SI9720045A - Azolo triazines and pyrimidines - Google Patents

Abstract

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

Description

AZOLO TRIAZINES AND PYRIMIDINES

FIELD OF THE INVENTION

The present invention relates to the treatment of psychiatric disorders and neurological diseases, including severe depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear paralysis and eating disorders, as well as the treatment of immunological, cardiovascular or cardiovascular disorders and colorectal hypersensitivity disorder and stress by administering certain [1,5-a] -pyrazolo-1,3,5-triazines, [1,5-aj-1,2,3triazolo-1,3,5-triazines, [1,5 -a] -pyrazolo-pyrimidines and [1,5-a] -1,2,3-triazolo-pyrimidines.

BACKGROUND OF THE INVENTION

The corticotropin release factor (referred to herein as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary lobe [J. Rivier et al., Off. Nat. Acad. Sci. [USA] 80: 4851 (1983); W. Vale et al., Science 213: 1394 (1981)]. In addition to its endocrine role on the pituitary, the immunohistochemical localization of CRF has shown that the hormone is widespread outside the hypothalamus, in the central nervous system, and produces a wide range of autonomic, electrophysiological, and behavioral effects consistent with the role of the neurotransmitter or neuromodulator in the brain [W. Vale et al., Pec. Prog. Horm. Pes. 39: 245 (1983); G.F, Koob, Persp. Behav. Med. 2:39 (1985); E.B. De Souza et al., J. Neurosci. 5: 3189 (1985)]. There is also evidence that CRF plays an important role in integrating the immune system response to physiological, psychological, and immunological stress factors [J.E. Blalock, Physiological Pevievvs 69: 1 (1989); J.E. Morley, Life Sci. 41: 527 (1987)].

Clinical data provide evidence that CRF plays a role in psychiatric and neurological disorders, including depression, anxiety-related disorders and eating disorders. CRF is also thought to play a role in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear paralysis and amyotrophic lateral sclerosis as far as these diseases are concerned.

-2 apply to dysfunction of CRF neurons in the central nervous system [for a review article, see E.B. De Souza, Hosp. Practice 23:59 (1988)].

In an emotional disorder, or severe depression, the level of CRF in the cerebral spinal cord (CSF) in individuals not taking the drug is significantly increased [C.B. Nemeroff et al., Science 226: 1342 (1984); C.M. Banks et al., Am. J. Psychiatry 144: 873 (1987); R.D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol. Psychiatry 25: 355 (1989)]. Further, the density of CRF receptors in the frontal cortex of suicide victims is significantly reduced, consistent with CRF hypersecretion [C.B. Nemeroff et al., Arch. Gen. Psychiatry 45: 577 (1988)]. In addition, a blunted response of adrenocorticotropin (ACTH) to CRF (given intravenously) was observed in depressed patients [P.W. Gold et al., Am. J. Psychiatry141: Q19 (1984); F. Hoisboers et al., Psychoneuroendocrinology9A47 (1984); P.W. Gotd et al., NewEng. J. Med. 314: 1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that CRF hypersecretion may be implicated in the symptoms seen in human depression [R.M. Sapolsky, Arch. Gen. Psychiatry 46: 1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the number of CRF receptors in the brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

CRF is also thought to play a role in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals, and interactions between benzodiazepine / non-benzodiazepine anxiolytics and CRF have been demonstrated in various models of behavioral anxiety [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 a putative CRF receptor antagonist, α-helical sheep CRF (9-41), in various behavioral paradigms, indicate that antagonists produce 'anxiolytic-like' effects that are qualitatively similar to the effects of benzodiazepines [C.W. Berridge and A.J. Dunn Horm. Behav. 21: 393 (1987), Brain Research Revievs 15:71 (1990)]. Neurochemical, endocrine, and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics and provided further evidence for CRF involvement in these disorders. Chlordiazepoxide in rats attenuates the 'anxiogenic' effects of CRF in both the conflict test [K.T. Britton et al., Psychopharmacology 86: 170 (1985); K.T. Britton et al., Psychopharmacology

-394: 306 (1988)], as in the acoustic excitation test [N.R. Swerdlow et al., Psychopharmacology 88: 147 (1986)]. The benzodiazepine receptor antagonist (Ro151788), alone without behavioral activity in a functioning conflict test, reversed the effects of CRF in a dose-dependent manner, while the benzodiazepine counterpart agonist (FG7142) increased the effects of CRF [K.T. Britton et al., Psychopharmacology 94: 306 (1988)].

The mechanisms and sites of action through which standard anxiolytics and antidepressants achieve their therapeutic effects remain to be elucidated. However, it is hypothesized that they are involved in stopping the hypersecretion of CRF observed in these disorders. It is of particular importance that preliminary studies investigating the effects of CRF receptor antagonist (α-screw CRF9-41) at different life patterns have shown that CRF antagonist achieves 'anxiolytic-like effects' qualitatively similar to those of benzodiazepines [for review see G.F. Koob and K.T. Britton, V: Corticotropin-Releasing Factor Basic and Clinical Studies of a Neuropeptide, E.B. De Souza and C.B. Nemeroff eds., CRC Press p. 221 (1990)].

Several publications describe the release factor corticotropin antagonist compounds and their use for the treatment of psychiatric disorders and neurological disorders. Examples of such publications include DuPont Merck PCT Application US94 / 11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727, and Pfizer EP 0778 277 A1.

To the extent known, [1,5-a] -pyrazolo-1,3,5-triazines, [1,5-a] -1,2,3-triazolo-1,3,5-triazines, [1, 5a] -pyrazolo-pyrimidines and [1,5-a] -1,2,3-triazolo-pyrimidines have not yet been listed as corticotropin release factor antagonist compounds useful in the treatment of psychiatric disorders and neurological diseases. However, there are some publications that list some of these compounds for other purposes.

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

3 where R is OH or alkanoyl, R is H, OH or SH and R is an unsaturated heterocyclic group, naphthyl! or substituted phenyl, and states that the compounds have inhibitory activity for xanthine oxidases and are useful for the treatment of gout.

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

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

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

where R ¹ is CH3, C2H5 or C6H5, X is H, ΟθΗδ, m-CH3C6H4, CN, COOEt, Cl, J or Br, Y is H, C6H5, O-CH3C6H4 or P-CH3C6H4 and Z is OH, H. CH3, C2H5, C6H5, n-C3H7,1-C3H7, SH, SCH3, NHC4H9 or N (C2H5) 2, and state that the compounds are c-AMP phosphodiesterase inhibitors and are useful as bronchodilators.

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

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

US 5,137,887 discloses pyrazolotriazines of formula

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

US 4,892,576 discloses pyrazolotriazines of formula

wherein X is O or S, Ar is a phenyl, naphthyl, pyridyl or thienyl group, R 6 -R 8 ^are H-alkyl, etc. and R8 is 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 containing, inter alia, a herbicidal compound of the formula

where A may be N, B may be CR3, R3 may be phenyl or substituted phenyl, etc., R is -N (R4) SO2R5 or -SO2N (Re) R7 and R-) and R2 may be combined to form

Y 2 Υ X D where X, Y and Z are H, alkyl, acyl, etc. and D is O or S.

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

where Z is H, OH, CH3, C2H5, C6H5, n-C3H7, iso-C3H7, SH, SCH3, NH (n-C4Hg) or N (C2H5) 2, R is H or CH3 and R1 is CH3 or C2H5. The reference lists eight therapeutic areas where cAMP phosphodiesterase inhibitors may be useful, such as: asthma, diabetes, female fertility control, male infertility, psoriasis, thrombosis, anxiety, and increased blood pressure.

-8WO95 / 35298 (Otsuka, 1995) discloses pyrazolopyrimidines and states that they are useful as analgesics. The compounds are represented by the formula

where Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond, alkylene or alkenylene, R ¹ is H,

3 alkyl, etc., R is naphthyl, cycloalkyl, heteroaryl, substituted phenyl or phenoxy, R is H, alkyl or phenyl, R is H, alkyl, alkoxycarbonyl, phenylalkyl, optionally phenylthio-substituted phenyl or halogen, R ⁵ and R ⁶ are H or alkyl.

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

-9 where R1, R2, R3 and R4 are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl or phenyl, R5 is SR6 or NR7R8, R6 is pyridyl or optionally substituted phenyl and R7 and Re are H or optionally substituted phenyl.

Springer et al., J. Med. Chem., 1976, vol. 19, no. 2, 291-296 and Springer's U.S. Patents 4021,556 and 3,920,652 disclose pyrazolopyrimidines of formula

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

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

wherein R ¹ is CF 3, C 2 F 5 or C 6 H 4 F and R 4 is CH 3, C 2 H 5, CF 3 or C 5 H 4 F.

-10Maquestiau et al., Buli. Soc. Belg., Vol. 101, no. 2, 1992, pages 131-136, discloses pyrazolo [1,5-a] pyrimidine of formula

Ibrahim et al., Arch. Pharm. (weinheim) 320, 487-491 (1987), discloses pyrazolo [1,5-

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

Other references disclosing azolopyrimidines include EP 0 511 528 (Otsuka, 1992), US 4,997,940 (Dow, 1991), EP 0 374 448 (Nissan, 1990), US 4,621,556 (ICN, 1997), EP 0 531 901 (Fujisawa, 1993), US 4,567,263 (BASF, 1986), EP 0 662 477 (Isagro, 1995), DE 4 243 279 (Bayer, 1994), US 5,397,774 (Upjohn, 1995), EP 0 521 622 (Upjohn, 1993), WO 94/109017 (Upjohn, 1994), J. Med. Chem., 24, 610-613 (1981) and J. Het. Chem., 22, 601 (1985).

-11 SUMMARY OF THE INVENTION

According to one aspect, the present invention provides novel compounds, pharmaceutical compositions, and methods that can be used to treat emotional disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear paralysis, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other eating disorders, symptoms after drug or alcohol withdrawal, drug addiction, inflammatory disorders, fertility problems, disorders that can be treated or accelerated by CRF antagonism, but not limited to disorders caused by or accelerated by CRF, or disorders selected from inflammatory disorders such as rheumatoid arthritis and .osteoarthritis, pain, asthma, psoriasis and allergies; general anxiety disorders; panic, phobia, obsessive-compulsive disorder; post-traumatic stress disorder; stress-induced sleep disorders; sensations of pain, such as fibromyalgia; mood disorders such as depression, including severe depression, individually episodic depression, recurrent depression, depression caused by child abuse and postpartum depression; dysthymia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer; human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, and postoperative ilius and colon hypersensitivity associated with psychopathological disorders or stress; eating disorders such as anorexia nervosa and bulimia nervosa; hemorrhagic stress; with the stress of triggered psychotic episodes; euthyroid disease syndrome; inadequate antidiarrheal hormone (ADH) syndrome; obesity; infertility; head trauma; spinal cord trauma; ischemic neuronal injuries (e.g., cerebral ischemia, such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and cardiac disorders, including hypertension, tachycardia, and congestive heart failure; drops; immune dysfunctions, including stress-induced immune dysfunctions (e.g., stress-induced chills, swine stress syndrome, volitional transport fever, equine paroxysmal fibrillation, and hen-confinement dysfunctions, sheep stress due to shearing, or stress in dogs - interacting with dogs) animal); muscle spasms; urinary incontinence;

-12 Alzheimer's type dementia; multiple dementia; amyotrophic lateral sclerosis; dependencies and addictions on chemical substances (e.g., dependence on alcohol, cocaine, heroin, benzodiazepines, or other drugs); symptoms after stopping the drug or alcohol; osteoporosis; psychosocial retardation and hypoglycemia in a mammal.

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

In another aspect, the present invention provides novel compounds of Formulas (1) and (2) (described below) that are useful as corticotropin release factor antagonists. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress hypersecretion of CRF. The present invention also includes pharmaceutical compositions containing such compounds of Formulas (1) and (2) and methods of using such compounds to suppress CRF hypersecretion and / or to treat anxiety disorders.

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

DETAILED DESCRIPTION OF THE INVENTION [1] The present invention provides a method of treating emotional disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear lameness, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa, nerve disorder drug addiction, symptoms after stopping drug or alcohol use, inflammatory diseases, cardiovascular or heart disease, fertility problems, infections with

-13 human immunodeficiency virus, hemorrhagic stress, obesity, infertility, head and spinal cord trauma, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycaemia or disorders whose treatment can be performed or accelerated by CRF antagonism, including but not limited to disorders caused or accelerated with CRF, in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of Formulas (1) or (2):

(D (2) and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its forms of pharmaceutically acceptable salts or prodrugs, wherein:

A is N or CR;

Z is N or CR ² ;

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2- benzopyranyl, tetralinyl, each Ar is optionally substituted by 1 to 5 R groups and each Ar is bonded to an unsaturated carbon atom;

R is at each occurrence independently selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl;

-14R ¹ at each occurrence is independently selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, CN, C1-C4 haloalkyl, C1-C-12 hydroxyalkyl, C2-C12 alkoxyalkyl, 9 10

C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR R, C1-C4 alkyl-NR ⁹ R ¹⁰ , NR ⁹ COR ¹⁰ , OR ¹¹ , SH or S (O) _n R ¹² ;

R is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN, -NR ⁶ R ⁷ , NR ⁹ COR ^W , NR ⁶ S (O) n R ^7, S (O) NAP ⁶ R ^7, C1-C4 haloalkyl, ^-OR7, SH or -S (O) _n R ^12;

R is selected from;

-H, OR ⁷ , SH, S (O) nR ¹³ , COR ⁷ , CO2R ⁷ , OC (O) R ¹³ A 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

-C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C12 cycloalkylalkyl or C6-C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents each at each occurrence selected from Ο-ι-Οθ alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 CO2R ¹³ NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ aryl, heteroaryl and heterocyclyl;

R is independently selected at each occurrence;

C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, NO2, halo, CN, C1-C4 haloalkyl, NR ⁶ R ⁷ , NR ⁸ COR ⁷ , NR ⁸ CO2R ⁷ , COR ⁷ , OR ⁷ , CONR ⁶ R ⁷ , CO (NOR ⁹ ) R ⁷ CO2R ⁷ or S (O) nR ⁷ , wherein each such is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 6 cycloalkyl and C4-C12 cycloalkylalkyl optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C4 alkyl, NO2, halo, CN, NR ⁶ R ⁷ NR ⁸ COR ⁷ NR ⁸ CO2R ^? COR ⁷ , OR ⁷ , CONR ⁶ R ⁷ , CO2R ⁷ CO (NOR ⁹ ) R ⁷ or S (O) nR ^? ;

R ⁸ and R ⁷ , R ^6a and R ^7a are independently selected at each occurrence;

-H,

-15-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl , which is each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n R ¹³ COR ^{14 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, or heterocyclyl,

-aryl, aryl (C1-C4 alkyl), heteroaryl, heteroaryl (C1-C4 alkyl), heterocyclyl or heterocyclyl (C1-C4 alkyl);

θ 7 6ct 7a alternatively, NR R and NR ^a R are independently piperidine, pyrrolidine, piperazine, Nmethylpiperazine, morpholine or thiomorpholine, each optionally substituted by 1-3 C 1 -C 4 alkyl groups;

Mr Rücker

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

10

R and R are at each occurrence independently selected from H, C1-C4 alkyl or C3-C6 cycloalkyl;

R ¹¹ is selected from H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 6 cycloalkyl;

R is C1-C4 alkyl or C1-C4 haloalkyl;

R is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4C12 cycloalkylalkyl, aryl, aryl (C1-C4 alkyl) -, heteroaryl or heteroaryl (C1-C4 alkyl) -;

R is selected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl or C4C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3- C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹⁵ , COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹⁵

-16NR ⁸ COR ¹⁵ N (COR ¹⁵ ) 2i nr ⁸ conr ¹⁶ r ¹⁵ , nr ⁸ co2r ¹⁵ , nr ¹⁶ r ¹⁵ , 16 16

CONR R, and C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl and C 1 -C 6 alkylsulfonyl;

16

R and R are at each occurrence independently selected from H, C 1 -C 8 alkyl, C 3 -C 10 15 cycloalkyl, C 4 -C 16 cycloalkylalkyl, except that for S (O) _n R 1, R 1 cannot be H;

aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹⁵ , COR ¹⁵ , CO2R 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 ;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazobutyl, 2,3-dihydrobenzyl, 2,3-dibenzylidene, 2,3-dibenzylidene, 2,3-dibenzylidene, 2,3-dibenzyl which is each optionally substituted with 1 to 5 substituents at each occurrence independently selected from C 1 -C 6 15 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n R, cor ¹⁵ , CO2R 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 a saturated or partially saturated heteroaryl optionally substituted with 1 to 5 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹⁵ , COR ¹⁵ , CO2R ¹⁵ OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ¹⁵ , NR ¹⁵ R ¹⁶ and CONR ¹⁶ R ¹⁵ ;

n is independently 0,1 or 2 at each occurrence.

[2] Preferred methods of the present invention are those wherein, in the compound of Formulas (1) or (2), Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 4

R substituents.

-17 [3] Further preferred methods of the above invention are those wherein in compound s

Formulas (1) or (2), A is N, Z is CR, Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6 trimethylphenyl, R ¹ and R ² are CH 3 and R ³ is NR ^6a R ^7a [4] The present invention comprises compounds of Formulas (1) or (2):

(D (2) and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their forms of pharmaceutically acceptable salts or prodrugs, wherein:

A is N or CR;

Z is N or CR ² ;

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinium, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2- benzopyranyl, tetralinyl, each Ar is optionally 4 substituted by 1 to 5 R groups and each Ar is attached to an unsaturated carbon atom;

R is at each occurrence independently selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl;

-18R ¹ at each occurrence is independently selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl, C2-C12 alkoxyalkyl, 9 10

C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR R, C1-C4 o 10 dm 11 19 alkyl-NR ^y R NR COR, OR, SH or S (O) _n R;

R is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, 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 is selected from:

-H, OR ⁷ , SH, S (O) nR ¹³ , COR ⁷ CO2R 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

-C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C12 cycloalkylalkyl or C6-C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents each at each occurrence selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 is independently selected at each occurrence from:

C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, ΝΟ2, halo, CN, C1-C4 haloalkyl, NR ⁶ R ⁷ , NR ⁸ COR ⁷ , NR ⁸ CO2R ⁷ , COR ⁷ , OR ⁷ , CONR ⁶ R ⁷ , CO (NOR ⁹ ) R ⁷ , CO2R ⁷ or S (O) nR ⁷ wherein each such is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C6 cycloalkyl and C4-C12 cycloalkylalkyl optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C4 alkyl, NO2, halo, CN, NR ⁶ R ⁷ NR ⁸ COR ⁷ NR ⁸ CC> 2R ⁷ COR ⁷ , OR ⁷ , CONR ⁶ R ⁷ CO2R ⁷ CO (NOR ⁹ ) R ⁷ or S (O) nR ⁷ ;

R ⁶ and R ⁷ , R ^6a and R ^7a are independently selected at each occurrence from:

-H,

-19-C- | -C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or Οθ- cik4 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n R ¹³ , COR ^{14 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 or heterocyclyl,

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

7 63 7a, alternatively, NR R and NR R are independently piperidine, pyrrolidine, piperazine, Nmethylpiperazine, morpholine or thiomorpholine, each optionally substituted by 1-3 C 1 -C 4 alkyl groups;

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

10

R and R are at each occurrence independently selected from H, C1-C4 alkyl or C3-C6 cycloalkyl;

R ¹¹ is selected from H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 6 cycloalkyl;

R is C1-C4 alkyl or C1-C4 haloalkyl;

R is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 C 12 cycloalkylalkyl, aryl, aryl (C 1 -C 4 alkyl) -, heteroaryl or heteroaryl (C 1 -C 4 alkyl) - ;

R is selected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl or C4C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-Cβ alkyl, C3- C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹⁵ , COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹⁵ ,

-20NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, nr ⁸ conr ¹⁶ r ¹⁵ , nr ⁸ co ₂ r ¹⁵ , nr ¹⁶ r ¹⁵ , CONR ¹⁸ R ¹⁵ and C- | -C6 alkylthio, Οι-Οθ alkylsulfinyl and Οι -Οθ alkylsulfonyl:

16

R and R are at each occurrence independently selected from H, C1-C6 alkyl, C3-C10 15 15 cycloalkyl, C4-C1 θ cycloalkylalkyl, except that for S (O) _n R, R cannot be H;

aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹⁵ , COR ¹⁵ , CO2R 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 ;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazobutyl, 2,3-dihydrobenzyl, 2,3-dibenzylidene, 2,3-dibenzylidene, 2,3-dibenzylidene, 2,3-dibenzyl which is each optionally substituted with 1 to 5 substituents at each occurrence independently selected from Οι-Οθ 15 15 alkyl, Ο3-Οθ cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR, SH, S (O) nR. COR ¹⁵ , CO2R 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 ^1e R ¹⁵ and CONR ¹⁶ R ¹⁵ ;

heterocyclyl is a saturated or partially saturated heteroaryl optionally substituted with 1 to 5 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹⁵ , COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ¹⁵ , NR ¹⁵ R ¹⁶ and CONR ¹⁶ R ¹⁵ ;

n is independently 0,1 or 2 at each occurrence, 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;

-21 (2) 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 5, n-C 3 H 7, i-C 3 H 7, SH, SCH3, NHC4H9 or N (C2Hs) 2, then Ar is not phenyl or m-CH3-phenyl;

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

(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) when A is CR and Z is CR ² , then R ² is not -NR ⁶ SO2R ^? or -SO ² NR ⁶ R ⁷ ;

(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) when A is N, Z is CR ² , R ¹ is methyl or ethyl, R ² is H and R ³ is H, OH, CH3, C2H5, ΟθΗδ, n-C3H7, IZO-C3H7, SH, SCH3, NH (n-C4Hg) or N (C2Hs) 2, then Ar is not unsubstituted phenyl or m-methylphenyl;

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

3 13 Ra 7a (9) when A is CR, Z is CR, R is H or alkyl, Ar is phenyl and R is SR or NR R, then R ¹³ is not aryl or heteroaryl and R ^6a and R ^7a are not 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-NHCOCH3-phenyl, p-CH3-phenyl, pyridyl or naphthyl;

2 3 (11) where A is CH, Z is CR, R is H, Ar is an unsubstituted phenyl and R is CH3, C2H5, CF3, or C6H4F, then ^R1 is CF3 or C2F5;

-22 (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-aminopyrid-2-yl .

[5] Preferred compounds of the above invention are compounds of Formulas (1) and (2) and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their pharmaceutically acceptable salts or prodrugs, with additional conditions that; (1) when A is N, R ¹ is H, C 1 -C 4 alkyl, halo, CN, C 1 -C 12 hydroxyalkyl, C 1 -C 4 alkoxyalkyl or SO 2 (C 1 -C 4 o 7Λ or 7p alkyl), R is NR R and R is unsubstituted C1-C4 alkyl, then R is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C3-C6 cycloalkyl; and (2) A is N, R ¹ is H, C 1 -C 4 alkyl, halo, CN, C 1 -C 12 hydroxyalkyl, C 1 -C 4 3 63 73 73 alkoxyalkyl or SO 2 (C 1 -C 4 alkyl), R is NR R and R is unsubstituted C1-C4 alkyl, 63 then R is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C3-C6 cycloalkyl.

[6] Preferred compounds of the above invention also include compounds of Formulas (1) and (2) and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their forms of pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl 4 or 2 , 3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R substituents.

[7] Preferred compounds of the above invention also include compounds of Formulas (1) and (2) and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their pharmaceutically acceptable salts or prodrugs, wherein A is N, Z is

12 3

CR, Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethiphenyl, R and R are CH3 and R is NR ^6a R ^7a .

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

-23 [12] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their forms of pharmaceutically acceptable salts or prodrugs.

[13] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,34 dihydrobenzofuranyl and each Ar is optionally substituted by 1 to 4 R substituents.

[14] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their form 3 6a 7a 7 pharmaceutically acceptable salts or prodrugs, wherein R is NR R or OR.

[15] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,34 3 dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R substituents and R is NR ^6a R ^7a or OR ⁷ .

[16] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their form 2 pharmaceutically acceptable salts or prodrugs, wherein Z is CR.

[17] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,34 dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R substituents.

[18] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their pharmaceutically acceptable salts or prodrugs, wherein R ³ is NR ^6a R ^7a or OR ⁷ .

-24 [19] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms and their form 6a of pharmaceutically acceptable salts or prodrugs, wherein R is independently selected from:

-H,

-CtC-fo alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C-10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl , which is each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ aryl, heteroaryl or heterocyclyl,

-aryl, aryl (C 1 -C 4 alkyl) -, heteroaryl, heteroaryl (C 1 -C 4 alkyl) -, heterocyclyl or heterocyclyl (C 1 -C 4 alkyl) -; and 7a

R is independently selected at each occurrence from:

-H,

-C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl each is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, O 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n 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 CO2R ¹³ NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ aryl, heteroaryl or heterocyclyl,

-aryl, aryl (C1-C4 alkyl), heteroaryl, heteroaryl (C1-C4 alkyl), heterocyclyl or heterocyclyl (C1-C4 alkyl);

alternatively, NR ⁶ R ⁷ and NR ^6a R ^{7a are} independently piperidine, pyrrolidine, piperazine, Nmethylpiperazine, morpholyl or thiomorpholyl, each optionally substituted by 1-3 C 1 -C 4 alkyl groups.

-25 [20] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their pharmaceutically acceptable salts or prodrugs, wherein R ^6a and R ^{7a are} identical and selected from:

-C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH , S (O) nR ¹³ , -COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) _2i NR ⁸ CONR ¹⁶ R ¹⁵ ,

NR ⁸ CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl, and

-aryl or heteroaryl.

[21] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrugs, wherein R is selected from:

-H,

-C1-C10 alkyl, C3 -C10 alkenyl, C3 -C10 alkynyl, C1 -C10 haloalkyl with 1-10 halogens, C ₂ -CS alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, which is each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n R ¹³ , COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2i NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ¹³ NR ¹⁶ R ¹⁵ CONR ¹⁶ R ¹⁵ aryl, heteroaryl or heterocyclyl,

-aryl, aryl (C1-C4 alkyl), heteroaryl, heteroaryl (C1-C4 alkyl), heterocyclyl or heterocyclyl (C1-C4 alkyl);

R ^7a is selected from:

-C 1 -C 4 alkyl and each such C 1 -C 4 alkyl is substituted with 1-3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 co2r ¹³ , nr ¹⁶ r ¹⁵ ,

15

CONR R, aryl, heteroaryl or heterocyclyl.

-26 [22] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their pharmaceutically acceptable salts or prodrugs, wherein one of R and R ^{d is} selected from:

-C3-C6 cycloalkyl, each such C3-C6 cycloalkyl is optionally substituted with 1-3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH. S (O) nR ¹³ , COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2i NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl,

-arila,

-heteroaryl or -heterocyclyl and the other of R and R is unsubstituted C1-C4 alkyl.

[23] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their forms 63 7a pharmaceutically acceptable salts or prodrugs, wherein R and R are independently H or C1-C10 alkyl, each such C 1 -C 10 alkyl is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 CO2R ¹³ NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl .

[24] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,34 θ dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R substituents and R is NR ^6a R ^7a or OR ⁷ .

[25] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their form 63 pharmaceutically acceptable salts or prodrugs, wherein R is independently selected from:

-H,

-27-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl , which is each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocycle,

-aryl, aryl (C1-C4 alkyl) -, heteroaryl, heteroaryl (C1-C4 alkyl) -, heterocyclic or heterocyclyl (C1-C4 alkyl);

7a

R is independently selected at each occurrence from:

-H,

-C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or Οθ-Οΐ4 cycloalkenylalkyl is each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ aryl, heteroaryl or heterocyclic,

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

7 6a 7a, alternatively, NR R and NR R are independently piperidine, pyrrolidine, piperazine, Nmethylpiperazine, morpholi or thiomorpholyl, each optionally substituted by 1-3 C 1 -C 4 alkyl groups.

[26] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their forms 6a 7a of pharmaceutically acceptable salts or prodrugs, wherein R and R are identical and selected from:

-28-C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl and

-aryl or heteroaryl.

[27] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their 6ci7ci forms of pharmaceutically acceptable salts or prodrugs, wherein R and R are identical and are -C 1 -C 4 alkyl, each such C 1 -C 4 alkyl is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 co2r ¹³ ,

C 4 £ H C H C

NR R, CONR R, aryl, heteroaryl or heterocyclyl.

[28] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their form 6a of pharmaceutically acceptable salts or prodrugs, wherein R is selected from:

-H,

-C1-C10 alkyl, C3 -C10 alkenyl, C3 -C10 alkynyl, C1 -C10 haloalkyl with 1-10 halogens, C ₂ -CS alkoxyalkyl, Ο3-Οθ cycloalkyl, C4-C- | ₂ cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents. gb in each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n 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 or heterocyclyl,

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

-29-C1-C4 alkyl and any such C1-C4 alkyl is substituted with 1-3 substituents independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH , S (O) nR 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 co2r ¹³ nr ¹⁶ r ¹⁵

15

CONR R, aryl, heteroaryl or heterocyclyl.

[29] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their forms 63 73 pharmaceutically acceptable salts or prodrugs, wherein one of R and R is selected from:

-C3-C6 cycloalkyl, each such C3-C6 cycloalkyl is optionally substituted with 1-3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH. S (O) nR ¹³ , COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹³ NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2i nr ⁸ conr ¹⁶ r ¹⁵ NR ⁸ CO ₂ R ¹³ NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl,

-arila,

-heteroaryl or

-heterocyclyl 63 73 and the second of R and R is unsubstituted C1-C4 alkyl.

[30] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their forms 63 73 pharmaceutically acceptable salts or prodrugs, wherein R and R are independently H or C1-C10 alkyl, each such C 1 -C 10 alkyl optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 CO2R ¹³ NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl.

[31] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their forms of pharmaceutically acceptable salts or prodrugs, wherein

-30-Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each such Ar is optionally substituted by 4

1 to 4 R substituents, " 3. _K1 _, 6a_7a .. __7.

-R is NR R or OR and

2

-R and R are independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.

[32] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their pharmaceutically acceptable salts or prodrugs, wherein R is independently selected from:

-H,

-C-1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl , which is each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n R ¹³ , COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) _2i NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl ,

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

7a

R is independently selected at each occurrence from:

-H,

-C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl each is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S {O) _n R ¹³ COR ¹⁵ , CO2R ¹⁵ OC (O) R ¹³ NR ⁸ COR ¹⁵ N (COR ¹⁵ ) 2, NR ⁸ CONR ¹⁸ R ¹⁵ NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl,

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

-316 7 Sa. 7a, alternatively, NR R and NR R are independently piperidine, pyrrolidine, piperazine, Nmethylpiperazine, morpholyl or thiomorphoyl, each optionally substituted by 1-3 C 1 -C 4 alkyl groups.

[33] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms and their forms 6a to 7% of pharmaceutically acceptable salts or prodrugs, wherein R and R ^{d are} identical and selected from:

-C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 1 k ή · 1 c cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) nR, -COR,

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 or heterocyclyl, and

-aryl or heteroaryl.

[34] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms and their forms 6a 7a of pharmaceutically acceptable salts or prodrugs, wherein R and R are identical and are

-C1-C4 alkyl, each such C1-C4 alkyl is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n 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 CO2R ¹³ NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl.

[35] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their form 63 pharmaceutically acceptable salts or prodrugs, wherein R is selected from:

• H,

-C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl each is optional

-32 substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n 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 or heterocyclyl,

-aryl, aryl (C1-C4 alkyl), heteroaryl, heteroaryl (C1-C4 alkyl), heterocyclyl or heterocyclyl (C1-C4 alkyl);

R is:

-C1-C4 alkyl and each such C1-C4 alkyl is substituted with 1 to 3 substituents at each occurrence independently selected from Ο-ι-Οθ alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH , S (O) nR 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 co2r ¹³ , nr ¹⁶ r ¹⁵ , i 6 f 5

GONR R, aryl, heteroaryl or heterocyclyl.

[36] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms and their forms 6ci 73.

pharmaceutically acceptable salts or prodrugs, wherein one of R and R is selected from: -C3-C6 cycloalkyl, each such C3-C6 cycloalkyl being optionally substituted with 1-3 substituents independently selected from C1-6 alkyl at each occurrence, C3- C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹³ COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ N (C0R ¹⁵ ) 2i nr ⁸ conr ¹⁶ r ¹⁵ NR ⁸ CO2R ¹³ , NR ¹⁵ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl,

-arila,

-heteroaryl or -heterocyclyl and the other of R and R is unsubstituted C1-C4 alkyl.

[37] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their form 73 pharmaceutically acceptable salts or prodrugs, wherein R and R are independently H or

Cf-ClO alkyl, ^each such C1-C10 alkyl is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4

-33haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 or heterocyclyl.

[38] Particularly preferred compounds of the above invention are compounds of Formula (50)

FORMULA (50) and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms and their forms of pharmaceutically acceptable salts or prodrugs selected from the group consisting of:

q 4-3 4b 4c 4d compound of Formula (50), wherein R is -NHCH (n-Pr) 2, R is Cl, R is H, R is Cl, R is H and R ^4e is H;

4a 4b 4c 4d compound of Formula (50), wherein R is -N (Et) (n-Bu), R is Cl, R is H, R is Cl, R is H and R ^4e is H;

43 4b 4c is a compound of Formula (50) wherein R is - (n-Pr) (CH2cPr), R is Cl, R is H, R is Cl,

-, 4d. ,,. _.4e. ,,

R is H and R is H;

4s 4b 4c compound of Formula (50) wherein R is -N (CH2CH2OMe) 2, R is Cl, R is H, R is

4d 4e

Cl, R is H and R is H;

-344a 4b 4c compound of Formula (50), wherein R is -NHCH (Et) (n-Bu), R is Cl, R is H, R is Cl,

4d 4e

R is H and R is H;

4a is a 4h compound of Formula (50), wherein R is -NHCH (Et) (CH2OMe), R is Cl, R is H, R is Cl, R ^4d is H, and R ^4e is H;

4a 4h 4p compound of Formula (50), wherein R is -NHCH (CH ₂ OMe) 2, R is Cl, R is H, R is

4d 4p

Cl, R is H and R is H;

4a. 4b 4c 4d compound of Formula (50) wherein R is-N (Et) ₂ , R is Cl, R is H, R is Cl, R is H and R ^4e is H;

4a 4h 4p compound of Formula (50), wherein R is -NHCH (CH ₂ OEt) ₂ , R is Cl, R is H, R is Cl,

R ^4d is H and R ^4e is H;

4a 4h 4r 4d compound of Formula (50), wherein R is -NHCH (Et) ₂ , R is Cl, R is H, R is Cl, R is H and R ^4e is H;

4a 4b 4c 4d compound of Formula (50), wherein R is -N (Me) (Ph), R is Cl, R is H, R is Cl, R is

H and R ⁴ ® is H;

4a 4b 4c 4d compound of Formula (50), wherein R is -N (n-Pr) ₂ , R is Cl, R is H, R is Cl, R is H and R ⁴ ® is H;

4a 4h 4c compound of Formula (50), wherein R is -NHCH (Et) (n-Pr), R is Cl, R is H, R is Cl,

4d 4e

R is H and R is H;

4a 4b 4c compound of Formula (50), wherein R is -NHCH (CH ₂ OMe) ₂ , R is Me, R is H, R is

Me, R ^4d is H and R ⁴ ® is Me;

-353 4b 4c compound of Formula (50), wherein R is -NHCH (CH2OMe) 2, R is Me, R is H, R is

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

4a 4b 4c is a compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Me, R is H, R is

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

* 3 Aa 4h ήρ is a compound of Formula (50), wherein R is -NHCH (Et) (CH2OMe), R is Me, R is H, R is Me, R ^4d is H and R ^4e is H;

4a 4b 4c is a compound of Formula (50) wherein R is -NHCH (Et) 2, R is Me, R is H, R is Me,

R ^4d is H and R ^4e is H;

4a 4b 4c 4d compound of Formula (50) wherein R is -OEt, R is Cl, R is H, R is Cl, R is H and

4e

R is H;

4a 4b 4c 4d compound of Formula (50), wherein R is -N (Et) 2, R is Me, R is H, R is Me, R is

H and R ^{4e is} H;

4a 4b 4c is a compound of Formula (50), wherein R is -N (CH 2 CN) 2, R is Me, R is H, R is Me,

4d 4e

R is H and R is H;

4a 4h 4p compound of Formula (50), wherein R is -NHCH (Me) (CH2OMe), R is Me, R is H, R is Me, R ^4d is H and R ^4e is H;

4a 4b 4c is a compound of Formula (50) wherein R is -OCH (Et) (CH2OMe), R is Me, R is H, R is

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

4a 4b 4c is a compound of Formula (50) wherein R is -N (n-Pr) (CH2cPr), R is Me, R is H, R is

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

4a is a 4h compound of Formula (50), wherein R is -NHCH (Me) (CH2N (Me) 2), R is Me, R is H,

R is Me, R is H and R is H;

-363 Δα 4h 4π compound of Formula (50), wherein R is -N (cPr) (CH2CH2CN), R is Me, R is H, R is Me, R ^4d is H and R ^4e is H;

4a 4h 4ρ compound of Formula (50), wherein R is -N (n-Pr) (CH 2 CH 2 CN), R is Me, R is H, R is Me, R ^4d is H and R ^4e is H;

4s 4h 4c compound of Formula (50), wherein R is -N (n-Bu) (CH 2 CN), R is Me, R is H, R is

Me, R ^4d is H and R ⁴ ® is H;

a compound of Formula (50) wherein R ³ is -NHCH (Et) (CH 2OMe), R ^4a is Me, R ^4b is H, R ⁴⁰ is Me, R ^4d is H and R ^4e is Me;

a compound of Formula (50) wherein R ³ is -NHCH (Et) 2, R ⁴³ is Me, R ^4b is H, R ^4c is Me,

-.40. ,,, _4e, ...

R is H and R is Me;

4a 4b 4c is a compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Me, R is H, R is

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

4a 4b 4c is a compound of Formula (50), wherein R is -NHCH (CH2OMe) 2, R is Br, R is H, R is

Ari 4 «

OMe, R is H and R is H;

Δα 4h Δρ compound of Formula (50), wherein R is -NHCH (Et) (CH2OMe), R is Br, R is H, R is

OMe, R ^4d is H and R ^4e is H;

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

Δα ΔΗ Δρ compound of Formula (50) wherein R is -NHCH (CH2OEt) 2, R is Me, R is H, R is

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

-373 4a is a compound of Formula (50) wherein R is -NHCH (CH2CH2OMe) (CH2OMe) 2, R is Me,

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

4-3 4b 4c 4d compound of Formula (50), wherein R is morpholino, R is Me, R is H, R is Me, R is

H and R ^4e is Me;

4a 4b 4c is a compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Br, R is H, R is

OMe, R ^4d is H and R ^4e is H;

4¾ 4b is a compound of Formula (50) wherein R is -NHCH (Et) 2, R is Br, R is H, R is OMe, _4d. ,,. -, 4e. ,,

R is H m R is H;

4a 4b 4c 4cf compound of Formula (50), wherein R is -N (Et) 2, R is Br, R is H, R is OMe, R is

H and R ^4e is H;

4a 4b 4c 4d compound of Formula (50) wherein R is -NH (c-Pr), R is Me, R is H, R is Me, R is

H and R ^4e is H;

4a 4b 4c is a compound of Formula (50) wherein R is -NHCH (CH2OMe) 2, R is CN, R is H, R is

OMe, R ^4d is H and R ^4e is H;

4a 4b 4c is a compound of Formula (50), wherein R is -N (c-Pr) (CH 2 CH 2 CN), R is Me, R is H, R is Me, R ^4d is H and R ^4e is Me;

4a 4b 4c is a compound of Formula (50) wherein R is -NCH (CH2OMe) 2, R is Me, R is H, R is

Br, R ^4d is H and R ^4e is H;

4a is a compound of Formula (50) wherein R is -NHCH (CH2OMe) (CH2CH2OMe), R is Me, R ^4b is H, R ^4c is Br, R ^4d is H and R ⁴ ® is H;

4a 4b 4c is a compound of Formula (50) wherein R is -NHCH (CH2OMe) 2, R is Me, R is H, R is

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

-38q 4a 4b 4c compound of Formula (50), wherein R is -N (CH2CH2OMe) 2 · R is Me, R is H, R is

OMe, R ^4d is Me In R ^4e is H;

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

4a 4b 4c 4d compound of Formula (50), wherein R is -N (Et) 2, R is Me, R is H, R is OMe, R is

Me and R ^4e is H;

4a 4b 4c is a compound of Formula (50) wherein R is -NHCH (CH2OMe) 2, R is Cl, R is H, R is

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

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

4a 4b 4c is a compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Cl, R is H, R is

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

o 4a 4h is a compound of Formula (50), wherein R is -NHCH (CH2OMe) (CH2CH2OMe), R is Cl, R is H, R ^4c is Me, R ^4d is H and R ^4e is H;

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

4a 4b 4c is a compound of Formula (50), wherein R is -N (c-Pr) (CH 2 CH 2 CN), R is Cl, R is H, R is

Cl, R ^4d is H and R ^4e is H;

4a is a compound of Formula (50) wherein R is (S) ~ NHCH (CH2OMe) (CH2CH2OMe), R is Cl,

R ^4b is H, R ⁴⁰ is Cl, R ^4d is H and R ^4e is H;

-39 a compound of Formula (50) wherein R ³ is -NHCH (CH 2OMe) (CH 2 CH 2OMe), R ^4a is Cl, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H;

4a 4h 4r * 4ri compound of Formula (50), wherein R is -NHCH (Et) 2, R is Me, R is H, R is Br, R is H and R ^4e is H;

4b to 4o is a compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Me, R is H, R is

Br, R ^4d is H and R ^4e is H;

4a is a 4b compound of Formula (50), wherein R is -NH (CH2OMe) (CH2-iPr), R is Me, R is H,

R is Me, R is H and R is H;

4a 4b 4c is a compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Me, R is H, R is

H, R ^4d is H and R ^4e is H;

4a 4b 4c is a compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Me, R is H, R is

NMe2, R ^4d R ^4e Jehin Z is H;

4a 4b is a compound of Formula (50), wherein R is -NHCH (CH2OMe) (n-Pr), R is Me, R is H, _4c. .. _4d. i ,. _n 4e, L,

R is Me, R is H m R is H;

4a 4h 4c compound of Formula (50), wherein R is -NHCH (CH2OEt) (Et), R is Me, R is H, R is

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

a compound of Formula (50) wherein R ³ is -NHCH (CH 2OMe) (CH 2 CH 2OMe), R ^4a is Me, R ^4b is H, R ⁴⁰ is NMe ₂ , R ^4d is H and R ^4e is H;

4a 4b 4c 4d compound of Formula (50), wherein R is -N (Et) 2, R is Me, R is H, R is Cl, R is H and R ^4e is H;

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

-403 4a 4b 4c compound of Formula (50), wherein R is -N (CH ₂ CH 2OMe) _2l R is Me, R is H, R is

4d 4e

Cl, R is H and R is H;

4a 4b 4c is a compound of Formula (50) wherein R is -NHCH (CH2OMe) 2, R is Me, R is H, R is

4d 4e

Cl, R ⁴⁰ is H and R is H;

4a 4b 4c 4d compound of Formula (50), wherein R is -N (Et) ₂ , R is Me, R is H, R is Br, R is H

4e and R is H;

4a 4b 4c 4d compound of Formula (50) wherein R is -N (Et) ₂ , R is Cl, R is H, R is Me, R is H and R ^4e is H;

4a 4b 4c 1d is a compound of Formula (50) wherein R is -NHCH (Et) ₂ , R is Cl, R is H, R is Me, R is H and R ^4e is H;

4a 4b 4c is a compound of Formula (50) wherein R is -NHCH (Et) ₂ , R is Me, R is H, R is NMe ₂ , R is H and R is H;

a compound of Formula (50) wherein R ³ is (S) -NHCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), R ^4a is Me, R ^4b is H, R ⁴⁰ is Me, R ^4d is H and R ^4e is H;

4a is a compound of Formula (50), wherein R is -NHCH (CH ₂ OMe) (CH ₂ CH ₂ OMe), R is Me, -4b. ., _4c. ,, _4d. ,,. _4e. ,,

R is H, R is Me, R is H and R is H;

a compound of Formula (50) wherein R ³ is (S) -NHCH (CH ₂ OMe) (CH ₂ CH 2OMe), R ^4a is Me, R is H, R is Cl, R is H and R is H;

4a is a compound of Formula (50) wherein R is -NHCH (CH2OMe) (CH ₂ CH ₂ OMe), R is Me,

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

-413 4a 4h 4c compound of Formula (50), wherein R is -N (c-Pr) (CH 2 CH 2 CN), R is Me, R is H, R is Cl, R ^4d is H and R ^4e is H;

a 4a 4h 4a compound of Formula (50), wherein R is -NH (Et) (CH 2 CN), R is Me, R is H, R is Cl,

4d 4e

R is H and R ® is H;

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

4a is a 4h compound of Formula (50) wherein R is -N (CH2CH2OMe) (CH2CH2OH), R is Cl, R is

H, R b is C, R ^4d is H and R ⁴ is H ®;

4a 4b 4c is a compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Me, R is Me, R is

OMe, R ^4d is H and R ⁴ ® is H;

4a 4b 4c is a compound of Formula (50) wherein R is -NHCH (Et) 2, R is Me, R is Me, R is OMe,

R is H and R is H;

4a 4b 4c compound of Formula (50), wherein R is -N (CH2C-Pr) (n-Pr), R is Me, R is H, R is

4d 4e

Cl, R is H and R is H;

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

4a 4h 4p compound of Formula (50), wherein R is -NHCH (Et) 2, R is Cl, R is H, R is OMe, _4d. _in . _4e. _in R is H and R is H;

4a 4b 4c 4d compound of Formula (50), wherein R is -N (Et) 2, R is Cl, R is H, R is OMe, R is

H and R ⁴ ® is H;

4a 4b Λλ is a compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Cl, R is H, R is

OMe, R ^{4d is} H and R ⁴ is H;

-424 »a ah Λρ is a compound of Formula (50), wherein R is -NHCH (Et) (CH2OMe), R is Cl, R is H, R is

4d 4e

OMe, R is H and R is H;

4a 4b 4c 4d compound of Formula (50), wherein R is -N (Et) 2, R is Cl, R is H, R is CN, R is H

- n ^4e · l.

m R is H;

43 4b 4c is a compound of Formula (50) wherein R is -N (c-Pr) (CH 2 CH 2 CN), R is Cl, R is H, R is

OMe, R ^4d is H and R ^4e is H;

43 4b 4c is a compound of Formula (50), wherein R is -NHCH (CH 2 OH) 2, R is Cl, R is H, R is Cl,

R ^4d is H and R ^4e is H; and

43 4b 4c is a compound of Formula (50), wherein R is N (CH2CH2OMe) 2, R is Me, R is H, R is

OMe, R ^4d is H and R ^4e is H.

[39] More particularly preferred is 4- (bis- (2-methoxyethyl) amino) -2,7-dimethyl-8- (2-methyl-4methoxyphenyl) - [1,5-a] pyrazolo-1,3. 5-triazine and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms, and its form of pharmaceutically acceptable salts or prodrugs.

[40] More particularly preferred is 4- (bis- (2-methoxyethyl) amino) -2,7-dimethyl-8- (2,5-dimethyl4-methoxyphenyl) - [1,5-a] pyrazolo-1. 3,5-triazine and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms, and its form of pharmaceutically acceptable salts or prodrugs.

[41] More preferred compounds of the above invention are compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their forms of pharmaceutically acceptable salts or prodrugs, wherein A is CR.

-43 [42] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their forms of pharmaceutically acceptable salts or prodrugs.

[43] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their forms of pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,34 dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R substituents.

[44] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their forms of pharmaceutically acceptable salts or prodrugs, wherein R ³ is NR ^6a R ^7a or OR ⁷ .

[45] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,34 3 dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R substituents and R is NR ^6a R ^7a or OR ⁷ .

[46] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their form 2 pharmaceutically acceptable salts or prodrugs, wherein Z is CR.

[47] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their forms of pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,34 dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R substituents.

[48] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their forms of pharmaceutically acceptable salts or prodrugs, wherein R ³ is NR ^6a R ^7a or OR ⁷ .

-44 [49] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,34 3 dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R substituents and R is NR ^6a R ^7a or OR ⁷ .

[50] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms and their forms 6a 73 of pharmaceutically acceptable salts or prodrugs, wherein R and R are independently H or C1-C10 alkyl and each such C 1 -C 10 alkyl is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 or heterocyclyl.

[51] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their pharmaceutically acceptable salts or prodrugs, wherein

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

-R ³ is NR ^6a R ^7a or OR ⁷ and 1 2

-R and R are independently selected from H, C1-C4 alkyl, C3-C10 cycloalkyl, C4-C10 cycloalkylalkyl.

[52] More preferred compounds of the above invention also include compounds and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms and their forms 63 73 pharmaceutically acceptable salts or prodrugs, wherein R and R are independently H or C1-C10 alkyl and each such C 1 -C 10 alkyl is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ aryl, heteroaryl or heterocyclyl.

-45 [53] Particularly preferred compounds of the above invention are compounds of Formula (51)

FORMULA (51) and their isomers, their stereoisomal forms or mixtures of their stereoisomal forms, and their forms of pharmaceutically acceptable salts or prodrugs selected from the group consisting of:

4a 4b 4c is a compound of Formula (51) wherein R is -NHCH (n-Pr) 2, R is Me, R is H, R is Me, _4d. ... _, 4e. ,,

R is H and R is H;

4a 4b 4c is a compound of Formula (51) wherein R is -NHCH (CH2OMe) 2, R is Me, R is H, R is

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

4a 4b 4c is a compound of Formula (51) wherein R is -N (CH2CH2OMe) 2, R is Me, R is H, R is

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

4a 4h 4c compound of Formula (51), wherein R is -N (c-Pr) (CH 2 CH 2 CN), R is Me, R is H, R is Me, R ^4d is H and R ^4e is H;

4a 4b 4c is a compound of Formula (51) wherein R is -N (CH2CH2OMe) 2, R is Cl, R is H, R is

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

-463 43 4h 4c compound of Formula (51), wherein R is -NHCH (CH2OMe> 2, R is Cl, R is H, R is

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

* 3 Ah Ar is a compound of Formula (51) wherein R is -NHCH (Et) 2, R is Cl, R is H, R is Me, R is H and R ^4e is H;

43 4b is a 4d compound of Formula (51) wherein R is -N (Et) 2, R is Me, R is H, R is Me, R is H and R ^4e is H;

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

o 43 4b 4c is a compound of Formula (51), wherein R is -N (n-Bu) (CH 2 CH 2 CN), R is Me, R is H, R is Me, R ^4d is H and R ^4e is H;

4a 4b is a compound of Formula (51) wherein R is -NHCH (n-Pr) (CH2OMe), R is Me, R is H, _4c. .. _, 4d. ... „4e. ,.

R is Me, R is H and R is H;

43 4b 4c is a compound of Formula (51), wherein R is -NHCH (Et) 2, R is Me, R is H, R is OMe,

4d 4e

R is H and R is H;

4a 4b 4c is a compound of Formula (51) wherein R is -NHCH (CH2OMe) 2, R is Me, R is H, R is

4d 4e

OMe, R is H and R is H;

4a 4b is a compound of Formula (51), wherein R is (S) -NH (CH2CH2OMe) CH2OMe, R is Me, R is H, R ⁴⁰ is Me, R ^4d is H and R ^4e is H;

4a 4b is a compound of Formula (51), wherein R is -NH (CH2CH2OMe) CH2OMe, R is Me, R is

H, R ⁴⁰ is Me, R ^4d is H and R ^4e is H;

-473 4a 4b 4 p compound of Formula (51), wherein R is -N (CH ₂ CH ₂ OMe) 2, R is Me, R is H, R is

Is Cl, R ^4d R ^4e Jehin Z is H;

4a 4b 4e 4d compound of Formula (51), wherein R is-NH (Et), R is Me, R is H, R is Me, R is

H and R ⁴ ® is H;

4 a. 4b is a 4c compound of Formula (51), wherein R is -NHCH (n-Pr) 2, R is Me, R is H, R is Cl,

_.4d. ... _4e. .,

R is H and R is H;

4a 4b 4c is a compound of Formula (51) wherein R is -NHCH (CH ₂ OMe) 2, R is Me, R is H, R is

Cl, R ^4d is H and R ⁴ ® is H;

q 4a is a 4h compound of Formula (51), wherein R is (S) -NH (CH2CH2OMe) CH ₂ OMe, R is Me, R is H, R ⁴⁰ is Cl, R ^4d is H and R ^4e is H;

4a 4b is a compound of Formula (51), wherein R is -NH (CH2CH2OMe) CH2OMe, R is Me, R is

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

a compound of Formula (51), wherein R ³ is -N (n-Pr) (CH ₂ CH ₂ CN), R ^4a is Me, R ^4b is H, R ⁴⁰ is OMe, R ^4d is H and R ^4e is H;

4a 4b 4c 4d compound of Formula (51), wherein R is -N (Et) 2, R is Me, R is H, R is OMe, R is

H and R ^{4e is} H;

a compound of Formula (51), wherein R is (S) -NH (CH ₂ CH ₂ OMe) CH ₂ OMe, R is Cl, R is H, R ⁴⁰ is Me, R ^4d is H and R ⁴ ® is H;

4a 4b is a compound of Formula (51), wherein R is -NH (CH2CH2OMe) CH ₂ OMe, R is Cl, R is H,

R ^4c is Me, R ^4d is H and R ⁴ ® is H;

4a 4b 4c 4d compound of Formula (51) wherein R is -N (Et) ₂ , R is Cl, R is H, R is Me, R is H and R ⁴ is H;

-483 4a 4h 4r compound of Formula (51), wherein R is -N (c-Pr) (CH 2 CH 2 CN), R is Me, R is H, R is OMe, R ^4d is H and R ^4e is H;

4a 4h 4c compound of Formula (51), wherein R is -N (c-Pr) (CH 2 CH 2 CN), R is Cl, R is H, R is

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

4a 4b is a compound of Formula (51), wherein R is -NHCH (n-Pr) (CH2OMe), R is Me, R is H,

R ⁴⁰ is OMe, R ^4d is H and R ^4e is H;

a compound of Formula (51), wherein R ³ is -NHCH (n-Pr) (CH 2OMe), R ^4a is Cl, R ^4b is H, R ⁴⁰ is Me, R ^4d is H and R ^4e is H;

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

43 4b 4c is a compound of Formula (51), wherein R is -NHCH (Et) 2, R is Br, R is H, R is OMe,

4d 4e

R is H and R is H;

4a 4b 4c is a compound of Formula (51), wherein R is -N (CH2CH2OMe) 2, R is Br, R is H, R is

4d 4a

OMe, R is H and R is H;

4a Ab 4c compound of Formula (51) wherein R is -NHCH (CH2OMe) 2, R is Br, R is H, R is

OMe, R ^4d is H and R ^4e is H;

o Aa Ah 4r * AH compound of Formula (51), wherein R is -N (Et) 2, R is Me, R is H, R is Cl, R is H and R ^4e is H;

4a 4b 4c 4d compound of Formula (51) wherein R is-N (Et) 2, R is Cl, R is H, R is OMe, R is

OMe and ^R4e is H;

-493 4a 4h 4r compound of Formula (51), wherein R is -NHCH (Et) ₂ , R is Cl, R is H, R is OMe,

R ^4d is OMe and R ^4e is H;

4a 4h 4p compound of Formula (51), wherein R is -N (CH ₂ CH ₂ OMe) 2, R is Cl, R is H, R is Cl,

_.4ό. ... _.4e. ,,

R is H m R is H;

4a 4b 4c is a compound of Formula (51), wherein R is -NHCH (CH ₂ OMe) 2, R is Cl, R is H, R is

Cl, R ^4d is H and R ⁴ ® is H;

4a 4h 4r compound of Formula (51), wherein R is -N (Pr) (CH ₂ CH ₂ CN), R is Cl, R is H, R is

Is Cl, R ^4d R ^4e Jehin Z is H;

4a 4h 4r 4d compound of Formula (51), wherein R is -N (Bu) (Et), R is Cl, R is H, R is Cl, R is

H and R ^4e is H;

4a 4b 4c is a compound of Formula (51) wherein R is -NHCH (Et) CH ₂ OMe, R is Cl, R is H, R is

4d 4e

Cl, R is H and R is H;

4a 4h 4r 4d compound of Formula (51), wherein R is -NHCH (Et) 2, R is Cl, R is H, R is Cl, R is H and R ^4e is H;

4a 4h 4r 4d compound of Formula (51), wherein R is -NHCH (Et) 2, R is Me, R is H, R is Me, R is H and R ^4e is H;

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

4a 4b 4c 4d compound of Formula (51), wherein R is -NHCH (Et) ₂ , R is Me, R is H, R is Cl, R is H and R ⁴ ® is H;

4a 4b 4c 4d compound of Formula (51) wherein R is-NEt 2, R is Me, R is H, R is OMe, R is H and R ⁴ ® is H; and

-50 is a compound of Formula (51), wherein R ³ is -N (Pr) (CH 2 CH 2 CN), R ^4a is Me, R ^4b is H, R ⁴⁰ is OMe, R ^4d isH and R ^4e isH.

[54] More particularly preferred is 7- (3-pentylamino) -2,5-dimethyl-3- (2-methyl-4-methoxyphenyl) [1,5-a] pyrazolopyrimidine and its isomers, stereoisomers, forms or mixtures thereof its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs.

[55] More particularly preferred is 7- (diethylamino) -2,5-dimethyl-3- (2-methyl-4-methoxyphenyl) [1,5-a] pyrazolopyrimidine and its isomers, its stereoisomal forms, or mixtures thereof stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs.

[56] More 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 stereoisomal forms thereof and pharmaceutically acceptable salts or prodrugs thereof.

The present invention also provides pharmaceutical compositions comprising compounds of Formulas (1) and (2) and a pharmaceutically acceptable carrier.

Many compounds of the present invention have one or more asymmetric centers or planes. Unless otherwise stated, all chiral (enantiome and diastereomy) and racemic forms are included in the present invention. Many geometric olefin isomers, C = N double bonds, and the like may also be present in the compounds, and all such stable isomers have been studied in the present invention. The compounds can be isolated in optically active or racemic forms. It is well known in the art to prepare optically active forms, such as by dissolving racemic forms or by synthesizing from optically active starting materials. All chiral (enantiomeric and diastereomemic) and racemic forms of the structure and all forms of the structure of the geomeric isomers are intended, unless the specific stereochemistry or isomeric form is specifically demonstrated.

The term "alkyl" includes both branched and straight chain alkyl having a specified number of carbon atoms. Commonly used abbreviations have the following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl. The prefix n means straight-chain alkyl. The prefix c is cycloalkyl. Prefix (S) stands for S snantiomer and Prefix (R) stands for R enantiomer. Alkenyl includes hydrocarbon chains of either straight or branched configuration and one or more unsaturated carbon-carbon bonds, which may be located at any stable point along the chain, such as ethenyl, propenyl and the like. Alkinyl includes hydrocarbon chains of either straight or branched configuration and one or more triple bonds, which may be located at any stable point along the chain, such as ethynyl, propynyl and the like. Haloalkyl is intended to include both branched and straight chain alkyl having a specified number of carbon atoms substituted with 1 or more halogens; alkoxy represents an alkyl group having the indicated number of carbon atoms bonded through an oxygen bridge; cycloalkyl is intended to include saturated ring groups, including mono-, bi- or polycyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on. Halo or halogen 'includes fluoro, chloro, bromo and iodo.

The term substituted as used herein means that one or more hydrogen at a given atom is replaced by a selection from said group, provided that the normal valence of the particular atom is not exceeded and that the substitution results in a stable compound. When the substituent is keto (i.e., = 0), then two hydrogens are substituted on the atom.

Combinations of substituents and / or variables are only permitted if such combinations result in stable compounds. By stable compound or stable structure is meant a compound sufficiently robust to withstand satisfactory purity to isolate the reaction mixture and formulation into an effective therapeutic agent.

The term suitable amino acid protecting group means any known group for the protection of amine or carboxyl groups in the field of organic synthesis. Such amine protecting groups include those listed in Greene and Wuts, Protective Groups and Organic Synthesis by John Wiley & Sons, New York (1991) and The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), whose disclosure

-52 is incorporated herein by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1- (pbiphenyl) -1-methylethoxycarbonyl and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyothioxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane, such as trimethylsilane; and 7) thiol-containing types such as phenylthiocarbonyl and dithiasuccinoyl.

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

The 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 in a mixture thereof; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are generally preferred. Lists of suitable salts are found in th

Reminqton's Pharmaceutical Sciences. 17 ed., Cat Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

The prodrugs are considered to be any covalently bound carriers that release the active parent drug of formula (1) or (2) in vivo when administered to a mammalian subject. The prodrugs of the compounds of formula (1) and (2) are prepared by modification in the compounds of the functional groups present in such a way that the modifications are cleaved to the parent compounds either by routine manipulation or in vivo. The prodrugs include compounds wherein the hydroxy, amine or sulfhydryl groups are attached to any group which, when given to a mammalian subject, is cleaved to form a free hydroxyl, amino or sulfhydryl group. Examples of prodrugs include, but are not limited to, the acetate, formate and benzoate derivatives of the alcohol and amine functional groups in the compounds of formulas (1) and (2); etc.

-53 The expression a therapeutically effective amount of a compound of this invention means such an effective amount that antagonizes the pathological level of CRF or treats symptoms of emotional disturbance, anxiety or depression in the host.

Synthesis

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

SCHEME 1

R H, + / - base, + / - solvent

->

Ar (1) A = N

Compounds of Formula (7) (wherein Y is O) may be treated with a halogenating agent or a sulfonyl agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from -80 ° C to 250 ° C to

-54 are products of Formula (8) (wherein X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkane-sulfonyloxy). Halogen agents include, but are not limited to, SOCI2, POCI3, PCI3, PCI5, POBr3, PBr3, or PBrs. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides or anhydride anhydride anhydride The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) , alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkannitriles (1 to 6 carbons, 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), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 carbons 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20 ° C to 1OO ° C.

3

Compounds of Formula (8) may be reacted with compounds of Formula RH (wherein R is defined as 3 7 2 7 above, except that R is not SH, COR, CO R, aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvents at reaction temperatures ranging from -80 ° C to 250 ° C to form compounds of Formula (1). The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) , alkali metal carbonates, alkali metal bicarbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-diisopropylN-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether),

-55cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamide (preferably dimethylformamide), Ν, Ν-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0 ° C to 140 ° C.

Scheme 2 describes methods for converting intermediate compounds of Formula (7) (wherein Y is S) into some compounds of Formula (1).

-56SHEMA2

Compounds of Formula (7) (where Y is S) can be treated with an alkylating agent R X (where 13 13

R is as defined above, except that R is not aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from -80 ° C to 250 ° C. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) , alkali metal carbonates, alkali metal hydroxides, bis (trialkylsilyl) alkali metal amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-di-isopropyl-N-ethyl amine or triethyl amine) or aromatic amines ( preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower

-57alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamide (preferably dimethylformamide), Ν, Ν-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -80 ° C to 100 ° C.

13

Compounds of Formula (12) (Formula (1) wherein R is SR) may then be reacted with compounds of

Formula R H to form compounds of Formula (1) using the same conditions and reagents as were used to convert compounds of Formula (8) into compounds of Formula (1) as described for Scheme 1 above. Alternatively, compounds of Formula (12) (Formula (1),

13 3 13 where R is SR) is oxidized to compounds of Formula (13) (Formula (1) where R is S (O) nR, n is 1, 2) by treatment with an oxidizing agent in the presence of an inert solvent at temperatures which range from -80 ° C to 250 ° C. Oxides include, but are not limited to, hydrogen peroxide, alkane, or aryl peracids (preferably peracetic acid or m-chloroperbenzoic acid), dioxane, oxone, or sodium periodate. Inert solvents may include, but are not limited to, alkanones (3 to 10 carbons, preferably acetone), water, alkyl alcohols (1 to 6 carbons), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane) or combinations thereof. The choice of oxidant and solvent is known to those skilled in the art (see Uemura, S., Oxidation of Sulfur, Selenium and Tellurium, in Comprehensive Organic Svnthesis, Trost, BM ed., (Elmsford, NY: Pergamon Press, 1991), 7, 762. -769).

Preferred reaction temperatures range from -20 ° C to 100 ° C. Compounds of Formula (13) 3 13 (Formula (1) wherein R is S (O) _n R, n is 1, 2) can then be reacted with compounds of Formula RH to form compounds of Formula (1) using of the same reaction conditions and reagents as were used to convert compounds of Formula (8) into compounds of Formula (1) as described for Scheme (1) above.

Compounds of Formula (1) wherein R ³ may be -NR ⁸ COR ⁷ , -N (COR ⁷ ) 2, 'NR ⁸ CONR ⁶ R ⁷ , fi 13 fi 7 8 7

-NR CO2R, -NR R, -NR SO2R can be prepared from compounds of Formula (7) wherein Y is NH by the procedures described in Scheme 3.

-58SHEMA 3

d)

A = N;

B? - NR ⁶ R ⁷ , NR ⁸ COR ⁷ ,

N (COR ⁷ ) 2, NK? CONR ⁶ R ⁷ , NR ⁸ CO2R ¹³

Reaction of compounds of Formula (7) wherein Y is NH, with alkyl agents, sulfonylating agents or acylating agents, or sequential reactions with combinations thereof in the presence or absence of a base in an inert solvent at reaction temperatures ranging from -80 ° C to 250 ° C, may give compounds of Formula (1) wherein R ³ may be -NR ⁸ COR ⁷ , -N (COR ⁷ ) 2, -NR ⁸ CONR ⁶ R ⁷ , -NR ⁸ CO2R ¹³ , -NR ⁶ R ⁷ , -NR ⁸ SO2R ⁷ Alkylating agents may include, but are not limited to, C1-C10 alkyl halides, -tosylates, -mesylates, or -triflates; C 1-10 haloalkyl (1-10 halogens) -halides, -tosylates, -desylates or triflates; C2-C8 alkoxyalkyl halides, -tosylates, -mesylates, or -triflates; C3-C6 cycloalkyl halides, -tosylates, -mesylates, or -triflates; C4-C12 cycloalkylalkyl-halides, -tosylates, -mesylates, or -triflates; aryl (C1-C4 alkyl) -halides, -tosylates, -mesylates, or -triflates; heteroaryl (C 1 -C 4 alkyl) -halides, -tosylates, -desylates or -triflates; or heterocyclyl (C 1 -C 4 alkyl) -halides, -tosylates, -mesylates, or -triflates. Acrylic agents may include, but are not limited to, C1-C10 alkanoyl halides or anhydrides, C1-C10 haloalkanoyl halides or anhydrides with 1-10 halogens, C2-C8 alkoxyalkanoyl halides or anhydrides, C3-C6 cycloalkanoyl halides or anhydrides, C4-C12 cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl (C 1 -C 4) alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl (C 1 -C 4) alkanoyl halides or anhydrides, halides or anhydrides of heterocyclyl cyclic acid or anhydride ) alkanoyl halides or anhydrides.

-59Sulfonylating agents include, but are not limited to, C1-C10 alkylsulfonyl halides or anhydrides, C-pC 10 io haloalkylsulfonyl halides or anhydrides with 1-10 halogens, C2-C8 alkoxyalkylsulfonyl halides or anhydrides, C3-C6 cycloalkylsulfonyl halides or anhydrides -C12 cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl (C1-C4 alkyl) -, heteroarylsulfonyl halides or anhydrides, heteroaryl (C1-C4 alkyl) sulfonyl halides or anhydrides, heterocyclylsulfonylalkyl or halide or anhydrides sulfonyl halides or anhydrides. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) , alkali metal carbonates, alkali metal bis (trialkylsilyl) amides. metals (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamide (preferably dimethylformamide), Ν, dial-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide) or aromatic hydrocarbons (or aromatic hydrocarbons or toluene). Preferred reaction temperatures range from 0 ° C to 100 ° C.

Scheme 4 describes the processes that can be used to prepare the 2-intermediates

Formula (7) wherein Y is O, S and Z is CR.

-60SHEMA4

AxCH ₂ CN

R ² COR ^b , base, solvent

->,

NH2NH2-H2O, solvent

Ar (3)

(7) Y = O, S; Z = CR ² b 2

Compounds of Formula ArCFfeCN are reacted with compounds of Formula R COR, wherein R is as defined above and R is halogen, cyano, lower alkoxy (1 to 6 carbons) or lower alkanoyloxy (1 to 6 carbons) in the presence of a base in an inert solvent in the reaction temperatures ranging from -78 ° C to 200 ° C to form compounds of Formula (3). The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) , alkali metal carbonates, alkali metal hydroxides, alkali metal bis (trialkylsilyl) amides

-61 metal (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably Ν, di-di-isopropylN-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), water, dialkyl ethers (preferably dialkyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamide (preferably dimethylformamide), Ν, dial-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide) or aromatic hydroxides (preferably benzene or toluene). Preferred reaction temperatures range 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 compounds of Formula (4). Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4 dioxane), Ν , Ν-dialkylformamide (preferably dimethylformamide), Ν, Ν-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene) or toluene (preferably benzene). Compounds of Formula (4) may be reacted with compounds of Formula (5) (wherein R ^{c is} alkyl (1-6 carbons)) in the presence or absence of acid in the presence of an inert solvent at temperatures ranging from 0 ° C to 200 ° C to form compounds of Formula (6). Acids may include, but are not limited to, alkanoic acids with 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2-10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid) acid), alkanesulfonic acid with 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, water, alkannitriles (1 to 6 carbons, preferably acetonitrile), halocarbons of 1 to 6 carbons and 1 to 6 halogens (preferably dichloromethane or chloroform), alkyl alcohols of 1 to 10 carbons (preferably ethanol), dialkyl ethers (4 to 12 carbons, preferably diethyl ether or diisopropylether) or cyclic ethers such as dioxane or tetrahydrofuran. Preferred temperatures range from ambient temperature to 100 ° C.

Compounds of Formula (6) can be converted into intermediates of compounds of Formula (7) by treatment with compounds Y = C (R ^a ) 2 (wherein Y is O or S and R is halogen (preferably chlorine), alkoxy (1 to 4) carbons) or alkylthio (1 to 4 carbons) in the presence or absence of a base in an inert solvent at reaction temperatures of -50 ° C to 200 ° C. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkoxides alkali metals (1-6 carbons) (preferably sodium methoxide or sodium ethoxide), alkali metal carbonates, alkali metal hydroxides, trialkyl amines (preferably N, N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine) Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) , Ν, Ν-dialkylformamide (preferably dimethylformamide), N , N-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably Nmethylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred temperatures are 0 ° C to 150 ° C.

Intermediate compounds of Formula (7) wherein Z is N can be synthesized according to the methods described in Scheme 5.

-63CHART 5 i

ArCH ₂ CN

reduce the solvent

-

(5) ^0R + / - acid, solvent

Y = C (R) ₂ , base, solvent

R ^J

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

NH

Compounds of Formula ArCH2CN are reacted with compounds of Formula R ^{C |} CH2N3 (where r ' ^{1 is a} phenyl group optionally substituted by H, alkyl (1 to 6 carbons) or alkoxy (1 to 6 carbons) in the presence or absence of a base in an inert solvent at temperatures ranging from 0 ° C to 200 To form compounds of Formula (9). The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide, sodium ethoxide or potassium t-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide),

-64 alkali metal carbonates, alkali metal hydroxides, bis (trialkylsilyl) alkali metal amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-di-isopropylN-ethyl amine or triethylamine) or aromatic amines (preferably pyridine) . Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamide (preferably dimethylformamide), Ν, Ν-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably aromatic hydrocarbons) benzene or toluene). Preferred reaction temperatures are. range from ambient temperature to 100 ° C.

The compounds of Formula (9) can be treated with a reducing agent in an inert solvent at

-100 ° C to 100 ° C to form products of Formula (10). Reducing agents include, but are not limited to, (a) hydrogen gas in combination with catalysts, precious metals, such as

Pd on carbon, PtO2, Pt on carbon, Rh on alumina or Raney nickel, (b) alkali metals (preferably sodium) in combination with liquid ammonia or (c) cerium ammonium nitrate. Inert solvents may include, but are not limited to, alkyl alcohols (1 to carbons, preferably methanol or ethanol), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamide (preferably dimethylformamide), Ν, ialdialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably Nmethylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide) or aromatic carbon dioxide ). Preferred reaction temperatures are

-50 ° C to 60 ° C. The compounds of Formula (9) are then converted to compounds of Formula (7) (where Z is

N) via intermediates of Formula (11) using the reagents and reaction conditions described in Scheme 4 to convert compounds of Formula (4) into compounds of Formula (7) (wherein Z is 2

CR).

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

-65SHEMA 6

(7) Υ = O, S; Z = N, CR ²

R H, +/- acid, +/- drying agent, +/- solvent

-> -

Compounds of Formula (7) may be reacted with compounds of Formula R H in the presence of a desiccant in an inert solvent at reaction temperatures ranging from 0 ° C to 250 ° C. Drying agents include, but are not limited to, P2O5, molecular sieves or inorganic or organic acids. Acids may include, but are not limited to, alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid , sulfuric acid or phosphoric acid. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably glim or digiim), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamide (preferably dimethylformamide), N, N-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably Nmethylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide), aromatic hydrocarbons (or hydrocarbons) ) or halogens with 1 to 10 carbons and 1 to 10 halogens (preferably chloroform). Preferred reaction temperatures range from ambient temperature to 150 ° C.

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

-66SHEMA 7

Intermediate compounds of Formula (14), where Z is defined above, can be reacted with 3 GG compounds of Formula RC (OR) 3, where R may be alkyl (1 to 6 carbons), in the presence or absence of an acid in an inert solvent at temperatures ranging from 0 ° C to 250 ° C. Acids may include, but are not limited to, alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid , sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkannitriles (1 to 6 carbons, 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), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 carbons 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 50 ° C to 150 ° C.

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

-67SHEMA 8

(15) OH = OH, SH NR ⁶ Z = N, CR ² ,

X = Br, Cl, J,

B (OR) ₂

ArM, + / - catalyst, solvent

-

7

Compounds of Formula (15), (wherein Y is OH, SH, NR R; Z is defined above, X is Br, Cl, J, O3SCF3 or B (OR) 2 and R is H or alkyl (1 to 6 carbons) ) can be reacted with a compound of Formula ArM (where M is halogen, alkali metal, ZnCI, ZnBr, ZnJ, MgBr, MgCI, MgJ, CeCl2, CeBr2, or copper halides) in the presence or absence of an organometallic catalyst in the presence or absence of a base in inert solvents at temperatures ranging from -100 ° C to 200 ° C. One of skill in the art will recognize that ArM reagents can be produced in situ. Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd (PPh3) 4), palladium halides or alkanoates (such as PdCl2 (PPh3) 2 or Pd (OAc) 2) or nickel complexes (such as NiCl2 (PPh3) 2) . The bases may include, but are not limited to, alkali metal carbonates or trialkyl amines (preferably N, N-di-isopropyl-Nethyl amine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably, benzene or toluene) or water. Preferred reaction temperatures range from -80 ° C to 100 ° C.

the choice of M and X is known to those skilled in the art (see, Imamoto, T., Organocerium Reagents and Comprehensive Organic Svnthesis. Trost, BM ed., (Elmsford, NY; Pergamon Press, 1991), 1, 231-250; Knochel. P., Organozinc,

-68Organocadmium and Organomercury Reagents in Comprehensive Organic Svnthesis,

Trost, B.M. ed., (Elmsford, NY: Pergamon Press, 1991), 1, 211-230; Knight, D.W., 2

Coupling Reactions betvveen sp Carbon Centers, and Comprehensive Organic Svnthesis. Trost, B.M. ed., (Elmsford, NY: Pergamon Press, 1991), 3, 481-520).

The compounds of Formula (1) can also be prepared using the methods shown in Scheme 9.

SCHEME 9

(16) X = Br, CI, J, B (0R) 2, O ₃ SCF ₃

ArM, + / - catalyst, solvent

->

3

Compounds of Formula (16) wherein A, Z, R and R are as defined above and X is Br, Cl, J, O3SCF3 or B (OR) 2 and R 'is H or alkyl (1 to 6 carbons) may be reacted with a compound of Formula ArM (wherein M is halogen, alkali metal, ZnCI, ZnBr, ZnJ, MgBr, MgCI, MgJ, CeCl2, CeBr2 or copper halides) in the presence or absence of an organometallic catalyst in the presence or absence of a base in inert solvents at temperatures, ranging from -100 ° C to 200 ° C. Those of skill in the art will recognize that ArM reagents can be produced in situ (see references above in Comprehensive Organic Svnthesis). Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd (PPh3) 4), palladium halides or alkanoates (such as PdCl2 (PPh3) 2 or Pd (OAc) 2) or nickel complexes (such as NiCl2 (PPh3) 2) . The bases may include, but are not limited to, alkali metal carbonates or trialkyl amines (preferably N, N-di-isopropyl-N-ethyl amine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, dial-dialkylformamide (preferably dimethylformamide), Ν, Ν-dialkylacetamide (preferably dimethylacetamide) , cyclic amides

-69 (preferably N-methylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably, benzene or toluene) or water. Preferred reaction temperatures range from -80 ° C to 100 ° C.

12

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

SCHEME 10

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

->

R ¹ C (OR ^e ) ₃ , +/- acid, solvent

-

(7) Y = O, S, NH; Z = CR ² ,

Compounds of Formula (3) may be reacted with compounds of Formula H2NNH (C = Y) NH2, wherein Y is O, S or NH, in the presence or absence of a base or acid in an inert solvent at temperatures from 0 ° C to 250 ° C, to form compounds of Formula (17). Acids may include, but are not limited to, alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid),

-70alkanesulfonic acid with 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) , alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane) ), N, N-dialkylformamide (preferably dimethylformamide), Ν, Ν-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or alkene or benzene or alkene) 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).

Preferred reaction temperatures range from 0 ° C to 150 ° C. Compounds of Formula (17) 1e may then be reacted with compounds of Formula RC (OR) 3 wherein R may be alkyl (1 to 6 carbons), in the presence or absence of an acid in an inert solvent at temperatures ranging from 0 ° C to 250 ° C. Acids may include, but are not limited to, alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably ptoluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Νdialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Nmethylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 halogens and 1 to 10 hydrocarbons dichloromethane). Preferred reaction temperatures range from 50 ° C to 150 ° C.

-713

Scheme 11 provides methods that can be used to convert compounds of Formula (1) wherein R is COR ⁷ , CO2R ⁷ , NR ⁸ COR ⁷ and CONR ⁶ R ⁷ , into other compounds of Formula (1), where R ³ is CH (OH) R ⁷ , CH ² OH, NR ⁸ CH ² R ⁷ and CH ² NR ⁶ R ⁷ by treatment with a reducing agent in an inert solvent at temperatures ranging from -80 ° C to 250 ° C.

SCHEME 11

(1) R ³ = COR ⁷ , CO ₂ R ⁷ , CONR ⁶ R ⁷ (1) R ³ = C (OH) R ⁷ ,

CH ₂ OH,

CH ₂ NR ⁶ R ⁷

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

Scheme 12 illustrates processes that can be used to convert compounds of Formula (1) wherein R ³ is COR ⁷ or CO2R ⁷ to other compounds of Formula (1) wherein R ³ is C (OH) (R ⁷ ) 2, 2 treatment with a reagent of Formula R ⁷ M in an inert solvent at temperatures ranging from -80 ° C to 250 ° C.

-72SHEMA 12

M is halogen, alkali metal, ZnCI, ZnBr, ZnJ, MgBr, MgCI, MgJ, CeCl2, CeBr2 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). Preferred reaction temperatures range from -80 ° C to 100 ° C.

Compounds of Formula (1) wherein R ³ can be -NR ⁸ COR ⁷ -N (C0R ⁷ ) 2, -NR ⁸ CONR ⁶ R ⁷ , -NR ⁸ CO2R ¹³ , -NR ⁶ R ⁷ , -NR ⁸ SO2R ⁷ , can be synthesized as shown in Scheme 13.

-73SHEMA 13

alkyl, sulfonyl or acylating agents + / - base, solvent

A = CR

R ³ = NR ⁶ R ⁷ ,,

N (COR ⁷ ) 2, NR ⁸ CONR ⁶ R ⁷ , nr ⁸ co2r ¹³

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 may give compounds of Formula (19) at moving temperatures from -50 ° C to 250 ° C. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides

-74 metals (1-6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropitamide), alkali metal carbonates, bis (trialkylsilyl) alkali metal amides (preferably sodium methyl bis) amide), trialkyl amines (preferably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamide (preferably dimethylformamide), N, Ndialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably Nmethylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide) or aromatic hydrocarbons (or hydrocarbons) . Preferred reaction temperatures range from 0 ° C to 100 ° C.

The compounds of Formula (19) may then be reacted with alkyl agents, sulfonyl agents or acylating agents, or sequential reactions with combinations thereof, in the presence or absence of a base in an inert solvent at reaction temperatures ranging from -80 ° C to o Q Ύ " 7

250 ° C may give compounds of Formula (1) wherein R may be -NR COR, -N (COR) 2, -NR ⁸ CONR ⁶ R ⁷ -NR ⁸ CO2R ¹³ , -NR ⁶ R ⁷ , -NR ⁸ SO2R ⁷ Alkylating agents may include, but are not limited to, C1-C10 alkyl halides, -tosylates, -mesylates, or -triflates; C 1-10 haloalkyl (1-10 halogens) -halides, -tosylates, -mesylates or -triflates; C2-C8 alkoxyalkyl halides, -tosylates, -mesylates, or -triflates; C3-C6 cycloalkyl halides, -tosylates, -mesylates, or -triflates; C4-C12 cycloalkylalkyl halides, -tosylates, -mesylates, or -triflates; aryl (C 1 -C 4 alkyl) -halides, -tosylates, -mesylates or -triflates; heteroaryl (C -) - C4 alkyl) -halides, -tosylates, -mesylates, or -triflates; or heterocyclyl (C 1 -C 4 alkyl) -halides, -tosylates, -mesylates, or -triflates. Acrylic agents may include, but are not limited to, C1-C10 alkanoyl halides or anhydrides, C1-C10 haloalkanoyl halides or anhydrides with 1 to 10 halogens, C2-C8 alkoxyalkanoyl halides or anhydrides, C3-C6 cycloalkanoyl halides or anhydrides, C4-C12 cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl (C 1 -C 4) alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl (C 1 -C 4) alkanoyl halides or anhydrides, halides or anhydrides heterocyclic heterocyclic heterocyclic or anhydride - | -C4) alkanoyl halides or anhydrides. Sulfonium agents include, but are not limited to, C1-C10 alkylsulfonyl halides or anhydrides, C1-C10 haloalkylsulfonyl halides or anhydrides with 1-10 halogens, C2-C8

-75alkoxyalkylsulfonyl halides or anhydrides, C3-C6 cycloalkylsulfonyl halides or anhydrides, C4-C12 cycloalkylalkylsulfonyl halides alt anhydrides, arylsulfonyl halides or anhydrides, aryl (C1-C4 alkyl) -, heteroarylsulfonyl halide halide sulfide alkylaryl sulfide alkylide or anhydrides, heterocyclylsulfonyl halides or anhydrides or heterocyclyl (C 1 -C 4 alkyl) sulfonyl halides or anhydrides. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) , alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably diisopropylethyl amine) or aromatic amines (preferably pyridine). Solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1 , 4-dioxane), Ν, ialdialkylformamide (preferably dimethylformamide), Ν, Ν-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide) or aromatic carbon (or preferably toluene carbon) ). Preferred reaction temperatures range from 0 ° C to 100 ° C.

Compounds of Formula (1) wherein A is CR and R is as defined above can be synthesized according to the methods described in Scheme 14.

-76SHEMA 14

R ¹ (10) 2 = N

R

R H, + / - base, + / - solvent (21) + / - base, solvent

Compounds of Formula (4) or (10) can be treated with compounds of Formula (20) wherein R and

R is defined above in the presence or absence of a base in an inert solvent at temperatures 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, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, dialkylamides

-77 alkali metals (preferably lithium di-isopropylamide), alkali metal carbonates, * bis (trialkylsilyl) alkali metal amides * (preferably sodium bis (trimethylsilyl) amide), · trialkyl amines (preferably di-isopropylethyl amine), or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν dialkylformamide (preferably dimethylformamide), Ν, dial-dialkylacetamide (preferably dimethylacetamide), cyclic amides, preferably N-methylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide) or aromatic hydrocarbon or aromatic hydrocarbon ).

Preferred reaction temperatures range from 0 ° C to 100 ° C. Alternatively, compounds of Formula (1) wherein A is CR and R is as defined above can be synthesized via intermediates (22) and (23).

Compounds of Formula (4) or (10) may be treated with compounds of Formula (21), wherein R ^{1 is as} defined above and R is alkyl (1-6 carbons), in the presence or absence of a base in an inert solvent at temperatures which range 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, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) , alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably diisopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4 dioxane), Ν, Ν-dialkylformamide (preferably dimethylformamide), N, N-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide) or aromatic hydrocarbons (or aromatic hydrocarbons or aromatic hydrocarbons or toluene). Preferred reaction temperatures range from 0 ° C to 100 ° C. Compounds of Formula (22) may be treated with a halogenating agent or a sulfonating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from -80 ° C to 250 ° C to form products with

-78Formulo (23) (wherein X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkanesulfonyloxy). Halogens include, but are not limited to, SOCI2; POGl3rPGl3r PCI5, * POBr3, PBr3 or PBr5. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides or anhydride anhydride anhydride The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) , alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, Ndialkylformamide (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 of 1 to 10 carbons and 1 to 10 carbons halogens (preferably dichloromethane). Preferred reaction temperatures range from -20 ° C to 100 ° C.

3

Compounds of Formula (23) may be reacted with compounds of Formula RH (wherein R is defined as 3 7 7 above except R is not SH, COR, CO2R, aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent in the reaction temperatures ranging from -80 ° C to 250 ° C to form compounds of Formula (1). The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) , alkali metal carbonates, alkali metal bicarbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-diisopropylN-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether),

-79cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamide (preferably dimethylformamide), Ν, dial-dialkylacetamide (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0 ° C to 140 ° C.

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

-80SHEMA 15

A compound of Formula (24) (R _c is a lower alkyl group and Ar is defined as above) may be reacted with hydrazine in the presence or absence of an inert solvent to form an intermediate of Formula (25) wherein Ar is defined as above. The conditions used 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), where A is N, may be reacted with reagents of Formula R ¹ C (= NH ) ORe>

-81 where R ^{1 is} defined above and R _e is a lower alkyl group) in the presence or absence of an acid in an inert solvent, followed by reaction with a compound of formula Y is C (Rd) 2 (where Y is O or S and Rd is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) in the presence or absence of a base in an inert solvent to form compounds of Formula (27) (where A is N and Y is O, S). The conditions for these transformations are the same as the conditions used for the conversion of a compound of Formula (4) to a compound of Formula (7) in Scheme 4.

Alternatively, compounds of Formula (25) wherein A is CR may be reacted with compounds of Formula

R ¹ (C = O) CHR (C = Y) ORc (where R ¹ and R are defined as above and Rc is a lower alkyl group) to form a compound of Formula (27) (where A is CR) using the conditions, similar to those used to convert compounds of Formula (21) into compounds of Formula (22) in the Scheme

14. Intermediates of Formula (27) (wherein Y is O) can be treated with halogenating agents or sulfonyl agents in the presence or absence of a base in an inert solvent, followed by a reaction with RH or RH in the presence or absence of a base in an inert solvent, to 2 compounds of Formula (1) are formed (where Z is CR).

Those of skill in the art will recognize that different combinations of 3 2 halogenating agents, co-sulfonylating agents, R H or R H can be used in different sequences of the reaction sequences in Scheme 15 to give compounds of Formula (1). For example, in some cases, it may be desirable for the compounds to react with stoichiometric amounts of 2 to 3 halogenating agents or co-sulfonylating agents, to react with RH (or RH), to then repeat the reaction with halogenating agents or sulfonylating agents and to react with RH 2 ( or RH) to form compounds of Formula (1). For these conditions, the reaction conditions and reagents used are similar to those used to convert the intermediates of compounds of Formulas (22) into (23) into (1) in Scheme 14 (for A is CR) or the conversion of intermediates of Formulas (7) to ( 8) in (1) in Scheme 1 (where A is N).

Alternatively, compounds of Formula (27) (where Y is S) can be converted to compounds of Formula (1) in Scheme 15. Intermediate compounds of Formula (27) can be alkylated with compound R ^ X (where R ^{1 is} lower alkyl and X is halogen, alkanesulfonyloxy or haloalkansulfonyloxy) in an inert solvent (then optionally oxidized with an oxidizing agent in an inert solvent) and then react with

R H in the presence or absence of a base in an inert solvent to form a compound of Formula (1).

The conditions and reactants used are similar to those used in the conversion of intermediates of Formulas (7) into (12) (or (13)) into compounds of Formula (1) in Scheme 2.

Compounds of Formula (1) can be prepared from compounds of Formula (24) using an alternative route as shown in Scheme 15. Compounds of Formula (24) can be converted to compounds of Formula (27) by reaction with compounds of Formula NH ₂ NH (C = NH) NH2 in the presence or absence of an acid in an inert solvent, followed by reaction with the compounds R ¹ C (OR _c ) 3 (where R _c is lower alkyl and R ¹ is defined as above), using the conditions used for converting compounds of Formulas (3) into (17) into (7) in Scheme 10.

Some of the compounds of Formula (2) can be prepared according to the methods illustrated in Scheme 16.

-83SHEMA 16

see text

14

Compounds of Formula (27b) can be treated with various alkylating agents R X (wherein R is defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to form structures of Formula (28). Compounds with

Formula (28) (Y is O) can then be converted to compounds of Formula (2) by treatment with halogenating agents or sulfonylating agents in the presence or absence of a base in an inert 3 solvent, followed by reaction with RH in the presence or absence of a base in an inert solvent to form compounds of Formula (2). The reaction conditions used for these conversions are similar to those used for the conversion of intermediate compounds (22) into (23) into (1) into

-84 Schemes 14 (for A is CR) or conversion of intermediates of Formulas (7) into (8) into (1) in Scheme 1 (where A is N). 'Alternatively, compounds of Formula (28) (Y is S) may is alkylated with compound R ^ 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 RH in the presence or absence of a base in an inert solvent, to form a compound of Formula (1). The conditions and reactants used are similar to those used in the conversion of intermediates of Formulas (7) into (12) (or (13)) into compounds of Formula (1) in Scheme 2.

Compounds of Formula (1) wherein Z is COH can be converted to compounds of Formula (2) as exemplified in Scheme 16. Treatment with various alkylating agents RX (wherein R is defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy ) in the presence or absence of a base in an inert solvent gives structures (2). One of skill in the art will recognize that the methods used in Scheme 16 can also be used to prepare compounds of Formula (1) wherein Z is COR ⁷

For Scheme 16, the terms base and inert solvent may have the meanings given below. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) , alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkyl amines (preferably N, N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkannitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, ialdialkylformamide (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 of 1 to 10 carbons and 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20 ° C to 100 ° C.

-85 EXAMPLES

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

The reagents were obtained by purchase from commercial sources and, where necessary, purified before use according to the general procedures described by D. Perrin and VV.L.F. Armarego, Purification of Laboratory Chemicals, 3rd ed., (New York: Pergamon Press, 1988). Chromatography was performed on silica gel using the solvent systems shown below. For mixed solvent systems, volume ratios are given. Otherwise, the parts and percentages are by weight.

The following examples are provided to further detail the invention. These examples, which explain the best currently considered way of carrying out the invention, are intended to explain the invention rather than to limit it.

EXAMPLE 1 Preparation

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 3, Z is C-CH 3, Ar is 2,4-dimethylphenyl)

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

Sodium pellets (9.8 g, 0.43 mol) were added portionwise at ambient temperature to a solution of 2,4-dimethylphenylacetonitrile (48 g, 0.33 mol) in ethyl acetate (150 mL). Reactionary

-86The mixture was heated to reflux temperature and stirred for 16 hours. The resulting suspension was cooled to room temperature and filtered. The collected precipitate was washed with plenty of ether and then air-dried. The solid was dissolved in water and 1N HCl solution was added until pH = 5-6. The mixture was extracted with ethyl acetate (3 X 200 mL); the combined organic layers were dried over MgSO4 and filtered. The solvent was removed in vacuo to give a white solid (45.7 g, 74% yield): NMR (CDCl3, 300MHz); CI-MS: 188 (M + H).

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

A mixture of 1-cyano-1- (2,4-dimethylphenyl) propan-2-one (43.8 g, 0.23 mol), hydrazine hydrate (22 mL, 0.46 mol), ice (45 mL, 0.78 mol) and toluene (500 mL) was stirred at reflux temperature for 18 hours in an apparatus equipped with a Dean-Stark trap. The reaction mixture was cooled to ambient temperature and the solvent removed in vacuo. The residue was dissolved in 6N HCl and the resulting solution extracted three times with ether. The concentrated ammonium hydroxide solution was added to the aqueous layer until pH = 11. The resulting half-solution was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. The solvent was removed in vacuo to give a pale brown viscous oil (34.6 g, 75% yield): NMR (CDCl 3, 300 MHz); 7.10 (s, 1H), 7.05 (d, 2H, J = 1), 2.37 (s, 3H), 2.10 (S, 3H); CI-MS: 202 (M + H).

C. 5-Acetamidino-4- (2,4-dimethylphenyl) -3methylpyrazole, acetic acid salt

Ethyl acetamidate hydrochloride (60 g, 0.48 mol) was quickly added to a rapidly stirring mixture of potassium carbonate (69.5 g, 0.50 mol), dichloromethane (120 mL) and water (350 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 X 120 mL). The combined organic layers were dried over MgSO4 and filtered. The solvent was removed by ordinary distillation and the residue in the flask, a clear pale yellow liquid (35.0 g), was used without further purification.

Ledocet (9.7 mL, 0.17 mol) was added to a stirred mixture of 5-amino-4- (2,4-dimethylphenyl) -3methylpyrazole (34 g, 0.17 mol), ethyl acetamidate (22 g, 0.25 mol) and acetonitrile (500 mL). ).

-87The resulting reaction mixture was stirred at room temperature for 3 days; after three days, we concentrated it in vacuo to about one third of its original volume. The resulting suspension was filtered and the collected solid was washed with large quantities of ether. The white solid was dried in vacuo (31.4 g, 61% yield); NMR (DMSO-d6, 300 MHz); 7.00 (s, 1H), 6.90 (dd, 2H, J = 7, 1), 2.28 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.90 (s, 3H), 1.81 ( s, 3H); CI-MS: 243 (M + H).

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

Sodium pellets (23 g, 1 mol) were added portionwise to ethanol (500 mL) with vigorous stirring. After all the sodium had reacted, 5-acetamidino-4- (2,4-dimethylphenyl) -3methylpyrazole, acetic acid salt (31.2 g, 0.1 mol) and diethyl carbonate (97 mL, 0.8 mol) were added. The resulting reaction mixture was heated to reflux temperature and stirred for 18 hours. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in water and slowly added 1N HCl until pH = 5-6. The aqueous layer was extracted three times with ethyl acetate; the combined organic layers were dried over MgSO4 and filtered. The solvent was removed in vacuo to give a pale yellow-brown solid (26 g, 98% yield); NMR (CDCl3, 300 MHz); 7.15 (s, 1H), 7.09 (s, 2H), 2.45 (s, 3H), 2.39 (s, 3H), 2.30 (s, 3H); CI-MS: 269 (M + H).

EXAMPLE 2 Preparation

5-methyl-3- (2,4,6-trimethylphenyl) [1,5-a] - [1,2,3] -triazolo- [1,3,5] -triazin-7 (6H) -one ( Formula 7, where Y is O, R is CH3, Z is N, Ar is 2,4,6-trimethylphenyl)

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

A mixture of 2,4,6-trimethylbenzyl cyanide (1.0 g, 6.3 mmol), benzyl azide (0.92 g, 6.9 mmol) and potassium t-butoxide (0.78 g, 6.9 mmol) in tetrahydrofuran (10 mL) was stirred at ambient temperature 2.5 days. The resulting suspension was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. The solvent was removed in vacuo to give a brown oil. Trituration with ether and

-88filtration afforded a yellow solid (1.12 g, 61% yield): NMR (CDCl3, 300 MHz): 7.607.30 (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). The reaction mixture was stirred until it was dark green. A solution of ammonium chloride (mL) was added and the mixture was stirred while warming to ambient temperature for 16 hours. 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 MgSO4 and filtered. The solvent was removed in vacuo to give a yellow solid (520 mg), which was homogeneous after determination by thin layer chromatography (ethyl acetate):

NMR (CDCl3, 300 MHz): 6.97 (s, 2H), 3.68-3.50 (br.s, 2H), 2.32 (s, 3H), 2.10 (s, 6H); CIMS: 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 ice (0.1 mL, 1.98 mmol) in acetonitrile (6 mL) was stirred. at 4 am. The resulting suspension was filtered and the collected solid was washed with large quantities of ether. Vacuum drying gave a white solid (490 mg, 82% yield): NMR (DMSOd 6, 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); CIMS: 244 (M + H).

D. 5-methyl-3- (2,4,6-trimethylphenyl) [1,5-a] - [1,2,3] -triazolo- [1,3,5] -triazin-7 (4H) - he

Sodium (368 mg, 16.2 mmol) was added under stirring to ethanol (10 mL) at room temperature. After sodium reacted, 4- (2,4,6-trimethylphenyl) -5-acetamidino-triazole was added,

-89 Acetic acid salt (490 mg, 1.6 mmol) and diethyl carbonate (1.6 mL, 13 mmol). The reaction mixture was stirred at reflux temperature for 5 hours, then cooled to room temperature. The reaction mixture was diluted with water; 1N HCl solution was added until pH = 5-6 and three extractions were performed with ethyl acetate. The combined organic layers were dried over MgSO4 and filtered. The solvent was removed in vacuo to give a yellow residue. Ether trituration and filtration gave a yellow solid (300 mg, 69% yield): NMR (CDCl 3, 300 MHz): 6.98 (s, 2H), 2.55 (s, 3H), 2.35 (s, 3H), 2.10 ( s, 6H); ClMS: 270 (M + H).

EXAMPLE 3

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

1,3,5-triazine (Formula 1, where R ³ is CH (CHCO 2 CH ³ ) 2, R ¹ is CH 3, Z is C-CH 3, Ar is 2,4-dimethylphenyl)

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

A mixture of 2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] pyrazolo-1,3,5-triazin-4-one (Example 1, 1.38 g,

4.5 mmol), N, N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) were stirred at reflux for 48 hours. Excess phosphorus oxychloride was removed in vacuo. The residue was poured onto a mixture of ice and water, briefly stirred and quickly extracted three times with ethyl acetate. The combined organic layers were washed with ice-cold water, then dried over MgSO4 and filtered. The solvent was removed in vacuo to give a brown oil. Flash column chromatography (ethyl acetate: hexane :: 1: 4) yielded one fraction (Rf = 0.5). The solvent was removed in vacuo to give a yellow oil (1.0 g, 68% yield): NMR (CDCl3, 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 hexane, decanted after each rinse and placed in anhydrous tetrahydrofuran (THF, 1 mL). A solution of diethyl malonate (0.32 g, 2 mmol) in THF (2 mL) was added dropwise over 5 min, meanwhile

-90There has been a strong evolution of gas over time. 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 mixture was then stirred under nitrogen atmosphere for 48 hours. The resulting suspension was poured into water and extracted three times with ethyl acetate. The combined organic layers were washed once with brine, dried over MgSO4 and filtered. The solvent was removed in vacuo to give a brown oil. Column chromatography (ethyl acetate: hexane:; 9) gave a pale yellow solid after removal of the solvent in vacuo (Rf = 0.2, 250 mg, 35% yield); m.p. (melting point) 5052 ° C; NMR (CDCl3, 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 (5 s, 12H), 1.4 (t, 3H, J = 7), 1.35-1.25 (m, 3H); CI-HRMS: Calculated: 411.2032, Found: 411.2023.

EXAMPLE 6

Preparation of 4- (1,3-dimethoxy-2-propylamino) -2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] pyrazolo 1,3,5-triazine (Formula 1, where R ³ is NHCH (CH 2 OCH 3) 2, R ¹ is CH 3, Z is C-CH 3, 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 for 48 hours. Excess phosphorus oxychloride was removed in vacuo. The residue was poured onto a mixture of ice and water, briefly stirred and quickly extracted three times with ethyl acetate. The combined organic layers were washed with ice-cold water, then dried over MgSC> 4 and filtered. The solvent was removed in vacuo to give a brown oil. Flash column chromatography (ethyl acetate: hexane :: 1: 4) yielded one fraction (Rf = 0.5). The solvent was removed in vacuo to give a yellow oil (1.0 g, 68% yield); NMR (CDCl3, 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- (1,3-Dimethoxy-2-propylamino) -2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] pyrazolo-1,3,5triazine

-91 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 MgSO4 and filtered. The solvent was removed in vacuo. Column chromatography (CH2Cl2: CH3OH :: 50: 1) gave one fraction. Removal of the solvent in vacuo gave a solid (250 mg, 35% yield): m.p. 118-120 ° C; NMR (CDCl3, 300 MHz): 7.50 (s, 1H), 7.28 (dd, 2H, J = 8.1),

6.75 (d, 1H, J = 8), 4.70-4.58 (m, 1H), 3.70-3.55 (m, 4H), 3.43 (s, 6H), 2.50 (s, 3H), 2.35 (s, 3H); CI-HRMS: calcd: 409.1072, found: 409.1085; Analysis calculated for C 18 H 21 Cl 2 N 5 O 2: 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, the following additional examples can be prepared from Tables 1-4.

The examples shown in TABEL11 can be prepared by the methods described in Examples 1, 2, 3 or 6. Common abbreviations used are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Pr . is an example.

-92TABLE 1

R ³ »A» -a

Ar

Ex. Z R_ Ar m.p. f ° C) 6 ^a C-Me NHCH (CH2OMe) 2 2,4-Cl2-Pb 118-120 ₇ b .. C-Me NHCHPr2 2,4-Cl ₂ -Ph 114-116 8 ^C C-Me NEtBu 2,4-Cl ₂ -Ph oil gd C-Me NPr (CH2-C-C3H5) 2,4-Cl2 ~ Ph oil 10 ^e C-Me N (CH2CH2OMe) 2 2,4-Cl2 ~ Ph oil 11 * C-Me NH-3-heptyl 2,4-Cl2 ~ Ph 90-92 129 C-Me NHCH (Et) 'CH2OMe 2,4-Cl2-Ph 179-181 13 ^h C-Me NEt2 2,4-Cl2 ~ Ph 133-134 14 * C-Me NHCH (CH2OEO 2 2,4-Cl2-Ph oil 153 C-Me ΝΗ-3-pentyl 2,4-Cl2 ~ Ph 139-140 16 ^k C-Me NMePh 2,4-Cl2 “Ph 60-62 17 ¹ C-Me N? Γ2 2,4-Cl2 ~ Ph oil 18 ^m C-Me N-3-hexyl 2,4-Cl2-Ph 130-132 19 C-Me morfolino 2,4-Cl2-Ph 20 C-Me N (CH2Ph) CH2CH2OMe 2,4-Cl ₂ -Ph 21 C-Me NHCH! CH2Ph) CH2OMe 2,4-Cl2-? H 22 C-Me nh - 4 - tet rah id rob ran and 1 2,4-Cl2Ph 23 C-Me NH-cyclopentyl 2,4-Cl2-Ph 24 C-Me 1,2,3,4-tetrahydro- isoquinolines 2,4-Cl2-Ph 25 C-Me CH2- (1,2,3,4-tetrahydro- isoquinolinyl) 2,4-Cl2-Ph 26 ⁿ C-Me OEt 2,4-Cl2-Ph 141-143 27 C-Me OCH (Et) CH2OMe 2,4-Cl2 ~ Ph

C-Me OCH ₂ Ph 2,4-Cl ₂ -Ph C-Me 0-3-pentyl 2,4-Cl ₂ -Ph C-Me SEC 2, 4-Cl ₂ -Ph C-Me S (O) Et 2,4-Cl ₂ -Ph C-Me SO ₂ Et 2,4-Cl ₂ -Ph C-Me CH (CO ₂ Et) ₂ 2,4-Cl ₂ -Ph C-Me C (EC.) (CO ₂ Et) 2 2,4-Cl ₂ -Ph C-Me CH (Et) CH ₂ OH 2,4-Cl ₂ -Ph C-Me CH (Et) CH ₂ OMe 2,4-Cl ₂ -Ph C-Me CONMe ₂ 2,4-Cl ₂ -Ph C-Me COCH3 2,4-Cl ₂ -Ph C-Me CH (OH) CH3 2,4-Cl ₂ -Ph C-Me c (oh) pi-1-3-pyridyl 2,4-Cl ₂ -Ph C-Me Ph 2,4-Cl ₂ -Ph C-Me 2-CF ₃ -Ph 2,4-Cl ₂ -Ph C-Me 2-Ph-Ph 2,4-Cl ₂ -Ph C-Me 3-pentyl 2,4-Cl ₂ -Ph C-Me cyclobutyl 2,4-Ci ₂ -Ph C-Me 3- pyridyl 2, 4-Cl ₂ -Ph C-Me CH (Et) CH ₂ CONMe ₂ 2,4-Cl ₂ -Ph C-Me CH (Ec) CH ₂ CH ₂ NMe ₂ 2,4-Cl ₂ -Ph C-Me NHCH (CH ₂ OMe) 2 2,4,6-Me3 ~ Ph 125-127 C-Me NHCHPr ₂ 2,4,6-Me3 ~ Ph C-Me NEtBu 2,4,6-Me3 ~ Ph C-Me NPr (CH2-C-C3H5) 2,4,6 ~ Me3 ~ Ph C-Me N (CH ₂ CH ₂ OMe) ₂ 2,4,6-Me3 ~ Ph 123-124 C-Me NH-3-heptyl 2,4,6-Me3-Ph C-Me NHCH (Et) CH ₂ OMe 2,4,6-Me3 ~ Ph 145-146 C-Me NEt ₂ 2,4,6-Me3 ~ Ph 88-90 C-Me NHCH (CH ₂ 0Et) 2 2,4,6-Me3 ~ Ph 132-134 C-Me NH-3-pentyl 2,4,6-Me3 ~ Ph 134-135 C-Me NMePh 2,4,6-Me3 ~ Ph C-Me NPr ₂ 2,4,6-Me3 ~ Ph C-Me N-3-hexyl 2,4,6-Me3-Ph C-Me morfolino 2,4,6-Me3-Ph C-Me N (CH ₂ Ph) CH ₂ CH ₂ OMe 2,4,6-Me3 ~ Ph

C-Me NHCH (CH2Ph) CH2OMe 2,4,6-Me3-Ph C-Me nh-4 - tetrahydropyranyl 2,4,6-Me3 ~ Ph C-Me NH-cyclopentyl 2,4,6-Me3 ~ Ph C-Me and, 2,3,4-tetrahydro- isoquinolinyl 2,4,6-Me3 ~ Ph C-Me CH2 - (1,2,3,4 - tetrahydro- isoquinolinyl) 2,4,6-Me3 ~ Ph C-Me OEt 2,4,6-Me3 ~ Ph C-Me OCH (Et) CH2OMe 2,4,6-Me3 ~ Ph C-Me OCH2Ph 2,4,6-Me3 ~ Ph C-Me ο-3-pentyl 2,4,6-Me3 ~ Ph C-Me SET 2,4,6-Me3 ~ Ph C-Me S (0) Et 2,4,6-Me3-Ph C-Me SO2Et 2,4,6-Me3 ~ Ph C-Me CH (CO2Et) 2 2,4,6-Me3-Ph C-Me C (Et) (CO2Et) 2 2,4,6-Me3-Ph C-Me CH (Et) CH 2 OH 2,4,6-Me3-Ph C-Me CH (Et) CH 2 O Me 2,4,6-Me3 ~ Ph C-Me C0NMe2 2,4,6-Me3 ~ Ph C-Me COCH3 2,4,6-Me3-Ph C-Me CH (OH) CH3 2,4,6-Me3 ~ Ph C-Me c (oh) Ph-3-pyridyl 2,4,6-Me3-Ph C-Me Ph 2,4,6-Me3-Ph C-Me 2-CE3-Ph 2,4,6-Me3 ~ Ph C-Me 2-Ph-Ph 2,4,6-Me3 ~ Ph C-Me 3- pentyl 2,4,6-Me3-Ph C-Me cyclobutyl 2,4,6-Me3 ~ Ph C-Me 3- pyridyl 2,4,6-Me3-Ph C-Me CH (Et) CH2CONMe2 2,4,6-Me3-Ph C-Me CH (Et) CH2CH2NMe2 2,4,6-Me3-Ph C-Me NHCH (CH2OMe) 2 2,4-Me2-Ph 44-45 C-Me N (CH2CH2OMe) 2 2,4-Me2 ~ Ph oil C-Me NHCH (Et) CH2 O Me 2,4-Me2 “Pb 102-104 C-Me NH-3-pentyl 2,4-Me2-Ph 102-104 C-Me NEt2 2,4-Me2 ~ Ph oil C-Me N (CH 2 CN) 2 2,4-Me2 ~ PL 148-150

C-Me NHCH (Me) CH ₂ OMe 2,4-Me ₂ -Ph 102-104 C-Me OCH (Et) CH ₂ OMe 2,4-Me ₂ -Ph oil C-Me NPr-c-C3H5 2,4-Me ₂ -Ph oil C-Me NHCH (Me) CH ₂ NMe ₂ 2,4-Me ₂ -Ph 47-48 C-Me N (C-C3H5) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph 117-118 C-Me N (Pr) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph oil C-Me N (Bu) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph oil C-Me NHCHPr ₂ 2,4-Me ₂ -Ph C-Me NEtBu 2,4-Me ₂ -Ph C-Me NPr (CH ₂ -c-C ₃ H 5) 2,4-Me ₂ -Ph C-Me nh-3 - heptyl 2,4-Me ₂ -Ph C-Me NEt ₂ 2,4-Me ₂ ~ Ph C-Me NHCH (CH ₂ OEt) ₂ 2,4-Me ₂ -Ph C-Me ΝΗ-3-pentyl 2,4-Me ₂ -Ph C-Me NMePh 2,4-Me ₂ -Ph C-Me NPr ₂ 2,4-Me ₂ ~ Ph C-Me nh-3 - hexyl 2,4-Me ₂ -Ph C-Me morfolino 2,4-Me ₂ ~ Ph C-Me N (CH ₂ Ph) CH ₂ CH ₂ OMe 2,4-Me ₂ -Ph C-Me NHCH (CH ₂ Ph) CH ₂ OMe 2,4-Me ₂ -Ph C-Me nh-4 - tetrahydropyranyl 2,4-Me ₂ -Ph C-Me NH-cyclopentyl 2,4-Me ₂ -Ph C-Me 1,2,3,4- tetrahydro- isoquinolinyl 2,4-Me ₂ -Ph C-Me ch ₂ - (1,2,3,4-tetrahydro-isoquinolinyl) 2,4-Me ₂ ~ Ph C-Me OEt 2,4-Me ₂ -Ph C-Me OCH (Et) CH ₂ OMe 2,4-Me ₂ ~ Ph C-Me OCH ₂ Ph 2,4-Me ₂ -Ph C-Me ο-3-pentyl 2,4-Me ₂ ^_ Ph C-Me SET 2,4-Me ₂ -Ph C-Me S (O) Et 2,4-Me ₂ -Ph C-Me SO ₂ Et 2,4-Me ₂ -Ph C-Me CH (CO ₂ Et) ₂ 2,4-Me ₂ ~ Ph 50-52 C-Me C (Et) (CO ₂ Et) ₂ 2,4-Me ₂ -Ph

130 C-Me CH (Et) CH 2 OH 2,4-Me2Ph 131 C-Me CH (Et) CH2OMe 2,4-Me2 ~ Ph 132 C-Me CH (Et) CH2OEt 2,4-Me2 ~ Ph 133 C-Me CONMe2 2,4-Μθ £ -ΡΗ 134 C-Me COCH3 2,4-Me2 “Ph 135 C-Me CH (OH) CH3 2,4-Me2 ~ Ph 136 C-Me c (OH) Ph-3-pyridyl 2,4-Me2 ~ Ph 137 C-Me Ph 2,4-Me2 ~ Ph 139 C-Me 2-CF3-Ph 2,4-Me2 ~ Ph 139 C-Me 2-Ph-Ph 2,4-Me2 ~ Ph 140 C-Me 3 - Pentyl 2,4-Me2 ~ Ph 141 C-Me cyclobutyl 2,4-Me2 ~ Ph 142 C-Me 3- pyridyl 2,4-Me2 ~ Ph 143 - C-Me CH (Et) CH2CONMe2 2,4-Me2 ~ Ph 144 C-Me CH (Et) CH2CH2NMe2 2,4-Me2 ~ Ph 14 5 ^bc C-Me NHCH (CH2OMe) 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) CH2OMe 2-Me-4-MeO-Ph 86-88 148 ^bf C-Me N (Pr) CH2CH2CN 2-Me-4-MeO-Ph oil 149 C-Me OCH (Et) CH2OMe 2-Me-4-MeO-Ph 150 ^af C-Me NHCH (CH2OMe) 2 2-Br-4-MeO-Ph 88-90 151 ^al C-Me N (CH2CH2OMe) 2 2-Br-4-MeO-Ph oil 152 ^{a <} 3 C-Me NHCH (Et) CH2OMe 2-Br-4-MeO-Ph 95-97 153 C-Me N (Pr) CH2CH2CN 2 “Br-4-MeO-Ph 154 C-Me OCH (Et) CHjOMe 2-Br-4-MeO-Ph 155 C-Me NHCH (CH2OMe) 2 2-Me-4-NMe2 ~ Ph 156 C-Me N (CH2CH2OMe) 2 2-Me-4-NMe2 ~ Ph oil 157 C-Me NHCH (Et) CH2OMe 2-Me-4-NMe2 ~ Ph 158 C-Me N (Pr) CH2CH2CN 2-Me-4-NMe2'Ph 159 C-Me OCH (Et) CH2OMe 2-Me-4-NMe2 ~ Ph 160 C-Me NHCH (CH2OMe) 2 2-Br-4-NMe2-Ph 161 C-Me N (CH2CH2OMe) 2 2-Br-4-NMe2 ~ Ph 162 C-Me NHCH (Et) CH2OMe 2-Br-4-NMe2'Ph 163 C-Me N (Pr) CH2CH2CN 2-Br-4-NMe2 ~ Ph 164 C-Me OCH (Et) CH2OMe 2-Br-4-NMe2 ~ Ph 165 C-Me NHCH (CH2OMe) 2 2-Br-4-i-Pr-Ph

C-Me N (CH2CH2OMe) 2 2-Br-4-i-Pr-Ph C-Me NHCH (Et) CH2OMe 2-Br-4-i-Pr-Ph C-Me N (Pr) CH2CH2CN 2-Br-4-i-Pr-Ph C-Me OCH (Et) CH2OMe 2-Br-4-i-Pr-Ph C-Me NHCH (CH2OMe) 2 2-Br-4-Me-Ph C-Me N (CH2CH2OMe) 2 2-Br-4-Me-Ph C-Me NHCH (Et) CH2OMe 2-Br-4-Me-Ph C-Me N (Pr) CH2CH2CN 2-Br-4-Me-Ph C-Me OCH (Et) CH2OMe 2-Br-4-Me-Ph C-Me NHCH (CH2OMe) 2 2-Me-4-Br-Ph C-Me N (CH2CH2OMe) 2 2-Me-4-Br-Ph C-Me NHCH (EtlCHoOMe 2-Me-4-Br-Ph C-Me N (Pr) CH2CH2CN 2-Me-4-Br-Ph C-Me OCH (EC) CH2OMe 2-Me-4-Br-Ph C-Me NHCH (CH ^ OMe) 2 2-C1-4,6-Me2 ~ Ph C-Me N (CH2CH2OMe) 2 2-C1-4,6-Me2 ~ Ph C-Me NHCH (CH2OMe) 2 4-Br-2,6- (Me) 2 ~ Ph C-Me N (CH2CH2OMe) 2 4-Br-2,6- (Me) 2 “Ph C-Me NHCH (CH2OMe) 2 4-i-Pr-2-SMe-Ph C-Me N (CH2CH2OMe) 2 4-i-Pr-2-SMe-Ph C-Me NHCH (CH2OMe) 2 2-Br-4-CE3 ~ Ph C-Me N (CH2CH2OMe) 2 2-Br-4-Cf3-Ph C-Me NHCH (CH2OMe) 2 2-Br-4,6- (MeO) 2 ~ Ph C-Me N (CH2CH2OMe) 2 2-Br-4,6- (MeO) 2 ~ Ph C-Me NHCH (CH2OMe) 2 2-C1-4,6- (MeO) 2 “Ph C-Me N (CH2CH2OMe) 2 2-C1-4,6- (MeO) 2Ph C-Me NHCH (CH2OMe) 2 2,6- (Me) 2 ^- 4-SMe-Ph C-Me N (CH2CH2OMe) 2 2,6- (Me) 2-4-SMe-Ph C-Me NHCH (CH2OMe) 2 4- (COMe) -2-Br-Ph C-Me N (CH2CH2OMe) 2 4- (COMe) -2-Br-Ph C-Me NHCH (CH2OMe) 2 2,4,6-Me3 ~ pyrid-3-i C-Me N (CH2CH2OMe) 2 2,4,6-Me3-pyrid-3-i C-Me NHCH (CH2OMe) 2 2,4- (Br) 2 ”Ph C-Me N (CH2CH2OMe) 2 2,4- (Br) 2 ~ Ph C-Me NHCH (CH2OMe) 2 4-i-Pr-2-SMe-Ph C-Me N (CH2CH2OMe) 2 4-i-Pr-2-SMe-Ph

C-Me NHCH (CH2OMe) 2 4-i-Pr-2-SO2Me-Ph C-Me N (CH2CH2OMe) 2 4-ip _r -2-SO2Me-Ph C-Me NHCH (CH2OMe) 2 2,6- (Me) 24-SMe-Ph C-Me N (CH2CH2OMe) 2 2,6- (Me) 2-4-SMe-Ph C-Me NHCH (CH2OMe) 2 2,6- (Me) 2-4-SO2Me-Ph C-Me N (CH2CH2OMe) 2 2,6- (Me) 2-4-SO2Me-Ph C-Me NHCH (CH2OMe) 2 2-J-4-i-Pr-Ph C-Me N (CH2CH2OMe) 2 2-J-4-i-Pr-Ph C-Me NHCH (CH2OMe) 2 2-ΒΓ-4-Ν (Me) 26-MeO-Ph C-Me N (CH2CH2OMe) 2 2-Br-4-N (Me) 26-MeO-Ph C-Me NHCH (CH2OMe) 2 2,4- [SMe] 2-Ph C-Me N (CH2CH2OMe) 2 2, 4- [SMe] 2-Ph C-Me NHCH (CH2OMe) 2 2, 4- [SC> 2Me] 2-Ph C-Me N (CH2CH2OMe) 2 2,4- (SO2Me) 2-Ph C-Me NHCH (CH2OMe) 2 4-i-Pr-2-SMe-Ph C-Me N (CH2CH2OMe) 2 4-i-Pr-2-SMe-Ph C-Me NHCH (CH2OMe) 2 4-i-Pr-2-SO2Me-Ph C-Me N (CH2CH2OMe) 2 4-i-Pr-2-SO2Me-Ph C-Me NHCH (CH2OMe) 2 2-N (Me) 2-4-Me-Ph C-Me N (CH2CH2OMe) 2 2-N (Me) 2-4-Me-Ph C-Me NHCH (CH2OMe) 2 2-MeS-4,6- (Me) 2 ~ Ph C-Me N (CH2CH2OMe) 2 2-MeS-4,6- (Me) 2-Ph C-Me NHCH (CH2OMe) 2 2- (CH3CO) -4.6- (Me) 2Ph C-Me N (CH2CH2OMe) 2 2- (CH3CO) -4,6- (Me) 2 ~ Ph H NHCH (CH2OMe) 2 2,4-Me2 ~ Ph H NHCH (CH2OMe) 2 2,4-Me2 ~ Ph CF3 N (CH2CH2OMe) 2 2,4-Me2 ^- Ph CF3 N (CH2CH2OMe) 2 2,4-Me2 ~ Ph N NHCH (CH2OMe) 2 2,4,6-Me3 ~ Ph N NHCHPr2 2,4,6-Me3-Ph N NEtBu 2,4,6-Me3 ~ Ph N NPr (CH2-C-C3H5) 2,4,6-Me3-Ph N N (CH2CH2OMe) 2 2,4,6-Me3-Ph N NH-3-heptyl 2,4,6-Me3-Ph N NHCH (Et) CH2OMe 2,4,6-Me3 ~ Ph N NEC2 2,4,6-Me3 ~ Ph

N NHCH (CH ₂ OEt) ₂ 2,4,6-Me3 ~ Ph N NH-3-pentyl 2,4,6-Me3 ~ Ph N NMePh 2,4,6-Me3 ~ Ph N NPr ₂ 2,4,6-Me3 ~ Ph N nh-3-hexyl 2,4,6-Me3 ~ Ph N morfolino 2,4,6-Me3 ~ Ph N N (CH ₂ Ph) CH ₂ CH ₂ OMe 2,4,6-Me3 ~ Ph N NHCH (CH ₂ Ph) CH ₂ OMe 2,4,6-Me3 ~ Ph N NH-4-tetrahydropyranyl 2,4,6-Me3-Ph N NH-cyclopentyl 2,4,6-Me3 ~ Ph N 1,2,3,4- tetrahydro- isoquinoinit 2,4,6-Me3-Ph N ch ₂ - (i, 2, 3,4-tetrahydro-isoquinolinyl) 2,4,6 ~ Me3 ~ Ph N OEt 2,4,6-Me3 ~ Ph N OCH (Et) CH ₂ OMe 2,4,6-Me3 ~ Ph N OCH ₂ Ph 2,4,6-Me3 ~ Ph N o-3-pentyl 2,4,6-Me3 ~ Ph N SET 2,4,6-Me3-Ph N S (O) Et 2,4,6-Me3 ~? H N SO ₂ Et 2,4,6-Me 3-Ph N CH (CO ₂ Et) 2 2,4,6-Me3 ~ Ph N C (Et) (CO ₂ Et) 2 2,4,6-Me3 ~ Ph N CH (Et) CH 2 OH 2,4,6-Me3 ~ Ph N CH (Et) CH ₂ O Me 2,4,6-Me3-Ph N C0NMe ₂ 2,4,6-Me3 ~ Ph N COCH3 2,4,6-Me3 ~ Ph N CH (OH) CH3 2,4,6-Me3 ~ Ph N C (OH) Ph-3-pyrides 2,4,6-Me3 ~ Ph N Ph 2,4,6-Me3-Ph N 2-CP3-Ph 2,4,6-Me3 ~ Ph N 2-Ph-Ph 2,4,6-Me3 ~ Ph N 3-pentyl 2,4,6-Me3-Ph N cyclobutyl 2,4,6-Me3-Ph N 3-pyrides 2,4,6-Me3 ~ Ph N CH (Et) CH ₂ CONMe ₂ 2,4,6-Me3 ~ Ph

-100-

N CH (Et) CH2CH2NMe2 2,4,6-Me3 ~ Ph N NHCH {CH2OMe) 2 2,4-Me2 ~ Ph N NHCHPr2 2,4-Me2 ^_ Ph N NEtBu 2,4-Me2 ^_ Ph N NPr (CH2-C-C3H5) 2,4-Me2Ph N N (CH2CH2OMe) 2 2,4-Me2 ~ Ph N nh-3-heptyl 2,4-Me2 ~ Ph N NHCH (Et) CH2OMe 2,4-Me2 ~ Ph N NEt2 2,4-Me2 “Ph N NHCH (CH2OEt) 2 2,4-Me2 ^- Ph N ΝΗ-3-pentyl 2,4-Me2 ^- Ph N NMePh 2,4-Me2 ^_ Ph N NPr2 2,4-Me2 ~ Ph N N-3-hexyl 2,4-Me2 ~ Ph N morfolino 2,4-Me2 ~ Ph N N (CH2Ph) CH2CH2OMe 2,4-Me2 ~ Ph N NHCH (CH2Ph) CH2OMe 2,4-Me2 “Ph N n h -4-tetrahydropyranyl 2,4-Me2 ~ Ph N NH- cyclopentia 2,4-Me2-Ph N 1,2,3,4-tetrahydro- isoquinolinyl 2,4-Me2 ~ Ph N CH2- d, 2,3,4-tetrahydroisoquinolines) 2,4-Me2 ~ Ph N OEC 2,4-Me2 ^- Ph N OCH (EC) CH2OMe 2,4-Me2 ^- Ph N OCH2Ph 2,4-Me2 ^- Ph N 0-3- pentyl 2,4-Me2 ~ Ph N SET 2,4-Me2 ^_ Ph N S (O) Et 2,4-Me2 ^_ Ph N SO2Et 2,4-Me2 ”Ph N CH (CO2Et) 2 2,4-Me2 ~ Ph N C (Et) (CO2EO2 2,4-Me2 ~ Ph N CH (Et) CH 2 OH 2,4-Me2 ~ Ph N CH (Et) CH2OMe 2,4-Me2-Ph N CONMe2 2,4-Me2 ^- Ph N COCH3 2,4-Me2 “Ph

-101-

306 N CH (OH) CH3 2,4-Me2 ~ Pb 307 N C {OH) Ph-3-pyridyl 2,4-Me2 ~ Ph 308 N Ph 2,4-Me2 ~ Ph 309 N 2-CF3-Ph 2,4-Me2 ^_ Ph 310 N 2-Ph-Ph 2,4-Me2Ph 311 N 3- pentyl 2,4-Me2 ^_ Ph 312 N cyclobutyl 2,4-Me2 ~ Ph 313 N 3-Pyridyl 2,4-Me2 ~ Ph 314 N CH (Et) CH2CONMe2 2,4-Me2 ~ Ph 315 N CH (Et) CH2CH2NMe2 2,4-Me2 ^- Ph 316 ^an C-Me NEt ₂ 2-Bc-4-MeO-Ph oil 317 ^am C-Me NH-3-pentyl 2-Br-4-MeO-Ph oil 318 ^a 3 C-Me NHCH (CH2CH2OMe) CH2OMe 2,4,6-Me3 ~ Ph 101-103 319 ^ao '  C-Me NH (C-C3H5) 2,4-Me2 ~ Ph oil 320 ^ak C-Me morfolino 2,4,6-Me3 ~ Ph 139-141 321 ^a P C-Me NHCH (CH2OMe) 2 2-CN-4-Me-Ph 152-153 322 ^ac and C-Me N (C-C3H5) CH2CH2CN 2,4,6-Me3 ~ Ph 149-151 324 ^as C-Me NHCH (CH2CH2OMe) CH2OMe 2-Me-4-Br-Ph 115-117 32 5 ^at C-Me NHCH (CH2OMe) 2 2,5-Me2 ~ 4-MeO-Ph 55-57 326 ^au C-Me N (CH2CH2OMe) 2 2,5-Me2 ~ 4-MeO-Ph 72 327 ^av C-Me NH-3-pentyl 2,5-Me2 ~ 4-MeO-Ph 45-47 328 ^aw C-Me NEt2 2,5-Me2 ~ 4-MeO-Ph oil 329 ^ax C-Me NHCH (CH2OMe) 2 2-Cl-4-MePh 80-81 330 ^a V C-Me NCH (Et) CH2OMe 2-Cl-4-MePh 77-79 33 l ^az C-Me N (CH2CH2OMe) 2 2-Cl-4-MePh oil 332 ^ba C-Me (S) -NHCH (CH2CH2OMe) CH2OMe 2-Cl-4-MePh 139-140 333 ^bb C-Me N (C-C3H5) CH2CH2CN 2.5-Me2 “4-MeOPh 120-122 334 ^bl ? C-Me NEt2 2-Me-4-MeOPh oil 335 ^bh C-Me OEt 2-Me-4-MeOPh oil 336 ^bi C-Me (S) -NHCH (CH2CH2OMe) CH2OMe 2-Me-4-MeOPh oil 337 ^b 3 C-Me N (C-C3H5) CH2CH2CN 2-Me-4-MeOPh 129 338 ^bk C-Me NHCH (CH2CH2OEt) 2 2-Me-4-MeOPh amorphous 339 C-Me N (C-C3H5) CH2CH2CN 2,4-Cl2-Ph 109-110 340 C-Me (S) -NHCH (CH2CH2OMe) CH2OMe 2,4-Cl2-Ph 93-94 341 C-Me NH-3-pentyl 2-Me-4-BrPh 118-119 342 C-Me N (CH2CH2OMe) 2 2-Me-4-BrPh oil

-102-

C-Me NHCH (CH2-iPr) CH2OMe 2,4-Me2 ~ Ph C-Me NHCH (Pr) CH 2 O Me 2,4-Me2 ~ Ph C-Me NHCH (Et) CH2OEt 2,4-Me2Ph C-Me NHCH (CH20Me) CH2CH2OMe 2-Me-4-Me2NPh C-Me NEt2 2-Me-4-ClPh C-Me NH-3-pentyl 2-Me-4-ClPh C-Me N (CH2CH2OMe) 2 2-Me-4-ClPh C-Me NHCH (CH2OMe) 2 2-Me-4-ClPh C-Me NEt2 2-Me-4-ClPh C-Me NEt2 2-Cl-4-MePh C-Me NH-3-pentyl 2-Cl-4-MePh C-Me NHCH (CH2OMe) 2 2-Cl-4-MeOPh C-Me N (CH2CH2OMe) 2 2-Cl-4-MeOPh 'C-Me NHCH {Et) CH2 OM 2-Cl-4-MeOPh C-Me N (c-Pr) CH2CH2CN 2-Cl-4-MeOPh C-Me NEt2 2-Cl-4-MeOPh C-Me nh-3-pentyl 2-Cl-4-MeOPh C-Me NHCH (Et) CH2CH2OMe 2-Cl-4-MeOPh C-Me NHCH (Me) CH2CH2OMe 2-Cl-4-MeOPh C-Me NHCH (Et) CH2CH2OMe 2-Br-4-MeOPh C-Me NHCH (Me) CH2CH2OMe 2-Br-4-MeOPh C-Me NHCH (Et) CH2CH2OMe 2-Me-4-MeOPh C-Me NHCH (Me) CH2CH2OMe 2-Me-4-MeOPh C-Me NHCH (CH2OMe) 2 2-C1-4,5- (MeO) 2Ph C-Me N (CH2CH2OMe) 2 2-C1-4,5- (MeO) 2PO C-Me NHCH (Et) CH2 O Me 2-C1-4, 5- (MeO) 2Ph C-Me N (c-Pr) CH2CH2CN 2-C1-4.5- (MeO, 2Ph C-Me NEt2 2-C1-4,5- (MeO) 2Ph C-Me nh-3-pentyl 2-C1-4,5- (MeO) 2Ph C-Me NHCH (Et) CH2CH2OMe 2-C1-4, S- (MeO) 2Ph C-Me NHCH (Me) CH2CH2OMe 2-C1-4,5- (MeO) 2Ph C-Me NHCH (CH2OMe) 2 2-Br-4,5- (MeO) 2? H C-Me N (CH2CH2OMe) 2 2-Br-4,5- {MeO) 2Ph C-Me NHCH (Et) CH2 O Me 2-Br-4,5- (MeO) 2Ph C-Me N (C-Pr) CH2CH2CN 2-Br-4,5- (MeO) £ Ph C-Me NEC2 2-Br-4,5- (MeO) 2? ^

oil

94-95

76- 77 oil oil

122-124 oil

122-123 oil oije

120-121 oil

108-110

127-129 oil

77- 79

137-138

147-148

52-58

-103-

C-Me nh-3-pentyl 2-Br-4,5- (MeO) ₂ Ph C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-Br-4,5- (MeO) ₂ Ph C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-Br-4,5- (MeO) ₂ Ph C-Me NHCH (CH ₂ OMe) 2 2-C1-4,6- (MeO) ₂ Ph C-Me N (CH ₂ CH ₂ OMe) ₂ 2-C1-4,6- (MeO) ₂ Ph C-Me NHCH (Et) CH ₂ OMe 2-C1-4,6- (MeO) ₂ Ph C-Me N (c-Pr) CH ₂ CH ₂ CN 2-C1-4,6- (MeO) ₂ Ph C-Me NEt ₂ 2-C1-4,6- (MeO) ₂ Ph C-Me NH-3-pentyl 2-C1-4,6- (MeO) ₂ Ph C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-C1-4,6- (MeO) ₂ Ph C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-C1-4,6- (MeO) ₂ Ph C-Me NHCH (CH ₂ OMe) 2 2-Me-4,6- (MeO) ₂ Ph C-Me N (CH ₂ CH ₂ OMe) 2 2-Me-4,6- (MeO) ₂ Ph C-Me NHCH (Et) CH ₂ OMe 2-Me-4,6- (MeO) ₂ Ph C-Me N (c-Pr) CH ₂ CH ₂ CN 2-Me-4,6- (MeO) ₂ Ph C-Me NEt ₂ 2-Me-4,6- (MeO) ₂ Ph C-Me NH-3-pentyl 2-Me-4,6- (MeO) ₂ Ph C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-Me-4,6- (MeO) ₂ Ph C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-Me-4,6- (MeO) ₂ Ph C-Me N (c-Pr) CH ₂ CH ₂ CN 2-Br-4,6- (MeO) ₂ Ph C-Me NEt ₂ '2-Br-4, 6- (MeO) ₂ Ph C-Me NH-3-pentyl 2-Br-4,6- (MeO) ₂ Ph C-Me • NHCH (Et) CH ₂ CH ₂ OMe 2-Br-4,6- (MeO) ₂ Ph C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-Br-4,6- (MeO) ₂ Pb C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-Me-4-MeOPh C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-Me-4-MeOPh C-Me NHCH (CH ₂ OMe) ₂ 2-MeO-4-MePh C-Me N (CH ₂ CH ₂ OMe) ₂ 2-MeO-4-MePh C-Me NHCH (Et) CH ₂ OMe 2-MeO-4-MePh C-Me N (c-Pr) CH ₂ CH ₂ CN 2-Me0-4-MePh C-Me NEt ₂ 2-MeO-4-MePh C-Me NH-3-pentyl 2-MeO-4-MePh C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-MeO-4-MePh C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-MeO-4-MePh C-Me NHCH (CH ₂ OMe) 2 2-MeO-4-MePh C-Me N (CH ₂ CH ₂ OMe) ₂ 2-MeO-4-MePh

-104-

416 C-Me NHCH (Et) CH ₂ O Me 2-MeO-4-MePh 417 C-Me N (c-Pr) CH ₂ CH ₂ CN 2-MeO-4-MePh 418 C-Me NEt ₂ 2-MeO-4-MePh 419 C-Me nh-3-pentyl 2-MeO-4-MePh 420 C-Me NHCH (Et) CH ₂ CH ₂ QMe 2-MeO-4-MePh 421 C-Me NHCH (Me) CH ₂ CH2OMe 2-MeO-4-MePh 423 ^bt C-Me NHCH (CH ₂ OMe) 2 2-MeO-4-ClPh 424 C-Me N (CH ₂ CH ₂ OMe) ₂ 2-MeO-4-ClPh 425 C-Me NHCH (Et) CH ₂ O Me 2-Me0-4-ClPh 426 C-Me N (C-Pr) CH ₂ CH ₂ CN 2-MeO-4-ClPh 427 C-Me NEt ₂ 2-MeO-4-ClPh 428 C-Me ΝΗ-3-pentyl 2-MeO-4-ClPh 429 C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-MeO-4-ClPh 430 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-MeO-4-ClPh

TABLE 1 NOTES:

a) Analysis: calculated: 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.

b) CI-HRMS: calc: 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 (CDCl3, 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, found: 392.1388 (M + H);

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

I. 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), 1.70-1.90 (m, 2H), 2.30 (s. 3H), 2.40 (s, 3H), 3.85-4.02 (m, 2H), 4.02-4.20 (m, 2H), 7.30 (s, 2H), 7.50 (s, 1H).

-105e) CI-HRMS: calcd: 424.1307, found: 424.1307 (M + H);

NMR (CDCl3, 300 MHz): 2.28 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.75 (t, J = 8, 4H), 4.20-4.45 (m, 4H), 7.30 (s, 2H), 7.50 (s, 1H).

f) CI-HRMS: calcd: 406.1565, found: 406.1578 (M + H);

NMR (CDCl3, 300 MHz): 0.90 (t, J = 8, 3H), 1.00 (t, J = 8, 3H), 1.28-1.45 (m, 4H), 1.50-1.80 (m, 4H), 2.35 ( s, 3H), 2.50 (s, 3H), 4.20-4.35 (m, 1H), 6.10-6.23 (m, 1H), 7.30 (s, 2H), 7.50 (s, 1H).

g) CI-HRMS: calcd: 394.1201, found: 394.1209 (M + H);

NMR (CDCl3, 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 (brs, 1H), 6.50-6.60 (m, 1H), 7.30 (s, 2H), 7.50 (s, 1H).

h) CI-HRMS: calcd: 364.1096, found: 364.1093 (M + H);

Analysis: Calculated: C: 56.05; H: 5.27; N, 19.23; CI: 19.46; found: C: 55.96; H: 5.24; N, 18.93; CI: 19.25;

NMR (CDCl3, 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) H).

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

NMR (CDCl3, 300 MHz): 1.22 (t, J = 8, 6H), 2.35 (s, 3H), 2.47 (s, 3H), 3.39 (q, J = 8, 4H), 3.65 (dd, J = 8.1, 2H), 3.73 (dd, J = 8.1, 2H), 4.55-4.65 (m, 1H), 6.75 (d, J = 8, 1H), 7.30 (d, J = 1. 2H), 7.50 (s, 1H).

j) CI-HRMS: calculated; 378.1252, found: 378.1249 (M + H);

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

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

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

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

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

NMR (CDCl3, 300 MHz): 2.05 (s, 3H), 2.50 (s, 3H), 3.78 (s, 3H), 7.20-7.45 (m, 7H), 7.50 (d, J = 1.1H).

l) CI-HRMS: calcd: 392.1409, found: 392.1391 (M + H);

-106NMR (CDCl3, 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 (CDCl3, 300 MHz); 0.90-1.05 (m, 6H), 1.35-1.55 (m, 2H), 1.55-1.85 (m, 4H),

2.35 (s, 3H), 2.48 (s, 3H), 4.20-4.35 (m, 1H), 6.15 (d, J = 8, 1H), 7.30 (s, 2H), 7.50 (d, J = 1.1H) ).

n) CI-HRMS: 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 (CDCl3, 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 = 8.1 H), 7.35 (dd, J = 8, 1.1 H), 7.55 (d, J = 1.1 H).

o) CI-HRMS: calcd: 383.2321, found: 383.2309 (M + H);

NMR (CDCl3, 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, 2H).

p) CI-HRMS: calculated: 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 (CDCl3, 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, 1 H), 6.70 (d, J = 8, 1 H), 7.05 (d, J = 8.1 H), 7.07 (d. J = 8, 1 H), 7.10 (s, 1 H).

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

NMR (CDCl3, 300 MHz): 2.16 (s, 3H), 2.25 (s, 3H), 2.35 (s, 3H), 2.39 (s, 3H), 3.40 (S, 6H), 3.77 (t, J = 8) , 4H), 4.20-4.45 (m, 4H), 7.02 (d, J = 8, 1H), 7.05 (s, 1H), 7.10 (d, J = 7.1 H).

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

Analysis: Calculated: C: 67.96; H, 7.71; N, 19.81; found: C: 67.56; H, 7.37; N, 19.60;

-107NMR (CDCl3, 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 = 8.1 H), 7.04 (d, J = 8.1 H), 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 (CDCl3, 300 MHz): 1.00 (t, J = 8, 6H), 1.55-1.70 (m, 2H), 1.70-1.85 (m, 2H), 2.19 (S, 3H), 2.30 (s, 3H) , 2.35 (s, 3H), 2.46 (s, 3H), 4.15-4.26 (m, 1H), 6.17 (d, J = 8.1 H), 7.06 (d, J = 8.1 H), 7.10 ( d, J = 1H), 7.13 (s, 1H).

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

NMR (CDCl3, · 300 MHz): 1.25 (t, J = 8, 6H), 2.16 (s, 3H), 2.28 (s, 3H), 2.35 (s, 3H).

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

u) 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 (CDCl3, 300 MHz); 2.15 (s, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 2.52 (s, 3H), 5.255.35 (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 (CDCl3, 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: calculated: 355.2134, found: 355.2134 (M + H);

NMR (CDCl3, 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), 5.705.80 (m, 1H), 7.00-7.20 (m, 3H).

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

NMR (CDCl3, 300 MHz): 0.35-0.43 (m, 2H), 0.50-0.60 (m, 2H), 0.98 (t, J = 8, 3H), 1.20-1.30 (m, 1H), 1.72-1.90 ( m, 2H), 2.18 (s, 3H), 2.28 (s, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 3.88-4.03 (m, 2H), 4.03-4.20 (m, 2H) , 7.00-7.15 (m, 3H).

-108y) Cl-HRMS: calcd: 353.2454, found: 353.2454 (M + H);

Analysis: Calculated: C: 68.15; H, 8.02; N, 23.84; found: C: 67.43; H, 7.81; N, 23.45;

NMR (CDCl3, 300 MHz): 1.38 (d, J = 8, 3H), 2.18 (s, 3H), 2.30-2.40 (m, 12H), 2.47 93, 3H), 2.60-2.75 (m, 2H). 4.30-4.50 (m, 1H), 6.60-6.70 (m, 1H), 7.00-7.15 (m, 3H).

z) Cl-HRMS: calcd: 361.2140, found: 361.2128 (M + H);

NMR (CDCl3, 300 MHz): 0.75-0.83 (ra, 2H), 1.00-1.10 (m, 2H), 2.17 (s, 3H), 2.30 (s, 3H), 2.36 (s, 3H), 2.47 (s , 3H), 2.85 (t, J = 8, 2H), 3.30-3.40 (m, 1H), 4.40-4.55 (m, 2H), 7.00-7.18 (m, 3H).

aa) Cl-HRMS: calcd: 363.2297, found: 363.2311 (M + H);

NMR (CDCl3, 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), 2.98 (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) Cl-HRMS: calcd: 363.2297, found: 363.2295 (M + H);

NMR (CDCl3, 300 MHz): 1.01 (t, 3H, J = 8), 1.35-1.55 (m, 2H), 1.75-1.90 (m, 2H).

2.15 (s, 3H), 2.30 (s, 3H), 2.36 (s, 3H), 2.46 (s, 3H), 4.10-4.30 (m, 2H), 4.95-5.10 (br S, 2H), 7.05 (d , 1 H, J = 8), 7.10 (d, 1 H, J = 8), 7.15 (s, 1 H).

ac) Cl-HRMS: calcd: 368.2450, found: 368.2436 (M + H);

Analysis: Calculated: C, 68.62, H, 7.95, N, 19.06; found: C, 68.73, H, 7.97, N, 19.09;

NMR (CDCl3, 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) Cl-HRMS: calculated: 352.2501, found: 352.2500 (M + Η):

Analysis: Calculated: C: 71.76; H, 8.33; N: 19.92; Found: C: 71.55; H: 8.15; N, 19.28;

NMR (CDCl3, 300 MHz): 1.01 (t, J = 8, 6H), 1.58-1.70 (m, 2H), 1.70-1.85 (m, 2H), 2.02 (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) Cl-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;

-109NMR (CDCl3, 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: calcd: 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; Nr. 17.44;

NMR (CDCl3, 300 MHz): 2.32 (s, 3H), 2.57 (s, 3H), 3.42 (s, 6H), 3.60 (q, J = 8, 2H), 3.69 (q, J = 8, 2H) , 3.82 (s, 3H), 4.60-4.70 (m, 1H), 6.73 (d, J = 8, 1H), 6.93 (dd, J = 8.1, 1H), 7.22 (d, J = 8. 1H).

ag) CI-HRMS: 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 (CDCl3, 300 MHz): 1.00-1.07 (m, 3H), 1.65-1.85 (m, 2H), 2.35 (s, 3H), 2.46, 2.47 (s, S, 3H), 3.40, 3.45 (s. S, 3H), 3.83 (s, 3H), 4.35-4.45 (m, 1H), 6.55 (d, J = 8, 1 H), 6.92 (dd, J = 8.1, 1 H), 7.20-7.30 (m, 2H).

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

Analysis: Calculated: C: 70.18; H: 8.06; N, 20.75; found: C: 70.69; H: 7.66; N, 20.34;

NMR (CDCl3, 300 MHz): 1.35 (t, J = 8, 6H), 2.01 (s, 6H), 2.15 (s, 3H), 2.30 (s, 3H).

2.38 (s, 3H), 4.07 (q, J = 8, 4H), 6.93 (s, 2H).

ai) CI-HRMS: 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 (CDCl3, 300 MHz): 1.24 (t, J = 8, 6H), 2.00 (s, 6H), 2.20 (s, 3H), 2.30 (s, 3H), 2.43 (s, 3H), 3.60 (q , J = 8, 4H), 3.66 (dd, J = 8, 3, 2H), 3.75 (dd, J = 8, 3, 2H), 4,554.65 (m, 1H), 6.75 (d, J = 8) , 1H), 6.95 (s, 2H).

aj) 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 (CDCl3, 300'MHz); 1.95-2.10 (m, 8H), 2.20 (s, 3H), 2.32 (s, 3H), 2.44 (s, 3H),

3.38 (s, 3H), 3.42 (s, 3H), 3.50-3.70 (m, 4H), 4.58-4.70 (m, 1H), 6.87 (d, J = 8, 1H), 6.95 (S, 2H).

ak) CI-HRMS: calcd: 338.1981, found: 338.1971 (M + H);

-110Analysis: Calculated: C: 67.63; H, 6.87; N, 20.06; found: C: 67.67; H: 6.82; N, 20.31;

NMR (CDCl3, 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 (CDCl3, 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: calcd: 418.1242, found: 418.1223 (M + H);

NMR (CDCl3, 300 MHz): 1.00 (t, d, J = 8, 1, 6H), 1.55-1.75 (m, 4H), 2.34 (s, 3H), 2.49 (s, 3H), 2.84 (s. 3H), 4.15-4.27 (m, 1H), 6.19 (d, J = 8, 1H), 6.93 (dd, J = 8, 1, 1H), 7.21-7.30 (m, 2H).

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

NMR (CDCl3, 300 MHz): 1.35 (t, J = 8, 6H), 2.28 (s, 3H), 2.40 (s, 3H), 3.83 (s, 3H), 3.90-4.08 (m, 2H), 4.08 -4.20 (m, 2H), 6.92 (dd, J = 8.1,1 H), 7.20-7.25 (m, 2H).

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

NMR (CDCl3, 300 MHz): 0.75-0.80 (m, 2H), 0.93-1.00 (m, 2H), 2.16 (s, 3H), 2.28 (s, 3H), 2.35 (s, 3H), 2.53 (s , 3H), 3.00-3.10 (m, 1H), 6.50-6.55 (m, 1H), 7.00-7.15 (m, 3H).

ap) CI-HRMS: calcd: 397.1988, found: 397.1984 (M + H);

NMR (CDCl3, 300 MHz): 2.43 (s, 3H), 2.50 (s, 3H), 3.43 (s, 3H), 3.61 (dd, J = 8, 8, 2H), 3.69 (dd, J = 8. 8, 2H), 3.88 (s, 3H), 4.58-4.70 (m, 1H), 6.75 (d, J = 8.1 H), 7.20 (dd, J = 8, 1, 1 H), 7.25 ( d, J = 1, 1 H), 7.40 (s, 1 H).

aq) CI-HRMS: calcd: 375.2297, found: 375.2286 (M + H);

Analysis: Calculated: C: 70.56; H, 7.01; N, 22.44; found: C: 70.49; H: 6.99; N, 22.45;

NMR (CDCl3, 300 MHz): 0.79-0.85 (m, 2H), 1.00-1.05 (m, 1H), 2.00 (s, 6H), 2.19 (s, 3H), 2.32 (s, 3H), 2.44 ( s, 3H), 2.84 (t, J = 8, 2H), 3.30-3.40 (m, 1H), 4.50 (t, J = 8, 2H), 6.95 (s, 2H).

ar) CI-HRMS: calcd: 434.1192, 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;

-111 NMR (CDCl3, 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 = 8.1 H), 7.08 (d, J = 8.1 H), 7.37 (dd , J = 8.1.1 H), 7.45 (d, J = 1.1 H).

as) 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; No: 13.03;

NMR (CDCl3, 300 MHz): 1.95-2.10 (m, 2H), 2.20 (s, 3H), 2.30 (s, 3H), 2.47 (s, 3H).

3.38 (s, 3H), 3.41 (s, 3H), 3.50-3.67 (m, 4H), 4.55-4.70 (m, 1H), 6.89 (d, J = 8, 1H), 7.05 (d, J = 8) , 1 H), 7.35 (dd, J = 8.1, 1 H), 7.47 (d, J = 1.1 H).

at) CI-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;

NMR (CDCl3, 300 MHz): 2.16 (s, 3H), 2.20 (s, 3H), 2.30 (S, 3H), 2.46 (s, 3H), 3.42 (s, 6H), 3.60 (q, J = 8) , 2H), 3.70 (q, J = 8, 2H), 3.85 (s, 3H), 4.59-4.70 (m, 1 H), 6.70 (d, J = 8.1 H), 6.76 (s, 1 H) ), 6.96 (s, 1H).

au) CI-HRMS: calcd: 414.2505, found: 414.2493 (M + H);

NMR (CDCl3, 300 MHz): 2.15 (s, 3H), 2.19 (s, 3H), 2.25 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.76 (t, J = 8) , 4H), 3.84 (s, 3H), 4.20-4.45 (m, 4H), 6.77 (s, 1H), 6.93 (s, 1H).

av) CI-HRMS: calculated: 368.2450, found: 368.2447 (M + H);

NMR (CDCl3, 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, found: 353.2197 (M + H);

NMR (CDCl3, 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; CI: 9.09; found: C: 58.95; H, 6.28; N, 17.73; CI; 9.15;

NMR (CDCl3, 300 MHz); 2.35 (s, 3H), 2.37 (s, 3H), 2.48 (s, 3H), 3.42 (s, 6H), 3.60 (dd, J = 8, 8, 2H), 3.68 (dd, J = 8, 8 , 2H), 4.59-4.72 (m, 1 H), 6.72 (d, J = 8, 1 H), 7.12 (d, J = 8.1 H), 7.23 (d, J = 8.1 H). 7.32 (s, 1H).

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

-112Analysis: 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 (CDCl3, 300 MHz): 1.01 (t, J = 8, 3H), 1.62-1.88 (m, 4H), 2.35 (s, 3H), 2.37 (s, 3H), 2.48 (d, J = 1. 3H), 3.40, 3.45 (s, s, 3H), 3.50-3.64 (m, 2H), 4.38-4.47 (m, 1H), 6.53 (d, J = 8.1 H), 7.12 (d, J = 8.1 H), 7.07 (d, J = 8.1 H), 7.12 (s, 1 H).

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

NMR (CDCl3, 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 = 8.1 H), 7.22 (d, J = 8, 1 H), 7.31 (s, 1 H).

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

Analysis: Calculated: 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 (CDCl3, 300 MHz): 1.95-2.08 (m, 2H), 2.35 (s, 3H), 2.38 (s, 3H), 2.46 (s, 3H).

3.38 (s, 3H), 3.41 (s, 3H), 3.50-3.65 (m, 4H), 4.56-4.70 (m, 1H), 6.85 (d, J = 8, 1H), 7.12 (d, J = 8) , 1 H), 7.45 (d, J = 8.1 H), 7.32 (s, 1 H).

bb) CI-HRMS: calcd: 391.2246, found: 391.2258 (M + H);

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

NMR (CDCl3, 300 MHz): 0.76-0.84 (m, 2H), 0.84-0.91 (m, 2H), 1.00-1.08 (m, 2H),

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

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

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

NMR (CDCl3, 300 MHz): 7.1 (d, 1H, J = 8), 6.9 (d, 1H, J = 1), 6.8 (dd, 1H, J = 8.1), 6.7 (br d, 1H) , J = 8), 4.7-4.6 (m, 1H), 3.85 (s, 3H), 3.70-3.55 (m, 4H), 3.45 (s, 6H),

2.5 (s, 3H), 2.3 (s, 3H), 2.15 (s, 3H).

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

NMR (CDCl3, 300 MHz): 7.1 (d, 1H, J = 7), 6.85 (d, 1H, J = 1), 6.75 (dd, 1H, J = 7.1), 4.45-4.25 (br.S, 4H) ), 3.75 (t, 4H, J = 7), 3.4 (s, 6H), 2.4 (s, 3H), 2.25 (s, 3H),

2.15 (s, 3H).

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

-113Analysis: Calculated: C: 65.02; H, 7.38; N, 18.96; found: C: 65.28; H, 7.27; N, 18.71;

NMR (CDCl3, 300 MHz): 7.1 (d, 1H, J = 8), 6.85 (d, 1H, J = 1), 6.8 (dd, 1H, J = 8.1),

6.5 (br.d, 1H, J = 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: calcd: 379.2246, found: 379.2248 (M + H);

NMR (CDCl3, 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, 3H), 2.2 (s, 3H), 1.9-1.8 (m. 2H), 1.0 (t, 3H, J = 7).

bg) CI-HRMS: calcd: 340.2137, found: 340.2122 (M + H);

NMR (CDCl3, 300 MHz): 7.1 (d, 1H, J = 8), 6.85 (d, 1H, J = 1), 6.75 (dd, 1H, J = 8, 1), 4.2-4.0 (no.m , 4H), 3.85 (s, 3H), 2.4 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.35 (t, 6H, J = 7).

bh) CI-HRMS: calcd: 313.1665, found: 313.6664 (M + H).

bi) CI-HRMS: calcd: 400.2349, found: 400.2346 (M + H);

NMR (CDCl3, 300 MHz): 7.1 (d, 1H, J = 7), 6.9-6.75 (m, 3H), 4.7-4.55 (m, 1H), 3.8 (s, 3H), 3.7-3.5 (m. 4H), 3.45 (s, 3H), 3.35 (S, 3H), 2.5 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 2.1-1.95 (m, 2H).

bj) CI-HRMS: calcd: 377.2090, found: 377.2092 (M + H);

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

NMR (CDCl3, 300 MHz): 7.1 (d, 1H, J = 8), 6.9 (d, 1H, J = 1), 6.8 (dd, 1H, J = 8, 1), 4.55-4.4 (m, 2H) ), 3.85 (s, 3H), 3.4-3.3 (m, 1H), 2.85 (t, 2H, J = 7), 2.5 (s, 3H), 2.3 (s, 3H), 2.2 (S, 3H) , 1.1-1.0 (m, 2H), 0.85-0.75 (m, 2H).

bk) CI-HRMS: calcd: 413.2427, found: 413.2416 (M + H);

NMR (CDCl3, 300 MHz); 7.1 (d, 1H, J = 8), 6.85 (d, 1H, J = 1), 6.75 (dd, 1H, J = 8, 1), 4.6 (m, 1H), 3.85 (s, 3H), 3.75 -3.6 (m, 4H), 3.6 (q, 4H, J = 7), 2.5 (s, 3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.25 (t, 6H, J = 7) .

bi) CI-HRMS: calcd: 420.1802, found: 420.1825 (M + H);

bm) CI-HRMS: calcd: 390.1697, found: 390.1707 (M + H);

bn) CI-HRMS: calcd: 397.1465, found: 397.1462 (M + H);

bo) CI-HRMS: calcd: 360.1513, found: 360.1514 (M + H);

-114bp) CI-HRMS: calcd: 374.1748, found: 374.1737 (M + H);

bq) CI-HRMS: calcd: 479.1155, found: 479.1154 (M + H);

br) CI-HRMS: calcd: 463.1219, found: 463.1211 (M + H);

Analysis: Calculated: C: 51.96, H: 5.23, N: 15.15, No: 17.28; found: C: 52.29, H: 5.62, N: 14.79, No: 17.47.

bs) CI-HRMS: calcd: 433.1113, found: 433.1114 (M, Br);

bt) NH3-CI MS: calculated: 406, found: 406 (M + H) +;

NMR (CDCl3, 300 MHz); δ 7.28 (d, J = 10Hz, 1H), 7.03 (d, J = 8Hz, 1H), 6.96 (s, 1H), 6.7 (d, J = 9, 1H), 4.63 (m, 1H), 3.79 ( s, 3H), 3.6 (m, 4H), 3.42 (s, 6H), 2.47 (s, 3H), 2.32 (s, 3H).

EXAMPLE 431

Preparation of 2,4,7-dimethyl-8- (4-methoxy-2-methylphenyl) [1,5-a] pyrazolo-1,3,5-triazine (Formula 1, wherein R ³ is CH 3, R ¹ is CH3, Z is C-CH3, Ar is 2,4-dimethylphenyl)

5-Acetamidino-4- (4-methoxy-2-methylphenyl) -3-methylpyrazole, acetic acid salt (602 mg, 2 mmol) was mixed with saturated NaHCO3 solution (10 mL). The aqueous mixture was extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was added to 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 and stirred for 16 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo to give an oily solid. Column chromatography (CHCl3: MeOH :: 9: 1) gave, after removal of the solvent in vacuo, a yellow viscous oil (Rf = 0.6, 210 mg, 37% yield); NMR (CDCl3, 300 MHz): 7.15 (d, 1H, J = 8), 6.9 (d, 1H, J = 1), 6.85 (dd, 1H, J = 8.1), 3.85 (s, 3H). 2.92 (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 1 3 (Formula 1, where A is CH, R is Me, R is OH, Z is C -Me, Ar is 2-chloro-4-methylphenyl)

-1155-Amino-4- (2-chloro-4-methylphenyl) -3-methylpyrazole (1.86 g, 8.4 mmol) was dissolved in ice (30 mL) with stirring. Ethyl acetoacetate (1.18 mL, 9.2 mmol) was then added dropwise to the resulting solution. The reaction mixture was then heated to reflux temperature and stirred for 16 hours, then cooled to room temperature. Ether (100 mL) was added and the resulting precipitate was collected by filtration. Vacuum drying gave a white solid (1.0 g, 42% yield): NMR (CDCl3, 300Hz): 8.70 (br.s, 1H), 7.29 (s, 1H), 7.21-7.09 (m, 2H), 5.62 (s, 1H), 2.35 (s, 6H), 2.29 (s, 3H); CI-MS: 288 (M + H).

EXAMPLE 433

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

A mixture of 7-hydroxy-5-methyl-3- (2-chloro-4-methylphenyl) -pyrazolo [1,5-a] pyrimidine (1.0 g, 3.5 mmol), phosphorus oxychloride (2.7 g, 1.64 mL, 17.4 mmol) , N, N-diethylaniline (0.63 g, 0.7 mL, 4.2 mmol) and toluene (20 mL) were stirred at reflux for 3 hours, then cooled to ambient temperature. The volatiles were removed in vacuo. Flash chromatography (EtOAc: 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 (CDCl3, 300Hz): 7.35 (s, 1H), 7.28-7.26 (m, 1H), 71.6 (d, 1H, J = 7), 6.80 (s, 1H), 2.55 (s. 3H), 2.45 (s, 3H),

2.40 (s, 3H); CI-MS: 306 (M + H).

EXAMPLE 434

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

A solution of 3-pentylamine (394 mg, 6.5 mmol) and 7-chloro-5-methyl-3- (2-chloro-4methylphenyl) pyrazolo [1,5-a] pyrimidine (200 mg, 0.65 mmol) in dimethylsulfoxide (DMSO, 10 mL) was stirred at 150 ° C for 2 hours; then we cooled it to ambient temperature. The reaction mixture was then poured into water (100 mL) and stirred. Three extractions with dichloromethane, washing the combined organic layers with brine, drying over MgSO4, filtration and removal of the solvent in vacuo gave a yellow solid. Flash chromatography

-116 (EtOAc: hexane :: 1: 4) gave a white solid (140 mg, 60% yield): m.p. 139-141 ° C; NMR (CDCl3, 300Hz): 7.32 (s, 1H), 7.27 (d, 1H, J = 8), 7.12 (d, 1H, J = 7), 6.02 (d, 1H, J = 9), ~ 5.78 ( S, 1H), 3.50-3.39 (m, 1H), 2.45 (s, 3H), 2.36 (s, 6H), 1.82-1.60 (m, 4H), 1.01 (t, 6H, J = 8); Analysis calculated for C20H25ClN4: C, 67.31, H, 7.06, N, 15.70, Cl, 9.93; found: C, 67.32, H, 6.95, N, 15.50, Cl, 9.93.

The examples shown in TABLE 2 can be prepared according to the methods described in Examples 1 A,

B, 432, 433, 434. Common abbreviations used are: Ph is phenyl, Pr is propyl, Me is methyl,

Et is ethyl, Bu is butyl, Pr. is an example, EtOAc is ethyl acetate.

-117-

Pl Z Βί Ar m.p. and ° C) 435 ^b C-Me N (CH2CH2OMe) 2 2,4-Cl2 ~ Ph 71-73 436 ^c C-Me N (Bu) Et 2,4-Cl ₂ -Ph 86-87 437 ^d C-Me NHCH (Et) CH2OMe 2,4-Cl2Ph 110-111 4 38 ^e C-Me N (Pr) CH2CH2CN 2,4-Cl2-Ph 83-85 439 ^f C-Me nh-3-pentyl 2,4-Cl2 ~ Ph 175-176 440 * 7 C-Me NHCH (CH2OMe) 2 2,4-Cl2-? H 107 441h C-Me NHCH (Et) 2 2,4-Me2 ^_ Ph oil 4 42 ¹ C-Me NHCH (CH2OMe) 2 2,4-Me2 ^- Ph 103-105 4433 C-Me N (CH2CH2OMe) 2 2,4-Me2 ^- Ph 87-89 444 ^k C-Me N (C-Pr) CH2CH2CN 2,4-Me2 ~? H 133 (dec.) 4 4 5 ¹ C-Me N (CH2CH2OMe) 2 2-C1,4-MePh 77-78 4 4 6 ^m C-Me NHCH (CH2OMe) 2 2-C1,4-MePh 131-133 447 ⁿ C-Me NHCH (Et) 2 2-C1,4-MePh 139-141 448 ° C-Me NEt2 2,4-Me2 ~ Ph 92-94 449P C-Me N (Pr) CH2CH2CN 2,4-Me2 ~ Ph 143-144 4 50Ή C-Me N (Bu) CH2CH2CN 2,4-Me2 ~ Ph 115-117 4 51 ^р C-Me NHCH (Et) CH2OMe 2,4-Me2 ~ Ph oil 452 ³ C-Me NHCH (Et) 2 2-Me, 4-MeOPh 104-106 453 ^b C-Me NHCH (CH2OMe) 2 2-Me, 4-MeOPh 115-116 454 ⁱⁿ C-Me N (CH2CH2OMe) 2 2-Me, 4-MeOPh oil 4 55 ^v C-Me (S) -NHCH (CH2CH2OMe) - 2-Me, 4-MeOPh oil (CHjOMe) 456 ^w C-Me (S) -NHCH (CH2CH2OMe) - 2,4-Me2 ^_ Ph oil

-118-

C-Me N (CH2CH2OMe) 2 2-Me, 4-ClPh oil C-Me NHEt 2,4-Me2-Ph oil C-Me NHCH (Et) 2 2-Me, 4-ClPh 94-96 C-Me NHCH (CH2OMe) 2 2-Me, 4-ClPh 113-114 C-Me N (Ac) Et 2,4-Me2-Ph oil C-Me (S) -NHCH (CH2CH2OMe) - (CH2OMe) 2-Me, 4-ClPh oil C-Me N (Pr) CH2CH2CN 2-Me, 4-MeOPh 118-119 C-Me NEt2 2-Me, 4-MeOPh 97-99 C-Me (S) -NHCH (CH2CH2OMe) - (CH2OMe) 2-C1,4-MePh 101-103 C-Me NEt2 2-C1,4-MePh 129-130 C-Me N (c-Pr) CH2CH2CN 2-Me, 4-MeOPh 177-178 C-Me N (c-Pr) CH2CH2CN 2-C1,4-MePh 162-163 C-Me NHCH (Et) CH2OMe 2-Me, 4-MeOPh oil C-Me NHCH (Et) CH2OMe 2-C1,4-MePh 111-113 C-Me NHCH (CH2OMe) 2 2-Cl-4-MeOPh C-Me N (CH2CH2OMe) 2 2-Cl-4-MeOPh C-Me NHCH (Et) CH2OMe 2-Cl-4-MeOPh C-Me N (c-Pr) CH2CH2CN 2-Cl-4-MeOPh C-Me NEt2 2-Ci-4-MeOPh C-Me ΝΗ-3-pentyl 2-Cl-4-MeOPh C-Me NHCH (Et) CH2CH2OMe 2-Cl-4-MeOPh C-Me NHCH (Me) CH2CH2OMe 2-Cl-4-MeOPh C-Me NHCH (Et) CH2CH2OMe 2-3r-4-MeOPh C-Me NHCH (Me) CH2CH2OMe 2-Br-4-MeOPh C-Me NHCH (Et) CH2CH2OMe 2-Me-4-MeOPh C-Me NHCH (Me) CH2CH2OMe 2-Me-4-MeOPh C-Me NHCH (CH2OMe) 2 2-C1-4,5- (MeO) 2Ph C-Me N (CH2CH2OMe) 2 2-C1-4,5- (MeO) 2Ph C-Me NHCH (Et) CH2OMe 2-C1-4,5- (MeO) 2Ph C-Me N (c-Pr) CH2CH2CN 2-C1-4,5- (MeO) 2Ph C-Me NEt2 2-C1-4,5- (MeO) 2Ph 99-101 C-Me ΝΗ-3-pentyl 2-C1-4,5- (MeO) 2Ph 169-170 C-Me NHCH (Et) CH2CH2OMe 2-C1-4,5- (MeO) 2Ph

-119-

C-Me NHCH (Me) CH2CH2OMe 2-C1-4,5- (MeO) 2? B c-Me NHCH (CH2OMe) 2 2-Br-4,5- (MeO) 2? B C-Me N (CH2CH2OMe) 2 2-Br-4,5- (MeO) 2Ph C-Me NHCH (Et) CH2OMe 2-Br-4,5- (MeO) 2Ph C-Me N (c-Pr) CH2CH2CN 2-Br-4,5- (MeO) £ Ph C-Me NEt2 2-Br-4,5- (MeO) 2Ph C-Me ΝΗ-3-pentyl 2-Br-4,5- (MeO) 2? H C-Me NHCH (Et) CH2CH2OMe 2-Br-4,5- (MeO) 2Ph C-Me NHCH (Me) CH2CH2OMe 2-Br-4,5- (MeO) 2Ph C-Me NHCH (CH2OMe) 2 2-C1-4,6- (MeO) 2Ph C-Me N (CH2CH2OMe) 2 2-C1-4,6- (MeO) 2Ph C-Me NHCH (Et) CH2OMe 2-C1-4,6- (MeO) 2? H C-Me N (c-Pr) CH2CH2CN 2-C1-4,6- (MeO) 2Ph C-Me NEt2 2-C1-4,6- (MeO) 2Ph C-Me ΝΗ-3-pentyl 2-C1-4,6- (MeO) 2Ph C-Me NHCH (Et) CH2CH2OMe 2-C1-4,6- (MeO) 2Ph C-Me NHCH (Me) CH2CH2OMe 2-C1-4,6- (MeO) 2Ph C-Me NHCH (CH2OMe) 2 2-Me-4,6- (MeO) 2Ph C-Me N (CH2CH2OMe) 2 2-Me-4,6- (MeO) 2? H C-Me NHCH (Et) CH2OMe 2-Me-4,6- (MeO) ₂ ? H C-Me N (c-Pr) CH2CH2CN 2-Me-4,6- (MeO) ₂ Ph C-Me NEt2 2-Me-4,6- (MeO) ₂ ? H C-Me. ΝΗ-3-pentyl 2-Me-4,6- (MeO) ₂ Ph C-Me NHCH (Et) CH2CH2OMe 2-Me-4,6- (MeO) ₂ Ph C-Me NHCH (Me) CH2CH2OMe 2-Me-4,6- (MeO) ₂ Ph C-Me N (c-Pr) CH2CH2CN 2-Br-4,6- (MeO) ₂ Ph C-Me NEt2 2-Br-4,6- (MeO) ₂ Ph C-Me ΝΗ-3-pentyl 2-Br-4,6- (MeO) ₂ Ph C-Me NHCH (Et) CH2CH2OMe 2-Br-4,6- (MeO) ₂ Ph C-Me NHCH (Me) CH2CH2OMe 2-Br-4,6- (MeO) ₂ Ph C-Me NHCH (Et) CH2CH2OMe 2-Me-4-MeOPh C-Me NHCH (Me) CH2CH2OMe 2-Me-4-MeOPh C-Me NHCH (CH2OMe) 2 2-MeO-4-MePh C-Me N (CH2CH2OMe) 2 2-MeO-4-MePh C-Me NHCH (Et) CH2OMe 2-MeO-4-MePh C-Me N (c-Pr) CH2CH2CN 2-MeO-4-MePh

-120-

526 C-Me NEt ₂ 2-Me0-4-MePh 527 C-Me nh-3-pentyl 2-MeO-4-MePh 528 C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-MeO-4-MePh 529 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-MeO-4-MePh 530 C-Me NHCH (CH ₂ OMe) ₂ 2-MeO-4-MePh 531 C-Me N (CH ₂ CH ₂ OMe) ₂ 2-MeO-4-MePh 532 C-Me NHCH (Et) CH ₂ O Me 2-MeO-4-MePh 533 C-Me N (c-Pr) CH ₂ CH ₂ CN 2-MeO-4-MePh 534 C-Me NEt ₂ 2-MeO-4-MePh 535 C-Me ΝΗ-3-pentyl 2-MeO-4-MePh 536 C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-Me0-4-MePh 537 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-MeO-4-MePh 538 C-Me NHCH (CH ₂ 0Me) ₂ 2-MeO-4-ClPh 539 C-Me N (CH ₂ CH ₂ OMe) ₂ 2-MeO-4-ClPh 540 C-Me NHCH (Et) CH ₂ OMe 2-MeO-4-ClPh 541 C-Me N (c-Pr) CH ₂ CH ₂ CN 2-MeO-4-ClPh 542 C-Me NEt ₂ 2-MeO-4-ClPh 543 C-Me NK-3-pentyl 2-MeO-4-Cl? H 544 C-Me NHCH (Et) CH ₂ CH ₂ OMe 2-MeO-4-ClPh 545 C-Me NHCH (Me) CH ₂ CH ₂ OMe 2-MeO-4-Cl? H

TABLE 2 NOTES;

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

c) Analysis: calculated: C, 61.38, H, 6.18, N, 14.32: found: C, 61.54, H, 6.12, N

14.37.

d) Analysis: Calculated: 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: calculated: C, 60.48, H, 5.89, N, 14.85; found: C, 60.62, H, 5.88, N

14.82.

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

-121i) Analysis: Calculated: C, 68.45, H, 7.669, N. 15.21; found: C, 68.35, H, 7.49, N ,. 14.91.

j) Analysis: Calculated: C, 69.08, H, 7.915, N, 14.65; found: C, 68.85, H, 7.83, N, 14.54.

k) Analysis: Calculated: C, 73.51, H, 7.01, N, 19.48; found: C, 71.57, H, 7.15, N, 19.12.

l) CI-HRMS: calculated: 403.1899; found: 403.1901 (M + H).

m) Analysis: Calculated: C, 61.77, H, 6.49, N, 14.41, Cl, 9.13; found: C, 61.90, H, 6.66, N, 13.62, Cl, 9.25.

n) Analysis: calculated: C, 67.31, H, 7.06, N, 15.70, Cl, 9.93; found: C, 67.32, H, 6.95, N, 15.50, Cl, 9.93.

o) Analysis: Calculated: C, 74.50, H, 8.14, N, 17.38; found: C, 74.43, H, 7.59, N, 17.16.

p) Analysis: Calculated: C, 73.10, H, 7.54, N, 19.37; found: C, 73.18, H, 7.59, N,

18.81.

q) Analysis: calculated: C, 73.57, H, 7.78, N, 18.65; found: C, 73.55, H, 7.79, N, 18.64.

r) CI-HRMS: calculated: 353.2333; found: 353.2341 (M + H).

s) Analysis: Calculated: C, 71.56, H, 8.02, N, 15.90; found: C, 71.45, H, 7.99, N, 15.88.

t) Analysis: Calculated: C, 65.60, H, 7.34, N, 14.57; found: C, 65.42, H, 7.24, N,

14.37.

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

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

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

x) CI-HRMS: calculated: 403.1887; found: 403.1901 (M + H).

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

z) 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: calculated: 337.2017; found: 337.2028 (M + H).

-122ac) CI-HRMS: calcd: 403.1893; found: 403.1901 (M + H).

ad) Analysis: Calculated: C, 70.00, H, 7.22, N, 18.55; found: C, 70.05, H _r 7.22, N, m 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: calculated: 369.2278; found: 369.2291 (M + H).

ak) Analysis: Calculated: C, 64.42, H, 6.77, N, 15.02; found: C, 64.59, H, 6.51, N,

14.81.

The examples shown in TABLE 3 can be prepared according to the methods described in 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. Ex. is an example.

TABLE 3 R ³

Ar

El Z Fr Ar m.p. (° C) 546 ^a C-Me NHCH (Et) 2 2-Me-4-Me2N-Ph 164-166 547 ^b C-Me S-NHCH (CH2CH2OMe) -CH20Me 2,4-Me2-Ph oil 548 ° C-Me S-NHCH (CH2CH2OMe) -CH20Me 2-Me-4-Cl-Ph oil 549 ^d C-Me N (c-Pr) CH2CH2CN 2-Me-4-Cl-Ph 115-116

-123-

C-Me NHCH (Et) CH2CN 2-Me-4-Cl-Ph 131-132 C-Me N {Et) 2 2,3-Me2 ~ 4-OMe-Ph oils C-Me N (CH2CH2OMe) CH2CH2OH 2,4-Cl2-Ph oil C-Me N (CH2CH2OMe) 2 2,3-Me2 ~ 4-OMe-Ph oil C-Me NHCH (Et) 2 2,3-Me2 ~ 4-OMePh 123-124 C-Me N (CH 2 ~ c-Pr) Pr 2-Me-4-Cl-Ph oil C-Me N {C-PDCH2CH2CN 2,3-Me2 ~ 4-OMePh 158-160 C-Me N (c-Pr) Et 2-Cl-4-OMePh C-Me N (c-Pr) Me 2-Cl-4-OMePh C-Me N (c-Pr) Pr 2-Cl-4-OMePh C-Me N (c-Pr, Bu 2-Cl-4-OMePh C-Me N (Et) 2 2-Cl-4-CN-Ph 115-117 C-Me N (c-Pr) 2 2-Cl-4-OMe 127-129 C-Me NHCH (CH2OH) 2 Z, 4-Cl2 ~ Ph 128-129 C-Me N (c-Pr) Et 2-Br-4,5- (MeO) 2Ph C-Me N (c-P r) Me 2-Br-4,5- (MeO) 2Ph C-Me NH-C-Pr 2-Me-4-MeOPh 126-128 C-Me NHCH (Et) CH 2 OH 2-Me-4-MeOPh 60-62 C-Me NMe2 2-Br-4,5- (MeO) 2Ph C-Me NHCH (Et) 2 2-Me-4-MeOPh 103-105 C-Me N (c-Pr) Et 2-Me-4-MeOPh 173-174 C-Me ΝΗ-2-pentyl 2,4-Cl2 ~ Ph 118-120 C-Me NHCH (Et) CH2CN '2, 4-Cl2-Ph 141-142 C-Me NHCH (Pr) CH2OMe 2,4-Cl2-? H 87-88 C-Me NHCH (CH2-iPr) CH2OMe 2,4-Cl2-Ph amorphous C-Me NH-2 - butyl 2,4-Me2 ~ Ph oil C-Me NH-2-pentyl 2,4-Me2 ^_ Ph oil C-Me N-2-hexyl 2,4-Me2 ~ Ph oil C-Me NHCH (i-Pr) Me 2,4-Me2 ^- Ph oil C-Me NHCH (Me) CH2-iPr 2,4-Me2Ph oil C-Me NHCH (Me) -C-C6H11 2, 4-Me2 ~ Ph oil C-Me N-2-indanyl 2,4-Me2 “Ph oil C-Me NH-i-indanyl 2,4-Me2 ~ Ph oil C-Me NHCH (Me) Ph 2,4-Me2 ~ Ph oil C-Me NHCH (Me) CH 2 ^- (4-ClPh) 2,4-Me2 ~ Ph oil

-124-

C-Me NHCH (Me) CH2COCH3 2,4-Me ₂ -Ph oil C-Me NHCH (Ph) CH ₂ Ph ... _ 2, 4-Me2-Ph .. „... .or j C-Me NHCH (Me) (CH ₂ ) 3NEt ₂ 2,4-Me ₂ -Ph oil · C-Me NH- (2-Ph-c-C3H4) 2,4-Me ₂ -Ph oil C-Me NHCH (Et) CH ₂ CN 2,4-Me ₂ -Ph 119-120 C-Me nh-3-hexyl 2,4-Me ₂ -Ph oil C-Me NEt ₂ 2-MeO-4-ClPh oil C-Me NHCH (Et) 2 2-MeO-4-ClPh oil C-Me NHCH (Et) CH ₂ OMe 2-MeO-4-ClPh oil C-Me NMe ₂ 2-MeO-4-ClPh oil C-Me NHCH (Et) 2 2-OMe-4-MePh oil C-Me NEt ₂ 2-OMe-4-MePh oil C-c-Pr NHCH (CH ₂ OMe) ₂ 2,4-Cl ₂ -Ph oil C-Me N (c-Pr, Et 2,4-Me ₂ -Ph C-Me N (c-Pr) Et 2,4-Cl ₂ -Ph C-Me N (c-Pr) Et 2,4,6-Me3 “Ph C-Me N (c-Pr) Et 2-Me-4-Cl-Ph C-Me N (c-Pr) Et 2-Cl-4-Me-Ph C-Me NHCH (c-Pr) ₂ 2,4-Cl ₂ -Ph C-Me NHCH (c-Pr) 2 2, 4-Me ₂ -Ph C-Me NHCH (C-Pr) 2 2-Me-4-Cl-Ph C-Me NHCH (c-Pr) 2 2-Cl-4-Me-Ph C-Me NHCH (c-Pr) 2 2-Me-4-OMe-Ph C-Me NHCH (c-Pr) ₂ 2-Cl-4-OMe-Ph C-Me NHCH (CH ₂ OMe) ₂ 2-C1-5-F-OMePh C-Me NEt ₂ 2-Cl-5-E-OMePh C-Me N (c-Pr) CH ₂ CH ₂ CN 2-Cl-5 -? - OMePh C-Me NHCH (Et) 2 2-Cl-5-F-OMePh C-Me N (CH ₂ CH ₂ OMe) ₂ 2-C1-5-F-OMePh C-Me NEt ₂ 2,6-Me ₂ -pyrid-3-yl C-Me N (c-Pr) CH ₂ CH ₂ CN 2,6-Me ₂ -picid-3-yl C-Me NHCH (Et) ₂ 2,6-Me ₂ ~ pi rid-3-i1 C-Me N (CH ₂ CH ₂ OMe) 2 2,6-Me ₂ -pyrid-3-yl C-OH NHCH (CH ₂ OMe) 2 2,4-Me ₂ -Ph C-OH NEt ₂ 2,4-Me ₂ ~ Ph C-OH N (c-Pr) CH ₂ CH ₂ CN 2,4-Me ₂ ~ Ph

-125-

621 C-OH NHCH (Et) 2 2,4-Me ₂ -Ph 623 C-OH N (CH ₂ CH ₂ OMe) ₂ 2,4-Me ₂ -Ph 624 C-NEC2 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-NEt2 NHCH (Et) ₂ 2, 4-Me ₂ -Ph 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 63Q C-Me N (CH ₂ CH ₂ OMe) ₂ 2-Me-4-CN-Ph

Notes for Table 3:

a) CI-HRMS: calcd: 367.2610, found: 367.2607 (M + H);

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

c) CI-HRMS: calcd: 404.1853, found: 404.1844 (M + H);

d) CI-HRMS: calcd: 381.1594, found: 381.1596 (M + H);

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: 369.1576 (M + H);

f) CI-HRMS: calcd: 354.2216, found: 354.2211 (M + H);

g) CI-HRMS: calculated: 410.1072, found: 410.1075 (M + H);

h) CI-HRMS: calcd: 414.2427, found: 414.2427 (M + H);

i) CI-HRMS: calcd: 368.2372, found: 368.2372 (M + H);

j) CI-HRMS: calcd: 384.1955, found: 384.1947 (M + H);

k) CI-HRMS: calcd: 391.2168, found: 391.2160 (M + H);

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

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

n) NH3-CI MS: calculated: 360, found: 360 (M + H) +;

o) NH3-CI MS: calculated: 374, found: 374 (M + H) +;

-126NMR (CDCl3, 300 MHz): δ 7.29 (d, J = 8.4Hz, 1H), 7.04 (dd, J = 1.8.8Hz, 1H), 6.96 (d, J = 1.8Hz, 1H), 6.15 (d, J = 10, 1H); 4.19 (m / 1H), 3.81 (s; 3H), 2.47 (s, 3H) r2.32 (sf - 3H), 1.65 (m, 4H), 0.99 (t, J = 7.32Hz, 6H);

p) NH3-CI MS: calculated: 390, found: 390 (M + H) +;

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

6.52 (d, J = 9Hz, 1H), 4.36 (m, 1H), 3.8 (s, 3H), 3.55 (m, 2H), 3.39 (s, 3H), 2.47 (s.

3H), 2.32 (s, 3H), 1.76 (m, 2H), 1.01 (t, J = 7.32Hz, 3H);

q) CI-HRMS: calcd: 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 shown in TABLE 4 can be prepared by the methods described in Examples 1 A, 1B, 432, 433, 434. The commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, e.g. is an example, EtOAc is ethyl acetate.

TABLE 4

El Z B? Ar m.p. f ° C) 631 C-Me. NHCH (Et) 2 2-Br-4,5- (MeO) 2Ph 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 (CH2OMe) 2 2-Br-4-MeOPh 128-130

-127-

C-Me N (Et) 2 2-Me-4-ClPh C-Me ' N (c-Pr! Ef 2,4-Cl2? H C-Me N (c-Pr) Et 2,4-Me2Ph C-Me N (c-Pr) Et 2,4,6-Me ₃ Ph C-Me N (c-Pr) Et 2-Me-4-MeOPh C-Me N (c-Pr) Et 2-Cl-4-MeOPh C-Me N (c-Pr) Et 2-Cl-4-MePh C-Me N (c-Pr) Et 2-Me-4-ClPh C-Me NHCH (c-Pr) 2 2,4-Cl2-Ph C-Me NHCH (c-Pr) 2 2,4-Me2 ~ Ph C-Me NHCH (c-Pr) 2 2-Me-4-Cl-Ph C-Me NHCH (c-Pr) 2 2-Cl-4-Me-Ph C-Me NHCH (c-Pr) 2 2-Me-4-OMe-Ph C-Me NHCH (c-Pr) 2 2-Cl-4-OMe-Ph C-Me NHCH (CH2OMe) 2 2-Cl-5-P-OMePh C-Me NEt2 2-Cl-5-P-OMePh C-Me N (c-Pr) CH2CH2CN 2-Cl-5-P-OMePh C-Me NHCH {'Et) 2 2-Cl-5-E-OMePh C-Me N (CH2CH2OMe) 2 2-Cl-5-P-OMePh C-Me NEt2 2,6-Me2 ^_ pyrid-3- C-Me N (c-Pr) CH2CH2CN 2,6-Me2 ~ pi rid-3- C-Me NHCH (Et) 2 2,6-Me2 ~ pi rid-3- C-Me N (CH2CH2OMe) 2 2,6-Me2 ~ pyrid-3- C-OH NHCH (CH2OMe) 2 2,4-Me2 ^- h C-OH NEt ₂ 2,4-Me2 ^_ Ph C-OH N (c-Pr) CH2CH2CN 2,4-Me2 ^- h C-OH NHCH (Et) 2 2,4-Me2 ~ Ph C-OH N (CH2CH2OMe) 2 2,4-Me2 ^- Ph C-NEt2 NHCH (CH2OMe) 2 2,4-Me2 ~ Ph C-NEt2 NEt2 2,4-Me2 “Ph C-NEC2 N (c-Pr) CH2CH2CN 2,4-Me2 ^- Pb C-NEt2 NHCH (Et) 2 2, 4-Me2 “Ph C-NEC2 N (CH2CH2OMe) 2 2,4-Me2 ~ Ph C-Me NHCH (Et) 2 2-Me-4-CN-Ph C-Me N (CH2CH2OMe) 2 . 2-Me-4-CN-Ph

-128Examples in Tables 5 or 6 can be prepared by the methods explained in Examples 1A, 1B, 2,

3, 6, 431, 432, 433, 434 or their respective combinations Common abbreviations used are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Pr. is an example.

TABLE 5

El R ¹⁴ R ³ Ar 670 Me NHCH <CH20Me) 2 2,4-Cl2 “Ph 671 Me NHCHPr2 2,4-C12-PH 672 Me NEtBu 2,4-Cl2-Ph 673 Me NPr (CH2-C-C3H5) 2,4-Cl2-Ph 674 Me N (CH2CH2OMe, 2 2,4-Cl2-Ph 675 Me NH-3-heptyl 2,4-Cl2-Ph 676 Me NHCH (Et) CH2OMe 2,4-Cl2 ~ Ph 677 Me NEt2 2,4-Cl2-Ph 678 Me NHCH (CH2OEt) 2 2,4-C12-PH 679 Me NH-3 - pentyl 2,4-Cl2 ~ Ph 680 Me NMePh 2,4-Cl2 “Ph 681 Me NPr2 2,4-Cl2 ~ Ph 682 Me NH-3 - hexyl 2,4-Cl2 “Ph 683 Me morfolino 2,4-Cl2 “Ph

-129-

Me N (CH ₂ Ph) CH ₂ CH ₂ OMe 2,4-Cl ₂ -Ph Me NHCH (CH ₂ Ph) CH ₂ OMe 2,4 -C 1 ₂ -P h Me nh-4 - tetrahydropyranyl 2,4-Cl ₂ -Ph Me NH-cyclopentyl 2,4-Cl ₂ -Ph Me OEt 2,4-Cl ₂ -Ph Me OCH (Et) CH ₂ O Me 2,4-Cl ₂ -Ph Me OCH ₂ Ph 2,4-Cl ₂ -Ph Me 0-3- pentyl 2,4-Cl ₂ -Ph Me SET 2,4-Cl ₂ -Ph Me S (0, Et 2,4-Cl ₂ -Ph Me SO ₂ Et 2,4-Cl ₂ -Ph Me Ph 2, 4-Cl ₂ -Ph Me 2-CF3-Ph 2,4-Cl ₂ -Ph Me 2-Ph-Ph 2,4-Cl ₂ -Ph Me 3 - Pentyl 2,4-Cl ₂ -Ph Me cyclobutyl 2,4-Cl ₂ -Ph Me 3-Pyridyl 2,4-Cl ₂ -Ph Me CH (Et) CH ' ₂ CONMe ₂ 2,4-Cl ₂ -Ph Me CH (Et) CH ₂ CH ₂ NMe ₂ 2,4-Cl ₂ -Ph Me NHCH (CH ₂ OMe) ₂ 2,4,6-Me3-Ph Me NHCHPr ₂ 2,4,6-Me3 ~ Ph Me NEtBu 2,4,6-Me3 ~ Ph Me NPr (CH2-C-C3H5) 2,4,6-Me3-Ph Me N (CH ₂ CH ₂ OMe) ₂ 2,4,6-Me3-Ph Me NH-3-heptyl 2,4,6-Me3 ~ Ph Me NHCH (Et) CH ₂ O Me 2,4,6-Me3-Ph Me NEt ₂ 2,4,6-Me3-Ph Me NHCH (CH ₂ 0Et) ₂ 2,4,6-Me3-Ph Me NH-3-pentyl 2,4,6-Me3-Ph Me NMePh 2,4,6-Me3-Ph Me NPr ₂ 2,4,6-Me3-Ph Me N-3-hexyl 2,4,6-Me3-Ph Me morfolino 2,4,6-Me3 ~ Ph Me N (CH ₂ Ph) CH ₂ CH ₂ 0Me 2,4,6-Me3-Ph Me NHCH (CH ₂ Ph) CH ₂ OMe 2,4,6-Me3-Ph Me nh-4 - tetrahydropyranyl 2,4,6-Me3-Ph

-130-

Me NH- cyclopentia 2,4,6-Me3-Ph Me OEt 2,4,6-Me3 ~ Ph Me OCH (Et) CH ₂ OMe 2,4,6-Me3 ~ Ph Me OCH ₂ Ph 2,4,6-Me3-Ph Me o-3-pentyl 2,4,6-Me3 ~ Ph Me SET 2,4,6-Me3 ~ Ph Me S (O) Et 2,4,6-Me3 ~ Ph Me SO ₂ Et 2,4,6-Me3 ~ Ph Me CH (CO ₂ Et) 2 2,4,6-Me3 ~ Ph Me C (Et) (CO2Et) 2 2,4,6-Me3 ~ Ph Me CH (Et) CH ₂ OH 2,4,6-Me3 ~ Ph Me CH (Et) CH ₂ OMe 2,4,6-Me3 ~ Ph Me CONMe ₂ 2,4,6-Me3-Ph Me COCH3 2,4,6-Me3 ~ Ph Me CH (OH) CH3 2,4,6-Me3 ~ Ph Me c (OH) ph-3-pyridyl 2,4,6-Me3 ~ Ph Me Ph 2,4,6-Me3 ~? H Me 2-first-Ph 2,4,6-Me3 ~ Ph Me 3-pentyl 2,4,6-Me3 ~ Ph Me cyclobutyl 2,4,6-Me3 ~ Ph Me 3-Pyridyl 2,4,6-Me3-? H Me CH (Et) CH ₂ CONMe ₂ 2,4,6-Me3 ~? H Me CH (Et) CH ₂ CH ₂ NMe ₂ 2,4,6-Me3-Ph Me NHCH (CH ₂ 0Me) 2 2,4-Me2-Ph Me N (CH ₂ CH ₂ OMe) 2 2,4-Me ₂ -Ph Me NHCH (Et) CH2OMe 2,4-Me ₂ ~ Ph Me nh-3 - pentyl 2,4-Me ₂ -Ph Me NEt ₂ 2,4-Me ₂ “Ph Me N (CH ₂ CN) 2 2,4-Me ₂ -Ph Me NHCH (Me) CH2OMe 2,4-Me ₂ -Ph Me OCH (Et) CH ₂ O Me 2,4-Me ₂ -Ph Me NPr-c-C3H5 2,4-Me ₂ -Ph Me NHCH (Me) CH ₂ NMe ₂ 2,4-Me ₂ -Ph Me N (C-C3H5) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph Me N (Pr) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph Me N (Bu) CH ₂ CH ₂ CN 2,4-Me ₂ -Ph

-131-

Me NHCHPr2 2,4-Me2 ~ Ph Me NEtBu 2,4-Me2-Ph Me NPr (CH2-C-C3H5) 2,4-Me2-Ph Me ΝΗ-3-heptyl 2,4-Me2 ~ Ph Me NEt2 2,4-Me2 ~ Ph Me NHCH (CH2OEt) 2 2,4-Me2 ~ Ph Me ΝΗ-3-pentyl 2,4-Me2 ~ Ph Me NMePh 2,4-Me2 ^- Ph Me NPr2 2,4-Me2 ~ Ph Me N-3-hexyl 2,4-Me2 ^- Ph Me morfolino 2,4-Meo-Ph Me N {CH2Ph) CH2CH2OMe 2,4-Me2 ~ Ph Me NHCH {CH2PH) CH2OMe 2,4-Me2-Ph Me nh-4 - tetrahydropyranyl 2,4-Me2 ~ Ph Me NH-cyclopentyl 2,4-Me2 ~ Ph Me NHCH (CH2OMe) 2 2-Me-4-MeO-Ph Me N (CH2CH2OMe) 2 2-Me-4-MeO-Ph Me NHCH (Et) CH2OMe 2-Me-4-MeO-Ph Me N (Pr) CH2CH2CN 2-Me-4-MeO-Ph Me OCH (Et) CH2 <0Me 2-Me-4-MeO-Ph Me NHCH (CH2OMe) 2 2-3r-4-MeO-Ph Me N (CH2CH2OMe) 2 2-Br-4-MeO-Ph Me NHCH (Et) CH2OMe 2-Br-4-MeO-Ph Me 'N (Pr) CH2CH2CN 2-Br-4-MeO-Ph Me OCH (Et) CH2OMe 2-Br-4-MeO-Ph Me NHCH (CH2OMe) 2 2-Me-4-NMe2 ^- Ph Me N (CH2CH2OMe) 2 2-Me-4-NMe2 ~ Ph Me NHCH (Et) CH2OMe 2-Me-4-NMe2 ~ Ph Me N (Pr) CH2CH2CN 2-Me-4-NMe2 ~ Ph Me OCH (Et) CH2OMe 2-Me-4-NMe2 ~ Ph Me NHCH (CH2OMe) 2 2-Br-4-NMe2 ~ Ph Me N (CH2CH2OMe) 2 2-Br-4-NMe2-Ph Me NHCH (Et) CH2OMe 2-Br-4-NMe2-Ph Me N (Pr) CH2CH2CN 2-Br-4-NMe2 ”Ph Me OCH (Et) CH2OMe 2-Br-4-NMe2 “Ph Me NHCH (CH2OMe) 2 2-Br-4-i-? R-Ph

-132-

Me N (CH ₂ CH ₂ OMe, 2 2-Br-4-i-Pr-Ph Me NHCH (Et) CH ₂ OMe 2-Br-4-i-Pr-Ph Me N (Pr) CH ₂ CH ₂ CN 2-Br-4-i-Pr-Ph Me OCH (Et) CH ₂ OMe 2-Br-4-i-Pr-Ph Me NHCH (CH ₂ OMe) ₂ 2-Br-4-Me-Ph Me N (CH ₂ CH ₂ OMe) ₂ 2-Br-4-Me-Ph Me NHCH (Et) CH ₂ OMe 2-Br-4-Me-Ph Me N (Pr) CH ₂ CH ₂ CN 2-3r-4-Me-Ph Me OCH (Et) CH ₂ OMe 2-Br-4-Me-Ph Me NHCH (CH ₂ OMe) ₂ 2-Me-4-Br-Ph Me N (CH ₂ CH ₂ OMe) ₂ 2-Me-4-Br-Ph Me NHCH (Et) CH ₂ OMe 2-Me-4-Br-Ph Me N (Pr) CH ₂ CH ₂ CN 2-Me-4-Br-Ph Me OCH (Et) CH ₂ OMe 2-Me-4-Br-Ph Me NHCH (CH ₂ OMe) ₂ 2-C1-4,6-Me ₂ -Ph Me N (CH ₂ CH ₂ OMe) ₂ 2-C1-4,6-Me ₂ -Ph Me NHCH (CH ₂ OMe) 2 4-Br-2,6- (Me) ₂ ~ Ph Me N (CH ₂ CH ₂ OMe) 2 4-Bc-2,6- (Me) ₂ -Ph Me NHCH (CH ₂ OMe) ₂ 4-i-? R-2-SMe-? H Me N (CH ₂ CH ₂ OMe) ₂ 4-i-Pr-2-SMe-? H Me NHCH (CH ₂ OMe) ₂ 2-3r-4-Cr3-Ph Me N (CH ₂ CH ₂ OMe) 2 2-Br-4-Cf3-Ph Me NHCH (CH ₂ OMe) ₂ 2-Br-4,6- (MeO) ₂ -Ph Me N (CH ₂ CH ₂ OMe) ₂ 2-Br-4,5- (MeO) ₂ -Ph Me NHCH (CH ₂ OMe) ₂ 2-C1-4,6- (MeO) ₂ -Ph Me N (CH ₂ CH ₂ OMe) ₂ 2-C1-4,6- (MeO) ₂ -Ph Me NHCH (CH ₂ OMe) ₂ 2,6- (Me) ₂ -4-SMe-Ph Me N (CH ₂ CH ₂ OMe) ₂ 2,6- (Me) ₂ -4-SMe-Ph Me NHCH (CH ₂ OMe) 2 4- (COMe) -2-Br-Ph Me N (CH ₂ CH ₂ OMe) ₂ 4- (COMe) -2-Br-Ph Me NHCH (CH ₂ OMe) ₂ 2,4,6-Me3-pyrid-3-yl Me N (CH ₂ CH ₂ OMe) ₂ 2,4,6-Me3-pyrid-3-yl Me NHCH (CH ₂ OMe) ₂ 2,4- (Br) ₂ -Ph Me N (CH ₂ CH ₂ OMe) 2 2,4- (Br) ₂ -Ph Me NHCH (CH ₂ OMe) ₂ 4-i-Pr-2-SMe-Ph Me N (CH ₂ CH ₂ OMe) ₂ 4-i-Pr-2-SMe-Ph

-133-

Me NHCH (CH ₂ OMe) ₂ 4-i-Pr-2-SO ₂ Me-Ph Me N (CH ₂ CH ₂ OMe) 2 4-i-Pr-2-SO ₂ Me-Ph Me NHCH (CH ₂ OMe) ₂ 2,6- (Me) 2-4-SMe-Ph Me N (CH ₂ CH ₂ OMe) ₂ 2,6- (Me) 2-4-SMe-Ph Me NHCH (CH ₂ OMe) ₂ 2,6- (Me) 2-4-SO ₂ Me-Ph Me N (CH ₂ CH ₂ OMe) ₂ 2,6- (Me) 2-4-SO ₂ Me-Ph Me NHCH (CH ₂ OMe) ₂ 2-J-4-i-Pr-Ph Me N (CH ₂ CH ₂ OMe) 2 2-J-4-i-Pr-Ph Me NHCH (CH ₂ OMe) 2 2-Br-4-N (Me) ₂ -6-MeO-Ph Me N (CH ₂ CH ₂ OMe) 2 2-Br-4-N (Me) 2-6-MeO-Ph Me NEt ₂ 2-3r-4-MeO-Ph Me NH-3 - pentyl 2-Br-4-MeO-Ph Me NHCH (CH ₂ OMe) ₂ 2-CN-4-Me-Ph Me N (C-C3H5) CH ₂ CH ₂ CN 2,4,6-Me3-Ph Me NHCH (CH ₂ CH ₂ OMe) CH ₂ OMe 2-Me-4-Br-Ph Me NHCH (CH ₂ OMe) 2 2,5-Me2 “4-MeO-Ph Me N (CH ₂ CH ₂ OMe) 2 2,5-Me ₂ -4-MeO-Ph Me NH-3 - pentyl 2,5-Me ₂ -4-MeO-Ph Me NEt ₂ 2,5-Me ₂ -4-MeO-Ph Me NHCH (CH ₂ OMe) ₂ 2-Cl-4-MePh Me NCH (Et) CH ₂ OMe 2-Cl-4-MePh Me N (CH ₂ CH ₂ OMe) ₂ 2-Cl-4-MePh Me (S) -NHCH (CH ₂ CH ₂ OMe) CH ₂ OMe 2-Cl-4-MePh ' Me N (C-C3H5) CH ₂ CH ₂ CN 2.5-Me ₂ -4-MeOPh Me NEt ₂ 2-Me-4-MeOPh Me OEt 2-Me-4-MeOPh Me (S) -NHCH (CH ₂ CH ₂ OMe) CH ₂ OMe 2-Me-4-MeOPh Me N (C-C3H5) CH ₂ CH ₂ CN 2-Me-4-MeOPh Me NHCH (CH ₂ CH ₂ OEt) ₂ 2-Me-4-MeOPh Me N (C-C3H5) CH ₂ CH ₂ CN 2,4-Cl ₂ -Ph Me NEt ₂ 2-Me-4-ClPh Me NH-3-pentyl 2-Me-4-ClPh Me N (CH ₂ CH ₂ OMe) ₂ 2-Me-4-ClPh Me NHCH (CH ₂ OMe) ₂ 2-Me-4-ClPh Me NEt ₂ 2-Me-4-ClPh Me NEt ₂ 2-Cl-4-MePh

-134-

Me nh-3-pentyl 2-Cl-4-MePh Me NHCH (CH2OMe) 2 2-Cl-4-MeOPh Me N {CH2CH2OMe) 2 2-Cl-4-MeOPh Me NHCH (Et) CH ₂ OMe 2-Cl-4-MeOPh Me N (c-Pr) CH2CH2CN 2-Cl-4-MeOPh Me NEt2 2-Cl-4-MeOPh Me NH-3-pentyl 2-Cl-4-MeOPh Me NHCH (Et) CH2CH2OMe 2-Cl-4-MeOPh Me NHCH (Me) CH2CH2OMe 2-Cl-4-MeOPh Me NHCH (Et) CH2CH2OMe 2-Br-4-MeOPh Me NHCH (Me) CH2CH2OMe 2-Br-4-MeOPh Me NHCH (Et) CH2CH2OMe 2-Me-4-MeOPh Me NHCH (Me) CH2CH2OMe 2-Me-4-MeOPh Me NHCH (CH2OMe) 2 2-C1-4,5- (MeO) 2? H Me N (CH2CH2OMe) 2 2-C1-4,5- (MeO) 2? H Me NHCH (Et) CH2OMe 2-C1-4,5- (MeO) 2Ph Me N (c-Pr) CH2CH2CN 2-C1-4,5- (MeO) 2Ph Me NEt ₂ 2-C1-4,5- (MeO) 2Ph Me NH-3 - pentyl 2-C1-4,5- (MeO) 2? H Me NHCH (Et) CH2CH2OMe 2-C1-4,5- (MeO) 2? H Me NHCH (Me) CH2CH2OMe 2-C1-4,5- (MeO) ₂ Ph Me NHCH (CH2OMe) 2 2-Br-4,5- (MeO) 2Ph Me N (CH2CH2OMe) 2 2-3r-4,5- (MeO) 2Ph Me NHCH (Et) CH2OMe 2-3r-4,5- (MeO) ₂ Ph Me N (C-Pr) CH2CH2CN 2-Br-4,5- (MeO) ₂ Ph Me NEt ₂ 2-Br-4,5- (MeO) ₂ Ph Me NH-3-pentyl 2-Br-4,5- (MeO) ₂ Ph Me NHCH (CH2OMe) 2 2-C1-4,6- (MeO) 2Ph Me N (CH2CH2OMe) 2 2-C1-4,6- (MeO) 2Ph Me NEt ₂ 2-C1-4,6- (MeO) ₂ Ph Me NH-3-pentyl 2-C1-4,6- (MeO) ₂ Ph Me NHCH (CH2OMe) 2 2-Me-4,6- (MeO) ₂ Ph Me N (CH2CH2OMe) 2 2-Me-4,6- (MeO) ₂ Ph Me NHCH (Et) CH2OMe 2-Me-4,6- (MeO) ₂ Ph Me NEt2 2-Me-4,6- (MeO) 2 P h Me NH-3-pentyl 2-Me-4,6- (MeO) ₂ Ph

-135-

Me NHCH (Et) CH ₂ CH ₂ OMe 2-Me-4-MeOPh Me NHCH (Me) CH ₂ CH ₂ OMe 2-Me-4-MeOPh Me NHCH (CH ₂ OMe) 2 2-MeO-4-MePh Me N (CH ₂ CH ₂ OMe) 2 2-MeO-4-MePh Me NHCH (Et) CH ₂ OMe 2-MeO-4-MePh Me N (c-Pr) CH ₂ CH ₂ CN 2-MeO-4-MePh Me NEt ₂ 2-MeO-4-MePh Me NH-3-pentyl 2-MeO-4-MePh Me NHCH (Et) CH ₂ CH ₂ OMe 2-Me0-4-MePh Me NHCH (Me) CH ₂ CH ₂ OMe 2-MeO-4-MePh Me NHCH (CH ₂ OMe) ₂ 2-Me0-4-MePh Me N (CH ₂ CH ₂ OMe) ₂ 2-MeO-4-MePh Me NHCH (Et) CH ₂ OMe 2-Me0-4-MePh Me N (c-Pr) CH ₂ CH ₂ CN 2-MeO-4-MePh Me NEt ₂ 2-MeO-4-MePh Me NH-3-pentyl 2-MeO-4-MePh Me NHCH (CH ₂ OMe) ₂ 2-MeO-4-ClPh Me N (CH ₂ CH ₂ OMe) ₂ 2-MeO-4-ClPh Me NHCH (Et) CH ₂ OMe 2-MeO-4-ClPh Me NEt ₂ 2-MeO-4-ClPh Me NH-3 - pentyl 2-MeO-4-ClPh

-136TABLE 6

R ³

R R_ Ar Me NHCH (CH ₂ OMe) 2 2,4-Cl ₂ -Ph Me NHCHPr ₂ 2,4-Cl ₂ -Ph Me NEtBu 2,4-Cl ₂ -? H Me NPr (CH2-C-C3H5) 2,4-Cl ₂ -Ph Me N (CH ₂ CH ₂ 0Me) 2 2,4-CI ₂ -Ph Me ΝΗ-3-heptyl 2,4-Cl ₂ -Ph Me NHCH (Et) CH ₂ OMe 2,4-Cl ₂ -Ph Me NEt ₂ 2,4-Cl ₂ -? H Me NHCH (CH ₂ OEt) ₂ 2,4-Cl ₂ -Ph Me nh-3-pentyl 2,4-Cl ₂ -Ph. Me NMePh 2,4-Cl ₂ -Ph Me NP r ₂ 2,4-Cl ₂ -Ph Me N-3-hexyl 2,4-Cl ₂ -Ph Me morfolino 2,4-Cl ₂ -Ph Me N (CH ₂ Ph) CH ₂ CH ₂ OMe 2,4-Cl ₂ -Ph Me NHCH (CH ₂ Ph) CH ₂ 0Me 2,4-Cl ₂ -Ph Me NH-4-tetrahydropyranyl 2, 4-Cl ₂ -Ph Me NH-cyclopentyl 2,4-C12-PH Me OEt 2,4-Cl ₂ -Ph Me OCH (Et) CH ₂ OMe 2,4-Cl ₂ -Ph Me OCH ₂ Ph 2,4-Cl ₂ -Ph Me 0-3-pentyl 2,4-Cl ₂ “Ph Me SET 2,4-Cl ₂ -Ph

-137-

Me S (O) Et 2,4-Cl ₂ -Ph Me SO ₂ Et 2, 4-Cl ₂ -Ph Me Ph 2,4-Cl ₂ -Ph Me 2-CF3 ~ Ph 2,4-Cl ₂ -Ph Me 2-Ph-Ph 2,4-Cl ₂ -Ph Me 3- pentyl 2,4-Cl ₂ -Ph Me cyclobutyl 2,4-Cl ₂ -Ph Me 3 - pyridyl 2,4-Cl ₂ -Ph Me CH (Et) CH ₂ CONMe ₂ 2,4-Cl ₂ -Ph Me CH (Et) CH2CH2NMe2 2,4-Cl ₂ -Ph Me NHCH (CH ₂ 0Me) 2 2,4,6-Me3 ~ Ph Me NHCHPr ₂ 2,4,6-Me3-Ph Me NEtBu 2,4,6-Me3-Ph Me NPr (CH2-C-C3H5) 2,4,6-Me3 ~ Ph Me N (CH ₂ CH ₂ OMe) 2 2,4,6-Me3-Ph Me NH-3-heptyl 2,4,6-Me3-Ph Me NHCH (Et, CH ₂ O Me 2,4,6-Me3-Ph Me NEt ₂ 2,4,6-Me3 ~ Ph Me NHCH (CH ₂ OEt) ₂ 2,4,6-Me3 ~ Ph Me NH-3-pentyl 2,4,6-Me3 ~ Ph Me NMePh 2,4,6-Me3-Ph Me NPr ₂ 2,4,6-Me3 ~ Ph Me NH-3 - hexyl 2 _,; 4, 6-Me3 ~ Ph Me morfolino 2,4,6-Me3 ~ Ph Me N (CH ₂ Ph) CH ₂ CH ₂ OMe 2,4,6-Me3 ~ Ph Me NHCH (CH ₂ Ph) CH ₂ OMe 2,4,6-Me3 ~ Ph Me nh -4 - tetrahydropyranyl 2,4,6-Me ₃ -Ph Me nh - cyclopentyl 2,4,6-Me3-Ph Me OEt 2,4,6-Me3-Ph Me OCH (Et) CH ₂ OMe 2,4,6-Me3-Ph Me OCH ₂ Ph 2,4,6-Me3-Ph Me 0-3- pentyl 2,4,6-Me3 ~ Ph Me SET 2,4,6-Me3-Ph Me S (0) Et 2,4,6-Me3-Ph Me SO ₂ Et 2,4,6-Me3 ~ Ph Me CH (CO ₂ Et) 2 2,4,6-Me3-Ph

-138-

Me C (Et) (CO2Et) 2 2,4,6-Me3-Ph Μβ CH (Et) CH 2 OH 2,4,6-Me3 ~ Ph Me CH (Et) CH2OMe 2,4,6-Me3 ~ Ph Me CONMe2 2,4,6-Me3 ~ Ph Me COCH3 2,4,6-Me3 ~ Ph Me CH (OH) CH3 2,4,6-Me3-Ph Me c (OH) Ph-3-pyridyl 2,4,6-Me3 ~ Ph Me Ph 2,4,6-Me3 ~ Ph Me 2-Ph-Ph 2,4,6-Me3 ~ Ph Me 3-pentyl 2,4,6-Me3 ~ Ph Me cyclobutyl 2,4,6-Me3 ~ Ph Me 3 - pyridyl 2,4,6-Me3 ~ Ph Me CH (Et) CH2CONMe2 2,4,6-Me3-Ph Me CH (Et) CH2CH2NMe2 2,4,6-Me3 ~ Ph Me NHCH (CH2OMe) 2 2,4-Me2 ^- Ph Me N (CH2CH2OMe) 2 2,4-Me2 ^- Ph Me NHCH (Et) CH2OMe 2,4-Me2 ~? H Me NH-3-pentyl 2,4-Me2 ^- Ph Me NEt2 2,4-Me2 ~? H Me N (CH 2 CN) 2 2,4-Me2 ~ Ph Me NHCH (Me) CH2OMe 2, 4-Μβ2Ρ · ^{> 1} Me OCH (Et) CH2OMe 2,4-Me2 ^_ Ph Me NPr-c-C3H5 2,4-Me2 ^- Ph Me NHCH (Me) CH2NMe2 2,4-Me2 ^_ Ph Me N (C-C3H5) CH2CH2CN 2,4-Me2 ~ Ph Me N (Pr) CH2CH2CN 2,4-Me2 ^_ Ph Me N (Bu) CH2CH2CN 2,4-Me2 ~ Ph Me NHCHPr2 2,4-Me2 ~ Ph Me NEtBu 2,4-Me2 ~ Ph Me NPr (CH2-C-C3H5) 2,4-Me2Ph Me NH-3-heptyl 2,4-Me2 ~ Pb Me NEt2 2,4-Me2 ~ Ph Me NHCH (CH2OEt) 2 2,4-Me2Ph Me ΝΗ-3-pentyl 2,4-Me2 ”Ph Me NMePh 2,4-Me2 “Ph Me NP Γ2 2,4-Me2 ~ Ph

-139-

Me N-3-hexyl 2,4-Me ₂ -Ph Me morfolino 2,4-Me ₂ -Ph Me N (CH ₂ Ph) CH ₂ CH ₂ OMe 2,4-Me ₂ -Ph Me NHCH (CH ₂ Ph) CH ₂ OMe 2,4-Me ₂ -Ph Me NH-4-tetrahydropyranyl 2,4-Me ₂ -Ph Me NH-cyclopentia 2,4-Me ₂ -Ph Me NHCH (CH ₂ OMe) ₂ 2-Me-4-MeO-Ph Me N (CH ₂ CH ₂ OMe) ₂ 2-Me-4-MeO-Ph Me NHCH (Et) CH ₂ OMe 2-Me-4-MeO-Ph Me N (Pr) CH ₂ CH ₂ CN 2-Me-4-MeO-Ph Me OCH (Et) CH ₂ OMe 2-Me-4-MeO-Ph Me NHCH (CH ₂ OMe) ₂ 2-Br-4-MeO-Ph Me N (CH ₂ CH ₂ OMe) ₂ 2-Br-4-MeO-Ph Me NHCH (Et) CH ₂ OMe 2-Br-4-MeO-Ph Me N (Pr) CH ₂ CH ₂ CN 2-Br-4-MeO-Ph Me OCH (Et) CH ₂ OMe 2-Br-4-MeO-Ph Me NHCH (CH ₂ OMe) ₂ 2-Me-4-NMe ₂ -Ph Me N (CH ₂ CH ₂ OMe) ₂ 2-Me-4-NMe ₂ -Ph Me NHCH (Et) CH ₂ OMe 2-Me-4-NMe ₂ ~ Ph Me N (Pr) CH ₂ CH ₂ CN 2-Me-4-NMe ₂ -Ph Me OCH (Et) CH ₂ OMe 2-Me-4-NMe ₂ -Ph Me NHCH (CH ₂ OMe) ₂ 2-Br-4-NMe ₂ -Ph Me N (CH ₂ CH ₂ OMe) ₂ 2-Br-4-NMe ₂ -Ph Me NHCH (Et) CH ₂ OMe 2-Br-4-NMe ₂ -Ph Me N (Pr) CH ₂ CH ₂ CN 2-3r-4-NMe ₂ -Ph Me OCH (Et) CH ₂ OMe 2-Br-4-NMe ₂ -Ph Me NHCH (CH ₂ OMe) ₂ 2-Br-4-i-P r-Ph Me N (CH ₂ CH ₂ OMe) ₂ 2-Br-4-i-Pr-Ph Me NHCH (Et) CH ₂ OMe 2-Br-4-i-Pr-Ph Me N (Pr) CH ₂ CH ₂ CN 2-Br-4-i-Pr-Ph Me OCH (Et) CH ₂ OMe 2-Br-4-i-Pr-Ph Me NHCH (CH ₂ OMe) ₂ 2-Br-4-Me-Ph Me N (CH ₂ CH ₂ OMe) ₂ 2-Br-4-Me-Ph Me NHCH (Et) CH ₂ OMe 2-Br-4-Me-Ph Me N (Pr) CH ₂ CH ₂ CN 2-Br-4-Me-Ph Me OCH (Et) CH ₂ OMe 2-Br-4-Me-Ph

-140-

Me NHCH (CH2OMe) 2 2-Me-4-Br-Ph Me N (CH2CH2OMe) 2 2-Me-4-Br-Ph Me NHCH (EC) CH2OMe 2-Me-4-Br-Ph Me N (Pr) CH2CH2CN 2-Me-4-Br-Ph Me OCH (Et) CH2OMe 2-Me-4-Br-Ph Me NHCH (CH2OMe) 2 2-C1-4,6-Me2-Ph Me N (CH2CH2OMe) 2 2-C1-4,6-Me2 ~ Ph Me NHCH (CH2OMe) 2 4-Br-2,6- (Me) 2 “Ph Me N (CH2CH2OMe) 2 4-Br-2,6- (Me) 2-Ph Me NHCH (CH2OMe) 2 4-i-Pr-2-SMe-Ph Me N (CH2CH2OMe) 2 4-i-Pr-2-SMe-Ph Me NHCH (CH2OMe) 2 2-Br-4-CF3 ~ Ph Me N (CH2CH2OMe) 2 2-Br-4-C? 3-Ph Me NHCH (CH2OMe) 2 2-Br-4,6- (MeO) 2? H Me N (CH2CH2OMe) 2 2-Br-4,6- (MeO) 2 ~ Ph Me NHCH (CH2OMe) 2 2-C1-4,6- (MeO) 2 ~ Ph Me N (CH2CH2OMe) 2 2-C1-4,6- (MeO) 2-Ph Me NHCH (CHgOMe) 2 2,6- (Me) 2 ^- 4-SMe-Ph Me N (CH2CH2OMe) 2 2,6- (Me) 24-SMe-Ph Me NHCH (CH2OMe) 2 4- (COMe) -2-Br-Ph Me N (CH2CH2OMe) 2 4- (COMe) -2-3r-Ph Me NHCH (CH2OMe) 2 2,4,6-Me3 ~ pi rid-3-ΪΙ Me N (CH2CH2OMe) 2 2,4,6-Me3-plrid-3-yl Me NHCH (CH2OMe) 2 2,4- (Br) 2-Ph Me N (CH2CH2OMe) 2 2,4- (Br) 2-Ph Me NHCH (CH2OMe) 2 4-i-Pr-2-SMe-Ph Me N (CH2CH2OMe) 2 4-i-Pr-2-SMe-Ph Me NHCH (CH2OMe) 2 4-i-Pr-2-SO2Me-Ph Me N (CH2CH2OMe) 2 4-i-Pr-2-SO2Me-Ph Me NHCH (CH2OMe) 2 2,6- (Me) 2-4-SMe-Ph Me N (CH2CH2OMe) 2 2,6- (Me) 2-4-SMe-Ph Me NHCH (CH2OMe) 2 2,6- <Me) 2-4-SO2Me-Ph Me N (CH2CH2OMe) 2 2,6- (Me) 2-4-SO2Me-Ph Me NHCH (CH2OMe) 2 2-J-4-i-Pr-Ph Me N (CH2CH2OMe) 2 2-J-4-i-Pr-Ph Me NHCH (CH2OMe) 2 2-Br-4-N (Me) 2-6-MeO-Ph

-141-

Me N (CH2CH2OMe) 2 2 -No-4-N (Me) 2 “6-MeO-Ph Me NEt2 2-Br-4-MeO-Ph Me NH-3-pentyl 2-Br-4-MeO-Ph Me NHCH (CH2OMe) 2 2-CN-4-Me-Ph Me N (C-C3H5) CH2CH2CN 2,4,6-Me3 ~ Ph Me NHCH (CH2CH2OMe) CH2OMe 2-Me-4-8r-Ph Me NHCH (CH2OMe) 2 2,5-Me2 ~ 4-MeO-Ph Me N (CH2CH2OMe) 2 2,5-Me24-MeO-Ph Me NH-3 - pentyl 2,5-Me2 ~ 4-MeO-Ph Me NEt2 2,5-Me2 ~ 4-MeO-Ph Me NHCH (CH2OMe) 2 2-Cl-4-MePh Me NCH (Et) CH2OMe 2-Cl-4-MePh Me N (CH2CH2OMe) 2 2-Cl-4-MePh Me (S) -NHCH (CH2CH2OMe) CH2OMe 2-Cl-4-MePh Me N (C-C3H5) CH2CH2CN 2.5-Me2 ~ 4-MeOPh Me NEt ₂ 2-Me-4-MeOPh Me OEt 2-Me-4-MeOPh Me (S) -NHCH (CH2CH2OMe) CH2OMe 2-Me-4-MeOPh Me N {C-C3H5) CH2CH2CN 2-Me-4-MeOPh Me NHCH (CH2CH2OEt) 2 2-Me-4-MeOPh Me N (C-C3H5) CH2CH2CN 2,4-Cl2 ~ Ph Me NEt2 2-Me-4-ClPh Me NH-3 - pentyl 2-Me-4-ClPh Me N (CH2CH2OMe) 2 2-Me-4-ClPh Me NHCH (CH2OMe) 2 2-Me-4-ClPh Me NEt2 2-Me-4-ClPh Me NEt2 2-Cl-4-MePh Me NH-3-pentyl 2-Cl-4-MePh Me NHCH (CH2OMe) 2 2-Cl-4-MeOPh Me N (CH2CH2OMe) 2 2-C1-4-MeOPh Me NHCH (Et) CH2OMe 2-Cl-4-MeOPh Me N (c-Pr) CH2CH2CN 2-Cl-4-MeOPh Me NEt ₂ 2-Cl-4-MeOPh Me NH-3-pentyl 2-Cl-4-MeOPh Me NHCH (Et) CH2CH2OMe 2-Cl-4-MeOPh Me NHCH (Me) CH2CH2OMe 2-Cl-4-MeOPh

-142-

Me NHCH (Et) CH2CH2OMe 2-3r-4-MeOPh Me NHCH (Me) CH2CH2OMe 2-Br-4-MeOPh Me NHCH {Et) CH2CH2OMe 2-Me-4-MeOPh Me NHCH (Me) CH2CH2OMe 2-Me-4-MeOPh Me NHCH (CH2OMe, 2 2-C1-4,5- (MeO) 2Ph Me N (CH2CH2OMe) 2 2-C1-4.5- (MeO, 2Ph Me NHCH (Et) CH2OMe 2-C1-4,5- (MeO) 2Ph Me N (c-Pr) CH2CH2CN 2-C1-4,5- {MeO) 2Ph Me NEt2 2-C1-4,5- (MeO) 2Ph Me NH-3-pentyl 2-C1-4,5- (MeO) 2Ph Me NHCH (Et) CH2CH2OMe 2-C1-4,5- (MeO) 2Ph Me NHCH (Me) CH2CH2OMe 2-C1-4,5- (MeO) 2Ph Me NHCH (CH2OMe) 2 2-Br-4,5- (MeO) 2? H Me N (CH2CH2OMe) 2 2-Br-4,5- <MeO) 2? H Me NHCH (Et) CH2OMe 2-Br-4,5- (MeO) 2Ph Me N (c-Pr) CH2CH2CN 2-Br-4,5- (MeO) 2? H Me NEt2 2-3r-4,5- (MeO) 2Ph Me NH-3-pentyl 2-3r-4,5- (MeO) 2Ph Me NHCH (CH2OMe) 2 2-C1-4,6- (MeO) 2Ph Me N (CH2CH2OMe) 2 2-C1-4,6- (MeO) 2Ph Me NEt2 2-C1-4,6- (MeO) 2Ph Me NH-3-pentyl 2-C1-4,6- (MeO) 2? H Me NHCH (CH2OMe) 2 2-Me-4,6- (MeO) 2 P h Me N (CH2CH2OMe) 2 2-Me-4,6- (MeO) 2? H Me NHCH (Et) CH2OMe 2-Me-4,6- (MeO) 2? H Me NEt ₂ 2-Me-4,6- (MeO) 2Ph Me NH-3 - pentyl 2-Me-4,6- (MeO, 2? H Me NHCH (Et) CH2CH2OMe 2-Me-4-MeOPh Me NHCH (Me) CH2CH2OMe 2-Me-4-MeOPh Me NHCH (CH2 <3Me) 2 2-MeO-4-MePh Me N (CH2CH2OMe) 2 2-MeO-4-MePh Me NHCH (Et) CH2OMe 2-Me0-4-MePh Me N (c-Pr) CH2CH2CN 2-Me0-4-MePh Me NEt2 2-MeO-4-MePh Me NH-3-pentyl 2-Me0-4-MePh Me NHCH (Et) CH2CH2QMe 2-MeO-4-MePh

-143-

1161 Me NHCH (Me) CH2CH2OMe 2-MeO-4-MePh 1162 Me NHCH (CH2OMe) 2 2-MeO-4-MePh 1163 Me N (CH2CH2OMe) 2 2-MeO-4-MePh 1164 Me NHCH (Et) CH2 O Me 2-MeO-4-MePh 1165 Me N (C-PDCH2CH2CN 2-MeO-4-MePh 1166 Me NEC2 2-MeO-4-MePh 1167 Me NH-3 - pentyl 2-MeO-4-MePh 1168 Me NHCH (CH2OMe) 2 2-MeO-4-ClPh 1169 Me N (CH2CH2OMe) 2 2-MeO-4-ClPh 1170 Me NHCH (Et) CH2 O Me 2-MeO-4-ClPh 1171 Me NEt2 2-MeO-4-ClPh 1172 Me nh-3-pentyl 2-MeO-4-ClPh

Utility

CRF-R1 receptor binding assay for evaluation of biological activity

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

Message RNA was isolated from the human hippocampus. mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR (polymerase chain reaction) from start to end codons. The resulting PCR fragment was cloned into the EcoRV site from pGEMV, from where the insert was obtained using Xhol + Xbal and cloned into the Xhol + Xbal sites of the pm3ar vector (containing the CMV promoter, SV40 't' junction and the original poly A signals, Epstein-Barrov viral replication origin and marker able to select hygromycin). The resulting expression vector, called phchCRFR, was transfected into 293EBNA cells and the episodic cells were selected in the presence of 400 μΜ hygromycin. Cells that survived 4 weeks of selection in hygromycin were collected, adjusted for growth in suspension, and used to generate membranes for the binding assay described

-144g below. Individual aliquots containing about 1X10 suspended cells were then centrifuged to form a pellet and frozen.

For the binding assay, the above described frozen pellet containing 293EBNA cells transfected with hCRFFU receptors was homogenized in 10 ml of ice-cold tissue buffer (50 mM HEPES pH 7.0 buffer containing 10 mM MgCl2, 2 mM EGTA, 1 jxg / l aprotinin, 1 gg / ml levpeptin and 1 gg / ml pepstatin). The homogenate was centrifuged at 40,000 x g for 12 min and the resulting pellet was homogenized again in 10 ml tissue buffer. After another centrifugation at 40,000 x g for 12 min, the pellet was resuspended to a protein concentration of 360 gg / ml for use in the assay.

Bonding tests are performed on 96-well plates; each well has 300 μΙ capacity. Add to each well 50 μ test of the dilution of the test drug (final drug concentration ranges from 1θ ^1θ -10 ⁵ M), 100 μΙ ¹²⁵ J-CRF ( ¹²⁵ Jo-CRF) (150 pM final concentration) and 150 μΙ cell homogenate described above. The plates were then incubated at room temperature for 2 hours before the incubate was filtered through GF / F filters (pre-soaked with 0.3% polyethyleneimine) using a suitable cell collector. The filters were washed twice with ice-cold test buffer before removing the individual filters and testing them for radioactivity on a gamma counter.

125

The inhibition curves of J-o-CRF binding to cell membranes at different dilutions of the test drug are analyzed with an iterative LIGAND program to calculate the fit of the data to the curve [P.J. Munson and D. Rodbard, Anal. Biochem. 107: 220 (1980)], which provides Kj values for inhibition, which are then used to determine biological activity.

A compound is considered to be active when it has a Kj value of less than about 10000nM for CRF inhibition.

Inhibition by CRF of stimulated adenylate cyclase activity

-145Inhibition of CRF-stimulated adenylate cyclase activity can be performed as described by G.

Battaglia et al. Synapse 1: 572 (1987). Briefly, the tests were performed at 37 ° C for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37 ° C), 10 mM MgCl 2, 0.4 mM EGTA,

0.1% BSA, 1 mM isobutylmethylxanthine (ΙΒΜΧ), 250 units / ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM oCRF, antagonist peptides -9-6 (concentration range 10 to 10 M), and 0.8 mg original wet tissue weight (ca. 32 mg)

40-60 mg protein). Reactions were started with the addition of 1 mM ATP / [P] ATP (approximately (7,414.8) χ 10 ⁷ Bq / tube) and ended with the addition of 100 ml of 50 mM Tris-HCl, 45 mM ATP, and 2% sodium dodecyl sulfate. Therefore, to monitor cAMP production, 1 μΙ [H] cAMP (approximately 40,000 dpm) was added to each tube prior to separation. The separation of 32 32 [P] cAMP from [P] ATP is performed by sequential elution via Dowex columns and alumina columns.

In vivo bioassay

The in vivo activity of the compounds of the present invention can be determined using any of the bioassays available and recognized in the art. Illustrative tests include the Acoustic Excitement Test, the Stair Climb Test, and the Chronic Administration Assay. These and other models useful for testing the compounds of the present invention are described in C.W. Berridge and A.J. Dunn Brain Research Reviews 15:71 (1990). The compounds can be tested on any type of rodent or small mammal.

The compounds of the present invention are useful in the treatment of imbalances associated with abnormal corticotropin release factor levels in patients suffering from depression, emotional distress and / or anxiety.

The compounds of the present invention can be administered to treat these diseases in such a way that contact of the active agent with the site of action of the agent in the mammalian body occurs. The compounds may be administered in any conventional manner suitable for use in combination with pharmaceutics, either as a single therapeutic agent or in combination of therapeutic agents. We can administer them ourselves, but typically we will administer them with a pharmaceutical carrier selected based on the route of administration chosen and standard pharmaceutical practice.

-146 A given dosage will vary depending on the use and known factors, such as the pharmacodynamic characteristics of each agent and its route and route of administration; age, weight and health of the recipient; the nature and extent of the symptoms; types of concomitant treatment; frequency of treatment; and the desired effect. For use in treating the aforementioned diseases or conditions, the compounds of this invention may be administered orally daily with a dosage of the active ingredient from 0.002 to 200 mg / kg body weight. Typically, the dose will be from 0.01 to 10 mg / kg, in divided doses, one to four times daily or in sustained-release formulation effective to achieve the desired pharmacological effect.

Suitable dosage forms (compositions) contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will typically be present in an amount of from about 0.5 to 95% by weight based on the total weight of the composition.

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

Gelatin capsules may be used to contain the active ingredient and a suitable carrier such as, but not limited to, lactose, starch, magnesium stearate, stearic acid or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to ensure continued drug release over a period of time. The compressed tablets may be sugar coated or film coated to cover any unpleasant taste, or the coats may be used to protect the active ingredients from the atmosphere or to allow selective disintegration of the tablet in the gastrointestinal tract.

Liquid dosage forms for oral administration may contain coloring agents or flavoring agents for better acceptance by patients.

-147. Generally, carriers for parenteral water solutions, pharmaceutically acceptable oils, water and salt solutions, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable. The solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, a stabilizing agent and, if necessary, a buffer of the substance. Suitable stabilizing agents are antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination. Citric acid and its salts and EDTA are also used. In addition, parenteral solutions may contain preservatives such as benzalkonium chloride, methyl or propyl paraben and chlorobutanol.

Suitable pharmaceutical carriers are described in Remingtoris Pharmaceutical Sciences, A. Osol, standard references in the art.

Useful pharmaceutical dosage forms for the administration of the compounds of the present invention can be illustrated as follows:

Capsules

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

Soft gelatin capsules

Prepare a mixture of the active ingredient in digestible oil, such as soybean oil, cottonseed oil or olive oil, and inject it into the gelatin by pumping with a positive shear to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are rinsed and dried.

Pills

-148Many tablets are prepared by conventional procedures such that the dosage unit is 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 of lactose. Appropriate coatings may be applied to increase the palatability or to retain adsorption.

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

Although the present invention has been described and exemplified by certain preferred embodiments, other embodiments will be apparent to those skilled in the art. Therefore, the invention is not limited to certain described and illustrated embodiments, but can be modified and modified without altering the meaning of the invention, the full scope of which is described by the appended claims.

Claims (4)

REQUIREMENTS A compound of formulas (1) or (2) · (D (2) and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its forms of pharmaceutically acceptable salts or prodrugs, wherein: A is N or CR; Z is N or CR ² ; Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2- benzopyranyl, tetralinyl, each Ar is optionally substituted by 1 to 5 R groups and each Ar is bonded to an unsaturated carbon atom; R is at each occurrence independently selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl; R ¹ is at each occurrence independently selected from H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halo, CN, C 1 -C 4 haloalkyl, C 1 -C 12 hydroxyalkyl, C 2 -C 12 alkoxyalkyl, 9 10 C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR R, C1-C4 Q m Q 10 11 19 alkyl-NR ^with R ¹ , NR COR, OR, SH or S (O) _n R; -1502 R is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN, -NR ⁶ R ⁷ , NR ⁹ COR ^{10 *,} NR ⁶ S (O) n R ^7, S (O) NAP ⁶ R ^7, C1-C4 haloalkyl, ^-OR7, SH or -S (O) _n R ^12; R ³ is selected from: -H, OR ⁷ , SH, S (O) nR ¹³ , COR ⁷ , CO2R 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 ^? ) R ⁶ , CONR ⁶ R ⁷ , aryl, heteroaryl and heterocyclyl, or -C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C12 cycloalkylalkyl or C1-C8 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents each independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 CO2R ¹³ , nr ¹⁶ r ¹⁵ , conr ¹⁶ r ¹⁵ , aryl, heteroaryl and heterocyclyl; R is independently selected at each occurrence from: C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, NO2, halo, CN, C1-C4 haloalkyl, NR ⁶ R ⁷ , NR ⁸ COR ⁷ , NR ⁸ CO2R ⁷ , COR ⁷ , OR ⁷ , CONR ⁶ R ⁷ , CO (NOR ⁹ ) R ⁷ , CO2R ⁷ or S (O) nR ⁷ , wherein each such is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 6 cycloalkyl and C4-C12 cycloalkylalkyl optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C4 alkyl, NO2, halo, CN, NR ⁶ R ⁷ , NR ⁸ COR ⁷ , NR ⁸ CO2R ⁷ , COR ⁷ , OR ⁷ , CONR ⁶ R ⁷ , CO2R ⁷ , CO (NOR ⁹ ) R ⁷ or S (O) nR ^? ; 6 7 6a 7a R and R, R and R are each independently selected from: -H, -C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl each is optionally substituted with 1 to 3 substituents at each occurrence independently selected -15115 from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR, SH, S (O) _n 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl, -aryl, aryl (C1-C4 alkyl), heteroaryl, heteroaryl (C1-C4 alkyl), heterocyclyl or heterocyclyl (C1-C4 alkyl); θ 7 gg alternatively NR R and NR R are independently piperidine, pyrrolidine, piperazine, Nmethylpiperazine, morpholine or thiomorpholine, each optionally substituted by 1-3 C 1 -C 4 alkyl groups; θ R is at each occurrence independently selected from H or C1-C4 alkyl; 9 10 R and R are at each occurrence independently selected from H, C1-C4 alkyl or C3-C6 cycloalkyl; R ¹¹ is selected from H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 6 cycloalkyl; R ¹² is C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; R ¹³ is selected from C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C ₂ -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C ₄ C- | ₂ cycloalkylalkyl, aryl, aryl (C 1 -C 4 alkyl) -, heteroaryl or heteroaryl (C 1 -C 4 alkyl) -; R is selected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl or C4C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹⁵ , COR ¹⁵ , CO2R 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 , 16 15 CONR R and C1-C6 alkylthio, C1-C6 alkylsulfinyl and C1-C6 alkylsulfonyl; 15 16 R and R are independently selected at each occurrence from H, C 1 -C 6 alkyl, C 3 -C 10 15 15 cycloalkyl, C4-C16 cycloalkylalkyl, except that for S (O) _n R, R cannot be H; -152aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O ) nR ¹⁵ , COR ¹⁵ , CO2R 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 ; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazobutyl, 2,3-dihydrobenzyl, 2,3-dibenzylidene, 2,3-dibenzylidene, 2,3-dibenzylidene, 2,3-dibenzyl which is each optionally substituted with 1 to 5 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹⁵ , COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹⁵ , nr ⁸ cor ¹⁵ , N (COR ¹⁵ ) 2, nr ⁸ conr ¹⁶ r ¹⁵ , NR ⁸ CO ₂ R ¹⁵ , NR ¹⁶ R ¹⁵ and CONR ¹⁶ R ¹⁵ ; heterocyclyl is a saturated or partially saturated heteroaryl optionally substituted with 1 to 5 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹⁵ , COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2i NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ¹⁵ , NR ¹⁵ R ¹⁶ and CONR ¹⁶ R ¹⁵ ; n is independently 0.1 or 2 _f at each onset for the preparation of a medication for the treatment of emotional disturbance, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear paralysis, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorders, drug addiction, symptoms of drug or alcohol withdrawal, inflammatory diseases, cardiovascular or cardiovascular disease, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord injuries, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycaemia or disorders whose treatment can be performed or accelerated by CRF antagonism, including but not limited to CRF-induced or accelerated disorders in mammals. -1532. The compound of claim 1, wherein in the compound of Formulas (1) or (2), Ar is phenyl, pyridyl or 2,3dihydrobenzofuranyl, each optionally substituted with 1 to 4 R ⁴ substituents. A compound according to claim 1, wherein in the compound of Formulas (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 ₃ and R ³ is NR ^6a R ^7a . 4. A compound of Formulas (1) or (2): (D (2) and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms and its form of pharmaceutically acceptable salts or prodrugs, wherein: A is N or CR; Z is N or CR ² ; Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2- benzopyranyl, tetralinyl, each Ar is optionally 4 substituted by 1 to 5 R groups and each Ar is attached to an unsaturated carbon atom; -154R is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl; R ¹ is at each occurrence independently selected from H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halo, CN, C 1 -C 4 haloalkyl, C 1 -C 12 hydroxyalkyl, C 2 -C 12 alkoxyalkyl, 9 10 C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR R, C1-C4 9 10 9 10 11 12 alkyl-NR ^y R, NR ^a COR, OR, SH or S (O) _n R; R is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN, -NR ^{4 * 6} R ⁷ , NR ⁹ COR ¹ °, NR ⁶ S (O) n R ^7, S (O) NAP ⁶ R ^7, C1-C4 haloalkyl, ^-OR7, SH or -S (O) _n R ^12; R is selected from: -H, OR ⁷ , SH, S (O) _n R ¹³ , COR ⁷ , CO2R 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 -C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C12 cycloalkylalkyl or Cg-C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents at each occurrence selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹³ COR ¹⁵ , CO2R 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; R is independently selected at each occurrence from: C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, NO2, halo, CN, C1-C4 haloalkyl, NR ⁶ R ⁷ , NR ⁸ COR ⁷ , NR ⁸ CO2R ⁷ , COR ⁷ , OR ⁷ , CONR ⁶ R ⁷ CO (NOR ⁹ ) R ⁷ , CO2R ⁷ or S (O) _n R ⁷ wherein each such is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 6 cycloalkyl, and C4-C12 cycloalkylalkyl optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C4 alkyl, NO2, halo, CN, NR ⁶ R ⁷ , NR ⁸ COR ⁷ , NR ⁸ CO2R ⁷ COR ⁷ , OR ⁷ , CONR ⁶ R ⁷ , CO2R ⁷ CO (NOR ⁹ ) R ⁷ or S (O) nR ⁷ ; -155R ⁶ and R ⁷ , R ^6a and R ^7a are independently selected at each occurrence from: -H, -C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl each is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n R ¹³ , COR ^{14 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 or heterocyclyl , -aryl, aryl (C1-C4 alkyl), heteroaryl, heteroaryl (C1-C4 alkyl), heterocyclyl or heterocyclyl (C1-C4 alkyl), alternatively NR ⁶ R ⁷ and NR ^6a R ^{7a are} independently piperidine, pyrrolidine, piperazine , Nmethylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C 1 -C 4 alkyl groups; Mr Rücker R is at each occurrence independently selected from H or C1-C4 alkyl; 9 10 R and R are at each occurrence independently selected from H, C1-C4 alkyl or C3-C6 cycloalkyl; R ¹¹ is selected from H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 3 -C 6 cycloalkyl; R is C1-C4 alkyl or C1-C4 haloalkyl; R is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4C12 cycloalkylalkyl, aryl, aryl (C1-C4 alkyl) -, heteroaryl or heteroaryl (C1-C4 alkyl ) -; R is selected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl or C4C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3- C6 cycloalkyl, halo, C1-C4 -156haloalkyl, cyano, QR ¹⁵ , SH, S (O) _n R ¹⁵ , GOR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹⁵ , NR ⁸ COR ¹⁵ N (COR ¹⁵ ) 2, nr ⁸ conr ¹⁶ r ¹⁵ , nr ⁸ cc> 2R 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; 15 16 R and R are at each occurrence independently selected from H, C 1 -C 10 alkyl, C 3 -C 10 15 cycloalkyl, C 4 -C 6 cycloalkylalkyl, except that for S (O) nR, R cannot be H; aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹⁵ , COR ¹⁵ , CO2R 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 ; heteroaryl is pyridinium, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolinyl, 2,3-dibenzolyl, 2,3-dibenzolyl, 2,3-pyrazolyl which is each optionally substituted with 1 to 5 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹⁵ , COR ¹⁵ , CO2R 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 a saturated or partially saturated heteroaryl optionally substituted with 1 to 5 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹⁵ , COR ¹⁵ , CO2R ¹⁵ , oc (O) R ¹⁵ , nr ⁸ cor ¹⁵ , n (cor ¹⁵ ) 2, nr ⁸ conr ¹⁶ r ¹⁵ , nr ⁸ co2R ¹⁵ , nr ¹⁵ r ¹⁶ and CONR ¹⁶ R ¹⁵ ; n is independently 0,1 or 2 at each occurrence, 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; -157 (2) when A is N, Z is CR ² , R ¹ is CH3 or C2H5, R ² is H and R ³ is OH, H, CH3, C2H5, ΟθΗβ, n-C3H7, 1-C3H7, SH. SCH3, NHC4H9 or N (C2Hs) 2, then Ar is not phenyl or m-CH3-phenyl; 2 2 3 (3) when A is N, Z is CR, R is H and Ar is pyridyl, pyrimidinyl or pyrazinyl and R is NR ^6a R ^7a , then R ^6a and R ^7a are not H or alkyl; (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) when A is CR and Z is CR ² , then R ² is not -NR ⁶ SO ² R ⁷ or -SO ² NR ⁶ R ⁷ ; (6) when A is N, Z is CR ² and R ² is -NR ⁶ SO2R ^? or -SO ² NR ⁶ R ⁷ then R ³ is not OH or SH; (7) when A is N, Z is CR ² , R ¹ is methyl or ethyl, R ² is H and R ³ is H, OH, CH3, C2H5, ΟβΗβ, n-C3H7, 1ZO-C3H7, SH, SCH3, NH (n-C4Hg) or N (C2H5) 2, then Ar is not unsubstituted phenyl or m-methylphenyl; (8) when A is CR, Z is CR ² , R ² is H, phenyl or alkyl, R ³ is NR ⁸ COR ⁷ and Ar is phenyl or phenyl substituted by phenylthio, then R ⁷ is not aryl, aryl (C- | -C4 alkyl), heteroaryl, heteroaryl (C1-C4 alkyl), heterocyclyl or heterocyclyl (C1-C4 alkyl); (9) when A is CR, Z is GR ² , R ² is H or alkyl, Ar is phenyl and R ³ is SR ¹³ or NR ^6a R ^7a , 13 6a 7a then R is not aryl or heteroaryl and R and R are not 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-NHCOCH3-phenyl, p-CH3-phenyl, pyridyl or naphthyl; 2 2 3 (11) where A is CH, Z is CR, R is H, Ar is an unsubstituted phenyl and R is CH3, C2H5, CF3, or C6H4F, then ^R1 is CF3 or C2F5; -158 (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-aminopyrid-2-yl . The compound of claim 4 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, with additional conditions that; (1) when A is N, R ¹ is H, C 1 -C 4 alkyl, halo, CN, C 1 -C 12 hydroxyalkyl, C 1 -C 4 alkoxyalkyl or SO 2 (C 1 -C ₄ alkyl), R ³ is NR ^6a R ^7a and R ^6a is 7a unsubstituted C1-C4 alkyl, then R is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C3-C6 cycloalkyl; and (2) A is N, R ¹ is 3 H, C1-C4 alkyl, halo, CN, C1-C12 hydroxyalkyl, C1-C4 alkoxyalkyl or SO2 (C1-C4 alkyl), R 63 7a 6a is NR R and R is unsubstituted C1-C4 alkyl, then R is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C3-C6 cycloalkyl. A compound according to claim 4 and its isomers, its stereoisomeric forms or mixtures of its stereoisomal forms and its pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R substituents. The compound of claim 6 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts ah 'prodrugs, 2 1 wherein A is N, Z is CR, Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R and R ² are CH3 and R ³ is NR ^6a R ^7a A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 6. -15910. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 7. A compound according to claim 4 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms and its form of pharmaceutically acceptable salts or prodrugs, wherein A is N. A compound of Formula (2) according to claim 11 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms and its form of pharmaceutically acceptable salts or prodrugs. A compound according to claim 12 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted by 4 1 to 4 R substituents. The compound of claim 12 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, wherein R is NR R or OR. A compound according to claim 12 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted by 1 to 4 R ^{4 is} substituents and R ³ is NR ^6a R ^7a or OR ⁷ . A compound of Formula (1) according to claim 11 and its isomers, its stereoisomeric forms or mixtures of its stereoisomal forms and its pharmaceutically acceptable 2 salts or prodrugs, wherein Z is CR. A compound according to claim 16 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms and its form of pharmaceutically acceptable salts or prodrugs, -160 wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted by 1 to 4 R substituents. A compound according to claim 16 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, wherein R ³ is NR ^6a R ^7a or OR ⁷ A compound according to claim 18 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms and its form of pharmaceutically acceptable salts or prodrugs, 6 wherein R is independently selected from: -H, -C-1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl , which is each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ aryl, heteroaryl or heterocyclyl , -aryl, aryl (C1-C4 alkyl) -, heteroaryl, heteroaryl (C1-C4 alkyl) -, heterocyclyl or heterocyclyl (C1-C4 alkyl) -; and 7a R is independently selected at each occurrence from: -H, -C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C-10 cycloalkenyl or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n 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 CO2R ¹³ NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ aryl, heteroaryl or heterocyclyl, -161-aryl, aryl (C 1 -C 4 alkyl), heteroaryl, heteroaryl (C 1 -C 4 alkyl), heterocyclyl or heterocyclyl (C 1 -C 4 alkyl); 6 7 63 7a, alternatively, NR R and NR R are independently piperidine, pyrrolidine, piperazine, Nmethylpiperazine, morpholyl or thiomorpholyl, each optionally substituted by 1-3 C 1 -C 4 alkyl groups. The compound of claim 18 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms and its pharmaceutically acceptable salts or prodrugs, 6a 7a wherein R and R are identical and selected from: -C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH , S (O) nR ¹³ , -COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2i NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl. 21. A compound according to claim 18 and its isomers, its stereoisomeric forms or mixtures of its stereoisomal forms and its form of pharmaceutically acceptable salts or prodrugs, 6a wherein R is selected from: -H. -C1-C10 alkyl, C3 -C10 alkenyl, C3 -C10 alkynyl, C1 -C10 haloalkyl with 1-10 halogens, _C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C- | ₂ cycloalkylalkyl, C5-C10 cycloalkenyl or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents each independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR , SH, S (O) _n R ¹³ COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2i NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO ₂ R ¹³ NR ¹⁶ R ¹⁵ CONR ¹⁶ R ¹⁵ aryl, heteroaryl or heterocyclyl, -aryl, aryl (C 1 -C 4 alkyl), heteroaryl, heteroaryl (C 1 -C 4 alkyl), heterocyclyl or heterocyclyl (C 1 -C 4 alkyl); R ^7a is selected from: -162-C 1 -C 4 alkyl and each such C 1 -C 4 alkyl is substituted with 1-3 substituents independently selected from C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH , S (O) _n 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 cc> 2R ¹³ nr ¹⁶ r ¹⁵ 16 15 CONR R, aryl, heteroaryl or heterocyclyl. The compound of claim 18 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms, and its pharmaceutically acceptable salt or prodrug form, 63 73 wherein one of R and R is selected from: -C3-C6 cycloalkyl, each such C3-C6 cycloalkyl is optionally substituted with 1-3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl, -arila, -heteroaryl or -heterocyclyl, 63 73 and the second of R and R is unsubstituted C1-C4 alkyl. A compound according to claim 18 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms, and its pharmaceutically acceptable salts or prodrugs, wherein R ^8a and R ^{7a are} independently H or C1-C10 alkyl, each such C1-C10 alkyl is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n 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 co2R ¹³ , nr ¹⁶ r ¹⁵ 16 15 CONR R, aryl, heteroaryl or heterocyclyl. A compound according to claim 16 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R ^{4 is} substituents and R ³ is NR ^6a R ^7a or OR ⁷ . -16325. The compound of claim 24 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, wherein R ^{8a is} independently selected from: -H, -C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, Ο2-Οθ alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl is each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n 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 or heterocyclyl, -aryl, aryl (C 1 -C 4 alkyl) -, heteroaryl, heteroaryl (C 1 -C 4 alkyl), heterocyclyl or heterocyclic (C 1 -C 4 alkyl); 7a R is independently selected at each occurrence from: -H, -C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or Cg-Cu cycloalkenylalkyl is each optionally substituted with 1 to 3 substituents at each occurrence independently selected from Cf-06 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR, 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl, -aryl, aryl (C 1 -C 4 alkyl), heteroaryl, heteroaryl (C 1 -C 4 alkyl), heterocyclyl or heterocyclyl (C 1 -C 4 alkyl), 6 7 θίϊ 7a alternatively, NR R and NR R are independently piperidine, pyrrolidine, piperazine, Nmethylpiperazine, morpholyl or thiomorpholyl, each optionally substituted by 1-3 C 1 -C 4 alkyl groups. -16426. The compound of claim 24 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and the pharmaceutically acceptable salts or prodrugs thereof, θθ. 7a '' ~ wherein R and R are identical and are selected from: -C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH , S (O) nR ¹³ , -COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹³ , nr ⁸ cor ¹⁵ , N (COR ¹⁵ ) 2i nr ⁸ conr ¹⁶ r ¹⁵ NR ⁸ CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl and -aryl or heteroaryl. A compound according to claim 24 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its forms of pharmaceutically acceptable salts or prodrugs, wherein R and R are identical and are -C1-C4 alkyl, each such C1-C4 alkyl is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR ¹³ , -COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2i nr ⁸ conr ¹⁶ r ¹⁵ , NR ⁸ CO2R ¹³ NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl. A compound according to claim 24 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its form of pharmaceutically acceptable salts or prodrugs, wherein R ^{8a is} selected from: -H, -C1-C10 alkyl, C3 -C10 alkenyl, C3 -C10 alkynyl, C1 -C10 haloalkyl with 1-10 halogens, C ₂ -CS alkoxyalkyl, C3-C6 cycloalkyl, C4-C- | ₂ cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents each independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH , S (O) _n 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 or heterocyclyl, -165-aryl, aryl (C 1 -C 4 alkyl), heteroaryl, heteroaryl (C 1 -C 4 alkyl), heterocyclyl or heterocyclyl (C 1 -C 4 alkyl); - - -R ^7a is: -C 1 -C 4 alkyl and each such C 1 -C 4 alkyl is substituted with 1-3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n R ¹³ , COR ¹⁵ , CC> 2R ¹⁵ , OC (O) R ¹³ , nr ⁸ cor ¹⁵ , n (cor ¹⁵ ) 2, nr ⁸ conr ¹⁶ r ¹⁵ nr ⁸ cc> 2R ¹³ nr ¹⁶ r ¹⁵ , 16 15 CONR R, aryl, heteroaryl or heterocyclyl. A compound according to claim 24 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms, and its pharmaceutically acceptable salts or prodrugs, wherein one of R ^6a and R ^{7a is} selected from; -C3-C6 cycloalkyl, each such C3-C6 cycloalkyl is optionally substituted with 1-3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH. S (O) _n 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁵ R ¹⁵ , aryl, heteroaryl or heterocyclyl, -arila, -heteroaryl or -heterocyclyl 6a 7a and the second of R and R is unsubstituted C 1 -C 4 alkyl. The compound of claim 24 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms, and its pharmaceutically acceptable salts or prodrugs, wherein R ° ^a and R ^{a are} independently H or C 1 -C 8 alkyl, each such C 1 -C 10 alkyl is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n 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 C02R ¹³ nr ¹⁶ r ¹⁵ 16 15 CONR R, aryl, heteroaryl or heterocyclyl. -16631. A compound according to claim 16 and its isomers, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof and the pharmaceutically acceptable solralf prodrugs thereof, * * wherein -Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each such Ar is optionally substituted by 4 1 to 4 R substituents, -R ³ is NR ^6a R ^7a or OR ⁷ and 1 2 -R and R are independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl. The compound of claim 31 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its form of pharmaceutically acceptable salts or prodrugs, wherein R ° is independently selected from: -H, -C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl is each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ aryl, heteroaryl or heterocyclyl, -aryl, aryl (C 1 -C 4 alkyl) -, heteroaryl, heteroaryl (C 1 -C 4 alkyl), heterocyclyl or heterocyclyl (C 1 -C 4 alkyl); 7a R is independently selected at each occurrence from: -H, -C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl of 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5C10 cycloalkenyl or C6-C14 cycloalkenylalkyl each is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR, SH, S (O) _n R ¹³ , COR ¹⁵ , CO2R ¹⁵ OC (O) R ¹³ , NR ⁸ COR ¹⁵ , N (COR ¹⁵ ) 2, -167NR ⁸ CONR ¹⁶ R ¹⁵ NR ⁸ CO2R ¹³ NR ¹⁶ R ¹⁵ CONR ¹⁶ R ¹⁵ aryl, heteroaryl or heterocyclyl, - * · · - - - '··· » -aryl, aryl (C 1 -C 4 alkyl), heteroaryl, heteroaryl (C 1 -C 4 alkyl), heterocyclyl or heterocyclyl (C 1 -C 4 alkyl), 6 7 6a 7a, alternatively, NR R and NR R are independently piperidine, pyrrolidine, piperazine, Nmethylpiperazine, morpholyl or thiomorpholyl, each optionally substituted by 1-3 C 1 -C 4 alkyl groups. The compound of claim 31 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms and its pharmaceutically acceptable salts or prodrugs, wherein R and R are identical and are selected from: -G1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH , S (O) nR ¹³ , -COR ¹⁵ , CO2R ¹⁵ , OC (O) R ¹³ , NR ⁸ COR ¹⁵ N (C0R ¹⁵ ) 2j NR ⁸ CONR ¹⁶ R ¹⁵ , NR ⁸ CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl. The compound of claim 31 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, wherein R and R are identical and are -C1-C4 alkyl, each such C1-C4 alkyl is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁵ R ¹⁵ , aryl, heteroaryl or heterocyclyl. The compound of claim 31 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its form of pharmaceutically acceptable salts or prodrugs, wherein R ^{8a is} selected from: -H -168-C 1 -C 8 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 1 -C 10 haloalkyl of 1-10 '' halogens, C 2 -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 12 cycloalkylalkyl, C 5 C 10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR, SH, S (O) _n 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 ^ie R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl, -aryl, aryl (C 1 -C 4 alkyl), heteroaryl, heteroaryl (C 1 -C 4 alkyl), heterocyclyl or heterocyclyl (C 1 -C 4 alkyl); _7a. R is: -C1-C4 alkyl and each such C1-C4 alkyl is substituted with 1 to 3 substituents at each occurrence independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 co2r ¹³ , nr ¹⁶ r ¹⁵ 16 15 CONR R, aryl, heteroaryl or heterocyclyl. The compound of claim 31 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its form of pharmaceutically acceptable salts or prodrugs, wherein one of R and R is selected from: -C 3 -C 6 cycloalkyl, each such C 3 -C 6 cycloalkyl is optionally substituted with 1-3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR ¹⁵ , SH. S (O) nR 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , CONR ¹⁶ R ¹⁵ , aryl, heteroaryl or heterocyclyl, -arila, -heteroaryl or -heterocyclyl 6ci 7 a and the other of R and R ^d is unsubstituted C 1 -C 4 alkyl. The compound of claim 31 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms and its form of pharmaceutically acceptable salts or prodrugs, -169 wherein R and R are independently H or C 1 -C 10 alkyl, each such C 1 -C 10 alkyl is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 8 alkyl, * C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 co2r ¹³ , nr ¹⁶ r ¹⁵ , 16 15 CONR R, aryl, heteroaryl or heterocyclyl. The compound of claim 31 of Formula (50) R ³ FORMULA (50) and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms and its pharmaceutically acceptable salts of alpha prodrugs, selected from the group consisting of: 3 4a 4b 4c 4d compound of Formula (50) wherein R is -NHCH (n-Pr) ₂ , R is Cl, R is H, R is Cl, R is H and R ⁴ is H; 3 4a 4b 4c 4d compound of Formula (50), wherein R is -N (Et) (n-Bu), R is Cl, R is H, R is Cl, R is H and R ⁴ is H; 3 4a 4b 4c compound of Formula (50), wherein R is - (n-Pr) (CH ₂ cPr), R is Cl, R is H, R is Cl, 4d 4e R is H and R is H; -170 is a compound of Formula (50) wherein R ³ is -N (CH 2 CH 2OMe) 2, R ^4a is Cl, R ^4b is H, R ^4c is 4d. 4e. * ~ CI, 'R isHirrR · is H; : ^j _; 3 4a 4h 4c compound of Formula (50), wherein R is -NHCH (Et) (n-Bu), R is Cl, R is H, R is Cl, 4d 4e R is H and R is H; Q Aa Ah 4p compound of Formula (50) wherein R is -NHCH (Et) (CH2OMe), R is Cl, R is H, R is 4d 4e Cl, R is H and R is H; q Aa Ah 4r compound of Formula (50) wherein R is -NHCH (CH2OMe) 2, R is Cl, R is H, R is Cl, R ^4d is H and R ^4e is H; 3 4a 4b 4c 40 compound of Formula (50), wherein R is -N (Et) 2, R is Cl, R is H, R is Cl, R is H and R ^4e is H; 3 4a 4b 4c compound of Formula (50), wherein R is -NHCH (CH2OEt) 2, R is Cl, R is H, R is Cl, 4d 4fi R is H and R is H; q 4a 4h 4r 4d compound of Formula (50), wherein R is -NHCH (Et) 2, R is Cl, R is H, R is Cl, R is H and R ^4e is H; 3 4a 4b 4c 4d compound of Formula (50), wherein R is -N (Me) (Ph), R is Cl, R is H, R is Cl, R is H and R ^4e is H; 3 4a 4b 4c 4d compound of Formula (50), wherein R is -N (n-Pr) 2, R is Cl, R is H, R is Cl, R is H 4e and R is H; 3 4a 4b 4c compound of Formula (50), wherein R is -NHCH (Et) (n-Pr), R is Cl, R is H, R is Cl, 4d 4e R is H and R is H; 3 4a 4b 4c compound of Formula (50) wherein R is -NHCH (CH2OMe) 2, R is Me, R is H, R is Me, R ^4d is H and R ^4e is Me; -1713 4a 4b 4c compound of Formula (50), wherein R is -NHCH (CH2OMe) 2, R is Me, R- is H, R is 4d 4e Me, R is H and R is H; 3 4a 4b 4c compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Me, R is H, R is 4d Me, R is H and R is H; 3 4a 4b 4c compound of Formula (50), wherein R is -NHCH (Et) (CH 2OMe), R is Me, R is H, R is Me, R ^4d is H and R ^4e is H; 3 4a 4b 4c compound of Formula (50), wherein R is -NHCH (Et) 2, R is Me, R is H, R is Me, _4d. l,. _4e. _in R is H m R is H; 3 4a 4b 4c 4d compound of Formula (50) wherein R is -OEt, R is Cl, R is H, R is Cl, R is H and R ^4e is H; 3 4a 4b 4c 4d compound of Formula (50) wherein R is -N (Et) 2, R is Me, R is H, R is Me, R is H and R ^4e is H; 3 4a 4b 4c compound of Formula (50), wherein R is -N (CH 2 CN) 2, R is Me, R is H, R is Me, _4d. ... _, 4e. .. R is H m R is H; 3 4a 4b 4c compound of Formula (50) wherein R is -NHCH (Me) (CH 2OMe), R is Me, R is H, R is Me, R ^4d is H and R ^4e is H; 3 4a 4b 4c compound of Formula (50), wherein R is -OCH (Et) (CH 2OMe), R is Me, R is H, R is 4d 4e Me, R is H and R is H; 3 4a 4b 4c compound of Formula (50), wherein R is -N (n-Pr) (CH2cPr), R is Me, R is H, R is 4d 4e Me, R is H and R is H; -1723 4a 4h compound of Formula (50), wherein R is -NHCH (Me) (CH2N (Me) 2), R is Me, R is H, .., -, 40. .. _4d. l ,. _, 4e. _in . R is Me, R is HmR is H; - * 3 4a 4h 4p compound of Formula (50), wherein R is -N (cPr) (CH 2 CH 2 CN), R is Me, R is H, R is Me, R ^4d is H and R ⁴⁶ is H; A 3 Aa 4h 4p compound of Formula (50) wherein R is -N (n-Pr) (CH 2 CH 2 CN), R is Me, R is H, R is Me, R ^4d is H and R ^{4e is} H; 3 4a 4b 4c compound of Formula (50), wherein R is -N (n-Bu) (CH 2 CN), R is Me, R is H, R is 4p Me, R is H and R is H; a compound of Formula (50) wherein R ³ is -NHCH (Et) (CH 2OMe), R ^4a is Me, R ^4b is H, R ⁴⁰ 4d 4fi is Me, R is H and R is Me; 3 4s 4b 4c compound of Formula (50), wherein R is -NHCH (Et) 2, R is Me, R is H, R is Me, 4d 4e R is H and R is Me; 3 4a 4b 4c compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Me, R is H, R is Me, R ^4d is H and R ⁴ ® is Me; 3 4a 4b 4c compound of Formula (50) wherein R is -NHCH (CH2OMe) 2, R is Br, R is H, R is 4d 4e OMe, R is H and R is H; 3 4a 4b 4c compound of Formula (50), wherein R is -NHCH (Et) (CH 2OMe), R is Br, R is H, R is 4d 4e OMe, R is H and R is H; 3 4a 4b 4c 4d compound of Formula (50), wherein R is -N (Et) 2, R is Me, R is H, R is Me, R is H 4θ and R is Me; 3 4a 4b 4c compound of Formula (50) wherein R is -NHCH (CH2OEt) 2, R is Me, R is H, R is 4d 4e Me, R is H and R is Me; -1733 4a compound of Formula (50), wherein R is -NHCH (CH2CH2OMe) (CH2OMe) 2, R is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ^4e is Me; 3 4a 4b 4c 4d compound of Formula (50), wherein R is morpholino, R is Me, R is H, R is Me, R is H and R ^4e is Me; 3 4a 4b 4c compound of Formula (50), wherein R is -N (CH 2 CH 2OMe) 2, R is Br, R is H, R is 4d 4e OMe, R is H and R is H; 3 4b 4c compound of Formula (50), wherein R is -NHCH (Et) 2, R is Br, R is H, R is OMe, 4d 4e R is H and R is H; 3 4a 4b 4c d compound of Formula (50), wherein R is -N (Et) 2, R is Br, R is H, R is OMe, R is H and R ⁴ ® is H; 3 4a 4b 4c 4d compound of Formula (50), wherein R is -NH (c-Pr), R is Me, R is H, R is Me, R is H and R ⁴ are H; 3 4a 4b 4c compound of Formula (50) wherein R is -NHCH (CH2OMe) 2, R is CN, R is H, R is 4d 4e OMe, R is H and R is H; 3 4a 4b 4c compound of Formula (50), wherein R is -N (c-Pr) (CH 2 CH 2 CN), R is Me, R is H, R 4ό 4e is Me, R is H and R is Me; 3 4a 4b 4c compound of Formula (50), wherein R is -NCH (CH2OMe) 2 · R is Me, R is H, R is 4d 4e Br, R is H and R is H; a compound of Formula (50) wherein R ³ is -NHCH (CH 2OMe) (CH 2 CH 2OMe), R ^4a is Me, R ^4b is H, R ⁴⁰ is Br, R ^4d is H and R ⁴ ® is H; -174 compound of Formula (50), wherein R ³ is -NHCH (CH 2OMe) 2, R ^4a is Me, R ^4b is H, R ^4c is 4d 4e OMe, R is Me and R is H; ~ «Z 2 4a 4b 4c compound of Formula (50), wherein R is -N (CH 2 CH 2OMe) 2, R is Me, R is H, R is 4d 4e OMe, R is Me and R is H; 3 4-3 4b 4c compound of Formula (50), wherein R is -NHCH (Et) 2, R is Me, R is H, R is OMe, _4d. ... „4e. R is Me and R is H; 3 4a 4b 4c 4d compound of Formula (50), wherein R is -N (Et) 2, R is Me, R is H, R is OMe, R is Me and R ^4e is H; a compound of Formula (50) wherein R ³ is -NHCH (CH 2OMe) 2, R ⁴³ is Cl, R ^4b is H, R ⁴⁰ is Me, R ^4d isH, and R ^4e isH; 3 4a 4b 4c compound of Formula (50), wherein R is -NHCH (Et) (CH 2OMe), R is Cl, R is H, R is Me, R ^4d is H and R ^4e is H; 3 4a 4b 4c compound of Formula (50), wherein R is -N (CH 2 CH 2OMe) 2, R is Cl, R is H, R is 4d 4p Me, R is H and R is H; <5 4a 4h compound of Formula (50), wherein R is -NHCH (CH2OMe) (CH2CH2OMe), R is Cl, R 4p 4d 4p is H, R is Me, R is H and R is H; 3 4a 4b 4c compound of Formula (50), wherein R is -N (c-Pr) (CH 2 CH 2 CN), R is Me, R is H, R is OMe, R ^4d is Me and R ^4e is H; 3 4a 4b 4c compound of Formula (50), wherein R is -N (c-Pr) (CH 2 CH 2 CN), R is Cl, R is H, R is 4d 4e Cl, R is H and R is H; a compound of Formula (50) wherein R ³ is (S) -NHCH (CH 2OMe) (CH 2 CH 2OMe), R ^4a is Cl, R ^4b is H, R ⁴⁰ is Cl, R ^4d is H and R ^4e is H; Is a compound of Formula (50), wherein R ³ is -NHCH (CH 2OMe) (CH 2 CH 2OMe), R ^4a is Cl, R ^4b 4r 4d 4f »is H, R is Cl, R is H and R is H; 3 4a 4b 4c 4d compound of Formula (50) wherein R is -NHCH (Et) 2, R is Me, R is H, R is Br, R is H and R ^4e is H; 3 43 40 ^ Ic compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Me, R is H, R is 4d 4e Br, R is H and R is H; 3 4a 4b compound of Formula (50), wherein R is -NH (CH2OMe) (CH2-iPr), R is Me, R is H, R is Me, R ^4d is H and R ⁴ is H ®; 3 4a 4b 4c compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Me, R is H, R is 4d 4e H, R is H and R is H; 3 4a 4b 4c compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Me, R is H, R is NMe2, R ^4d Jehin R ^4e is H; 3 4a 4b compound of Formula (50), wherein R is -NHCH (CH 2OMe) (n-Pr), R is Me, R is H, R ^4c is Me, R ^4d is H and R ^4e is H; A 3 Aa 4b 4c compound of Formula (50), wherein R is -NHCH (CH2OEt) (Et), R is Me, R is H, R is 4d 4e Me, R is H and R is H; a compound of Formula (50) wherein R ³ is -NHCH (CH 2OMe) (CH 2 CH 2OMe), R ^4a is Me, 4h 4c 4d 4p R is H, R is NMe2, R is H and R is H; 3 4a 4b 4c 40 compound of Formula (50), wherein R is -N (Et) 2, R is Me, R is H, R is Cl, R is H and R ^4e is H; -176 compound of Formula (50), wherein R ³ is -NHCH (Et) 2, R ^4a is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^{4e is} H; 3 4a 4b 4c compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Me, R is H, R is 4d 4e Cl, R is H and R is H; 3 43 4b 4c compound of Formula (50), wherein R is -NHCH (CH2OMe) 2, R is Me, R is H, R is 4d 4e Cl, R is H and R is H; 3 4a 4b 4 c 4cl compound of Formula (50) wherein R is -N (Et) 2, R is Me, R is H, R is Br, R is H and R ⁴ ® is H; 3 4a 4b 4c 4d compound of Formula (50), wherein R is -N (Et) 2, R is Cl, R is H, R is Me, R is H 4e and R is H; 3 4a 4h 4r 4ri compound of Formula (50) wherein R is -NHCH (Et) 2, R is Cl, R is H, R is Me, R is H and R ^4e is H; 3 4a 4b 4 c compound of Formula (50), wherein R is -NHCH (Et) 2, R is Me, R is H, R is NMe2, 4d 4e R is H and R is H; a compound of Formula (50) wherein R ³ is (S) -NHCH (CH 2OMe) (CH 2 CH 2OMe), 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 2OMe) (CH 2 CH 2OMe), R ^4a is Me, R ^4b is H, R ^4c is Me, R ^4d is H and R ⁴ ® is H; A 3a compound of Formula (50), wherein R is (S) -NHCH (CH2OMe) (CH2CH2OMe), R is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ^4e is H; A 4a compound of Formula (50) wherein R is -NHCH (CH2OMe) (CH2CH2OMe), R is Me, R ^4b is H, R ^4c is Cl, R ^4d is H and R ⁴ ® is H; -177 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 4d 4e is Cl, R is H and R is H; a compound of Formula (50), wherein R ³ is -NH (Et) (CH 2 CN), R ⁴³ is Me, R ^4b is H, R ⁴⁰ is Cl, 4d 4fi R is H and R is H; 3 43 4b 4c 4d compound of Formula (50), wherein R is -N (Et) 2, R is Me, R is Me, R is OMe, R is H and R ^4e is H; o / a 4-b compound of Formula (50), wherein R is -N (CH2CH2OMe) (CH2CH2OH), R is Cl, R is H, R ⁴⁰ is Cl, R ^4d is H and R ^4e is H; A 3 4s 4b 4c compound of Formula (50), wherein R is -N (CH2CH2OMe) 2, R is Me, R is Me, R is 4d 4e OMe, R is H and R is H; 3 43 4b 4c compound of Formula (50), wherein R is -NHCH (Et) 2, R is Me, R is Me, R is OMe, 4d 4e R is H and R is H; 3 43 4b 4c compound of Formula (50), wherein R is -N (CH 2 C-Pr) (n-Pr), R is Me, R is H, R is 4d 4e Cl, R is H and R is H; 3 43 4b 4c compound of Formula (50), wherein R is -N (c-Pr) (CH 2 CH 2 CN), R is Me, R is Me, R is OMe, R ^4d isH and R ^4e isH; 3 43 4b 4c compound of Formula (50), wherein R is -NHCH (Et) 2, R is Cl, R is H, R is OMe, 4d 4e R is H and R is H; 3 4a 4b 4c 4d compound of Formula (50), wherein R is -N (Et) 2, R is Cl, R is H, R is OMe, R is H and R ^4e is H; -1783 4a 4b 4c compound of Formula (50), wherein R is -N (CH ₂ CH ₂ OMe) ₂ , R is Cl, R is H, R is Ari Afi OMe, R is H and R is H; q Aa Ah Ap compound of Formula (50) wherein R is -NHCH (Et) (CH ₂ OMe), R is Cl, R is H, R is 4d 4e OMe, R is H and R is H; 3 43 Ah 4c 4d compound of Formula (50), wherein R is -N (Et) _2l R is Cl, R is H, R is CN, R is H and R ⁴ ® is H; 3 4a 4b 4c compound of Formula (50), wherein R is -N (c-Pr) (CH ₂ CH ₂ CN), R is Cl, R is H, R is 4d 4e OMe, R is H and R is H; 3 4a 4h Af * compound of Formula (50), wherein R is -NHCH (CH ₂ OH) _2l R is Cl, R is H, R is Cl, R ^4d is H and R ^4e is H; and 3 4a 4b 4c compound of Formula (50), wherein R is N (CH ₂ CH ₂ OMe) ₂ , R is Me, R is H, R is 4d 4e OMe, R is H and R is H. The compound of claim 31 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, wherein said compound is 4- (bis- (2-methoxyethyl) amino) -2,7-dimethyl -8- (2-methyl-4methoxyphenyl) - [1,5-a] -pyrazolo-1,3,5-triazine. The compound of claim 31 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, wherein said compound is 4- (bis- (2-methoxyethyl) amino) -2,7-dimethyl -8- (2,5-dimethyl-4methoxyphenyl) - [1,5-a] pyrazolo-1,3,5-triazine. The compound of claim 4 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its form of pharmaceutically acceptable salts or prodrugs, wherein A is CR. -17942. A compound of Formula (2) according to claim 41 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms and its form of pharmaceutically acceptable salts or prodrugs. A compound according to claim 42 and its isomers, its stereoisomeric forms or mixtures of its stereoisomal forms and its pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted by 4 1 to 4 R substituents. The compound of claim 42 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms and its pharmaceutically acceptable salts or prodrugs, wherein R ³ is NR ^6a R ^7a or OR ⁷ . A compound of claim 42 and its isomers, its stereoisomeric forms or mixtures of its stereoisomal forms and its pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted by 4 3 6a 7a 7 1 to 4 R is substituents and R is NR R or OR. A compound of Formula (1) according to claim 41 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable 2 salts or prodrugs, wherein Z is CR. A compound according to claim 46 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted by 4 1 to 4 R substituents. The compound of claim 46 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, wherein R is NR R or OR. -18049. A compound according to claim 46 and its isomers, its stereoisomeric forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R ⁴ substituents and R ³ is NR ^6a R ^7a or OR ⁷ . A compound according to claim 49 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, wherein R ^oa and R are independently H or C 1 -C 10 alkyl and each such C 1 -C 10 alkyl is optionally substituted with 1 to 3 substituents at each occurrence independently selected from Ο-ι-Οθ alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) _n 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 CO2R ¹³ , NR ¹⁶ R ¹⁵ , 16 15 CONR R, aryl, heteroaryl or heterocyclyl. The compound of claim 46 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its form of pharmaceutically acceptable salts or prodrugs, wherein -Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R substituents, _, 3. _K , _6a_7a .. ~ _o 7. -R is NR R or OR and 1 2 -R and R are independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl. The compound of claim 51 and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, wherein R 7 and R 4 are independently H or C 1 -C 10 alkyl and each such C 1 -C 10 alkyl is optionally substituted with 1 to 3 substituents at each occurrence independently selected from C 1 -C 6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR ¹⁵ , SH, S (O) nR 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 C02R ¹³ nr ¹⁶ r ¹⁵ , 16 15 CONR R, aryl, heteroaryl or heterocyclyl. The compound of claim 51 of Formula (51) -181- FORMULA (51) and its isomers, its stereoisomal forms or mixtures of its stereoisomal forms, and its pharmaceutically acceptable salts or prodrugs, selected from the group consisting of: 3 4a 4b 4c compound of Formula (51), wherein R is -NHCH (n-Pr) 2, R is Me, R is H, R is Me, 4d 4e R is H and R is H; O Aa 4b Λ p is a compound of Formula (51), wherein R is -NHCH (CH2OMe) 2, R is Me, R is H, R is Me, R ^4d is H and R ^4e is H; 3 4a 4b 4 c compound of Formula (51), wherein R is -N (CH2CH2OMe) 2, R is Me, R is H, R is 4d 4e Me, R is H and R is H; 3 4a 4b 4c compound of Formula (51), wherein R is -N (c-Pr) (CH 2 CH 2 CN), R is Me, R is H, R 4d 4e is Me, R is H and R is H; 3 4a 4b 4c compound of Formula (51), wherein R is -N (CH2CH2OMe) 2, R is Cl, R is H, R is 4d 4e Me, R is H and R is H; -1823 4a 4h 4c compound of Formula (51), wherein R is -NHCH (CH2OMe) 2, R is Cl, R is H, R is Me, R ^4d is H and R ⁴ ® is H; 3 4a 4h 4c 4d compound of Formula (51) wherein R is -NHCH (Et) 2, R is Cl, R is H, R is Me, R is H and R ^4e is H; 3 4a 4b 4c 4d compound of Formula (51) wherein R is -N (Et) 2, R is Me, R is H, R is Me, R is H and R ^4e is H; 3 4a 4b 4c compound of Formula (51), wherein R is -N (n-Pr) (CH 2 CH 2 CN), R is Me, R is H, R 4d 4p is Me, R is H and R is H; 3 4a 4b 4c compound of Formula (51), wherein R is -N (n-Bu) (CH 2 CH 2 CN), R is Me, R is H, R is Me, R ^4d is H and R ⁴ ® is H; 3 4a 4b compound of Formula (51), wherein R is-NHCH (n-Pr) (CH 2 OMe), R is Me, R is H, R is Me, R ^4d Jehin R ^4e is H; * 3 Aa Ah 4Γ compound of Formula (51), wherein R is -NHCH (Et) 2, R is Me, R is H, R is OMe, 4d 4e R is H and R is H; 3 4a 4h 4c compound of Formula (51), wherein R is -NHCH (CH2OMe) 2, R is Me, R is H, R is 4d 4e OMe, R is H and R is H; 3 4a 4h compound of Formula (51), wherein R is (S) -NH (CH2CH2OMe) CH2OMe, R is Me, R 4p 4d 4p is H, R is Me, R is H and R is H; 3 4a 4b compound of Formula (51), wherein R is -NH (CH2CH2OMe) CH2OMe, R is Me, R is 4r 4d 4p H, R is Me, R is H and R is H; 3 4a 4b 4c compound of Formula (51), wherein R is -N (CH 2 CH 2OMe) 2, R is Me, R is H, R is 4d 4e Cl, R is H and R is H; -1833 4a 4b 4c 4d compound of Formula (51), wherein R is -NH (Et), R is Me, R is H, R is Me, R is H and R ⁴ ® is H; 3 4a 4b 4c compound of Formula (51), wherein R is -NHCH (n-Pr) 2, R is Me, R is H, R is Cl, 4d 4e R is H and R is H; 3 4a 4h 4c compound of Formula (51), wherein R is -NHCH (CH ₂ OMe) 2, R is Me, R is H, R is Ari 4o Cl, R is H and R is H; 3 4a 4b is a compound of Formula (51) wherein R is (S) -NH (CH ₂ CH 2OMe) CH ₂ OMe, R is Me, R is H, R ⁴⁰ is Cl, R ^4d is H and R ^4e is H; 3 4a 4b compound of Formula (51), wherein R is -NH (CH ₂ CH ₂ OMe) CH ₂ OMe, R is Me, R is Ap 4rl 4p H, R is Cl, R is H and R is H; 3 4n 4h 4r compound of Formula (51), wherein R is -N (n-Pr) (CH ₂ CH ₂ CN), R is Me, R is H, R 4d 4e is OMe, R is H and R is H; 3 4a 4b 4c 4d compound of Formula (51), wherein R is -N (Et) ₂ , R is Me, R is H, R is OMe, R is H and R ⁴ ® is H; 3 4a 4b compound of Formula (51), wherein R is (S) -NH (CH ₂ CH ₂ OMe) CH ₂ OMe, R is Cl, R is .. _4c. ,. _.4d. .,. _4e. .. H, R is Me, R is H and R is H; 3 4a 4b compound of Formula (51), wherein R is -NH (CH ₂ CH ₂ OMe) CH ₂ OMe, R is Cl, R is H, 4r 4H 4o R is Me, R is H and R is H; 3 4a 4h 4c 40 compound of Formula (51) wherein R is -N (Et) ₂ , R is Cl, R is H, R is Me, R is H and R ^4e is H; -1843 4a 4h 4c compound of Formula (51), wherein R is -N (c-Pr) (CH 2 CH 2 CN), R is Me, R is H, R is OMe, R ^4d is H and R ^4e is H; a compound of Formula (51) wherein R ³ is -N (c-Pr) (CH 2 CH 2 CN), R ^4a is Cl, R ^4b is H, R ⁴⁰ is 4d 4e Me, R is H and R is H; 3 4a 4b compound of Formula (51), wherein R is -NHCH (n-Pr) (CH 2OMe), R is Me, R is H, R ⁴⁰ is OMe, R ^4d is H and R ^4e is H; o 4λ 4h 4r compound of Formula (51), wherein R is -NHCH (n-Pr) (CH2OMe), R is Cl, R is H, R is Me, R ^4d is H and R ^4e is H; 3 4a 4b 4c compound of Formula (51) wherein R is -NHCH (Et) 2, R is Br, R is H, R is OMe, R ^4d is OMe and R ^4e is H; 3 4a 4b 4c compound of Formula (51), wherein R is -NHCH (Et) 2, R is Br, R is H, R is OMe, 4d 4-p R is H and R is H; 3 4a 4b / jc is a compound of Formula (51) wherein R is -N (CH 2 CH 2OMe) 2, R is Br, R is H, R is 4d 4e OMe, R is H and R is H; 3 4a 4b 4c compound of Formula (51), wherein R is -NHCH (CH2OMe) 2, R is Br, R is H, R is 4d 4e OMe, R is H and R is H; 3 4a 4b 4c 4d compound of Formula (51) wherein R is -N (Et) 2, R is Me, R is H, R is Cl, R is H and R ^4e is H; 3 4a 4b 4c 4d compound of Formula (51), wherein R is -N (Et) 2, R is Cl, R is H, R is OMe, R is OMeinR ^{4e is} H; 3 4a 4b 4c compound of Formula (51), wherein R is-NHCH (Et) 2, R is Cl, R is H, R is OMe, 4d 4p R is OMe and R is H; -185 compound of Formula (51), wherein R ³ is -N (CH ₂ CH 2OMe) 2, R ^4a is Cl, R ^4b is H, R ^4c is Cl, 4d 4e R is H and R is H; 3 4a 4h 4p compound of Formula (51), wherein R is -NHCH (CH2OMe) ₂ , R is Cl, R is H, R is 4d 4e Cl, R is H and R is H; a compound of Formula (51) wherein R ³ is -N (Pr) (CH 2 CH 2 CN), R ^4a is Cl, R ^4b is H, R ⁴⁰ is 4d 4e Cl, R is H and R is H; Aa Ah is a compound of Formula (51) wherein R is -N (Bu) (Et), R is Cl, R is H, R is Cl, R is H and R ^4e is H; Ah is a 4 p compound of Formula (51) wherein R is -NHCH (Et) CH ₂ OMe, R is Cl, R is H, R is 4d 4e Cl, R is H and R is H; 3 Aa Ah Ap Ari compound of Formula (51) wherein R is -NHCH (Et) 2, R is Cl, R ^D is H, R is Cl, R is H and R ^4e is H; q A a Ah Ap Ari compound of Formula (51) wherein R is -NHCH (Et) ₂ , R is Me, R is H, R is Me, R is H and R ^4e is H; Q Aa Ah 4p Ari a compound of Formula (51) wherein R is -NHCH (Et) ₂ , R is Cl, R is H, R is Me, R is H, and R ^4e is H; q Aa Ah Ap Ari a compound of Formula (51) wherein R is -NHCH (Et) 2, R is Me, R is H, R is Cl, R is H, and R ^4e is H; 3 43 4b 4c 4d compound of Formula (51), wherein R is -NEt 2, R is Me, R is H, R is OMe, R is H 4 © and R is H; and -1863 4a 4b 4c compound of Formula (51), wherein R is -N (Pr) (CH 2 CH 2 CN), R is Me, R is H, R is 4d 4e OMe, R is H and R is H. The compound of claim 51 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs, wherein said compound is 7- (3-pentylamino) -2,5-dimethyl-3- (2 -methyl-4-methoxyphenyl) [1,5-a] -pyrazolopyrimidine. A compound according to claim 51 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrugs, wherein said compound is 7- (diethylamino) -2,5-dimethyl-3- (2-methyl -4-methoxyphenyl) - [1,5a] -pyrazolopyrimidine. The compound of claim 51 and its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms, and its pharmaceutically acceptable salts or prodrugs, wherein said compound is 7- (N- (3-cyanopropyl) -N-propylamino) -2, 5-dimethyl-3- (2,4-dimethylphenyl) - [1,5-a] pyrazolopyrimidine. 57. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4. 58. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 24. 59. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 38. 60. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 39. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 40. -18762. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 53. 63. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 54. 64. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 55. 65. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 56. 66. A compound of claim 4 for the preparation of a medicament for the treatment of emotional disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear paralysis, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorders, drug addiction, symptoms after stopping drug or alcohol use, inflammatory diseases, cardiovascular or heart disease, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, strokes, ulcers, amyotrophic lateral sclerosis, hypoglycaemia or disorders of which treatment can be effected or accelerated by CRF antagonism, including but not limited to disorders induced or accelerated by CRF, in a mammal comprising administering to the mammal a therapeutically effective amount. A compound of claim 24 for the preparation of a medicament for the treatment of emotional disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear paralysis, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorders, drug addiction, symptoms after drug or alcohol withdrawal, inflammatory diseases, cardiovascular or cardiac related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, -188 ulcers, amyotrophic lateral sclerosis, hypoglycaemia or disorders whose treatment can be performed or accelerated by CRF antagonism, including but not limited to CRF-induced or accelerated disorders, in a mammal comprising administering to the mammal a therapeutically effective amount of a compound. The compound of claim 38 for the preparation of a medicament for the treatment of emotional disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear paralysis, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorders, drug addiction, symptoms of drug or alcohol withdrawal, inflammatory disease, cardiovascular or cardiac disease, fertility problems, human immunodeficiency virus infection, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, strokes, ulcers amyotrophic lateral sclerosis, hypoglycaemia or disorders of which treatment may be effected or accelerated by CRF antagonism, including but not limited to disorders induced or accelerated by CRF, in a mammal comprising administering to the mammal a therapeutically effective amount of a compound. A compound according to claim 39 for the preparation of a medicament for the treatment of emotional disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear paralysis, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorders, drug addiction, symptoms after stopping drug or alcohol use, inflammatory diseases, cardiovascular or heart disease, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, strokes, ulcers, amyotrophic lateral sclerosis, hypoglycaemia, or disorders whose treatment can be performed or accelerated by CRF antagonism, including but not limited to CRF-induced or accelerated disorders, in a mammal comprising administering to the mammal a therapeutically effective amount of a compound. A compound of claim 40 for the preparation of a medicament for the treatment of emotional disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, -189supranucleosity, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorders, drug addiction, post-drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or cardiovascular diseases, fertility problems, infectious diseases, immunodeficiency, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or disorders that can be treated or accelerated by CRF antagonism, including but not limited to CRF-induced or accelerated disorders, in a mammal comprising administering to the mammal a therapeutically effective amount of a compound. The compound of claim 53 for the preparation of a medicament for the treatment of emotional disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear lameness, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorders, drug addiction, symptoms after stopping drug or alcohol use, inflammatory diseases, cardiovascular or heart disease, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, strokes, ulcers, amyotrophic lateral sclerosis, hypoglycaemia, or disorders whose treatment can be performed or accelerated by CRF antagonism, including but not limited to CRF-induced or accelerated disorders, in a mammal comprising administering to the mammal a therapeutically effective amount of a compound. A compound according to claim 54 for the preparation of a medicament for the treatment of emotional disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear lameness, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorders, drug addiction, symptoms after stopping drug or alcohol use, inflammatory diseases, cardiovascular or heart disease, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, strokes, ulcers, amyotrophic lateral sclerosis, hypoglycaemia, or disorders whose treatment can be performed or accelerated by CRF antagonism, including but not limited to CRF-induced or accelerated disorders, in a mammal comprising administering to the mammal a therapeutically effective amount of a compound. -19073. A compound according to claim 55 for the preparation of a medicament for the treatment of emotional disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear paralysis, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorders, addiction drug, post-withdrawal symptoms, alcohol or inflammatory disease, cardiovascular or cardiac disease, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, strokes, ulcers, amyotrophic lateral sclerosis, hypoglycaemia or disorders of which treatment can be effected or accelerated by CRF antagonism, including but not limited to disorders induced or accelerated by CRF, in a mammal comprising administering to the mammal a therapeutically effective amount of a compound. 74. A compound of claim 56 for the preparation of a medicament for the treatment of emotional disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear paralysis, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other eating disorders, drug addiction, symptoms after stopping drug or alcohol use, inflammatory diseases, cardiovascular or heart disease, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, strokes, ulcers, amyotrophic lateral sclerosis, hypoglycaemia, or disorders whose treatment can be performed or accelerated by CRF antagonism, including but not limited to CRF-induced or accelerated disorders, in a mammal comprising administering to the mammal a therapeutically effective amount of a compound.