRMS: calcd: 382.0759, found: 382.0765 (M + H);

n) NH ₃ -CI MS: calcd: 360, Found: 360 (M + H) ⁺ ;

O) NH ₃ -CI MS: Calculated: 374, Found: 374 (M + H) ⁺ ;

NMR (CDC1 _3, 300 MHz): δ 7.29 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 8 8 Hz, 1 H), 6.96 (d, J = 8Hz, 1H), 6.15 (d, J = 10, 1H), 4.19 (m, 1H), 3.81 (s, 3H), 2.47 (s, 3H),

2.32 (s, 3H), 1.65 (m, 4H), 0.99 (t, J = 7.32Hz, 6H).

p) NH ₃ -CI MS: calcd: 390, Found: 390 (M + H) ⁺ ;

NMR (CDC1 _3, 300 MHz): δ 7.28 (d, J = 8 Hz, 1H), 7.03 (d,

J = 8Hz, 1H), 6.96 (s, 1H), 6.52 (d, J = 9Hz, 1H), 4.36 (m, 1H), 3.8 (s, 3H), 3.55 (m, 2H), 3.39 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H), 1.76 (m, 2H), 1.01 (t,

J = 7.32Hz, 3H).

q) CI-HRMS: Calc'd: 354.2294, Found: 354.2279 (M + H) ⁺ ;

r) CI-HRMS: calculated; 340.2137, Found: 340.2138 (M + H) ⁺ ;

s) CI-HRMS: calcd: 436.1307, Found, 436.1296 (M + H) ⁺ ;

The examples given in Table 4 can be prepared according to the procedures given in Examples ΙΑ, 1B, 432, 433, 434. Generally used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Pr is for example, EtOAc is ethyl acetate.

151 Table 4

Pr- from Rr Δχ ______H. (° C)

631 C-Me NHCH (Et) 2 2-Br-4,5- (MeO) 2 Ph 160-161 632 C-Me NHCH (Et) ₂ 2-Br-4-MeOPh 110-111 633 C-Me N (CH2CH2OMe) 2 2-Br-4-MeOPh 74-76 634 C-Me NHCH (CH20Me) 2 2-Br-4-MeOPh 128-130

45λ

635 C-Me N (Et) ₂ 2-Me-4-ClPh 636 C-Me N (c-Pr) Et 2,4-Cl ₂ Ph 537 C-Me N (c-Pr) Et ' 2,4-Me ₂ Ph 638 C-Me N (c-Pr) Et 2,4,6-Me ₃ Ph 639 C-Me N (c-Pr) Et 2-Me-4-MeOPh 640 C-Me N (c-Pr) Et 2-Cl-4-MeOPh 641 C-Me N (c-Pr) Et • 2-Cl-4-MePh 642 C-Me N (c-Pr) Et 2-Me-4-ClPh 643 C-Me NHCH (c-Pr) ₂ 2,4-Cl ₂ -Ph 644 C-Me NHCH (c-Pr) ₂ 2,4-Me ₂ -Ph 64 5 C-Me NHCH (c-Pr) ₂ 2-Me-4-Cl-Ph 646 C-Me NHCH (c-Pr) 2 2-Cl-4-Me-Ph 647 C-Me NHCH (c-Pr) ₂ 2-Me-4-OMe-Ph 648 C-Me NHCH (c-Pr) ₂ 2-Cl-4-OMe-Ph 649 C-Me NHCH (CH ₂ OMe) ₂ 2-C1-5-F-OMePh 650 C-Me NEt ₂ 2-Cl-5-F-OMePh 651 C-Me N (c-Pr) CH ₂ CH ₂ CN 2-Cl-5-F-OMePh 652 C-Me NHCH (-Et) ₂ 2-Cl-5-F-OMePh 653 C-Me N (CH ₂ CH ₂ OMe) ₂ 2-Cl-5-F-OMePh 654 C-Me NEt ₂ 2,6-Me ₂ -pyrid-3-yl 655 C-Me N (c-Pr) CH ₂ CH ₂ CN 2,6-Me 2 ~ pyridin-3-yl 656 C-Me NHCH (Et) 2 2,6-Me ₂ -pyrid-3-yl 657 C-Me N (CH ₂ CH ₂ OMe) ₂ 2,6-Me 2 ^- pyridin-3-yl 658 C-OH NHCH (CH ₂ OMe) ₂ 2,4-Me ₂ -Ph 659 C-OH NEt ₂ 2,4-Me ₂ -Ph 660 C-OH N (c-Pr) CH ₂ CH ₂ CN 2,4-Me 2 "Ph 661 C-OH NHCH (Et) ₂ 2,4-Me 2 Ph ~ 662 C-OH N (CH ₂ CH ₂ OMe) ₂ 2,4-Me 2 "Ph 663 C-NEt ₂ NHCH (CH ₂ OMe) ₂ 2,4-Me 2 Ph ~ 664 C-NEt 2 NEt 2 2,4-Me 2 "Ph 665 C-NEt 2 N (c-Pr) CH ₂ CH ₂ CN 2,4-Me 2 Ph ~ 666 C-NEt ₂ NHCH (Et) ₂ 2,4-Me ₂ -Ph 667 C-NEt ₂ N (CH ₂ CH ₂ OMe) ₂ 2,4-Me 2 Ph ~ 668 C-Me NHCH (Et) 2 2-Me-4-CN-Ph 669 C-Me N (CH ₂ CH ₂ OMe) ₂ 2-Me-4-CN-Ph

- 453 The examples given in Table 5 or 6 can be prepared according to the procedures given in Examples ΙΑ, 1B, 2,

3 6 431

432 433

434 or suitable combinations thereof. Commonly used abbreviations are:

Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl,

Bu is butyl, Pr is an example.

Table 5

I'r. Bjlä bi Ar 670 Me NHCH (CH 2 OMe) 2 2,4-Cl ₂ -Ph 671 Me NHCHPr2 2,4-Cl ₂ -Ph 672 Me NetBt 2,4-C12-Ph 673 Me NPr (CH2-C-C3H5) 2,4-C12-Ph 674 Me N (CH ₂ CH ₂ OMe) ₂ 2,4-C12-PH 675 Me ΝΗ-3-heptyl 2,4-C12-Ph 676 Me NHCH (Et) CH 2 OMe 2,4-Cl ₂ -Ph 677 Me NEt 2 2,4-C12-Ph 678 Me -NHCH (CH 2 OEt) 2 2,4-C12-P6 679 Me ΝΗ-3-pentyl 2,4-C 12 ~ Ph 680 Me NMePhe 2,4-C12-Ph 681 Me NPr2 2,4-C12-Ph 682 Me ΝΗ-3-hexyl 2,4-C 12 ~ Ph 683 Me morpholino 2,4-C12-PH

4-NO

664 Me N (CH 2 Ph) CH2CH2OMe 2,4-C 12 ~ Ph 685 Me NHCH (CH 2 Ph) CH 2 OMe 2,4-C 12 ~ Ph 686 Me ΝΗ-4-tetrahydropyranyl 2,4-C12Ph 687 Me NH-cyclopentyl 2,4-Cl ₂ -Ph 688 Me OEt 2,4-Cl ₂ -Ph 689 Me OCH (Et) CH 2 OMe 2,4-C 12 ~ Ph 690 Me OCH2Ph 2,4-Cl ₂ -Ph 691 Me Ο-3-pentyl 2,4-C12-Ph 692 Me Set 2,4-C12-Ph 693 Me S (0) Et 2,4-C 12 ~ Ph 694 Me SO2E 2,4-C 12 ~ Ph 695 Me ph 2,4-C 12 ~ Ph 696 Me 2-CP3-Ph 2,4-C 12 ~? H 697 Me 2-Ph-Ph 2,4-C12-Ph 698 Me 3-pentyl 2,4-C 12 ~ Ph 699 Me cyclobutyl 2,4-C12-Ph 700 Me 3-pyridyl 2,4-Cl ₂ -Ph 701 Me CH (Et) CR2Ct »NMe2 ' 2,4-C12-Ph 702 Me CH (Et) CH2CH2NMe2 2.4-C12 “Ph. 703 Me NHCH (CH 2 OMe) 2 2,4,6-Me ₃ -Ph 704 Me NHCHPr2 2,4,6-Me ₃ -Ph 705 Me NetBt 2,4,6-Me ₃ -Ph 706 Me NPr (CH2-C-C3H5) 2,4,6-Me ₃ -Ph 707 Me N (CH 2 CH 2 OMe) 2 2,4,6-Me ₃ -Ph 708 Me ΝΗ-3-heptyl 2,4,6-Me ₃ -Ph 709 Me NHCH (Et) CH 2 OMe 2,4,6-Me ₃ -Ph 710 Me NEt 2 2,4,6-Me ₃ -Ph 711 Me -NHCH (CH 2 O £ t) 2 2,4,6-Me ₃ -Ph 712 Me ΝΗ-3-pentyl 2,4,6-Me ₃ -Ph 713 Me NMePhe 2,4,6-Me ₃ -Ph 714 Me NPr2 2,4,6-Me ₃ -Ph 715 Me ΝΗ-3-hexyl 2,4,6-Me ₃ -Ph 716 Me morpholino 2,4,6-Me ₃ -Ph 717 Me N (CH 2 Ph) CH2CH2OMe 2,4,6-Me ₃ -Ph 718 Me NHCH (CH 2 Ph) CH 2 OMe 2,4,6-Me ₃ -Ph 719 Me ΝΗ-4-tetrahydropyranyl 2,4,6-Me ₃ -Ph

720 Me NH-cyclopentyl 2,4,6-Me3 ~ Ph 721 Me OEt 2,4,6-Me3 ~ Ph 722 Me OCH (Et) CH ₂ OMe 2,4,6-Me3-Ph 723 Me OCH ₂ Ph 2,4,6-Me3-Ph 724 Me Ο-3-pentyl 2,4,6-Me3 ~ Ph 72S Me • ' Set 2,4,6-Me3 ~ Ph 726 Me S (O) Et, 2,4,6-Me3 ~ Ph 727 Me SO ₂ Et 2,4,6-Me3-Ph 728 Me CH (CO ₂ Et) 2 2,4,6-Me3 ~ Ph 729 Me C (Et) (CO ₂ Et) ₂ 2,4,6-Me3 ~ Ph 730 Me CH (Et) CH ₂ OH 2,4,6-Me3 ~ Ph 731 Me CH (Et) CH ₂ OMe 2,4,6-Μθ3-Ρίι 732 Me CONMe ₂ 2,4,6-Me3-Ph 733 Me COCH3 2,4,6-Me3 ~ Ph 734 Me CH (OH) CH 3 2,4,6-Me3-Ph 735 Me C (OH) Ph-3-pyridyl 2,4,6-Me3-Ph 736 Me ph 2,4,6-Me3 ~ Ph 737 Me 2-Ph-Ph * 2,4,6-Me3-Ph 738 Me 3-pentyl 2,4,6-Me3 ~ Ph 739 Me cyclobutyl 2,4,6-Me3 ~ Ph 740 Me 3-pyridyl 2,4,6-Me3-Ph 741 Me CH (Et) CH ₂ CO ₂ Me ₂ 2,4,6-Me3 ~ Ph 742 Me CH (Et) CH ₂ CH ₂ NMe ₂ 2,4,6-Me3-Ph 743 Me NHCH (CH 2 OMe) 2 2,4-Me ₂ -Ph 744 Me N (CH ₂ CH ₂ OMe) 2 2,4-Me ₂ -Ph 745 Me NHCH (Et) CH ₂ OMe 2,4-Me ₂ -Ph 746 Me ΝΗ-3-pentyl 2,4-Me ₂ -Ph 747 Me NEt ₂ 2,4-Me ₂ -Ph 748 Me N (CH ₂ CN) 2 2,4-Me ₂ -Ph 749 Me NHCH (Me) CH ₂ OMe 2,4-Me ₂ -Ph 750 Me OCH (Et) CH ₂ OMe 2,4-Me ₂ -Ph 751 Me NPr-c-C3H5 2,4-Me ₂ -Ph 752 Me NHCH (Me) CH ₂ NMe ₂ 2,4-Me ₂ -Ph 753 Me N (C-C ₃ H ₅ ) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph 754 Me N (Pr) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph 755 Me N (Bu) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph

156 -

756 Me NHCHPr ₂ 2,4-Me 2 Ph ~ 757 Me NetBt 2,4-Me 2 Ph ~ 758 Me NPr (CH2-C-C3H5) 2,4-Me2-Ph 759 Me ΝΗ-3-heptyl 2,4-Me 2 Ph ~ 760 Me NEt ₂ 2,4-Me 2 Ph ~ 761 Me -NHCH (CH 2 OEt) 2 2, 4-Me ₂ -Ph 762 Me ΝΗ-3-pentyl 2,4-Me2-Ph 763 Me NMePhe 2,4-Me 2 Ph ~ 764 Me NPr ₂ 2,4-Me 2 Ph ~ 765 Me ΝΗ-3-hexyl 2,4-Me ₂ -Ph 766 Me morpholino 2,4-Ph _2-Me 767 Me N (CH ₂ Ph) CH ₂ CH ₂ OMe 2,4-Me 2 Ph ~ 768 Me NHCH (CH ₂ Ph) CH ₂ OMe 2,4-Me 2 Ph ~ 769 Me NH-4-tetrahydropyranyl 2,4-Me ₂ -Ph 770 Me NH-cyclopentyl 2,4-Me ₂ -Ph 771 Me NHCH (CH 2 OMe) 2 2-Me-4-MeO-Ph 772 Me N (CH ₂ CH ₂ OMe) 2 2-Me-4-MeO-Ph 773 Me NHCH (Et) CH ₂ OMe 2-Me-4-MeO-Ph 774 Me. N (Pr) CH ₂ CH ₂ CN 2-Me-4-MeO-Ph 775 Me OCH (Et) CH ₂ OMe 2-Me-4-MeO-Ph 776 Me NHCH (CH ₂ OMe) ₂ 2-Br-4-MeO-Ph 777 Me N (CH ₂ CH ₂ OMe) 2 2-Br-4-MeO-Ph 778 Me NHCH (Et) CH 2 OMe 2-Br-4-MeO-Ph 779 Me N (Pr) CH ₂ CH ₂ CN 2-Br-4-MeO-Ph 780 Me OCH (Et) CH ₂ OMe 2-Br-4-MeO-Ph 781 Me NHCH (CH ₂ OMe) 2 2-Me-4-NMe ₂ -Ph 782 Me N (CH2CH2OMe) 2 2-Me-4-NMe ₂ -Ph 783 Me NHCH (Et) CH ₂ OMe 2-Me-4-NMe ₂ -Ph 784 Me N (Pr) CH ₂ CH ₂ CN 2-Me-4-NMe ₂ -Ph 785 Me OCH (Et) CH ₂ OMe 2-Me-4-NMe ₂ -Ph 786 Me NHCH (CH ₂ OMe) 2 2-Br-4-NMe2-Ph 787 Me N (CH2CH2OMe) 2 2-Br-4-NMe ₂ -Ph 788 Me NHCH (Et) CH 2 OMe 2-Br-4-NMe ₂ -Ph 789 Me N (Pr) CH ₂ CH ₂ CN 2-Br-4-NMe2 ~ Ph 790 Me OCH (Et) CH ₂ OMe 2-Br-4-NMe ₂ -Ph 791 Me NHCH (CH ₂ OMe) ₂ 2-Br-4-iPr-Ph

792 Me N (CH2CH2OMe) 2 2-Br-4-iPr-Ph 793 Me NHCH (Et) CH 2 OMe 2-Br-4-iPr-Ph 794 Me N (Pr) CH2CH2CN 2-Br-4-iPr-Ph 795 Me OCH (Et) CH 2 OMe 2-Br-4-iPr-Ph 796 Me NHCH (CH 2 OMe) 2 2-Br-4-Me ~ Ph 797 Me N (CH ₂ CH ₂ OMe) 2 2-Br-4-Me-Ph 798 Me NHCH (Et) CH 2 OMe. 2-Br-4-Me-Ph 799 Me N (Pr) CH2CH2CN 2-Br-4-Me-Ph 8 C ϋ- Me OCH (Et) CH 2 OMe 2-Br-4-Me-Ph δΟΙ Me NHCH (CH 2 OMe) 2 2-Me-4-Br-Ph 802 Me N (CH2CH2OMe) 2 2-Me-4-Br-Ph 803 Me NHCH (Et) CH 2 OMe 2-Me-4-Br-Ph 804 Me N (Pr) CH 2 CH 2 CN 2-Me-4-Br-Ph 805 Me OCH (Et) CH ₂ OMe 2-Me-4-Br-Ph 806 Me NHCH (CH 2 OMe) 2 2-C1-4,6-Me2 ~ Ph 807 Me N (CH2CH2OMe) 2 2-C1-4,6-Me2-Ph 808 Me NHCH (CH 2 OMe) 2 4-Br-2,6- (Me) 2-Ph 809 Me N (CH2CH2OMe) 2 4-Br-2,6- (Me) 2 "Ph 810 Me NHCH (CH 2 OMe) 2 4-i-Pr-2-SMe-Ph 811 Me N (CH2CH2OMe) 2 4-i-Pr-2-SMe-Ph 812 Me NHCH (CH 2 OMe) 2 2-Br-4-CF 3 Ph ~ 813 Me N (CH2CH2OMe) 2 2-Br-4-CF3-Ph 814 Me NHCH (CH 2 OMe) 2 2-Br ~ 4,6- (MeO) 2-Ph 815 Me N (CH2CH2OMe) 2 2-Br-4,6- (MeO) 2-Ph 816 Me NHCH (CH 2 OMe) 2 2-C1-4,6- (MeO) 2 "Ph 817 Me N (CH2CH2OMe) 2 2-C1-4,6- (MeO) ₂ -Ph 818 Me NHCH (CH 2 OMe) 2 2,6- (Me) 2-4-SMe-Ph 819 Me N (CH2CH2OMe) 2 2,6- (Me) 2-4-SMe-Ph 820 Me NHCH (CH 2 OMe) 2 4- (COMe) -2-Br-Ph 821 Me N (CH2CH2OMe) 2 4- (COMe) -2-Br-Ph 822 Me NHCH (CH 2 OMe) 2 2,4,6-Me3 ~ pyridin-3-yl 823 Me N (CH2CH2OMe) 2 2,4,6-Me3 ~ pyridin-3-yl 824 Me NHCH (CH 2 OMe) 2 2,4 (Br) 2-Ph 825 Me N (CH2CH2OMe) 2 2,4 (Br) 2 "Ph 826 Me NHCH (CH 2 OMe) 2 4-i-Pr-2-SMe-Ph 827 Me N (CH2CH2OMe> 2 4-i-Pr-2-SMe-Ph

458

828 Me NHCH (CH ₂ OMe) 2 4-i-Pr-2-SO2 Me-Ph 829 Me N (CH2CK2OMe) 2 4-i-Pr-2-SO2 Me-Ph 830 Me NHCH (CH ₂ OMe) ₂ 2,6- (Me) 2-4-SMe-Ph 831 Me N (CH ₂ CH ₂ OMe) ₂ 2,6- (Me) ₂ -4-SMe-Ph 832 Me NHCH (CH ₂ OMe) 2 2,6- (Me) 2-4-SO ₂ Me-Ph 833 Me N (CH ₂ CH ₂ OMe) 2 2,6- (Me) 2-4-SO 2 Me-Ph 834 Me NHCH (CH ₂ OMe) ₂ 2-I-4-i-Pr-Ph 835 Me N (CH2CH2OMe) 2 2-1-4-i-Pr-Ph 835 Me NHCH (CH ₂ OMe) 2 2-Br-4-N (Me) 2-6-MeO-Ph 837 Me. N (CH ₂ CH ₂ OMe) ₂ 2-Br-4-N (Me) 2-6-MeO-Ph 838 Me NEt ₂ 2-Br-4-MeO-Ph 839 Me ΝΗ-3-pentyl 2-Br-4-MeO-Ph 840 Me NHCH (CH ₂ OMe) ₂ 2-CN-4-Me-Ph 841 M e N (C-C 3 H 5) CH 2 CH 2 CN 2,4,6-Me3 ~ Ph 842 Me NHCH (CH ₂ CH ₂ OMe) CH ₂ OMe 2-Me-4-Br-Ph 843 Me NHCH (CH ₂ OMe) ₂ 2,5-Me ₂ -4-MeO-Ph 844 Me N (CH ₂ CH ₂ OMe) ₂ 2,5-Me ₂ -4-MeO-Ph 845 Me ΝΗ-3-pentyl 2,5-Me ₂ -4-MeO-Ph 846 Me NEt ₂ 2,5-Me ₂ 4-MeO-Ph 847 Me NHCH (CH ₂ OMe) 2 2-Cl-4-MePh 848 Me CH (Et) CH ₂ OMe 2-Cl-4-MePh 849 Me N (CH ₂ CH ₂ OMe) ₂ 2-Cl-4-MePh 850 Me (S) -NHCH (CH ₂ CH ₂ OMe) CH ₂ OMe 2-Cl-4-MePh 851 Me N (C-C 3 H 5) CH 2 CH 2 CN 2,5-Me ₂ -4-MeOPh 852 Me KEt ₂ 2-Me-4-MeOPh 853 Me OEt 2-Me-4-MeOPh 854 Me (S) -NHCH (CH 2 OMe CH ₂₎ CH ₂ OMe 2-Me-4-MeOPh 855 Me N (C-C 3 H 5) CH 2 CH 2 CN 2-Me-4-MeOPh 856 Me -NHCH (CH 2 OEt CH ₂₎ 2 2-Me-4-MeOPh 857 Me N (C-C ₃ H ₅ ) CH ₂ CH ₂ CN 2,4-Cl ₂ -Ph 858 Me NEt ₂ 2-Me-4-ClPh 859 Me ΝΗ-3-pentyl 2-Me-4-ClPh 860 Me N (CH ₂ CH ₂ OMe) 2 2-Me-4-ClPh 861 Me NHCH (CH ₂ OMe) 2 2-Me-4-ClPh 862 Me NEt ₂ 2-Me-4-ClPh 863 Me NEt 2 2-Cl-4-MePh

Ί59

664 Me ΝΗ-3-pentyl 2-Cl-4-MePh. 865 Me NHCH (CH ₂ OMe) ₂ 2-Cl-4-MeOPh 866. Me N (CH ₂ CH ₂ OMe) 2 2-Cl-4-MeOPh 867 Me NHCH (Et) CH ₂ OMe 2-Cl-4-MeOPh 868 Me N (C-Pr) CH ₂ CH ₂ CN 2-Cl-4-MeOPh 869 Me NEt ₂ 2-Cl-4-MeOPh 870 Me ΝΗ-3-pentyl 2-Cl-4-MeOPh ' 871 Me NHCH (Ec) CH ₂ CH ₂ OMe 2-Cl-4-MeOPh 872 Me NHCH (Me) CH ₂ CH ₂ OMe 2-Cl-4-MeOPh 873 Me NHCH (Ec) CH ₂ CH ₂ OMe 2-Br-4-MeOPh 874 Me NHCH (Me) CH ₂ CH ₂ OMe 2-Br-4-MeOP.h 875 Me NHCH (Et) CH ₂ CH ₂ OMe 2-Ile-4-MeOPh 876 Me NHCH (Me) CH ₂ CH ₂ OMe 2-Ms-4-MeOPh 877 Me NHCH ₂ CH ₂ OMe) 2 2-C1-4,5- (MeO) ₂ Ph 878 Me N (CH ₂ CH ₂ OMe) ₂ 2-C1-4,5- (MeO) ₂ Ph 879 Me NHCH (Et) CH ₂ OMe 2-C1-4,5- (MeO) ₂ Ph 880 Me N (C-Pr) CH ₂ CH ₂ CN 2-C1-4,5- (MeO) ₂ Ph 881 Me NEt ₂ 2-C1-4,5- (MeO) ₂ Ph 882 Me ΝΗ-3-pentyl 2-C1-4,5- (MeO) ₂ Ph 883 Me NHCH (Et) CH 2 OMe CH ₂ 2-C1-4,5- (MeO) ₂ Ph 884 Me NHCH (Me) CH ₂ CH ₂ OMe 2-C1-4,5- (MeO) ₂ Ph 885 Me NHCH (CH ₂ OMe) 2 2-Br-4,5- (MeO) ₂ Ph 886 Me N (CH ₂ CH ₂ OMe) ₂ 2-Br-4,5- (MeO) ₂ Ph 887 Me NHCH (Et) CH ₂ OMe 2-Br-4,5- (MeO) ₂ Ph 888 Me N (c-Pr) CH ₂ CH ₂ CN 2-Br-4,5- (MeO) ₂ Ph 889 Me NEt ₂ 2-B '-4,5- (MeO) ₂ Ph 890 Me ΝΗ-3-pentyl 2-Br-4,5- (MeO) ₂ Ph 891 Me NHCH (CH ₂ OMe) ₂ 2-C1-4,6- (MeO) ₂ Ph 892 Me N (CH ₂ CH ₂ OMe) ₂ 2-C1-4,6- (MeO) ₂ Ph 893 Me NEt ₂ 2-C1-4,6- (MeO) ₂ Ph 894 Me ΝΗ-3-pentyl 2-C1-4,6- (MeO) ₂ Ph 895 Me NHCH (CH ₂ OMe) 2 2-He-4,6- (MeO) ₂ Ph 896 Me N (CH ₂ CH ₂ OMe) ₂ 2-Me-4,6- (MeO) ₂ Ph 897 Me NHCH (Et) CH ₂ OMe 2-Me-4,6- (MeO) ₂ Ph 898 Me NEt ₂ 2-Me-4,6- (MeO) ₂ Ph 899 Me ΝΗ-3-pentyl 2-Me-4,6- (MeO) ₂ Ph

- 'iCQ -

900 Me NHCH (Et) CH 2 CH 2 OMe 2-Me-4-MeOPh 901 Me NHCH (Me) CH ₂ CH ₂ OMe 2-Me-4-MeOPh 902 Me NHCH (CH ₂ OMe) ₂ 2-MeO-4-MePh 903 Me N (CH ₂ CH ₂ OMe) ₂ 2-MeO-4-MePh 904 Me NHCH (Et) CH ₂ OMe 2-MeO-4-MePh 905 Me N (c-Pr) CH ₂ CH ₂ CN 2-Me0-4-MePh 906 Me NEt ₂ 2-MeO-4-MePh 907 Me ΝΗ-3-pentyl 2-MeO-4-MePh 9C8 Me NHCH (Et) CH ₂ CH ₂ OMe 2-MeO-4-MePh 909 Me NHCH (Me) CH ₂ CH ₂ OMe 2-MeO-4-MePh 910 Me NHCH (CH ₂ OMe) ₂ 2-MeO-4-MePh 911 Me N (CH ₂ CH ₂ OMe) ₂ 2-Me0-4-MePh 912 M e NHCH (Et) CH ₂ OMe 2-Me0-4-MePh 913 M e N (c-Pr) CH ₂ CH ₂ CN 2-MeO-4-MePh 914 M e NEt ₂ 2-Me0-4-MePh 915 Me ΝΗ-3-pentyl 2-MeO-4-MePh 916 Me NHCH (CH ₂ OMe) ₂ 2-Me0-4-ClPh 917 Me N (CH ₂ CH ₂ OMe) ₂ 2-MeO-4-ClPh 918 Me NHCH (Et) CH ₂ OMe 2-MeO-4-ClPh 919 Me NEt ₂ 2-Me0-4-ClPh 920 Me ΝΗ-3-pentyl 2-Me0-4-ClPh

- 7à7 Table 6

Pi. Bi 4 bj Ar 921 Me NHCH (CH 2 OMe) 2 2,4-C 12 ~ Ph 922 M e NHCHPr2 2,4-C 12 ~ Ph 923 Me NetBt 2,4-C 12 ~ Ph 924 Me NPr (CH2-C-C3H5) 2,4-C12 "Ph 925 Me N (CH2CH2OMe) 2 2,4-C12Ph 926 Me ΝΗ-3-heptyl 2,4-C 12 ~ Ph 927 Me NHCH (Et) CH 2 OMe 2,4-C12 "Ph 928 Me NEt 2 2,4-C 12 ~ Ph 929 Me -NHCH (CH 2 OEt) 2 2,4-C 12 ~ Ph 930 Me ΝΗ-3-pentyl 2,4-C12 "Ph 931 Me NMePhe 2,4-C12 "Ph 932 Me NPr2 2,4-C12Ph 933 Me ΝΗ-3-hexyl 2,4-C12-Ph 934 Me morpholino 2,4-C 12 ~ Ph 935 Me N (CH 2 Ph) CH2CH2OMe 2,4-C12-Ph 936 Me NHCH (CH 2 Ph) CH 2 OMe 2,4-C12Ph 937 Me ΝΗ-4-tetrahydropyranyl 2,4-C12Ph 938 Me NH-cyclopentyl 2,4-C 12 ~ Ph 939 Me OEt 2,4-C12 "Ph 940 Me OCH (Et) CH 2 OMe 2,4-C12-Ph 941 Me OCH2Ph 2,4-C 12 ~ Ph 942 Me Ο-3-pentyl 2,4-C12Ph 943 Me Set 2,4-C 12 ~ Ph

944 Me S (0) Et 2,4-Cl ₂ -Ph 945 Me SO ₂ Et 2,4-Cl ₂ -Ph 946 Me ph 2,4-C12 "Ph 947 Me 2-CF3-Ph 2,4-Cl ₂ -Ph 948 Me 2-Ph-Ph 2,4-Cl ₂ -Ph 949 Me 3-pentyl 2,4-Cl ₂ -Ph ' 950 Me cyclobutyl 2,4-Cl ₂ -Ph 951 Me 3-pyridyl 2,4-Cl ₂ -Ph 952 Me CH (Et) CH2CONMe2 2,4-Cl ₂ -Ph 953 Me CH (Et) CH2CH2NMe2 2,4-Cl ₂ -Ph 954 Me NHCH (CH 2 OMe) 2 2,4,6-Me3 ~ Ph 955 Me NHCHPr2 2,4,6-Me3-Ph 956 Me NetBt 2,4,6-Me3 ~ Ph 957 Me NPr (CH2-C-C3H5) 2,4,6-Me3-Ph 958 Me N (CH2CH2OMe) 2 2,4,6-Me3-Ph 959 Me ΝΗ-3-heptyl 2,4,6-Me3-Ph 960 Me NHCH (Et) CH ₂ Me 2,4,6-Me3-Ph 961 Me NEt ₂ 2,4,6-Me3-Ph 962 Me. -NHCH (CH ₂ OEt) ₂ 2,4,6-Me3 ~ Ph 963 Me ΝΗ-3-pentyl 2,4,6-Me3 ~ Ph 964 Me NMePhe 2,4,6-Me3-Ph 965 Me NP r 2 2,4,6-Me3-Ph 966 Me ΝΗ-3-hexy1 2,4,6-Me3-Ph 967 Me morpholino 2,4,6-Me3 ~ Ph 968 Me N (CH ₂ Ph) CH ₂ CH ₂ OMe 2,4,6-Me3-Ph 969 Me NHCH (CH ₂ Ph) CH ₂ OMe 2,4,6-Me3 ~ Ph 970 Me ΝΗ-4-tetrahydropyranyl 2,4,6-Me3 ~ Ph 971 Me NH-cyclopentyl 2,4,6-Me3-Ph 972 Me OEt 2,4,6-Me3 ~ Ph 973 Me OCH (Et) CH ₂ Me 2,4,6-Me3-Ph 974 Me OCH ₂ Ph 2,4,6-Me3 ~ Ph ⁹⁷⁵ Me Ο-3-pentyl 2,4,6-Me3-Ph 976 Me Set 2,4,6-Me3 ~ Ph 977 Me S (0) Et 2,4,6-Me3-Ph 978 Me S0 ₂ Et 2,4,6-Me3-Ph 979 Me CH (CO ₂ Et) 2 2,4,6-Me3-Ph

- / 63 -

980 Me C (Et) (CO ₂ Et) 2 2,4,6-Me3 ~ Ph 981 Me CH (Et) CH 2 OH 2,4,6-Me3 ~ Ph 982 Me CH (Et) CH ₂ OMe 2,4,6-Me3-Ph 983 Me CONMe ₂ 2,4,6-Me3-Ph 984 Me COCH3 2,4,6-Me3 ~ Ph 985 Me CH (OH) CH 3 2,4,6-Me3-Ph 986 Me C (OH) Ph-3-pyridyl - 2,4,6-Me3 ~ Ph 987 Me ph 2,4,6-Me3 ~ Ph 98 8 Me 2-Ph-Ph 2,4,6-Me3 ~ Ph 989 Me 3-pentyl 2,4,6-Me3 ~ Ph 990 Me cyclobutyl 2,4,6-Me3-Ph 991 Me 3-pyridyl 2,4,6-Me3 ~ Ph 992 Me CH (Et) CH ₂ CONMe ₂ 2,4,6-Me3-Ph 993 Me CH (Et) CH ₂ CH ₂ NMe ₂ 2,4,6-Me3 ~ Ph 994 Me NHCH (CH ₂ OMe) 2 2,4-Me ₂ -Ph 995 Me N (CH ₂ CH ₂ OMe) 2 2,4-Ph _2-Me 996 Me NHCH (Et) CH ₂ OMe 2,4-Me ₂ -Ph 997 Me ΝΗ-3-pentyl 2,4-Me ₂ -Ph 998 Me NEt ₂ 2,4-Ph _2-Me 999 Me N (CH ₂ CN) 2 2,4-Me ₂ -Ph 1000 Me NHCH (Me) CH ₂ OMe 2,4-Me ₂ -Ph 1001 Me OCH (Et) CH 2 OMe 2,4-Me ₂ -Ph 1002 Me NPr-c-C3H5 2,4-Me ₂ -Ph 1003 Me NHCH (Me) CH ₂ NMe ₂ 2,4-Me ₂ -Ph 1004 Me N (C-C ₃ H ₅ ) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph 1005 Me N (Pr) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph 1006 Me N (Bu) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph 1007 Me NHCHPr ₂ 2,4-Me ₂ -Ph 1008 Me NetBt 2,4-Me ₂ -Ph 1009 Me NPr (CH2-C-C3H5) 2,4-Me ₂ -Ph 1010 Me ΝΗ-3-heptyl 2,4-Me ₂ -Ph 1011 Me NEt ₂ 2,4-Me ₂ -Ph 1012 Me -NHCH (CH 2 OEt) 2 2,4-Me ₂ -Ph 1013 Me ΝΗ-3-pentyl 2,4-Me ₂ -Ph 1014  Me NMePhe 2,4-Me ₂ -Ph 1015 Me NPr ₂ 2,4-Ph _2-Me

_ -

1016 Me ΝΗ-3-hexyl 2,4-Me 2 ^- Ph 1017 Me rnorfolino. . 2,4-Me 2 Ph ~ 1018 Me N (CH 2 Ph) CH2CH2OMe 2,4-Me 2 Ph ~ 1019 Me NHCH (CH 2 Ph) CH 2 OMe 2,4-Me 2 Ph ~ 1020 Me NH-4-tetrahydropyranyl 2,4-Me 2 Ph ~ 1021 Me NH-cyclopentyl 2,4-Me 2 "Ph 1022 Me NHCH (CH 2 OMe) 2 2-Me-4-MeO-Ph 1023 Me N (CH2CH2OMe) 2 2-Me-4-MeO-Ph 1G24 Me NHCH (Et) CH 2 OMe 2-Me-4-MeO-Ph 1025 Me N (Pr) CH 2 CH 2 CN 2-Me-4-MeO-Ph 1026 Me OCH (Et) CH 2 OMe 2-Me-4-MeO-Ph 1027 Me NHCH (CH 2 OMe) 2 2-Br-4-MeO-Ph 1028 Me N (CH 2 CH 2 OMe) 2 2-Br-4-MeO-Ph 1029 Me NHCH (Ec) CH 2 OMe 2-Br-4-MeO-Ph 1030 Me N (Pr) CH2CH2CN . 2-Br-4-MeO-Ph 1031 Me OCH (Et) CH 2 OMe 2-Br-4-MeO-Ph 1032 Me NHCH (CH 2 OMe) 2 2-Me-4-NMe2 ~ Ph 1033 Me N (CH2CH2OMe) 2 2-Me-4-NMe 2 ^- Ph 1034 Me NHCH (Et) CH 2 OMe 2-Me-4-NMe 2 "Ph 1035 Me N (Pr) CH 2 CH 2 CN 2-Me-4-NMe2-Ph 1036 Me OCH (Et) CH 2 OMe 2-Me-4-NMe 2 ^- Ph 1037 Me NHCH (CH 2 OMe) 2 2-Br-4-NMe2 ~ Ph 1038 Me N (CH 2 CH 2 OMe) 2 2-Br-4-NMe 2 "Ph 1039 Me NHCH (Et) CH 2 OMe 2-Br-4-NMe2 ~ Ph 1040 Me N (Pr) CH 2 CH 2 CN 2-Br-4-NMe2 ~ Ph 1041 Me OCH (Et) CH 2 OMe 2-Br-4-NMe2 ~ Ph 1042 Me NHCH (CH 2 OMe) 2 2-Br-4-iPr-Ph 1043 Me N (CH2CH2OMe) 2 2-Br-4-iPr-Ph 1044 Me NHCH (Et) CH 2 OMe 2-Br-4-iPr-Ph 1045 Me N (Pr) CH 2 CH 2 CN 2-Br-4-iPr-Ph in 1046 Me OCH (Et) CH 2 OMe 2-Br-4-iPr-Ph 1047 Me NHCH (CH 2 OMe) 2 2-Br-4-Me-Ph 1048 Me N (CH2CH2OMe) 2 2-Br-4-Me-Ph 1049 Me NHCH (Et) CH 2 OMe 2-Br-4-Me-Ph 1050 Me N (Pr) CH 2 CH 2 CN 2-Br-4-Me-Ph in 1051 Me OCH (Et) CH 2 OMe 2-Br-4-Me-Ph

- ~ Ί ·

1052 Me NHCH (CH ₂ OMe) 2 2-Me-4-Br-Ph 1053 Me N (CH ₂ CH ₂ OMe) ₂ 2-Me-4-Br-Ph 1054 Me NHCH (Et) CH ₂ OMe 2-Me-4-Br-Ph 1055 Me N (Pr) CH ₂ CH ₂ CN 2-Me-4-Br-Ph 1056 Me OCH (Et) CH ₂ OMe 2-Me-4-Br-Ph 1,057 Me NHCH (CH ₂ OMe) _{2 2-C1-4,6-Me2-Ph} 1058 Me N (CH2CH2OMe) 2 _{2-C1-4,6-Me2-Ph} 1059 Me NHCH (CH ₂ OMe) 2 4-Br-2,6- (Me) ₂ -Ph 1060 Me N (CH ₂ CH ₂ OMe) 2 4-Br-2,6- (Me) ₂ -Ph 1061 Me NHCH (CH ₂ OMe) 2 4-i-Pr-2-SMe-Ph 1062 Me N (CH ₂ CH ₂ OMe) 2 4-i-Pr-2-SMe-Ph 1063 Me NHCH (CH ₂ OMe) 2 2-Br-4-CF 3 Ph ~ 1064 Me N (CH ₂ CH ₂ OMe) 2 2-Er-4-CF3-Ph 1065 Me NHCH (CH 2 OMe) 2 2-Br-4,6- (MeO) ₂ -Ph 1066 Me N (CH ₂ CH ₂ OMe) 2 2-Br-4,6- (MeO) 2-Ph 1067 Me NHCH (CH ₂ OMe) 2 2-C1-4,6- (MeO) ₂ -Ph 1068 Me N (CH ₂ CH ₂ OMe) 2 2-C1-4,6- (MeO) ₂ -Ph 1069 Me NHCH (CH ₂ OMe) 2 2,6- (Me) 2-4-SMe-Ph 1070 Me N (CH ₂ CH ₂ OMe) ₂ 2,6- (Me) 2-4-SMe-Ph 1071 Me NHCH (CH ₂ OMe) 2 4- (COMe) -2-Br-Ph 1072 Me N (CH ₂ CH ₂ OMe) ₂ 4- (COMe) -2-Br-Ph 1073 Me NHCH (CH ₂ OMe) ₂ 2,4,6-Me3 ~ pyridin-3-yl 1074 Me N (CH ₂ CH ₂ OMe) 2 2,4,6-Me3-pyrid-3-yl 1075 Me NHCH (CH ₂ OMe) ₂ 2,4- (Br) ₂ -Ph 1076 Me N (CH ₂ CH ₂ Me) ₂ 2,4- (Br) ₂ -Ph 1077 Me NHCH (CH 2 OMe) 2 4 ~ i-Pr-2-SMe-Ph 1078 Me N (CH2CH2OMe) 2 4-i-Pr-2-SMe-Ph 1079 Me NHCH (CH 2 OMe) 2 4-i-Pr-2-SO ₂ Me-Ph 1080 ' Me N (CH ₂ CH ₂ OMe) ₂ 4-i-Pr-2-SO ₂ Me-Ph 1081 Me NHCH (CH ₂ OMe) 2 2,6- (Me) 2-4-SMe-Ph 1082 Me N (CH ₂ CH ₂ OMe) ₂ 2,6- (Me) ₂ -4-SMe-Ph 1083 Me NHCH (CH ₂ OMe) ₂ 2,6- (Me) 2-4-SO ₂ Me-Ph 1084 Me N (CH ₂ CH ₂ OMe) ₂ 2,6- (Me) 2-4-SO ₂ Me-Ph 1085 Me NHCH (CH ₂ OMe) 2 2-I-4-i-Pr-Ph 1086 Me N (CH ₂ CH ₂ OMe) _{2 2-} I-4-i-Pr-Ph 1087 Me NHCH (CH ₂ OMe) 2 2-Br-4-N (Me) ₂ 6-MeO-Ph

ή η

1088 Me N (CH2CH2OMe) 2 2-Br-4-N (Me) 2-6-MeO-Ph 1089 Me NEt 2 2-Br-4-MeO-Ph 1090 Me ΝΗ-3-pentyl 2-Br-4-MeO-Ph 1091 Me NHCH (CH ₂ OMe) ₂ 2-CN-4-Me-Ph 1092 Me N (C-C 3 H 5) CH 2 CH 2 CN 2,4,6-Me3 ~ Ph 1093. Me NHCH (CH2CH2OMe) 2 OMe 2-Me-4-Br-Ph 1094 Me NHCH (CH 2 OMe) 2 2,5-Me 2 ^- 4-MeO-Ph 1095 Me N (CH2CH2OMe) 2 2,5-Me 2 "4-MeO-Ph 1096 Me ΝΗ-3-pentyl 2,5-Me 2 "4-MeO-Ph 1097 Me NEt 2 2,5-Me2-4-MeO-Ph 1098 Me NHCH (CH 2 OMe) 2 2-Cl-4-MePh 1099 Me CH (Et) CH 2 OMe 2-Cl-4-MePh 1100 Me N (CH2CH2OMe) 2 2-Cl-4-MePh 1101 Me (S) -NHCH (CH2CH2OMe) 2 OMe 2-C1-4-MePh 1102 Me N (c-C3H5) CH2CH2CN 2,5-Me 2 -4-MeOPh 1103 Me NEt 2 2-Me-4-MeOPh 1104 Me OEt 2-Me-4-MeOPh 1105 Me (S) -NHCH (CH2CH2OMe) 2 OMe 2-Me-4-MeOPh 1106 Me N (C-C 3 H 5) CH 2 CH 2 CN 2-Me-4-MeOPh 1107 Me NHCH (CH2CH2OEt) 2 2-Me-4-MeOPh 1108 Me N (c-C3H5) CH2CH2CN 2,4-C12 "Ph 1109 Me NEt 2 2-Me-4-ClPh 1110 Me ΝΗ-3-pentyl 2-Me-4-ClPh 1111 Me N (CH2CH2OMe) 2 2-Me-4-ClPh 1112 Me NHCH (CH 2 OMe) 2 2-Me-4-ClPh 1113 Me NEt 2 2-Me-4-ClPh 1114 Me NEt 2 2-Cl-4-MePh 1115 Me ΝΗ-3-pentyl 2-Cl-4-MePh 1116 Me NHCH (CH ₂ OMe) 2 2-Cl-4-MeOPh · 1117 Me N (CH2CH2OMe) 2 2-Cl-4-MeOPh 1118 Me NHCH (Et) CH 2 OMe 2-Cl-4-MeOPh 1119 Me N (c-Pr) CH2CH2CN 2-Cl-4-MeOPh 1120 Me NEt ₂ 2-Cl-4-MeOPh 1121 Me NH-3-pentyl 2-Cl-4-MeOPh 1123 Me NHCH (Et) CH2CH2OMe 2-Cl-4-MeOPh 1124 Me NHCH (Me) CH2CH2OMe 2-Cl-4-MeOPh

1125 Me NHCH (Et) CH2CH2OMe 2-Br-4-MeOPh 1126 Me NHCH (Me) CH2CH2OMe 2-Br-4-MeOPh 1127 Me NHCH (Et) CH2CH2OMe 2-Me-4-MeOPh 1128 Me NHCH (Me) CH2CH2OMe 2-Me-4-MeOPh 1129 Me NHCH (CH ₂ OMe) ₂ 2-C 1-4 -4- (MeO) ₂ ? H 1130 Me N (CH ₂ CH ₂ OMe) ₂ 2-C1-4,5- (MeO) ₂ Ph 1131 Me NHCH (Et) CH 2 OMe 2-C1-4,5- (MeO) 2? H 1132 Me N (c-Pr) CH ₂ CH ₂ CN 2-C1-4,5- (MeO) ₂ Ph 1133 Me NEt 2 2-C1-4,5- (MeO) 2 ^ h 1134 Me ΝΗ-3-pentyl 2-C1-4,5- (MeO) ₂ Ph 1135 Me NHCH (Et) CH 2 OMe CH ₂ 2-C1-4,5- (MeO) 2 Ph 1136 Me NHCH (Me) CH2CH2OMe 2-C1-4,5- (MeO) 2? H 1137 Me NHCH (CH 2 OMe) 2 2-Br-4,5- (MeO) ₂ Ph 1138 Me N (CH2CH2OMe) 2 2-Br-4,5- (MeO) 2 Ph 1139 Me NHCH (Et) CH ₂ OMe 2-Br-4,5- (MeO) 2 Ph 1140 Me N (c-Pr) CH ₂ CH ₂ CN 2-Br-4,5- (MeO) 2 Ph 1141 Me NEt ₂ 2-Br-4,5- (MeO) 2? H 1142 Me ΝΗ-3-pentyl 2-Br-4,5- (MeO) 2 Ph 1143 Me NHCH (CH ₂ OMe) 2 2-C1-4,6- (MeO) 2 Ph 1144 Me N (CH 2 CH 2 OMe) 2 2-C1-4,6- (MeO) 2 Ph 1145 Me NEt 2 2-C1-4,6- (MeO) 2? H 1146 Me ΝΗ-3-pentyl 2-C1-4,6- (MeO) 2 Ph 1147 Me NHCH (CH 2 OMe) 2 2-Me-4,6- (MeO) 2 Ph 1148 Me N (CH2CH2OMe) 2 2-Me-4,6- (MeO) 2 Ph 1149 Me NHCH (Et) CH 2 OMe 2-Me-4,6- (MeO) 2 Ph 1150 Me NEt 2 2-Me-4,6- (MeO) 2? H 1151 Me ΝΗ-3-pentyl 2-Me-4,6- (MeO) 2 Ph 1152 Me NHCH (Et) CH2CH2OMe 2-Me-4-MeOPh 1153 Me NHCH (Me) CH 2 CH 2 O ^M e 2-Me-4-MeOPh 1154 Me NHCH (CH 2 OMe) 2 2-MeO-4-MePh. 1155 Me N (CH2CH2OMe) 2 2-MeO-4-MePh 1156 Me NHCH (Et) CH 2 OMe 2-MeO-4-MePh 1157 Me N (c-Pr) CH2CH2CN 2-MeO-4-MePh 1158 Me NET-2 2-MeO-4-MePh 1159 Me ΝΗ-3-pentyl 2-MeO-4-MePh 1160 Me NHCH (Et) CH2CH2OMe 2-MeO-4-MePh

1161 Me NHCH (Me) CH ₂ CH ₂ OMe 2-MeO-4-MePh 1162 Me NHCH (CH ₂ OMe) ₂ 2-Me0-4-MePh 1163 Me N (CH ₂ CH ₂ OMe) ₂ 2-MeO-4-MePh 1164 Me NHCH (Et) CH ₂ OMe 2-MeO-4-MePh 1165 Me N (c-Pr) CH ₂ CH ₂ CN 2-MeO-4-MePh 1166 Me NEt ₂ 2-MeO-4-MePh 1167 Me ΝΗ-3-pentyl 2-MeO-4-MePh 1168 Me NHCH (CH ₂ OMe) ₂ 2-MeO-4-ClPh 11Ô9 Me N (CH ₂ CH ₂ OMe) ₂ 2-MeO-4-ClPh 1170 Me NHCH (Et) CH ₂ OMe 2-MeO-4-ClPh 1171 Me NEt ₂ 2-MeO-4-ClPh 1172 Me ΝΗ-3-pentyl 2-MeO-4-ClPh

169

usefulness

CRF-R1 Receptor Binding Assay for Evaluation of Biological Activity

The following describes the isolation of cell membranes containing cloned human CRF-R1 receptors for use in the standard binding assay, as well as the assay itself.

Messenger RNA was isolated from the human hippocampus. The mRNA is back-transferred using oligo (dt) 12-18 and the coding region extends from start to end of the codon. The resulting PCR fragment was cloned into the EcoRV side of pGEMV, from where the insert was regenerated using XhoI + XbaI and cloned into the XhoI + XbaI side of the pm3ar vector (containing the CMV promoter, SV40 'junction and starting poly A signals, EpsteinBaar viral origin of replication and hydromycin) selectable marker). The resulting expression vector, called phchCRFR, is transferred to 293EBNA cells and the episode-retaining cells are separated in the presence of 400 µM hygromycin. Cells that survive 4 weeks of selection in hygromycin are pooled, adapted to grow in suspension, and used to generate membranes for the binding assay described below. The aliquots containing approximately 1 x 10 ⁸ suspended cells are then centrifuged into a pellet and frozen.

For the binding assay, the frozen pellet described above containing 293EBNA cells transfected with hCRFR1 receptors is homogenized in 10 ml ice-cold buffer (50 mM HEPES buffer, pH 7.0, containing 10 mM MgCl ₂ , 2 mM EGTA, 1 ng / ml). 1 aprotinin, 1 ng / ml leupeptin and 1 ng / ml pepsatin). The homogenate is centrifuged at 40,000 xg for 12 minutes

170 and the resulting pellet was re-homogenized in 10 ml of tissue buffer. After further centrifugation at 40,000 x g for minutes, the pellet is resuspended to a protein concentration of 360 mg / ml and used in the assay.

The binding assay is performed on 96-well plates; Each well has a capacity of 300 μΐ. To each well is added 50 μΐ of test drug solution (final drug concentration is 10 -10 ¹⁰ -10 ⁵ M), 100 μΐ ¹²⁵ I-sheep-CRF ( ¹²⁵ Io-CRF) (150 µM final concentration), and 150 μunk cell homogenate described above. The plates are then incubated at room temperature for 2 hours, the incubate is filtered through GF / F filters (soaked in 0.3% polyethyleneimine) using a suitable cell collector. The filters are then rinsed twice with ice-cold assay buffer, separated and the radioactivity is counted on a gamma counter.

¹²⁵ Io-CRF inhibition curves bound to cell membranes at various dilutions of test drug are analyzed by an iterative suitable LIGAND program [PJ Munson and D. Rodbard, Anal. Biochem. 107: 220 (1980)), which provides Ki values for inhibition, which is then used to assess biological activity.

A compound is considered to be active if it has a Ki of less than about 10,000 nM to inhibit CRF.

Inhibition of CRF-stimulated adenylate cyclase activity

Inhibition of CRF-stimulated adenylate cyclase activity was performed by the method described by G. Battaglia et al., Synapse 1: 572 (1987). Briefly, assays were rotated at 37 ° C for 10 minutes in 200 mL of buffer containing 100 mM Tris HCl (pH 7.4, at 37 ° C), 10 mM magnesium chloride, 0.4 mM EGTA, 1% BSA, 1 mM isobutyl methylxanthine (IBMX), 250 units / ml phosphocreatine kinase, 5 mM creatiphosphonate, 100 mM guanosine-5'-triphosphate, 100 nM oCFR antagonizing peptides (concentration between 10 ⁹ and 10 o M) and 0.8 mg of native wet weight tissue (about 40 to 60 mg protein). Reactions were initiated by the addition of 1 mM ATP [ ³² P] ATP (about 2-4 mCi / tube) and terminated by the addition of 100 mL of 50 mM Tris-HCl, 45 mM ATP and 2% sodium dodecyl sulfate. To monitor cAMP isolation, 1 μΐ [ ³ H] cAMP (about 40,000 decays per minute) is added to each tube prior to separation. [ ³² P] cAMP separation from [ ³² P] ATP was performed by sequential elution on Dowex and alumina columns.

In vivo bioassay

The in vivo efficacy of the compounds of the invention can be evaluated using some of the available bioassays available in the art. Examples of these tests include: the acoustic startle assay, the stair climbing test, and the chronic administration assay. These and other models suitable for testing compounds of the invention are described in C.V. Berridge and A.J. Dunn, Brain Research Reviewses 15:71 (1990). Compounds can be tested using various types of rodents or small mammals.

The compounds of the invention are useful in the treatment of disorders associated with abnormal levels of the release factor

172 corticotropin in patients suffering from depression, emotional disorders and / or anxiety.

The compounds of the present invention can be administered to treat these abnormalities by contacting the active agent with the site of action in the mammalian body. The compounds may be administered by any conventional means suitable for use in conjunction with pharmaceuticals, either as an individual therapeutic agent or in combination with therapeutic agents. They may be administered alone, or they may generally be administered with pharmaceutical carriers selected on the basis of the selected route of administration and standard pharmaceutical practice.

The dose of administration will vary depending on the use and known factors such as the pharmacokinetic nature of the individual agent and the route and route of administration, the recipient's age, weight and health, the nature and extent of the symptoms, the type of concurrent treatment, frequency of treatment and the effect desired. For use in the treatment of said diseases or conditions, the compounds of the invention may be administered daily in doses of active ingredient of from 0.002 to 200 mg / kg body weight. The usual dose to achieve the desired effect is 0.01 to 10 mg / kg in divided doses one to four times daily or in a sustained release formulation.

Dosage forms (compositions) suitable for administration contain about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient is usually present in an amount of from about 0.5 to 95% by weight based on the total weight of the composition.

The active ingredient may be administered orally in solid dosage forms such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups and / or suspensions.

173

The compounds of the present invention may be administered in a sterile liquid dosage formulation.

Gelatin capsules containing the active ingredient and a suitable carrier such as, but not limited to, lactose, starch, magnesium stearate, stearic acid or cellulose derivatives may be used. Similar diluents may be used to prepare compressed tablets. Both tablets and capsules can be manufactured as sustained release products to achieve continuous drug release. Compressed tablets may be coated with sugar or film to mask any unpleasant taste or to protect the active ingredients from the atmosphere or to selectively disintegrate the tablet in the gastrointestinal tract.

Liquid dosage forms may contain coloring or flavoring to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline solutions, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or poylethylene glycol are used as suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, butter substances. Suitable stabilizing agents are antioxidants, such as sodium bisulfite, sodium sulfite or ascorbic acid alone or in combination. Citric acid and its salts and EDTA are also used. Further, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propylparaben and chlorobutanol.

Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences, A. Osol, a standard reference in the art.

174

Suitable pharmaceutical dosage forms for administration of the compounds of the present invention may be illustrated as follows:

The capsules

A plurality of capsules are prepared by filling standard gelatin capsules, each containing 100 mg of the powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules A mixture of the active ingredient in a digestible oil, such as soybean oil, cottonseed oil or oil, is prepared and injected into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried.

tablets

Multiple tablets are prepared by conventional methods such that the dosage unit contains 100 mg of active ingredient, 0.2 mg of colloidal silica, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and

98.8 mg lactose. Appropriate coatings may be applied to improve taste or delay adsorption.

The compounds of the present invention may also be used as reagents or standards in a biochemical study of neurological function, dysfunction and disease.

The preferred embodiments set forth in the description of the present invention are given by way of illustration only and are not to be construed as limiting the scope of the invention as set forth in the claims.

Claims (34)

PATENT CLAIMS (1) when A is N, Z is CR ² , R ² is H, R ³ is -OR ^{7 * * *} or -OCOR ¹³ , and R ⁷ is H, then R ¹ is not H, OH or SH; 1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R ⁴ groups and each Ar attached to an unsaturated carbon atom; R is independently selected from H, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₇ cycloalkylalkyl, halogen, CN, C C ₁ -C ₄ haloalkyl; 416 R ¹ is independently selected from H, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, halogen, CN, C ₁ -C ₄ haloalkyl, C ₁ -C ₁₂ hydroxyalkyl, C C ₂ -C ₁₂ alkoxyalkyl, C ₂ -C ₁₀ cycloalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₀ cycloalkylalkyl, NR R, C ₁ -C ₄ alkyl-NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , OR ¹¹ , SH or S (O) _n R ¹² ; R ² is selected from the group consisting of H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 10 cycloalkylalkyl, C 1 -C 4 hydroxyalkyl, halogen, CN, -NR ⁶ R ⁷ , NR ⁹ COR ¹⁰ , - NR ⁶ S (O) n R ⁷ , S (O) n NR ⁶ R ⁷ , C 1 -C ₄ haloalkyl, -OR ⁷ , SH or -S (O) _n R ¹² ; R ³ is selected from the group consisting of - H, OR ⁷ , SH, S (O) n R ¹³ , COR ⁷ , CO ² R ⁷ , OC (O) R ¹³ , NR ® CO ⁷ , N (COR ⁷ ) 2, NR ⁸ CONR ⁶ R ⁷ , NR ⁸ CO ² R ¹³ , NR ⁶ R ⁷ , NR ^6a R ^7a , N (OR ⁷ ) R ⁶ , CONR ⁶ R ⁷ , aryl, heteroaryl and heterocyclyl or - C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₈ cycloalkyl, C ₅ -C ₈ cycloalkenyl, C ₄ -C ₁₂ cycloalkylalkyl or C ₆ -C ₁₀ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH S (O) _n R ¹³ COR ¹⁵ , CO2R ¹⁵ , 0C (0) R ¹³ , NR ^8, COR ¹⁵ , N (COR ¹⁵ ) 2, NR ^8, CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl; 417 R ⁴ is independently selected from the group consisting of _The C ~ C alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, N0 _2, halogen, CN, C ₁ -C ₄ haloalkyl, NR ⁶ R ^7, NR ⁸ COR ^7, NR ⁸ CO 2 R ^7, oR ^7, CONR ⁸ R ^7, CO (NOR ⁹⁾ R ^7, CO 2 R ^7, or S (O) n R ^7, wherein each Ci-C alkyl, C2C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl is optionally substituted with 1 to 3 substituents selected from the group consisting of C ₁ -C ₄ alkyl, NO ₂ , halogen, CN, NR ⁶ R ⁷ , NR ⁸ COR ^7, NR ⁸ CO 2 R ^7, COR ^7, oR ^7, CONR ⁶ R ^7, CO 2 R ^7, CO (NOR ⁹⁾ R ⁷ or S (O) _n R ^7; R ⁶ and R ⁷ , R ^6a and R ^7a are independently selected from the group consisting of: - H, - C ^ C ^ alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C _x -C ₁₀ haloalkyl with 1-10 halogens, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl or C ₆ -C ₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ - C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) n R ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ® CR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl, - aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C _x -C ₄ _ alkyl), heterocyclyl or heterocyclyl (C ₁ -C ₄ alkyl); alternatively, NR ⁶ R ⁷ and NR ^6a R ^7a each independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or & tiomorfoΊ 7 each of which is optionally substituted with 1 to 3 C ₁ -C ₄ alkyl groups; g R is independently selected from H or C ₁ -C ₄ alkyl; A compound of the general and its isomers, stereoisomeric forms or mixtures of its stereoisomeric forms and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein: A is N or CR; Z is N or CR; Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro- 2 or a prodrug form thereof, wherein Z is CR. A compound according to claim 1 and its isomers, stereoisomeric forms thereof, or mixtures of its stereoisomeric forms, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, with the proviso that: (1) when A is N, R ¹ is H, C _x 4S2 C ₄ alkyl, halogen, CN, C ₁ -C ₁₂ hydroxyalkyl, C ₁ -C ₄ alkoxyalkyl or SO ₂ (C ₁ -C ₄ alkyl), R ³ is NR ^{6a and} R ^7a and R ^6a is unsubstituted C ₁ -C ₄ alkyl, then R ^7a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furyl, benzofuranyl, benzothiazolyl, indolyl or C 3 -C ₆ cycloalkyl; and (2) A is N, R ¹ is H, C 1 -C 4 alkyl, halogen, CN, C 1 -C 12 hydroxyalkyl, C 3 -C 4 alkoxyalkyl or SO 2 (C 1 -C 4 alkyl), R ³ is NR ^6a, R ^7a and R ^7a is unsubstituted C 1 -C ₄ alkyl, then R ^6a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furyl, benzofuranyl, benzothiazolyl, indolyl or C ₃ -C ₆ cycloalkyl. 2-yl. (2) when A is N, Z is ^{CR2, R1} is CH3 or C2H5, ^R2 is H and ^R3 is OH, H, CH 3, C ₂ H _5, C ₆ H _5, nC ₃ H _7, iC ₃ H ₇ , SH ₃ NHC ₄ H ₉ , or N (C ₂ H ₅ ) ₂ , then R is not phenyl or m-CH ₃ phenyl; A compound according to claim 1 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 substituents. (3) when A is N, Z is CR ² , R ² is H and Ar is pyridyl, pyrimidinyl or pyrazinyl and R ³ is NR ^{6a and} R ^7a , then R ^6a and R ^7a are not H or alkyl; A compound according to claim 3 and its isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt or prodrug form thereof, wherein A is N, Z is CR ² , Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R ¹ and R ³ is NR ^{6a and} R ^7a . (4) when A is N, Z is CR ² and R ² is SO ₂ NR ⁶ R ⁷ , then R ³ is not OH or SH; 5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1. (5) where A is CR and Z is CR ^2, then R ² is -NR ⁶ SO 2 R ⁷ or -SO 2 NR ⁶ R ^7; 6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3. (6) when A is N, Z is CR ² and R ² is -NR ⁶ SO ² R ⁷ or -SO ² NR ⁶ R ⁷ , then R ³ is not OH or SH; 7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4. (7) when A is N, Z is CR ^2, R ¹ is CH ₃ or C ₂ H _5, R ² is H and R ³ is OH, H, CH _3, C ₂ H _5, C ₆ H, _s, NC ₃ H ₇ , iso-C ₃ H ₇ , SH, SCH ₃ , NH (nC ₄ H ₉ ) or N (C ₂ H ₅ ) ₂ , then A is not unsubstituted phenyl or m-CH ₃ -phenyl; 481 A compound according to claim 1 and its isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein A is N. (8) when A is CR, Z is CR ² , R ² is H, phenyl or alkyl, R ^{3 * *} is not NR ⁸ COR ⁷ and Ar is phenyl or phenyl substituted with phenylthio, then R ⁷ is not aryl, aryl ( C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C ₁ -C ₄ alkyl), heterocyclyl or heterocyclyl (C ₁ -C ₄ alkyl); A compound of formula 2 according to claim 8 and its isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof. (9) when A is CR, Z is CR ² , R ² is H or alkyl, Ar is phenyl and R ³ is SR ¹³ or NR ^{6a and} R ^7a then R ¹³ is not aryl or heteroaryl and R ^6a and R ^7a are not are H or aryl; or 9 10 R 1 and R 2 are independently selected from H, C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl; R ¹¹ is independently selected from H, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl or C ₃ -C ₆ cycloalkyl; R is C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; R ¹³ is selected from C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₈ cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, aryl, aryl (C ₁ -C 4) ₍ Alkyl) -, heteroaryl or heteroaryl (C ₁ -C ₄ alkyl) -; R ¹⁴ is selected from C 1 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 8 cycloalkyl or C 4 -C 12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected from C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, halogen , C 4 haloalkyl, cyano, OR ^15, SH, S (O) n R ^15, COR ^15, CO 2 R ^15, OC (O) R ^15, NR®COR ^15, N (COR ¹⁵⁾ 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹⁵ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ and C 1 -C 6 alkylthio, C 1 -C ₆ alkylsulfinyl and C 1 -C ₆ alkylsulfonyl; R ¹⁵ and R ¹⁶ are independently selected from the group consisting of H, Ci-Cgalkyl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₁₆ cycloalkylalkyl, except that for S (O) _n R ¹⁵ R ¹⁵ can not be H; aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halo, C ₁ -C ₆ haloalkyl, cyano, OR ¹⁵ , SH, S ( 0) _n R ^15, COR ^15, CO 2 R ^15, OC (O) R ^15, NR ⁸ COR ^15, N (COR ¹⁵⁾ 2, NR ⁸ CONR ¹⁶ R ^15, NR ⁸ CO ₂ R ^15, NR ¹⁶ R ^15, and CONR ¹⁶ R ¹⁵ ; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furyl, pyranyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofur, is optionally substituted with 1 to 5 substituents independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹⁵ , COR ^15, CO 2 R ^15, OC (O) R ^15, NR ⁸ COR ^15, N (COR ¹⁵⁾ 2, NR ⁸ CONR ¹⁶ R ^15, NR ⁸ CO ₂ R ^15, NR ^s R ¹⁵ and CONR ¹⁶ R ^15; heterocyclyl is a saturated or partially saturated heteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ^15, COR ^15, CO 2 R ^15, OC (O) R ^15, NR ⁸ COR ^15, N (COR ¹⁵⁾ 2, NR ⁸ CONR ¹⁶ R ^15, NR ⁸ CO ₂ R ^15, NR ¹⁶ R ¹⁵ and CONR ¹⁶ R ¹⁵ ; n is independently 0, 1 or 2, HO saying that: A compound according to claim 9 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R ⁴ . (10) when A is CH, Z is CR ² , R ¹ is OR ¹¹ , R ² is H, R ³ is OR ⁷ and R ⁷ and R ¹¹ are both H, then Ar is not phenyl, p-Br-phenyl , p-Cl-phenyl, p-NHCOCH ₃ -phenyl, p-CH ₃ -phenyl, pyridyl or naphthyl; A compound according to claim 9 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein R ³ is NR ^{6a and} R ^7a or OR ⁷ . (11) when A is CH, Z is CR ² , R ² is H, Ar is unsubstituted phenyl and R ³ is CH ₃ , c ₂ h ₅ , CF ₃ or c ₅ h ₄ f then R ¹ no is a CF ₃ or c ₂ f ₅ (12) when A is a CR, R j e H, Z is CR ² , R ² j e OH and R ^1, and R ³ are H, then Ar not is phenyl; (13) when A is a CR, R is H, Z is CR ² , R ² is OH or nh ₂ , r ¹ and R ³ are CH ₃ , then Ar is not 4-phenyl-3-cyano-2-aminopyrid- The compound of claim 9 and its isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to And R ³ is NR ^{6a and} R ^7a or OR ⁷ . A compound of formula 1 according to claim 8 and its isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof. A compound according to claim 13 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 sub-. . 4 stituents of R. A compound according to claim 13 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein R ³ is NR ^{6a and} R ^7a or OR ⁷ . A compound according to claim 15 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms thereof, wherein R ^6a is independently selected from the group consisting of: - H, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C ₁ -C ₁₀ haloalkyl of 1 to 10 halogen atoms, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C 10 ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl or C 6 -C ₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently or 85 85 selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) n R ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl, - aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C _x -C ₄ _ alkyl), heterocyclyl or heterocyclyl (C _x -C ₄ alkyl); and R ^7a is independently selected from the group consisting of: - H, - C ₅ -C ₁₀ alkyl, C ₃ -C _{x 0} alkenyl, C ₃ -C ₁₀ alkynyl, C _x -C _xo haloalkyl with 1-10 halogens, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, C 5 C _x0 cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from: C _x -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR, SH, S (O) _n R ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ® COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl, - aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C _x -C ₄ _ alkyl), heterocyclyl or heterocyclyl (C _x -C ₄ alkyl); alternatively, NR ⁶ R ⁷ and NR ^6a R ^7a each independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1 to 3 C _x -C ₄ alkyl. A compound according to claim 15 and its isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug thereof. 6a and 7a, _{from the} drug form, wherein R and R are the same and are selected from a file comprising: -C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected from C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano , OR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl, aryl or heteroaryl. A compound according to claim 15 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein R ^6a is independently selected from the group consisting of: - H, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C 1 -C 10 haloalkyl of 1 to 10 halogen atoms, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C 10 ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of C-Cgalkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, , cyano, OR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl, - aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C _x -C ₄ _ (C 1-7 alkyl), heterocyclyl or heterocyclyl (C ₁ -C ₄ alkyl); and R ^7a is independently selected from the group consisting of - H, - C ₁ -C ₄ alkyl and each such C ₁ -C ₄ alkyl is substituted with 1 to 3 substituents independently selected from the group consisting of Cj-Cgalkyl, C ₃ -C ₆ cycloalkyl, halogen, C _x -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, nr ⁸ conr ¹⁶ r ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁸ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl. A compound according to claim 15 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein R ^6a and R ^7a are identical and are selected from the group consisting of: C ₃ -C ₆ cycloalkyl, each such C ₃ -C ₆ cycloalkyl optionally substituted with 1 to 3 substituents independently selected from: C ₁ -C ₆ alkyl, C ₃ -C _e cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, , cyano, OR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl, - aryl, heteroaryl, or - heterocyclyl. and the other R ^6a and R ^7a are unsubstituted C ₁ -C ₄ alkyl. A compound according to claim 15 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt or prodrug form thereof, wherein R ^6a and R ^7a are independently selected from the group consisting of: - H or C ₁ -C 4 alkyl, each such C ₁ -C ₁₀ alkyl being optionally substituted with 1 to 3 substituents independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ¹³ , NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl. A compound according to claim 13 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R ⁴ and R ³ are NR ^{6a and} R ^7a or OR ⁷ . A compound according to claim 21 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein R ^6a is independently selected from the group consisting of: - H, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C ₁ -C ₁₀ haloalkyl of 1 to 10 halogen atoms, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C 10 ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl or C ₆ -C ₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from C 1 -C 6 alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C 6 ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) n R ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl, - aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C _x -C ₄ _ alkyl), heterocyclyl or heterocyclyl (C ₁ -C ₄ alkyl); R ^7a is independently selected from the group consisting of H, - C ₅ -C ₁₀ alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C ₁ -C ₁₀ haloalkyl of 1 to 10 halogen atoms, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C 10 ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of Cl-Cgalkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, , cyano, OR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl, - aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C _x -C ₄ _ alkyl), heterocyclyl or heterocyclyl (C _x -C ₄ alkyl); alternatively, NR ⁶ R ⁷ and NR ⁶ R ^7a independently are piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1 to 3 C 1 -C ₄ alkyl groups. A compound according to claim 21 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug thereof, Wherein the R ^6a and R ^7a are identical and selected from the group consisting of: C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl each optionally substituted with 1 to 3 substituents independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl, aryl or heteroaryl. A compound according to claim 21 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein R ^6a and R ^7a are the same and selected from the group consisting of: - C ₁ -C ₄ alkyl, each such C ₁ -C ₄ alkyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of Cl-Cgalkyl, C ₃ -C _e cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, , OR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl. A compound according to claim 21 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein R ^6a is independently selected from the group consisting of: H, C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C 1 -C 10 haloalkyl of 1 to 10 halogen atoms, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C 10 ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl or C ₆ -C ₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ - C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) n R ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl, - aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C _x -C ₄ _ alkyl), heterocyclyl or heterocyclyl (C ₁ -C ₄ alkyl); R ^7a is independently selected from the group consisting of C ₁ -C ₄ alkyl, each such C ₁ -C ₄ alkyl being optionally substituted with 1 to 3 substituents independently selected from C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano , OR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ® COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl. The compound of claim 21 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein one of R ^6a and R ^7a is selected from the group consisting of: C ₃ -C ₆ cycloalkyl, each such C ₃ -C ₆ cycloalkyl being optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1 -C ₆ alkyl, C ₃ -C ₆ cyclo132 alkyl, halogen, C ₁ -C ₄ haloalkyl, cyano , OR ¹⁵ , SH, S (O) _n R ^13, COR ^15, CO 2 R ^15, OC (O) R ^13, NR®COR ^15, N (COR ¹⁵⁾ 2, NR ⁸ CONR ¹⁶ R ^15, NR ⁸ CO ₂ R ^13, NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl ·, - aryl heteroaryl, or heterocyclyl and the other R ^6a and R ^7a are unsubstituted C ₁ -C ₄ alkyl. A compound according to claim 21 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt or prodrug form thereof, wherein R and R are independently selected from the group consisting of: - H or C ₁ -C ₁₀ alkyl, each such C 1 -C 6 alkyl being optionally substituted with 1 to 3 substituents independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₆ alkyl; ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) n R ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl. A compound according to claim 13 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein: Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 substituents - R ³ is NR ^6a R ^7, OR ^7, and - R ¹ and R ² are independently selected from H, C _x -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₀ cycloalkylalkyl. A compound according to claim 28 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein R is independently selected from the group consisting of: - H, - C _x -C _xo alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C _x -C _xo haloalkyl with 1-10 halogens, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl, or C ₆ -C ₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of C _x -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) n R ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ® CR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl, - aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C _x -C ₄ _ alkyl), heterocyclyl or heterocyclyl (C _x -C ₄ alkyl); R ^7a is independently selected from the group consisting of -H. - C ₅ -C _{x 0} alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C _x -C _xo haloalkyl with 1-10 halogens, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₆ cycloalkyl, C _{4-C x2} cycloalkylalkyl, C ₅ -C _xo cycloalkenyl, or C _{6 X 4} -C cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from: Cj-Cgalkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ - C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) n R ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl, - aryl, aryl (C _x -C ₄ alkyl), heteroaryl, heteroaryl (0χ-0 _ ₄ alkyl), heterocyclyl or heterocyclyl (C ₁ -C ₄ alkyl); alternatively, NR ⁶ R ⁷ and NR ^6a R ^7b independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1 to 3 C _x -C ₄ alkyl. A compound according to claim 28 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein R ^6a and R ^7a are identical and are selected from the group consisting of: C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano , OR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl, aryl or heteroaryl. A compound according to claim 28 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug thereof, 495 drug forms wherein R ^6a and R ^7a are the same and selected from the group consisting of: C ₁ -C ₄ alkyl, each such C ₁ -C ₄ alkyl being optionally substituted with 1 to 3 substituents independently selected from C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl. A compound according to claim 28 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein R ^6a is selected from the group consisting of: - H, "Ci ^- C ₁₀ alkyl, C ₃ -C ₁₀ alkenyl, C ₃ -C ₁₀ alkynyl, C ^ C ^ haloalkyl with 1-10 halogens, C ₂ -C ₈ alkoxyalkyl, C ₃ -C ₆ cycloalkyl, C ₄ -C ₁₂ cycloalkylalkyl, C ₅ -C ₁₀ cycloalkenyl or C ₆ -C ₁₄ cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) n R ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ® COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl, aryl, aryl (C ₁ -C ₄ alkyl), heteroaryl, heteroaryl (C 1 -C ₄ alkyl), heterocyclyl or heterocyclyl (C ₁ -C ₄ alkyl); _7a R is C ₁ -C ₄ alkyl, each such C ₁ -C ₄ alkyl being 436 optionally substituted with 1 to 3 substituents independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) n R ¹³ , COR ¹⁵ , CO 2 R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ² R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl and heterocyclyl. A compound according to claim 28 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt or prodrug form thereof, wherein one of R ^6a and R ^7a is selected from the group consisting of: C ₃ -C ₆ cycloalkyl, each such C ₃ -C ₆ cycloalkyl being optionally substituted with 1 to 3 substituents independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ¹³ , NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl, - aryl, heteroaryl, or heterocyclyl and the other R ^6a and R ^7a are unsubstituted C ₁ -C ₄ alkyl. A compound according to claim 28 and isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and a pharmaceutically acceptable salt thereof, or a prodrug form thereof, wherein R ^6a and R ^7a are independently selected from the group consisting of: 137 - or C 1 -C 4 alkyl, each such C 1 -C 4 alkyl being optionally substituted with 1 to 3 substituents independently selected from the group consisting of C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, halogen, C ₁ -C ₄ haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹³ , COR ¹⁵ , CO ² R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ¹³ , NR ¹⁶ R ^15, CONR ¹⁶ R ^15, aryl, heteroaryl and heterocyclyl.