Azolo triazines and pyrimidines

FIELD OF INVENTION

The present invention relates to certain [1,5-a] -pyrazolo-1,3,5-triazines, [1,5-a] -1,2,3-triazolo-1,3,5-triazines, [ 1,5-a] -pyrazolopyrimidines and [1,5-a] 1,2,3-triazolopyrimidines and their use in the treatment of mammalian mental disorders and neurological diseases including deep depression, anxiety disorders, post-traumatic stress, nuclear paralysis and eating disorders, treatment, as well as immunological disorders, for the treatment of cardiovascular and cardiac diseases, for the treatment of colon / colon hypersensitivity associated with psychopathological disorder and stress.

ASSUMPTIONS FOR DISCLOSURE

Corticotropin-releasing factor (hereafter referred to as CRF), a 41-amino acid peptide, is the primary physiological regulator of peptide-proopiomelanocortin (POMC) derivative secretion from the anterior pituitary [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80: 4851 (1983); W. Vale et al., Science 213: 1394 (1981)]. In addition to its endocrine role in the pituitary, immunohistochemical localization of CRF has shown that this hormone has a broad non-hypothalamic distribution in the central nervous system, and produces a wide range of autonomic, electrophysiological, and behavioral effects associated with nerve signaling or neuromodulation in the brain. Vale et al., Pec. Prog. Horm. Fri 39: 245 (1983); GF Koob, Persp. Behav. Med. 2:39 (1985); EB De Souza et al., J. Neurosci. 5: 3189 (1985)]. There is also evidence that CRF plays an important role in integrating the immune system's response to physiological, psychological, and immunological stressors [JE Blalock, Physiological Peviews 69: 1 (1989); JE Morley, Life Sci. 41: 527 (1987)].

Clinical evidence suggests that CRF plays a role in mental disorders and neurological diseases, including depression, anxiety-related disorders, and eating disorders. It is also assumed that CRF plays a role in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, advanced myocardial paralysis, and amyotrophic lateral sclerosis, as these disorders are associated with CRF neuronal dysfunction [for review]. EB De Souza, Hosp. Practice 23:59 (1988)].

In affective psychosis or profound depression, CRF levels in the cerebrospinal fluid (CSF) of untreated individuals are significantly elevated [CB Nemeroff et al., Science 226: 1342 (1984); CM Banki et al., Am. J. Psychiatry 144: 873 (1987): RD France et al., Biol. Psychiatry 28:86 (1988): M. Arato et al., Biol. Psychiatry 25: 355 (1989)] In addition, CRF receptor density is greatly reduced in suicidal forebrain, which is in agreement with CRF hypersecretion [CB Nemeroff et al., Arch. Gen. Psychiatry 45: 577 (1988)]. Also, depressed adrenocorticotropin (ACTH) response to CRF (IV administered) is observed in depressed patients [PW Gold et al., Am. J. Psychiatry 141: 619 (1984): F. Holsboer et al.

Psychoneuroendocrinology 9: 147 (1984); PW Gold et al., New Eng. J. Med. 314: 1129 (1986)]. Preclinical studies in rats and non-human primates also support the hypothesis that hypersecretion of CRF may be associated with symptoms associated with depression in humans [RM Sapolsky, Arch. Gen. Psychiatry 46: 1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter levels of CRF and thereby modulate the number of CRF receptors in the brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

It has also been assumed that CRF plays a role in the etiology of anxiety-related illness. CRF produces anxiety effects in animals, and interactions between benzodiazepine / non-benzodiazepine anxiolytics and CRF have been demonstrated in various models of behavioral anxiety [DR Britton et al., Life Sci. 31: 363 (1982); CW Berridge and AJ Dun, Regul. Peptides 16:83 (1986)]. Preliminary studies using the well-known CRF receptor antagonist γ-helical sheep CRF (9-41) in various behavioral models indicate that this antagonist produces "anxiolytic" effects that are qualitatively similar to those of benzodiazepines [CW Berridge and AJ Dunn, Horm. Behav. 21: 393 (1987), Brain Research Reviews 15:71 (1990)]. All neurochemical, endocrine, and receptor-binding studies have shown an interaction between CRF and benzodiazepine anxiolytics, providing further confirmation that CRF is involved in such disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF both in the conflict assay [KT Britton et al., Psychopharmacology 86: 170 (1985); KT Britton et al.,

Psychopharmacology 94: 306 (1988), as well as in the acoustic fright test [NR Swerdlow et al., Psychopharmacology 88: 147 (1986)] in rat studies. The benzodiazepine receptor antagonist (Ro15-1788), which alone has no effect on conflict behavior, abolishes CRF effects in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) potentiates CRF effects [KT Britton et al., Psychopharmacology 94: 306 ( 1988)].

The mechanisms and sites of action through which standard anxiolytics and antidepressants produce therapeutic effects have not yet been elucidated. However, it is presumed that they are involved in the reduction of CRF hypersecretion observed in such disorders. Of particular interest is that preliminary CRF receptor antagonist (α-helical CRF₉.₄(i) Studies in a variety of behavioral models have shown that this CRF antagonist produces' analgesic effects that are qualitatively similar to those of benzodiazepines [for review see: GF Koob and K.T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of Neuropeptide, EB De Souza and CB Nemeroff eds., CRC Press, 1990, p.221.

Several publications describe compounds as corticotropin releasing factor antagonists and their use in the treatment of mental disorders and neurological diseases. Examples of such publications include DuPont Merck

PCT Application US94 / 11050, Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer

WO 95/33727 and Pfizer EP 0778277 A1.

As far as is known, [1,5-a] -pyrazolo-1,3,5-triazines, [1,5-a] -1,2,3-triazolo-1,3,5-triazines, [1 , 5-a] -pyrazolopyrimidines and [1,5a] -1,2,3-triazolopyrimidines are antagonists of corticotropin-releasing factor and are useful in the treatment of mental disorders and neurological diseases. However, there are publications that some of these compounds have different uses.

For example, EP 0269859 (Ostuka, 1988) describes pyrazolotriazines of the formula:

<img file="LT4680B_D0001.tif" />

in which R¹ is OH or alkanoyl, R² is H, OH or SH, and R³ is an unsaturated heterocyclic group, naphthyl or substituted phenyl, and these compounds are said to be xanthine oxidase inhibitors and are useful in the treatment of gout.

EP 0594149 (Ostuka, pyrazolopyrimidines of the formula:

1994) describe pyrazolotriazines and

<img file="LT4680B_D0002.tif" />

wherein A is CH or N, R ° and R³ is H or alkyl and R¹ and R² is H, alkyl, alkoxyl, alkylthio, nitro, etc., and these compounds are found to inhibit androgen and are useful in the treatment of benign prostatic hypertrophy and prostate carcinoma.

US 3910907 (ICI, 1975) describes pyrazolotriazines of the formula:

<img file="LT4680B_D0003.tif" />

Y

X where R¹ is CH₃, C₂H₅ or ΟθΗδ, X is H, C₆H₅, m-CH₃C6H₄, CN, COOEt, Cl, I or Br, Y is H, C₆H₅, o-CH₃C₆H₄ or p-CH₃C₆H₄, and Z is OH, H, CH₃, C₂H₅, C₆H_5i nC₃H₇, iC₃H₇, SH, SCH₃, NHC₄H₉ or N (C₂H₅)₂, and these compounds are said to be inhibitors of c-AMP phosphodiesterase and are useful as bronchodilators.

US 3995039 describes pyrazolotriazines of the formula:

<img file="LT4680B_D0004.tif" />

in which R¹ is H or alkyl, R² is H or alkyl, R³ is H, alkyl, alkanoyl, carbamoyl or lower alkylcarbamoyl, and R is pyridyl, pyrimidinyl or pyrazinyl, and these compounds are found to be suitable as bronchodilators.

US 5137887 describes pyrazolotriazines of the formula:

<img file="LT4680B_D0005.tif" />

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

US 4892576 describes pyrazolotriazines of the formula:

<img file="LT4680B_D0006.tif" />

wherein X is O or S, Ar is phenyl, naphthyl, pyridyl or thienyl, R 6 -R e is H, alkyl, etc., and R₉ H, alkyl, phenyl, etc. The patent states that the compounds are suitable as herbicides and plant growth regulators.

US 5484760 and WO 92/10098 describe herbicidal compositions comprising, among other components, a herbicidal compound of the formula:

<img file="LT4680B_D0007.tif" />

wherein A may be N, B may be CR₃, R3 can be phenyl or phenyl substituted with, etc., R is -N (R₄) SO₂R5 or -SO₂N (R₆) R7, and R1 and R2 can be taken together to form:

ZYZYXD —N = C — C = C- or —N = C - N — C -

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

US 3910907 and Senga et al. et al., J. Med. Chem., 1982, 25, 243-249 describes triazolotriazines, cAMP phosphodiesterase inhibitors of the formula:

<img file="LT4680B_D0008.tif" />

wherein Z is H, OH, CH₃, C₂H₅, C₆H₅, nC₃H₇, iso-C₃H₇, SH, SCH₃, NH (nC₄Hg) or N (C₂H₅)₂, R is H or CH₃, and R1 is CH₃ or C₂H₅. This literature lists eight therapeutic areas where cAMP phosphodiesterase inhibitors may be useful: asthma, diabetes mellitus, female fertility control, male infertility, psoriasis, thrombosis, anxiety, and hypertension.

WO95 / 35298 (Otsuka, 1995) describes pyrazolopyrimidines and is found to be useful as analgesics. The following compounds are represented by the formula:

R *&gt; 1— (NH) - - QA-r²

<img file="LT4680B_D0009.tif" />

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

EP 0591528 (Otsuka, 1991) describes pyrazolopyrimidines represented by the formula;

<img file="LT4680B_D0010.tif" />

in which Ri, R₂, R₃ and R₄ is H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl or phenyl, R₅ is SR₆ or NR₇R₈, Re is pyridyl or phenyl which may be substituted, and R₇ and R₈ is H or phenyl which may be substituted as an anti-inflammatory agent.

Springer et al., J. Med. Chem., 1976, vol. 19, no.2, 291-296 and Springer, U.S. Patents 4021556 and 3920652, describe pyrazolopyrimidines of the formula:

<img file="LT4680B_D0011.tif" />

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

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

<img file="LT4680B_D0012.tif" />

in which R¹ is CF 3, C 2 F 5 or C 6 H 4 F, and R² is CH3) C₂Hs, CF.₃ or C₆H₄F.

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

<img file="LT4680B_D0013.tif" />

Ibrahim et al., Arch. Pharm. (Weinheim) 320, 481-491 (1987) describe pyrazolo [1,5-a] pyrimidines of the formula:

<img file="LT4680B_D0014.tif" />

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

Other references describing azolopyrimidines include: EP

0511528 (Otsuka, 1992), US 4997940 (Dow, 1991), EP 0374448 (Nissan, 1990), US 4621556 (ICN, 1997), EP 0531901 (Fujisawa, 1993) US 4567263 (BASF, 1986), EP 0662477 (Isagro, 1995), DE 4243279 (Bayer, 1994), US 5397774 (Upjohn, 1995), EP 0521622 (Upjohn, 1993), WO 94/109017 (Upjohn, 1994), J. Med. Chem., 24, 610-613 (1981) and J. Het. Chem., 22, 601 (1985).

SUMMARY OF THE INVENTION

In one aspect, the present invention provides novel compounds, pharmaceutical compositions and methods for use in the treatment of affective psychosis, anxiety, depression, intestinal irritation syndrome, post-traumatic stress, cerebral palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, or the like. nutritional disorders, drug or alcohol withdrawal symptoms, drug abuse, inflammatory disorders, fertility problems, ie treating disorders that can be treated or alleviated by antagonizing CRF, including but not limited to those induced or promoted by CRF, or disorders selected from inflammatory disorders such as rheumatoid arthritis or osteoarthritis, pain, asthma, psoriasis, and allergies; generalized anxiety; panic, phobias, obesity-related disorder, post-traumatic stress; stress-related sleep disorders; pain sensation such as fibromyalgia; mood disorders such as depression, including profound depression, lump depression, recurrent depression, miscarriage-induced depression, and postnatal depression; dysthymia; bipolar disorder; cyclothymia; fatigue syndrome; stress-induced headaches; 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, intestinal irritation syndrome, Crohn's disease, colon spasms, diarrhea and postoperative ileus, and colonic hypersensitivity associated with psychopathological excitement or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced mental attacks; euthyroid disease syndrome; inadequate antidiabetic hormone (ADH) syndrome; obesity; infertility; head injuries; spinal cord injury; ischemic neuronal disorders (e.g., cerebral ischaemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and cardiac disorders including hypertension, tachycardia and congestive heart failure; apoplexy; immune dysfunctions, including stress-induced immune dysfunctions (e.g., stress-induced fever, swine stress syndrome, bovine transport fever, equine paroxymal fibrillation and dysfunction in small-volume enclosed chickens, severe sheep-related stress in humans or canine stress) ; muscle spasms; urinary incontinence; Alzheimer's-type senile dementia; multifarct dementia; lateral amyotrophic sclerosis; drug addiction to chemicals (eg alcohol, cocaine, heroin, benzodiazepines or other drugs); symptoms of drug and alcohol withdrawal; osteoporosis; psycho-social dementia and hypoglycemia in mammals.

The present invention provides novel compounds that bind to corticotropin-releasing factor receptors and thereby reverse the anxiety-induced effects of CRF secretion. The compounds of the present invention are useful in the treatment of mammalian mental and neurological diseases, anxiety-related disorders, post-traumatic stress disorders, nuclear paralysis and eating disorders, as well as immunological disorders, cardiovascular and cardiac figs and colon / colon hypersensitivity associated with psychosis. for the treatment of disorders and stress.

In another aspect, the present invention provides novel compounds of formulas (1) and (2) (given below) which are useful as corticotropin releasing factor antagonists. The compounds of the present invention have antagonistic effects on the corticotropin releasing factor; and appear to inhibit CRF hypersecretion. The present invention also encompasses pharmaceutical compositions comprising the compounds of formulas (1) and (2) and the use of such compounds for the inhibition of CRF hypersecretion and / or for the treatment of disorders caused by anxiety.

In yet another aspect of the present invention, the compounds of the present invention (especially the radiolabelled compounds of the present invention) can also be used as standards and reagents for determining the potential binding of a drug to the CRF receptor.

DETAILED DESCRIPTION OF THE INVENTION [1] The present invention encompasses mammalian affective disorders such as psychosis, anxiety, depression, headache, intestinal irritation syndrome, post-traumatic stress, extracellular paralysis, immune suppression, Alzheimer's disease, gastrointestinal disorders, anorexia nervosa, drugs, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart disease, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, brain and spinal cord injuries, epilepsy, apoplexy, ulcers, amyotrophic lateral sclerosis, hypoglycaemia, or a disease that can be treated or alleviated by, but not limited to, antagonizing CRF inducing or promoting CRF, a method of treatment comprising administering to such a mammal a therapeutically effective amount of a compound of formula (1) or (2):

<img file="LT4680B_D0015.tif" />

<img file="LT4680B_D0016.tif" />

where:

A is N or CR;

Z is N or CR²;

Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indahyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, and in each Ar may be 1-5 R⁴ groups as substituents and each Ar is attached to an unsaturated carbon atom;

R is independently at each occurrence selected from H, Ci-C₄-alkyl, C₂C₄-alkenyl, C₂-C₄-alkynyl, C₃-C₆-cycloalkyl, C₄-C₇-cycloalkylalkyl, halogen, CN, C_rC₄-haloalkyl;

R¹ is independently at each occurrence selected from H, C 1 -C 4 alkyl, C 2 C 4 alkenyl, C 2 -C 4 alkynyl, halogen, CN, C 1 -C 4 haloalkyl, C 1 -C 12 hydroxyalkyl, C 2 -C 12 alkoxyalkyl, C 2 -C 10 cyanoalkyl, C3-C6cycloalkyl, C4-C10cycloalkylalkyl, NR⁹R¹⁰, C 1 -C 4 alkyl-NR⁹R¹⁰,

NR⁹COR¹⁰, OR¹¹, SH, or S (O)_nR¹²:

R² is selected from H, CrC₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₃-C₆cycloalkyl, C₄-Cw-cycloalkylalkyl, C1-C₄-hydroxyalkyl, halogen, CN,

-NR⁶R⁷, NR⁹COR¹⁰, -NR⁶S (O) n R⁷, S (O) nNR⁶R⁷, C₁-C₄-haloalkyl,

OR⁷, SH, or S (O)_nR¹²;

R³ is selected from:

- H, OR⁷, SH, S (O) n R¹³, COR⁷, CO2R⁷, OC (O) R¹³, NR⁸COR⁷, N (COR⁷) 2, NR⁸CONR⁶R⁷, NR⁸CO2R¹³, NR⁶R⁷, NR^6aR^7a, N (OR⁷) R⁶, CONR^eR⁷, aryl, heteroaryl and heterocyclyl, or

- C 1 -C 10 alkyl, C₂-C 10 alkenyl, C₂-Ci₀-alkynyl, C₃-C₈-cycloalkyl, C₅-C₈cycloalkenyl, C₄-Ci₂-cycloalkylalkyl or C 6 -C 10 -cycloalkenylalkyl, each of which may have from 1 to 3 substituents independently selected from C 1 -C 6 in each case₆-alkyl, C₃-C₆-cycloalkyl, halogen, CrC₄haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵,

OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2, NR⁸CONR¹⁶R¹⁵, NR⁸CO2R¹³,

NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl;

R⁴ is independently at each occurrence selected from: Ci-C₁₀-alkyl, C₂C 1-4 alkenyl, C₂-Ci₀-alkynyl, C₃-C₆-cycloalkyl, C₄-Ci₂-cycloalkylalkyl,

NO₂, halogen, CN, CrC₄-haloalkyl, NR^SR⁷, NR⁸COR⁷,

NR⁸CO2R⁷, COR⁷, OR⁷, CONR⁶R⁷, CO (NOR⁹) R⁷, CO2R⁷or S (O) n R⁷wherein in each such C 1 -C 10 alkyl, C 2 -C 10₀-alkenile, C₂-Ci₀-alkinile, C₃C 6 -cycloalkyl and C₄-Ci₂-cycloalkylalkyl may be substituted with 1-3 substituents independently selected at each occurrence from C1-C₄-alkyl, NO₂, halogen, CN, NR^SR⁷, NR⁸COR⁷, NR⁸CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷,

CO₂R⁷, CO (NOR⁹) R⁷ or S (O)_nR⁷;

R⁶ and R⁷, R^6a and R^7a are independently selected in each case from:

-H,

- C 1 -C 10 alkyl, C₃-Ci₀-alkenyl, C₃-C₁₀-alkynyl, C 1 -C 12₀-haloalkyl with

1-10 halogens, C₂-C₈-alkoxyalkyl, C₃-C 6 -cycloalkyl, C₄-C₁₂cycloalkylalkyl, C₅-Ci₀-cycloalkenyl or C₆-C₁₄-cycloalkenylalkyl, each of which may have from 1 to 3 substituents independently selected at each occurrence from C 1 -C 6 alkyl, C₃-C₆-cycloalkyl, halogen, C 1 -C₄-haloalkyl, cyano, OR¹⁵, SH,

S (O)_nR¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2i NR^sCONR¹⁶R¹⁵, NR^sCO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl,

- aryl, aryl (Ci-C₄-alkyl), heteroaryl, heteroaryl (C 1 -C 6)₄-alkyl), heterocyclyl or heterocyclyl (C 1 -C 6)₄-alkyl);

otherwise NR⁶N⁷ and NR^6aR^7a independently selected from piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each of which may contain from 1 to 3 Ci-C₄-alkyl groups;

R⁸ is independently selected at each occurrence from H or C 1 -C 4 alkyl; R⁹ and R¹⁰ are independently selected at each occurrence from H, C 1 -C 4 alkyl, or

C₃-C₆-cycloalkyl;

R¹¹ is selected from H, Ci-C₄-alkyl, CrC₄-haloalkyl or C₃-C₆cycloalkyl;

R¹² is CrC₄-alkyl or C1-C₄-haloalkyl;

R¹³ is selected from Ci-C₄-alkyl, C1-C₄-alkyl, C1-C₄-haloalkyl, C₂-C₈alkoxyalkyl, C₃-C₆-cycloalkyl, C₄-Ci₂-cycloalkylalkyl, aryl, aryl (C₁-C₄alkyl) -, heteroaryl or heteroaryl (C1-C4-alkyl) -;

R¹⁴ is selected from Ci-C₁₀-alkyl, C₃-C₁₀-a! arose, C₃-Ci₀-alkenyl, C₃-Cwalkinyl, C₃-C₈-cycloalkylalkyl or C₄-C₁₂-cycloalkylalkyl, and may be substituted with 1 to 3 substituents independently selected at each occurrence

Cr C₆-alkyl, C₃-C₈-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹⁵, COR¹⁵, CO2R¹⁵, OC (O) R¹⁵,

NR⁸COR¹⁵, N (COR¹⁵) 2i NR⁸CONR¹⁶R¹⁵, no⁸co2r¹⁵, no¹⁶r¹⁵, CONR¹⁶R¹⁵ and C1-C6 alkylthio groups, C1-C₆-alkylsulfinyl and Ci-C₆alkylsulfonyl;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, C 1 -C 6 alkyl, C₃C 10 -cycloalkyl, C₄-Ci₆-cycloalkylalkyl, except that S (O)_nR¹⁵ case,

R¹⁵ cannot be H;

aryl is phenyl or naphthyl, and may be substituted with 1 to 5 substituents each independently selected from C 1 -C 6 alkyl, C₃-C₆cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH,

S (O) n R¹⁵, COR¹⁵, CO2R¹⁵, OC (O) R¹⁵, NR⁸COR¹⁵, N (COR¹⁵)2,

NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR^1SR¹⁵ and CONR¹⁶R¹⁵;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolanil, 2,3-pyrazolyl, 2,3-pyrazolyl, of which there may be 1 to 5 substituents independently selected in each case from C_rC6 alkyl, C₃-C₆cycloalkyl, halogen, C_rC₄-haloalkyl, cyano, OR¹⁵, SH,

S (O)_nR¹⁵, COR¹⁵, CO2R¹⁵, OC (O) R¹⁵, NR⁸COR¹⁵, N (COR¹⁵) 2i NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵ and CONR¹⁶R¹⁵;

heterocyclyl is a saturated or partially saturated heteroaryl which may have from 1 to 5 substituents independently selected at each occurrence from C 1 -C 6 alkyl;₃C 6 -cycloalkyl, halogen, C 1 -C 6₄-haloalkyl, cyano, OR¹⁵, SH,

S (O)_nR¹⁵, COR¹⁵, CO2R¹⁵, OC (O) R¹⁵, NR⁸COR¹⁵, N (COR¹⁵)2,

NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹⁵, NR¹⁶R¹⁵ and CONR^ieR¹⁵;

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

its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms and its pharmaceutically acceptable salts or prodrug forms.

[2j] More preferred methods of the present invention are those wherein Ar in the compound of formula (1) or (2) is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each of which may be substituted with 1 to 4 R⁴.

[3] More preferred methods of the present invention are those wherein A in Formula (1) or (2) is N, Z is CR², Is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R¹ and R² is CH₃, and R³ is NR^6aR^7a.

[4]

This invention includes compounds

<img file="LT4680B_D0017.tif" />

<img file="LT4680B_D0018.tif" />

in which:

A is N or CR;

Z is N or CR²;

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, and in each Ar may be 1-5 R substituents⁴a group and each Ar is attached to an unsaturated carbon atom;

R is independently at each occurrence selected from H, Ci-C₄-alkyl, C₂C₄-alkenyl, C₂-C₄-alkynyl, C3-C₆-cycloalkyl, C₄-C₇-cycloalkylalkyl, halogen, CN, C 1 -C₄-haloalkyl;

R¹ is independently at each occurrence selected from H, C 1 -C 4 alkyl, C 2 C 4 alkenyl, C 2 -C 4 alkynyl, halogen, CN, C 1 -C 4 haloalkyl, C 1 -C 12 hydroxyalkyl, C 2 -C 12 alkoxyalkyl, C 2 -C 10 cyanoalkyl, C3-C6cycloalkyl, C4-C10cycloalkylalkyl, NR⁹R¹⁰, C 1 -C 4 alkyl-NR⁹R¹⁰, NR⁹COR¹⁰, OR¹¹, SH, or S (O)_nR¹²;

R² is selected from H, CrC₄-alkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₃-C₆cycloalkyl, C₄-C₁₀-cycloalkylalkyl, C1-C₄-hydroxyalkyl, halogen, CN, -NR⁶R⁷, NR⁹COR¹⁰, -NR⁶S (O) n R⁷, S (O) nNR⁶R⁷, CrC₄-haloalkyl, OR⁷, SH, or S (O)_nR¹²;

R³ is selected from:

- H, OR⁷, SH, S (O) n R¹³, COR⁷, CO2R⁷, OC (O) R¹³, NR⁸COR⁷, N (COR⁷)₂,

NR⁸CONR⁶R⁷, NR⁸CO₂R¹³, NR⁶R⁷, NR^6aR^7a, N (OR⁷) R⁶,

CONR⁶R⁷, aryl, heteroaryl and heterocyclyl, or

- C, -C 10 alkyl, C₂-C₁₀-alkenyl, C₂-Ci₀-alkynyl, C₃-C₈-cycloalkyl, C₅-C₈cycloalkenyl, C₄-Ci₂-cycloalkylalkyl or C₆-C 10 -cycloalkenylalkyl, and may be substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 8₆-alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH,

S (O)_nR¹³, COR¹⁵, CO2R¹⁵, OC (0) R¹³, NR^sCOR¹⁵, N (COR¹⁵) 2, NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl;

R⁴ is independently at each occurrence selected from: Ci-C₁₀-alkyl, C₂C 10 -alkenyl, C₂-Ci₀-alkynyl, C₃-C₆-cycloalkyl, C₄-Ci₂-cycloalkylalkyl,

NO₂, halogen, CN, C, -C₄-haloalkyl, NR⁶R⁷, NR⁸COR⁷,

NR⁸CO2R⁷, COR⁷, OR⁷, CONR⁶R⁷, CO (NOR⁹) R⁷, CO2R⁷or S (O) n R⁷wherein in each such C 1 -C 10 alkyl, C₂-Ci₀-alkenile, C₂-Ci₀-alkinile, C₃C 6 -cycloalkyl and C₄-Ci₂-cycloalkylalkyl may be substituted with 1-3 substituents independently selected at each occurrence from C1-C₄-alkyl, NO₂, halogen, CN, NR⁶R⁷, NR⁸COR⁷, NR⁸CO₂R⁷, COR⁷, OR⁷, CONR⁶R⁷,

CO₂R⁷, CO (NOR⁹) R⁷ or S (O)_nR⁷:

R⁶ and R⁷, R^You and R^7a are independently selected in each case from:

-H,

- C 1 -C 10 alkyl, C₃-C 10 alkenyl, C₃-Ci₀-alkynyl, C 1 -C 12₀-haloalkyl with

1-10 halogens, C₂-C₈-alkoxyalkyl, C₃-C₆-cycloalkyl, C₄-C_i2cycloalkylalkyl, C₅-Ci₀-cycloalkenyl or C₆-Ci₄-cycloalkenylalkyl, each of which may have from 1 to 3 substituents independently selected at each occurrence from C1-C₆-alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH,

S (O)_nR¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵ N (COR¹⁵)2,

NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl,

- aryl, aryl {CrC₄-alkyl), heteroaryl, heteroaryl (C_rC₄-alkyl), heterocyclyl or heterocyclyl (C 1 -C₄-alkyl);

otherwise. in the case of NR⁶N⁷ and NR^6aR^7a independently is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine, and may each contain from 1 to 3 Ci-C₄-alkyl groups;

R⁸ is independently selected at each occurrence from H or C 1 -C 4 alkyl; R⁹ and R¹⁰ are independently selected at each occurrence from H, C 1 -C 4 alkyl, or

C₃-C₆-cycloalkyl;

R¹¹ is selected from H, Ci-C₄-alkyl, C1-C₄-haloalkyl or C₃-C₆cycloalkyl;

R¹² is Ci-C₄-alkyl or C1-C₄-haloalkyl;

R¹³ is selected from CrC₄-alkyl, C1-C₄-alkyl, C1-C₄-haloalkyl, C₂-C₈alkoxyalkyl, C₃-C₆-cycloalkyl, C₄-Ci₂-cycloalkylalkyl, aryl, aryl (C 1 -C 6)₄alkyl) -, heteroaryl or heteroaryl (C 1 -C 6)₄-alkium) -;

R¹⁴ is selected from Ci-Ci₀-alkyl, C₃-Ci₀-alkyl, C₃-Ci₀-alkenyl, C₃-Cwalkinyl, C₃-C₈-cycloalkylalkyl or C₄-Ci₂-cycloalkylalkyl, and may be substituted with 1 to 3 substituents independently selected at each occurrence

C_r C 5 -alkyl, C₃-C₆-cycloalkyl, halogen, C 1 -C 4 haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹⁵, COR¹⁵, CO2R¹⁵, OC (O) R¹⁵, NR⁸COR¹⁵, N (COR¹⁵) 2i no⁸conr¹⁶r¹⁵, no⁸co2r¹⁵, no¹⁶r¹⁵, CONR¹⁶R¹⁵ and Ci-C₈-alkylthio groups, Ci-C₆-alkylsulfinyl and Ci-C₆alkylsulfonyl;

R¹⁵ and R¹⁶ are independently selected at each occurrence from H, Ci-C₆-alkyl, C₃C 10 -cycloalkyl, C₄-C₁₆-cycloalkylalkyl, except that S (O)_nR¹⁵ in the case of R¹⁵ cannot be H;

aryl is phenyl or naphthyl and may be substituted with 1 to 5 substituents independently selected at each occurrence from C 1 through C₆-alkyl, C₃-C₆cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹⁵, COR¹⁵, CO2R¹⁵, OC (O) R¹⁵, NR⁸COR¹⁵, N (COR¹⁵) 2, NR⁸CONR¹⁶R¹⁵, NR⁸CO2R¹⁵, NR¹⁶R¹⁵ and CONR¹⁶R¹⁵;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolanil, 2,3-pyrazolyl, 2,3-pyrazolyl, they may be 1 to 5 substituents independently selected at each occurrence from C 1 to C 3_s-alkyl, C₃-C₆cycloalkyl, halogen, C 1 -C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹⁵, COR¹⁵, CO2R¹⁵, OC (O) R¹⁵, NR⁸COR¹⁵, N (COR¹⁵) 2, NR⁸CONR¹⁶R¹⁵, NR⁸CO2R¹⁵, NR¹⁶R¹⁵ and CONR¹⁶R¹⁵;

heterocyclyl is a saturated or partially saturated heteroaryl which may be substituted with 1 to 5 substituents independently selected at each occurrence from C 1 -C 6;₆-alkyl, C₃C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹⁵, COR¹⁵, CO2R¹⁵, OC (O) R¹⁵, NR⁸COR¹⁵, N (COR¹⁵) 2, NR⁸CONR¹⁶R¹⁵, NR^sCO2R¹⁵, NR¹⁶R¹⁵ and CONR¹⁶R¹⁵;

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

provided that:

(1) when A is N, Z is CR², R² is H, R³ is -OR⁷ or -OCOR¹³, and R⁷ is H, this is R¹ no H, OH or SH:

(2) when A is N, Z is CR², R¹ is CH 3 or C 2 H 5, R² is H and R³ is OH, H, CH 3, C₂H₅, C₆H₅, nC₃H₇, iC₃H₇, SH, SCH₃, NHC₄H₉ or N (C₂H₅)₂is Ar is not phenyl or m-OH₃-phenyl;

(3) when A is N, Z is CR², R₂ is H and Ar is pyridyl, pyrimidinyl or pyrazinyl, and R³ is NR^6aR^7a, this is R^6a and R^7a is not H or alkyl;

(4) when A is N, Z is CR², and R² is SO₂NR⁶R⁷, this is R³no OH or SH;

(5) when A is CR and Z is CR², this is R² no -NR⁶SO2R⁷ or -SO 2 NR⁶R⁷;

(6) when A is N, Z is CR², and R² is -NR⁶SO2R⁷ or -SO 2 NR⁶R⁷, this is R³ no OH or SH;

(7) when A is N, Z is CR², R¹ is methyl or ethyl, R² is H and R³ is H, OH, CH³, C₂H₅, C_sH₅, nC₃H₇, iso-C₃H₇, SH, SCH₃, NH (nC₄H₉) or N (C₂H₅)₂is Ar is not unsubstituted phenyl or m-methylphenyl;

(8) when A is CR, Z is CR², R² is H, phenyl or alkyl, R³ is NR⁸COR⁷, and Ar is phenyl or phenyl substituted with phenylthio is R⁷ is not aryl, aryl {CiC₄alkyl), heteroaryl, heteroaryl (C 1 -C 6)₄-alkyl), heterocyclyl or heterocyclyl (C 1 -C 6)₄alkyl);

(9) when A is CR, Z is CR², R² is H or alkyl, Ar is phenyl, and R³ is SR¹³ or NR^6aR^7a, this is R¹³ is not aryl or heteroaryl, and R^6a and R^7a is not H or aryl; or (10) when A is CH, Z is CR², R¹ is OR¹¹, R² is H, R³ is OR^{6 7}, and R⁷, and R¹¹ is H, is Ar is not phenyl, p-Br-phenyl, p-Cl-phenyl, p-NHCOCH₃-phenyl, p-CH₃-phenyl, pyridyl or naphthyl;

(11) when A is CH, Z is CR², R² is H, Ar is phenyl unsubstituted, and R³ is CH3, C2H5, CF3 or CeH4F, it is R¹ there is no CF3 or C₂F₅;

(12) when A is CR, R is H, Z is CR², R² is OH and R¹ and R³ is H, that is Ar is not phenyl;

(13) when A is CR, R is H, Z is CR², R² is Oh or NH 2, R¹ and R³ is CH 3, then Ar is not 4-phenyl-3-cyano-2-aminopyrid-2-yl;

their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms, [5] More preferred compounds of the present invention are the following compounds of formulas (1) and (2), their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms, the compounds being further provided that; (1) when A is N, R¹ is H, C 1 -C 4 alkyl, halogen, CN, C 1 -C 12 hydroxyalkyl, C 1 -C 4 alkoxyalkyl or SO 2 (C 1 -C 4 alkyl) R³ is NR^6aR^7a, and R^6a is C 1 -C 4 alkyl unsubstituted, it is R^7ais not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C 3 -C 6 cycloalkyl; and (2) when A is N, R¹ is H, C 1 -C 4 alkyl, halogen, CN, C 1 -C 12₂-hydroxyalkyl, C_rC₄-alkoxyalkyl or SO₂(Ci-C₄-alkyl) R³ is NR^6aR^7a and R^7a is C 1 -C 4 alkyl unsubstituted, it is R^You is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or -Ca -C6 -cycloalkyl.

[6] More preferred compounds of the present invention also include such compounds of formulas (1) and (2), their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms wherein Ar is phenyl, pyridyl or 2 , 3dihydrobenzofuranyl which may be substituted with 1 to 4 R⁴.

[7] More preferred compounds of the present invention also include such compounds of formulas (1) and (2), their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms wherein A is N, Z is CR², Is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R¹ and R² is CH₃, and R³ is NR^6aR^7a.

[11] More preferred compounds of the present invention are those compounds of formulas (1) and (2), their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrug forms wherein A is N.

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

[13] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and in each Ar may be 1-4 substituents R⁴.

[14] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein R³ is NR^6aR^7a or OR⁷.

[15] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and in each Ar may be 1-4 substituents R⁴, and R³ is NR^5aR^7a or OR⁷.

[16] More preferred compounds of the present invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrug forms wherein Z is CR².

[17] More preferred compounds of the present invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and in each of Ar may be 1-4 substituents R⁴.

[18] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein R³ is NR^6aR^7a or OR⁷.

[19] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein R^6a is independently selected from;

-H,

- C 1 -C 10 alkyl, C₃-C, -O-alkenyl, C₃-Cw-alkynyl, C1 -C3 -haloalkyl with 1-10 halogens, C₂-C₈-alkoxy! kilo, C₃-C₆-cycle! arose, C₄-Ci₂cycloalkylalkyl, C₅-Ci₀-cycloalkenyl or C₆-Ci₄-cycloalkenylalkyl, each of which may have from 1 to 3 substituents independently selected at each occurrence from C1-C₆-alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH,

S (O)_nR¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵)2,

NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR^1SR¹⁵, aryl, heteroaryl and heterocyclyl,

- aryl, aryl (Ci-C₄-alkyl), heteroaryl, heteroaryl (C 1 -C 6)₄-alkyl), heterocyclyl or heterocyclyl (C 1 -C 6)₄-alkyl); o

R^7a is independently selected in each case from:

-H,

- C 5 -C 10 alkyl, C₃-C 10 alkenyl, C₃-Ci₀-alkynyl, C 1 -C 12₀-haloalkyl with

1-10 halogens, C₂-C₈-alkoxyalkyl, C₃-C₆-cycloalkyl, C₄-Ci₂cycloalkylalkyl, C₅-Ci₀-cycloalkenyl or C₆-C₁₄-cycloalkenylalkyl, each of which may have from 1 to 3 substituents independently selected at each occurrence from C1-C₆-alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2i NR^sCONR¹⁶R¹⁵, NR^sCO2R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl,

- aryl, aryl (Ci-C₄-alkyl), heteroaryl, heteroaryl (C 1 -C 6)₄-alkyl), heterocyclyl or heterocyclyl (C 1 -C 6)₄-alkyl);

otherwise NR⁶N⁷ and NR^6aR^7a independently is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, and may each contain from 1 to 3 CrC₄-alkyl groups.

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

- CrC₄-alkyl or C₃-C₆-cycloalkyl, and each may be substituted with 1 to 3 substituents independently selected at each occurrence from Cr C₆-alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵,

OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2i NR⁸CONR¹⁶R¹⁵, NR⁸CO2R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵ and aryl or heteroaryl.

[21] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein R^You is selected from;

-H,

- C 1 -C 10 alkyl, C₃-C 10 alkenyl, C₃-C ₁₀-alkynyl, C 1 -C 12₀-haloalkyl with

1-10 halogens, C₂-C 8 alkoxyalkyl, C₃-C₆-cycloalkyl, C₄-Ci₂cycloalkylalkyl, C₅-C,₀-cycloalkenyl or C₆-C₁₄-cycloalkenylalkyl, each of which may have from 1 to 3 substituents independently selected at each occurrence from C1 to C₆-alkyl, C₃-C 6 -cycloalkyl, halogen, C 1 -C 6₄-haloalkyl, cyano, OR¹³, SH,

S (O)_nR¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR^sCOR¹⁵, N (COR¹⁵) 2&gt; NR^sCONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl,

- aryl, aryl (Ci-C₄-alkyl), heteroaryl, heteroaryl (C 1 -C 6)₄-alkyl), heterocyclyl or heterocyclyl (C 1 -C 6)₄-alkyl);

R^7a is selected from:

Ci-C₄-alkyl, and in each such Ci-C₄-alkyl may be 1 to 3 substituents independently selected at each occurrence from CrC₆alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2, NR^sCONR¹⁶R¹⁵, no⁸co2r¹³, no¹⁶r¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

[22] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein one of R^6a and R^7a is selected from:

- C₃-C 6 -cycloalkyl, and in each such C₃-C 6 -cycloalkyl may be substituted with 1 to 3 substituents independently selected at each occurrence from CrC₆alkyl, C₃-C₆-cycloalkyl, halogen, C, -C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³,

NR⁸COR¹⁵, N (COR¹⁵) 2, no⁸conr¹⁶r¹⁵, no⁸co2r¹³, no¹⁶r¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl,

- aryl,

- heteroaryl or

- heterocyclyl and the other of R^6a and R^7a is Ci-C₄-alkyl unsubstituted.

[23] More preferred compounds of the present invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrug forms thereof, wherein R^6a and R^7a independently H or C 1 -C 10 alkyl, and each such C 1 -C 10 alkyl may be substituted with 1 to 3 substituents independently selected at each occurrence from C₆alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵)₂,

NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

[24] More preferred compounds of the present invention also include the compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and in each Ar may be 1-4 substituents R⁴, and R³ is NR^6aR^7a or OR⁷.

[25] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein R^You is selected from;

-H,

- C 1 -C 10 alkyl, C₃-C 1-4 alkenyl, C₃-Ci₀-alkynyl, C 1 -C 7 -haloalkyl with

1-10 halogens, C₂-C₈-alkoxyalkyl, C₃-C₆-cycloalkyl, C₄-Ci₂cycloalkylalkyl, C₅-Ci₀-cycloalkenyl or C₆-Ci₄-cycloalkenylalkyl, each of which may have from 1 to 3 substituents independently selected at each occurrence from C1-C₆-alkyl, C₃-C₆-cycloalkyl, halogen, CrC₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2i NR^sCONR¹⁶R¹⁵, NR⁸CO2R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl,

- aryl, aryl (Ci-C₄-alkyl), heteroaryl, heteroaryl (C 1 -C 6)₄-alkyl), heterocyclyl or heterocyclyl (C_rC₄-alkyl);

R^7a is independently selected in each case from:

- H,

- C₅-C 10 alkyl, C₃-C 10 alkenyl, C₃-Ci₀-alkynyl, C₃-Ci₀-haloalkyl with

1-10 halogens, C₂-C₈-alkoxyalkyl, C₃-C 6 -cycloalkyl, C₄-Ci₂cycloalkylalkyl, C₅-Ci₀-cycloalkenyl or C₆-C₁₄-cycloalkenylalkyl, each of which may have from 1 to 3 substituents independently selected at each occurrence from C1-C₆-alkyl, C₃-C₆-cycloalkyl, halogen, CrC₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2, NR⁸CONR¹⁶R¹⁵, NR⁸CO2R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl,

- aryl, aryl (Ci-C₄-alkyl), heteroaryl, heteroaryl (C 1 -C 6)₄-alkyl), heterocyclyl or heterocyclyl (C 1 -C 6)₄-alkyl);

otherwise NR⁶N⁷ and NR^6aR^7a independently is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine, or thiomorpholine, and may each contain from 1 to 3 Ci-C₄-alkyl groups.

[26] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein R^You and R^7a are the same and are selected from:

Ci-C₄-alkyl or C₃-C₆-cycloalkyl, and may be substituted with 1 to 3 substituents independently selected at each occurrence from CrC₆alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³,

NR⁸COR¹⁵, N (COR¹⁵) 2i no⁸conr¹⁶r¹⁵, no⁸co2r¹³, no¹⁶r¹⁵,

CONR¹⁶R¹⁵, aryl heteroaryl or heterocyclyl, and

- aryl or heteroaryl.

[27] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein R^You and R^7a are the same and are

Ci-C₄-aikil, and in each such C, -C₄-alkyl may be 1 to 3 substituents independently selected at each occurrence from C1-C₆-alk,

C3-C6-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵,

SH, S (O)_nR¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2i NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR^1SR¹⁵, CONR¹⁶R¹⁵, aryl heteroaryl or heterocyclyl. ²⁸ [28] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein R^6a is selected from:

-H,

- C 1 -C 10 alkyl, C₃-C 10 alkenyl, C₃-Ci₀-alkynyl, C_rC 10 -haloalkyl with

1-10 halogens, C₂-C₈-alkoxyalkyl, C₃-C₆-cycloalkyl, C₄-C,₂cycloalkylalkyl, C 5 -C 10 -cycloalkenyl or C 6 -C 12₄-cycloalkenylalkyl, each of which may have from 1 to 3 substituents independently selected at each occurrence from C1 to C₆-alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH,

S (O)_nR¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2i NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl,

- aryl, aryl (Ci-C₄-alkyl), heteroaryl, heteroaryl (C 1 -C 6)₄-alkyl), heterocyclyl or heterocyclyl (C₁-C₄-alkyl);

R^7a is:

- C 1 -C 4 alkyl, and in each such C 1 -C 4₄-alkyl may be 1 to 3 substituents independently selected at each occurrence from C1-C₆-alk,

C3-C₆- cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵,

SH, S (O)_nR¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2i NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR^1SR¹⁵, aryl heteroaryl or heterocyclyl.

[29j] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein one of R^You and R^7a is selected from:

- C₃-C₆-cycloalkyl, and in each such C₃-C₆-cycloalkyl may be substituted with 1 to 3 substituents independently selected at each occurrence from CrC₆alkyl, C₃-C 6 -cycloalkyl, halogen, C 1 -C₄-halogenalkyl, cyano groups, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2, no⁸conr¹⁶r¹⁵, no⁸co2r¹³, no¹⁶r¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl,

- aryl,

- heteroaryl or

- heterocyclyl and the other of R^You and R^7a is Ci-C₄-alkyl unsubstituted.

More preferred compounds of the present invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrug forms thereof, wherein R^6a and R^7a independently H or -C 1 -C 10 alkyl, and each such C 1 -C 10 alkyl may be substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 10 alkyl.₆alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵)₂,

NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR^1SR¹⁵, aryl, heteroaryl or heterocyclyl.

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

- is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and in each

Can be 1-4 substituents R⁴,

- R³ is NR^6aR^7a or OR⁷ and

- R¹ and R² are independently selected from H, Ci-C₄-alkyl, C₃-C₆cycloalkyl, C₄-Ci₀-cycloalkylalkyl, [32] More preferred compounds of the present invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms thereof, wherein R^6a is independently selected from:

- H,

- C 1 -C 10 alkyl, C₃-C 10 alkenyl, C₃-Ci₀-alkynyl, C 1 -C 7 -haloalkyl with

1-10 halogens, C₂-C₈-alkoxyalkyl, C₃-C₆-cycloalkyl, C₄-Ci₂cycloalkylalkyl, C₅-Ci₀-cycloalkenyl or C6-Ci₄-cycloalkenylalkyl, each of which may have from 1 to 3 substituents independently selected at each occurrence from C1-C₆-alkyl, C₃-C₆-cycloalkyl, halogen, CrC₄-haloalkyl, cyano, OR¹⁵, SH,

S (O)_nR¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2, NR^sCONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵ aryl, heteroaryl and heterocyclyl,

- aryl, aryl (Ci-C₄-alkyl), heteroaryl, heteroaryl (C 1 -C 6)₄-alkyl), heterocyclyl or heterocyclyl (C 1 -C 6)₄-alkyl);

R^7a is independently selected in each case from:

-H,

- C₅-C 10 alkyl, C₃-C₁₀-alkenyl, C₃-Ci₀-alkynyl, C 1 -C 12₀-haloalkyl with

1-10 halogens, C₂-C₈-alkoxyalkyl, C₃-C₆-cycloalkyl, C₄-Ci₂cycloalkylalkyl, C₅-Ci₀-cycloalkenyl or C6-Ci₄-cycloalkenylalkyl, each of which may have from 1 to 3 substituents independently selected at each occurrence from C 1 -C 6 alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2i NR⁸CONR¹⁶R¹⁵, NR⁸CO2R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl,

- aryl, aryl (Ci-C₄-alkyl), heteroaryl, heteroaryl (C 1 -C 6)₄-alkyl), heterocyclyl or heterocyclyl (C 1 -C 6)₄-alkyl);

otherwise NR⁶N⁷ and NR^6aR^7a independently is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, and may each contain from 1 to 3 Ci-C₄-alkyl groups.

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

- CrC₄-alkyl or C₃-C 6 -cycloalkyl, and may be substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 6 alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2, no⁸conr¹⁶r¹⁵, no⁸co2r¹³, no¹⁶r¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl and

- aryl or heteroaryl. ^{34 *} [34] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein R^6a and R^7a are the same and are:

Ci-C₄-alkyl, and in each such CrC₄-alkyl may be 1 to 3 substituents independently selected at each occurrence from C1-C₆-alk,

C₃-C₆- cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵,

SH, S (O)_nR¹³, COR¹⁵, CO., LTD₂R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2, NR⁸CONR¹⁶R¹⁵, NR⁸CO2R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl.

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

- H,

- C 1 -C 10 alkyl, C₃-Ci₀-alkenyl, C₃-Ci₀-alkynyl, C 1 -C 12₀-haloalkyl with

1-10 halogens, C2-C₈-alkoxyalkyl, C₃-C 6 -cycloalkyl, C₄-C₁₂cycloalkylalkyl, C₅-C,₀-cycloalkenyl or C₆-Ci₄-cycloalkenylalkyl, each of which may have from 1 to 3 substituents independently selected at each occurrence from C1-C₆-alkyl, C₃-C₆-cycloalkyl, halogen, CrC₄-haloalkyl, cyano, OR¹⁵, SH,

S (O)_nR¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2i NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl,

- aryl, aryl (Ci-C₄-alkyl), heteroaryl, heteroaryl (C 1 -C 6)₄-alkyl), heterocyclyl or heterocyclyl (C 1 -C 6)₄-alkyl);

R^7a is:

Ci-C₄-alkyl, and in each such Ci-C₄-alkyl may be 1 to 3 substituents independently selected at each occurrence from C 1 -C 8 alkyl,

C₃-C₆- cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵,

SH, S (O)_nR¹³, COR¹⁵, CO., LTD₂R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2, NR⁸CONR¹⁶R¹⁵, NR⁸CO2R¹³, NR¹⁶R¹⁵ CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl. ³⁶ [36] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein one of R^6a and R^7a is selected from:

- C₃-C₆-cycloalkyl, and in each such C₃-C₆-cycloalkyl may be substituted with 1 to 3 substituents independently selected at each occurrence from CrC₆alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³. COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵) 2i no⁸conr¹⁶r¹⁵, no⁸co2r¹³, no¹⁶r¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl or heterocyclyl,

- aryl,

- heteroaryl or

- heterocyclyl and the other of R^6a and R^7a is Ci-C₄-alkyl unsubstituted.

[37] More preferred compounds of the present invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms thereof, wherein R^You and R^7a independently is H or Ci-C₁₀-alkyl, and each such C1-C10 alkyl may be substituted with 1-3 substituents independently selected at each occurrence from C1-C₆alkyl, C₃-C₆-cycloalkyl, halogen, C1-C₄-haloalkyl, cyano, OR¹⁵,

SH, S (O)_nR¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵)2,

NR⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR^1SR¹⁵, aryl, heteroaryl or heterocyclyl.

[38] Particularly suitable compounds of the present invention are compounds of formula (50): R³

<img file="LT4680B_D0019.tif" />

_R4a _R4b (50) THE FORMULA and its isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms thereof, selected from the group consisting of:

A compound of formula (50) wherein R³ is -NHCH (n-Pr)₂, R^4a is Cl, R^4b is H, R^4Cis Cl, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -N (Et) (n-Bu), R^4a is Cl, R^4b is H, R^4C is Cl, R^4disHir R^4eis H;

A compound of formula (50) wherein R³ is - (n-Pr) {CH₂c-Pr), R^4a is Cl, R^4b is H,

R^4c is CI, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -N {CK₂CH₂OMe)₂, R^4a is Cl, R^4b is H, R^4c is Cl, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -NHCH (Et) (n-Bu), R^4a is Cl, R^4b is H, R^4cis CI, R^4dare H and R^4eis H;

A compound of formula (50) wherein R³ is -NHCH (Et) {CH₂OMe), R^4a is Cl, R^4bis H, R^4c is Cl, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is Cl, R^4b is H, R^4c is Cl, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -N (Et)₂, R^4a is Cl, R^4b is H, R^4c is Cl, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OEt)₂, R^4a is Cl, R^4b is H, R^4C is Cl, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (Et)₂, R^4a is Cl, R^4b is H, R^4cis CI, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (Me) (Ph), R^4a is Cl, R^4b is H, R^4Cis CI, R^4dis H and R⁴®is H;

A compound of formula (50) wherein R³ is -N (n-Pr)₂, R^4a is Cl, R^4b is H, R^4c is Cl, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (Et) (n-Pr), R^4a is Cl, R^4b is H, R^4C is CI, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is Me, R^4b is H, R^4c is Me, R^4d are H and R^4eis Me;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is Me, R^4b is H, R^4c is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (CH₂CH₂OMe)₂, R^4a is Me, R^4b is

H, R^4c is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (Et) {CH₂OMe), R^4a is Me, R^4b is H, R^4c is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (Et)₂, R^4a is Me, R^4b is H, R^4cis Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -OEt, R^4a is Cl, R^4b is H, R^4c is Cl,

R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (Et)₂, R^4a is Me, R^4b is H, R^4C is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (CH₂CN)₂, R^4a is Me, R^4b is H, R^4cis Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (Me) {CH₂OMe), R^4a is Me, R^4bis H, R^4C is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -OCH (Et) {CH₂OMe), R^4a is Me, R^4bis H, R^4C is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (n-Pr) {CH₂cPr), R^4a is Me, R^4b is H, R^4c is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (Me) {CH₂N (Me)₂), R^4a is Me,

R^4b is H, R^4c is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NH (cPr) {CH₂CH₂CN), R^4a is Me, R^4bis H, R^4c is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NH (n-Pr) {CH₂CH₂CN), R^4a is Me, R^4bis H, R^4c is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NH (n-Bu) {CH₂CN), R^4a is Me, R^4bis H, R^4c is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (Et) {CH₂OMe), R^4a is Me, R^4bis H, R^4c is Me, R^4d are H and R⁴® is Me;

A compound of formula (50) wherein R³ is -NHCH (Et)₂, R^4a is Me, R^4b is H, R^4cis Me, R^4d are H and R⁴® is Me;

A compound of formula (50) wherein R³ is -N (CH₂CH₂OMe)₂, R^4a is Me, R^4b is H, R^4c is Me, R^4d are H and R⁴® is Me;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is Br, R^4b is

H, R^4c is OMe, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (Et) {CH₂OMe), R^4a is Br, R^4b is H, R^4C is OMe, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (Et)₂, R^4a is Me, R^4b is H, R^4C is

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

A compound of formula (50) wherein R³ is -NHCH (CH₂OEt)₂, R^4a is Me, R^4b is

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

A compound of formula (50) wherein R³ is -NHCH (CH₂CH₂OMe) (CH₂OMe)₂, R^4ais Me, R^4b is H, R^4c is Me, R^4d are H and R^4e is Me;

A compound of formula (50) wherein R³ is a morpholine residue, R^4a is Me, R^4b is H, R^4c is Me, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -N (CH₂CH₂OMe)₂, R^4a is Br, R^4b is H, R^4cisOMe, R^4d is H and R^4eis H;

A compound of formula (50) wherein R³ is -NHCH (Et)₂, R^4a is Br, R^4b is H, R^4Cis OMe, R^4d are H and R^4eis H;

A compound of formula (50) wherein R³ is -N (Et)₂, R^4a is Br, R^4b is H, R^4C is OMe, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -NH (c-Pr), R^{&gt; 4a} is Me, R^4b is H, R^4cis Me, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is CN, R^4b is H, R^4c is OMe, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -N (c-Pr) {CH₂CH₂CN), R^4a is Me, R^4bis H, R^4c is Me, R^4d are H and R⁴® is Me;

A compound of formula (50) wherein R³ is -NCH (CH₂OMe)₂, R^4a is Me, R^4b is H, R^4c is Br, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe) (CH₂CH₂OMe), R^4ais Me, R^4b is H, R^4c is Br, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is Me, R^4b is H, R^4c is OMe, R^4d are Me and R⁴® is H;

A compound of formula (50) wherein R³ is -N (CH₂CH₂OMe)₂, R^4a is Me, R^4b is H, R^4c is OMe, R^4d are Me and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (Et)₂, R^4a is Me, R^4b is H, R^4Cis OMe, R^4d are Me and R⁴® is H;

A compound of formula (50) wherein R³ is -N (Et)₂, R^4a is Me, R^4b is H, R^4c is OMe, R^4d are Me and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is Ci, R^4b is

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

A compound of formula (50) wherein R³ is -NHCH (Et) {CH₂OMe), R^4a is Cl, R^4b is H, R^4c is Me, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -N (CH₂CH₂OMe)₂, R^4a is Cl, R^4b is H, R^4C is Me, R^4d are H and R⁴⁸ is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe) (CH₂CH₂OMe), R^4ais Cl, R^4b is H, R^4C is Me, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -N (c-Pr) {CH₂CH₂CN), R^4a is Me, R^4bis H, R^4C is Me, R^4d are Me and R^4e is H;

A compound of formula (50) wherein R³ is -N (c-Pr) {CH₂CH₂CN), R^4a is Cl, R^4bis H, R^4c is Cl, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is fS) -NHCH (CH₂OMe) (CH₂CH₂OMe), R^4ais Cl, R^4b is H, R^4c is Cl, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe) (CH₂CH₂OMe), R^4ais Cl, R^4b is H, R^4c is Cl, R^4d are H and R⁴⁸ is H;

A compound of formula (50) wherein R³ is -NHCH (Et)₂, R^4a is Me, R^4b is H, R^4cis Br, R^4d are H and R⁴⁸ is H:

A compound of formula (50) wherein R³ is -N (CH₂CH₂OMe)_2l R^4a is Me, R^4b is H, R^4c is Br, R^4d are H and R⁴⁸ is H;

A compound of formula (50) wherein R³ is -NH (CH₂OMe) (CH₂-iPr), R^4a is Me,

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

A compound of formula (50) wherein R³ is -N (CH₂CH₂OMe)₂, R^4a is Me, R^4b is H, R^4c is H, R^4d are H and R⁴⁸ is H;

A compound of formula (50) wherein R³ is -N (CH 2 CH 2 OMe) 2, R^4a is Me, R^4b is H, R^4c is NMe2, R^4d are -H and R^4e is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe) (n-Pr), R^4a is Me,

R^4b is H, R^4C is Me, R^4d are H and R⁴⁸ is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OEt) (Et), R^4a is Me, R^4bis H, R^4c is Me, R^4d are H and R⁴⁸ is H;

A compound of formula (50) wherein R³ is -NHCH (CH2OMe) (CH2CH2OMe), R^4ais Me, R^4b is H, R^4c is NMe2, R^4d are H and R⁴⁸ is H;

A compound of formula (50) wherein R³ is -N (Et)₂, R^4a is Me, R^4b is H, R^4c is

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

A compound of formula (50) wherein R³ is -NHCH (Et)₂, R^4a is Me, R^4D is H, R^4C is CI, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -N (CH₂CH₂OMe)₂, R^4a is Me, R^4b is H, R^4c is CI, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is Me, R^4b is H, R^4C is Cl, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -N (Et)₂, R^4a is Me, R^4b is H, R^4C is Br, R^4d are H and R⁴³ is H;

A compound of formula (50) wherein R³ is -N (Et)₂, R^4a is Cl, R^4b is H, R^4C is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (Et)₂, R^da is Cl, R^4b is H, R^4Cis Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (Et) 2, R^4a is Me, R^4b is H, R^4cis NMe2, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is (S) -NHCH (CH₂OMe) (CH₂CH₂OMe), R^4ais Me, R^4b is H, R⁴⁰ is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe) (CH₂CH₂OMe), R^4ais Me, R^4b is H, R^4c is Me, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is (S) -NHCH (CH₂OMe) (CH₂CH₂OMe), R^4ais Me, R^4b is H, R^4c is Cl, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OMe) (CH₂CH₂OMe), R '^ais Me, R^4b is H, R^4c is Cl, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (c-Pr) {CH₂CH₂CN), R^4a is Me, R^4bis H, R^4c is Cl, R^4d are H and.R⁴® is H;

A compound of formula (50) wherein R³ is -NH (Et) {CH₂CN), R^4a is Me, R⁴⁰ is H,

R^4C is Cl, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (Et)₂, R^4a is Me, R^4b is Me, R⁴'is OMe, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (CH₂CH ₂OMe) (CH₂CH₂OH), R^4a is Cl, R^4b is H, R^4C is Cl, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (CH₂CH₂OMe) 2, R^4a is Me, R^4b is

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

A compound of formula (50) wherein R³ is -NHCH (Et)₂, R^4a is Me, R^4b is Me,

R^4c is OMe, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (CH₂c-Pr) (N-Pr), R^4a is Me, R^4b is H, R^4c is Cl, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -N (c-Pr) {CH₂CH₂CN), R^4a is Me, R^4bis Me, R^4c is OMe, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -NHCH (Et)₂, R^4a is Cl, R^4b is H, R⁴⁰is OMe, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (Et)₂, R^4a is Cl, R^4b is H, R^4C is OMe, R^4d are H and R^4e is H;

A compound of formula (50) wherein R³ is -N (CH₂CH₂OMe)₂, R^4a is Cl, R^4b is H, R^4c is OMe, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -NHCH (Et) {CH₂OMe), R^4a is cl, R^4bis H, R^4C is OMe, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (Et)₂, R^4a is Cl, R^4b is H, R^4C is CN, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (c-Pr) {CH₂CH₂CN), R^4a is Cl, R^4bis H, R^4c is OMe, R^4d are H and R⁴³ is H;

A compound of formula (50) wherein R³ is -NHCH (CH₂OH), R^4a is CI, R^4d is H, R^4C is Cl, R^4d are H and R⁴® is H;

A compound of formula (50) wherein R³ is -N (CH₂CH₂OMe)₂, R^4a is Me, R^4b is H, R^4c is OMe, R^4d are H and R⁴³ is H.

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

[40] More specifically, 4- (bis) - (2-methoxyethyl) amino) 2,7-dimethyl-8- (2,5-dimethyl-4-methoxyphenyl) - [1,5-a] -pyrazolo-1 is more suitable. , 3,5-triazine, its isomers, its stereoisomeric forms or mixtures of its stereoisomeric forms, and its pharmaceutically acceptable salts or prodrug forms thereof.

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

[42] More preferred compounds of the present invention also include the compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrug forms.

[43] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts or prodrug forms thereof, wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and in each of Ar may be 1-4 substituents R⁴.

[44] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein R³ is NR^5aR^7a or OR⁷.

[45] More preferred compounds of the present invention also include the compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and in each of Ar may be 1-4 substituents R⁴, and R³ is NR^6aR^7a or OR⁷.

[46] More preferred compounds of the present invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrug forms wherein Z is CR².

[47] More preferred compounds of the present invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and in each of Ar may be 1-4 substituents R⁴.

More preferred compounds of the present invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or prodrug forms thereof wherein R³ is NR^6aR^7a orOR⁷.

More preferred compounds of the present invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and in each of Ar be 1-4 substituents R⁴, and R³ is NR^6aR^7a or OR⁷.

[50] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein R^5a and R^7a independently is H or CrC₁₀-alkyl, and in each such CC,_oalkyl may be 1 to 3 substituents independently selected at each occurrence from C_;-C₆alkyl, C₃-C 6 -cycloalkyl, halogen, C 1 -C 6₄-haloalkyl, cyano, OR¹⁵, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR^1S)₂,

R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR¹⁶R¹⁵, CONR¹⁶R¹⁵, ario, heteroaryl and heterocyclyl.

More preferred compounds of the present invention also include compounds and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms and their pharmaceutically acceptable salts or prodrug forms thereof, wherein

- is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and in each

Can be 1-4 substituents R⁴,

- R³ is NR^6aR^7a or OR⁷ and

- R¹ and R² are independently selected from H, Ci-C₄-alkyl, C₃-C₆cycloalkyl, C₄-Ci₀-cycloalkylalkyl.

[52] More preferred compounds of the present invention also include compounds and their isomers, stereoisomeric forms thereof, or mixtures of their stereoisomeric forms, and pharmaceutically acceptable salts thereof, or prodrug forms thereof, wherein R^You and R^7a independently H or C 1 -C 10 alkyl, and each such C-C 10 alkyl may be substituted with 1 to 3 substituents independently selected at each occurrence from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR¹⁼, SH, S (O) n R¹³, COR¹⁵, CO2R¹⁵, OC (O) R¹³, NR⁸COR¹⁵, N (COR¹⁵)2,

R⁸CONR¹⁶R¹⁵, NR⁸CO₂R¹³, NR^1SR¹⁵, CONR¹⁶R¹⁵, aryl, heteroaryl and heterocyclyl.

[53J] Particularly suitable compounds of the present invention are compounds of formula (51):

R³

<img file="LT4680B_D0020.tif" />

^ 4c (51) FORMULAS and their isomers, their stereoisomeric forms or mixtures of their stereoisomeric forms, and their pharmaceutically acceptable salts or their prodrug forms, selected from the group consisting of:

A compound of formula (51) wherein R³ is -NHCH (n-Pr)₂, R^4a is Me, R^4b is H,

R^4c is Me, R^4d are H and R^4e is H:

A compound of formula (51) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is Me, R^4b is H, R^4c is Me, R^4d are H and R⁴³ is H;

A compound of formula (51) wherein R³ is -N (CH₂CH₂OMe)₂, R^4a is Me, R^4b is H, R^4c is Me, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -N (c-Pr) {CH₂CH₂CN), R^4a is Me, R^4dis H, R^4c is Me, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -N (CH₂CH₂OMe)₂, R^4a is Ci, R^4b is H, R^4c is Me, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is Cl, R^4b is H, R^4C is Me, R^4d are H and R⁴³ is H;

A compound of formula (51) wherein R³ is -NHCH (Et)₂, R^4a is Cl, R^4b is H, R^4cis Me, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -N (Et)₂, R^4a is Me, R^4b is H, R⁴⁰ is Me, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -N (n-Pr) {CH₂CH₂CN), R^4a is Me, R^4bis H, R^4C is Me, R^4d are H and R^4s is H;

A compound of formula (51) wherein R³ is -N (n-Bu) {CH₂CH₂CN), R^4a is Me, R^4bis H, R^4c is Me, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -N (n-Pr) {CH₂OMe), R^4a is Me, R^4b is H, R^4c is Me, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -NHCH (Et)₂, R^4a is Me, R^4b is H, R^4Cis OMe, R^4d are H and R⁴³ is H;

A compound of formula (51) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is Me, R^4b is H, R^4c is OMe, R^4d are H and R⁴³ is H;

A compound of formula (51) wherein R³ is (S) -NH (CH₂CH₂OMe) CH₂OMe, R^4a is Me, R^4b is H, R^4c is Me, R^4d are H and R⁴³ is H;

A compound of formula (51) wherein R³ is -NH (CH₂CH₂OMe) CH₂OMe, R^4a is Me, R^4b is H, R^4C is Me, R^4d are H and R⁴³ is H;

A compound of formula (51) wherein R³ is -N (CH₂CH₂OMe)₂, R^4a is Me, R^4b is H, R⁴³ is Cl, R^4d are H and R⁴³ is H;

A compound of formula (51) wherein R³ is -NH (Et), R^4a is Me, R^4b is H, R^4C is Me, R^4dare H and R^4e is H;

A compound of formula (51) wherein R³ is -NHCH (n-Pr)₂, R^4a is Me, R^4b is H, R^4cis CI, R^4d are H and R⁴® is H;

A compound of formula (51) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is Me, R^4b is H, R^4c is Cl, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -NH (CH₂CH₂OMe) CH₂OMe, R^4a is Me, R^4b is H, R^4C is Cl, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -NH (CH₂CH₂OMe) CH₂OMe, R^4a is Me, R^4b is H, R^4C is Cl, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -N (n-Pr) {CH₂CH₂CN), R^4a is Me, R^4bis H, R^4c is OMe, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -N (Et)₂, R^4a is Me, R^4b is H, R^4C is OMe, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is {SJ-NH {CH₂CH₂OMe) CH₂OMe, R^4a is Cl, R^4b is H, R^4c is Me, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -NH (CH₂CH₂OMe) CH₂OMe, R^4a is Cl, R^4b is H, R⁴⁰ is Me, R^4d are H and R^4e is H:

A compound of formula (51) wherein R³ is -N (Et)₂, R^4a is Cl, R^4b is H, R^4c is Me, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -N (c-Pr) {CH₂CH₂CN), R^4a is Me, R^4bis H, R^4c is OMe, R^4d are H and R⁴® is H:

A compound of formula (51) wherein R³ is -N (c-Pr) {CH₂CH₂CN), R^4a is Cl, R^4bis H, R^4c is Me, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -NHCH (n-Pr) {CH₂OMe), R^4a is Me, R^4b is H, R^4C is OMe, R^4d are H and R⁴⁸ is H:

A compound of formula (51) wherein R³ is -NHCH (n-Pr) {CH₂OMe), R^4a is Cl, R^4bis H, R^4c is Me, R^4d are H and R⁴⁸ is H;

A compound of formula (51) wherein R³ is -NHCH (Et)₂, R^4a is Br, R^4b is H, R^4Cis OMe, R^4d are OMe and R^4e is H;

A compound of formula (51) wherein R³ is -NHCH (Et)₂, R^4a is Br, R^4b is H, R^4c is OMe, R^4d are H and R⁴⁸ is H;

A compound of formula (51) wherein R³ is -N (CH₂CH₂OMe)₂, R^4a is Br, R^4b is

H, R^4c is OMe, R^4d is H and R^4eis H;

A compound of formula (51) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is Br, R^4b is H, R^4c is OMe, R^4d are H and R⁴® is H;

A compound of formula (51) wherein R³ is -N (Et)₂, R^4a is Me, R^4b is H, R^4c is Ci, R^4d are H and R⁴® is H;

A compound of formula (51) wherein R³ is -N (Et)₂, R^4a is Cl, R^4b is H, R^4c is OMe, R^4d are OMe and R⁴® is H;

A compound of formula (51) wherein R³ is -NHCH (Et)₂, R^4a is Cl, R^4b is H, R^4Cis OMe, R^4d are OMe and R⁴® is H;

A compound of formula (51) wherein R³ is -N (CH₂OH₂OMe)₂, R^4a is Cl, R^4t) is H, R^4C is Cl, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -NHCH (CH₂OMe)₂, R^4a is Cl, R^4b is H, R^4C is Cl, R^4d are H and R⁴⁸ is H;

A compound of formula (51) wherein R³ is -N (Pr) {CH₂CH₂CN), R^4a is Cl, R^4b is H, R^4c is Ci, R^4d are H and R⁴® is H;

A compound of formula (51) wherein R³ is -N (Bu) (Et), R^4a is Ci, R^4b is H, R^4Cis Cl, R^4d are H and R⁴³ is H;

A compound of formula (51) wherein R³ is -NHCH (Et) CH₂OMe, R^4a is Cl, R^4b is H, R^4C is Ci, R^4d are H and R⁴® is H;

A compound of formula (51) wherein R³ is -NHCH (Et)₂, R^4a is Cl, R^4b is H, R⁴⁰is C), R^4d are H and R⁴® is H;

A compound of formula (51) wherein R³ is -NHCH (Et)₂, R^4a is Me, R^4b is H, R^4cis Me, R^4d are H and R⁴® is H;

A compound of formula (51) wherein R³ is -NHCH (Et)₂, R^4a is Cl, R^4b is H, R^4Cis Me, R^4d are H and R⁴® is H;

A compound of formula (51) wherein R³ is -NHCH (Et)₂, R^4a is Me, R^4b is H, R^4cis Cl, R^4d are H and R^4e is H;

A compound of formula (51) wherein R³ is -N (Et)₂, R^4a is Me, R^4b is H, R^4C is OMe, R^4d are H and R⁴® is H; and a compound of formula (51) wherein R³ is -N (Pr) {CH₂CH₂CN), R^4a is Me, R^4b is H, R^4c is OMe, R^4d are H and R⁴® is H.

[54] More specifically, 7- (3-pentylamino) -2,5-dimethyl-3- (2-methyl-4-methoxyphenyl) - [1,5-a-pyrazolopyrimidine, its isomers, stereoisomeric forms or mixtures of stereoisomeric forms and the pharmaceutically acceptable salts or prodrug forms thereof.

[55] More specifically, 7- (diethylamino) -2,5-dimethyl-3- (2-methyl-4-methoxyphenyl) - [1,5-a] -pyrazolopyrimidine, its isomers, its stereoisomeric forms or its stereoisomeric forms are more suitable. mixtures thereof and pharmaceutically acceptable salts or prodrug forms thereof.

[55] More specifically, 7- (N- (3-cyanopropyl) -N-propylamino-2,5-dimethyl-3- (2,4-dimethylphenyl) - [1,5-a-pyrazolopyrimidine, its isomers, its isomers are more suitable. stereoisomeric forms or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts or prodrug forms 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 (enantiomeric and diastereomeric) and racemic forms are within the scope of the present invention. The compounds may also contain many olefins, C = N double bonds and similar geometric isomers, and all such stable isomers are also encompassed by the present invention. Compounds of optically active or racemic forms may be isolated. Those skilled in the art will know how to make optically active forms, for example, by resolving racemic forms or synthesizing them from optically active starting materials. The invention encompasses all chiral (enantiomeric and diastereomeric) and racemic forms and all forms of geometric isomers of the structure unless specific stereochemistry or isomeric forms are indicated.

The term "alkyl" includes both branched and unbranched alkyl having the specified number of atoms. Commonly used abbreviations have the following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl.

The prefix 'n' refers to straight-chain alkyl. The prefix "c" represents cycloalkyl. The prefix (S) represents the S enantiomer, and the prefix (R) 'represents the R enantiomer. "Alkenyl" includes straight or branched hydrocarbon chains and one or more carbon-carbon unsaturated bonds which may be present at any stable position on the chain, such as ethenyl, propenyl and the like. "Alkynyl" includes straight or branched chain hydrocarbon chains and one or more carbon-carbon triple bonds which may be present at any stable position on the chain, such as ethynyl, propynyl and the like. "Haloalkyl" includes both branched and unbranched alkyl having the specified number of atoms substituted by 1 or more halogens; "Alkoxy" means an alkyl group of a specified number of carbon atoms attached through an oxygen bridge; "Cycloalkyl" includes saturated ring groups, Including mono-, bi- or polycyclic ring systems such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Hal "or halogen" includes fluorine, chlorine, bromine and iodine.

As used herein, the term "substituted" means that one or more hydrogens at the specified atom are substituted with one of the specified groups, provided that the normal valence of the indicated atom is not exceeded and that the substituted compound is stable. When the substituent is a keto group (ie = 0) then 2 hydrogens are substituted at the atom.

Combinations of substituents and / or variables are permissible only if they yield stable compounds. The term "stable compound or" stable structure "means a compound that is sufficiently resistant to isolation from the reaction mixture and purification to an appropriate degree of purity as well as conversion to an effective therapeutic agent.

The term "suitable amino acid protecting group" refers to any group known in the art of organic synthesis for the protection of an amino group or a carboxy group of this acid. Such amino-blocking groups include those listed by Greene and Wuts, "Protective Groups in Organic Synthesis" by John Wiley &amp; amp; Sons, New York (1991) and The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), which are cited as references. Any known amino-protecting group can be used. Examples of amino-protecting groups include, but are not limited to, the following: (1) acyl-type groups such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate type groups such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyl, 1- (p-biphenyl) -1-methylethoxycarbonyl and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate type groups such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl; 4) cyclic alkylcarbamate type groups such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;

5) alkyl type groups such as triphenylmethyl and benzyl; 6) trialkylsilanes such as trimethylsilane; and 7) thiol-containing groups such as phenylthiocarbonyl and dithiazuccinol.

The term "pharmaceutically acceptable salts" includes salts of the compounds of formulas (1) and (2) with acids or bases. Examples of pharmaceutically acceptable salts include, but are not limited to, basic residues such as amino groups, salts of mineral or organic acids; acidic residues such as carboxy groups, alkali metals or organic salts; and etc.

Pharmaceutically acceptable salts of the compounds of the present invention may be prepared by reacting the free acid or base forms of these compounds with stoichiometric amounts of the corresponding base or acid in water or in an organic solvent, or in a mixture thereof; non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are generally preferred.

A list of suitable salts can be found at Remington's Pharmaceutical Sciences,

17th ed., Mac Publishing Company, Easton, PA, 1985, p.1418, which is incorporated herein by reference. · '' Any covalently bonded carrier which delivers the active parent drug of formula (1) or (2) in inks is considered to be inactive. in vivo when administered to a mammal. Prodrugs of the compounds of formulas (1) and (2) are prepared by modifying the functional groups present in the compounds such that such modifications are cleaved either by conventional manipulation or in vivo to the parent compounds. Prodrugs include compounds wherein the hydroxyl, amino, or sulfhydryl groups are attached to a group such that when prodrugs are used by a mammal, they are cleaved to form the corresponding hydroxyl, amino, or sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of the alcohol and amino functional groups of the compounds of formulas (1) and (2); and etc.

The term therapeutically effective amount of a compound of the present invention refers to an amount that effectively antagonizes the abnormal amount of CRF or ameliorates symptoms of affective psychosis, anxiety, or depression in the subject.

Synthesis

Some of the compounds of formula (I) may be prepared from intermediates of formula (7) using the procedures outlined in Scheme 1:

scheme

<img file="LT4680B_D0021.tif" />

halogenating agent or sulfonylating agent +/- base, +/- solvent

<img file="LT4680B_D0022.tif" />

(8)

R³H, +/- base, +/- solvent - -. , - -, -, -. w

<img file="LT4680B_D0023.tif" />

Compounds of formula (7) (wherein Y is O) may be reacted with a halogenating agent or a sulfonylating agent, in the presence or absence of a base, in an inert solvent or solvent at a temperature of -80 to 250 ° C, to afford products of formula (8) halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkanesulfonyloxy). Halogenating agents include, but are not limited to, SOCIg, POCI₃, PCI₃, PCI₅, POBr₃, PBr₃ or PBr₅. Sulfonylating agents include (but are not limited to) alkansulfonrūgščių halides or anhydrides (such as methanesulfonic anhydride or metansuifoniichloridas) arilsulfonrūgščių halides or anhydrides (such as ptoluensulfonilchloridas or anhydride), or halides or anhydrides halogenalkilsulfonrūgščių (preferably trifluormetansulfonrūgšies anhydride). The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) , alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide) ), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes containing from 1 to 10 carbon atoms and from 1 to 10 halogen atoms (preferably dichloromethane). Suitable reaction temperatures are in the range of -20 to 100 ° C.

Compounds of formula (8) may be exposed to R³Of formula H (wherein R³ is as described for heights except that R³ is a SH, COR⁷, CO., LTD₂R⁷, aryl or heteroaryl) in the presence or absence of a base, in an inert solvent or solvent free at a temperature in the range of -80 to 250 ° C, to afford the products of formula (1). Bases can be (but. but not limited to) alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal acid carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably NN-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having from 1 to 10 carbon atoms and from 1 to 10 halogen atoms (preferably dichloromethane). Suitable reaction temperatures are in the range of 0 to 140 ° C.

schematically illustrates procedures for converting compounds of formula (7) (wherein Y is S) into some compounds of formula (1).

scheme

<img file="LT4680B_D0024.tif" />

Compounds of formula (7) (wherein Y is S) may be reacted with an alkylating agent R¹³X (where R¹³ is as described for heights except that R¹³ is aryl or heteroaryl) in the presence or absence of a base, in an inert solvent or solvent free at a temperature of -80 to 250 ° C. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) , alkali metal carbonates, alkali metal hydroxides, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine or trlethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having from 1 to 10 carbon atoms and from 1 to 10 halogen atoms (preferably dichloromethane). Suitable reaction temperatures are in the range of -80 to 100 ° C.

Thereafter, compounds of formula (12) wherein R³ is SR¹³) can be exposed to Rs³Compounds of formula H to give compounds of formula (1) using the same conditions and reagents used to convert compounds of formula (8) to compounds of formula (1) as described in Scheme 1 above. Alternatively, compounds of formula (12) wherein R³ is SR¹³) may be oxidized to form compounds of formula (13) wherein R³ is S (O) n R¹³ n is 1,2) under the action of an oxidizing agent in an inert solvent over a temperature range of -80 to 250 ° C. Oxidizing agents include, but are not limited to, hydrogen peroxide, alkanoic or aryl acid (preferably peroxyacetic acid or chlorobenzene peroxycarboxylic acid), dioxirane, oxone or sodium periodate. Inert solvents may include, but are not limited to, alkanones (3 to 10 carbon atoms, preferably acetone), water, alkyl alcohols (1 to 6 carbon atoms), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes containing 1 to 10 carbon atoms atoms and 1-10 halogen atoms (preferably dichloromethane), or combinations thereof. The principles of choice of oxidant and solvent are known to those skilled in the art. Uemura, S., Oxidation of Sulfur, Selenium and Tellurium, in Comprehensive Organic Synthesis, Trost, BM ed., (Elmsford, NY: Pergamon Press, 1991), 7, 762769). Suitable reaction temperatures are in the range of -20 to 100 ° C. Thereafter, compounds of formula (13) are compounds of formula (1) wherein R³ is S (O) n R¹³ n is 1,2) can be exposed to R³Compounds of formula H to give compounds of formula (1) using the same conditions and reagents used to convert compounds of formula (8) to compounds of formula (1) as described in Scheme 1 above.

Compounds of formula (1) wherein R³ may be -NR⁸COR⁷, -N (COR⁷) 2, -NR⁸CONR^SR⁷, -NR⁸CO2R¹³, -NR⁶R⁷, -NR⁸SO₂R⁷, may be prepared from compounds of formula (7) wherein Y is NH according to the procedures outlined in Scheme 3.

scheme

<img file="LT4680B_D0025.tif" />

alkylating, sulfonylating or acylating agents +/- base, solvent

<img file="LT4680B_D0026.tif" />

A = N;

R³ = NR⁶R⁷, NR³COR⁷, N (COR⁷) 2- NR³CONR⁵R⁷, NR³CO2R^!3 Reaction or stepwise reaction of compounds of formula (7) wherein Y is NH with alkylating agents, sulfonylating agents or acylating agents in the presence or absence of a base in an inert solvent at reaction temperatures in the range -80 to 250 ° C can be obtained (1). ) compounds of the formula wherein R³ may be -NR⁸COR⁷, -N (COR⁷) 2, -NR⁸CONR^sR⁷, -NR⁸CO2R¹³, -NR⁶R⁷, -NR⁸SO₂R⁷. Alkylating agents may include, but are not limited to, C 1 -C 10 alkyl halides, tosylates, methanesulfonates or triflates; C 1 -C 10 haloalkyl (1-10 halo halides, tosylates,

-methanesulfonates tosylates,

-methanesulfonates tosylates,

-methanesulfonates or triflates; C₄-C₁₂-cycloalkylalkyl-halides, tosylates, or triflates; aryl (Ci-C₄-alkyl) -halides or triflates; C₂-C8-alkoxyalkyl halides or triflates;

C3-C₆-cycloalkyl halides,

-methanesulfonates tosylates,

-methanesulfonates tosylates,

-methanesulfonates or triflates;

or -triflates; heteroaryl (C 1 -C 6)₄-alkyl) -halides, or heterocyclyl (C 1 -C₄-alkyl) -halides,-tosylates, -methanesulfonates or triflates. Acylating agents may include, but are not limited to, Ci-Ci₀-alkanoyl halides or anhydrides, C 1 -C 10 haloalkanoyl halides or anhydrides with 1-10 halogen atoms, C₂-C 8 alkoxyalkanoyl halides or anhydrides, C₃-C_s-cycloalkanoyl halides or anhydrides, C₄-Ci₂-cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl (Ci-C)₄) alkanoyl halides or anhydrides, heteroaryl halides or anhydrides, heteroaryl (CiC)₄) alkanoyl halides or anhydrides, halides or anhydrides of heterocyclylcarboxylic acids or heterocyclyl (C1-C)₄) alkanoyl halides or anhydrides. Sulfonimine agents include, but are not limited to, CrC₁₀alkylsulfonyl halides or anhydrides, C 1 -C 10 haloalkylsulfonyl halides or anhydrides with 1 to 10 halogen atoms, C₂-C₈-alkoxyalkylsulfonyl halides or anhydrides, C 5 -C 6 -cycloalkylsulfonyl halides or anhydrides, C₄-Ci₂cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl (C₁-C₄) alkyl, heteroarylsulfonyl halides or anhydrides, heteroaryl (C 1 -C₄-alkyl) sulfonyl halides or anhydrides, heterocyclylsulfonyl halides or anhydrides or heterocycles (C₁-C₄-alkii) 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 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) , alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures are the procedures outlined in the scheme 0-100 ° C which may be used for intermediates of formula (7) wherein Y is O, S and Z is CR², made.

<img file="LT4680B_D0027.tif" />

scheme

ArCH₂CN

R²COR^b, base, solvent

NH₂NH₂ - h₂o, the solvent

Ar

<img file="LT4680B_D0028.tif" />

(7) Y = O, S; Z = CR²

ArCH₂Compounds of formula CN are exposed to R²COR^b compounds of the formula wherein R² is as described above and R^b is halogen, cyano, lower alkyl (1 to 6 carbon atoms) or lower alkanoyloxy (1 to 6 carbon atoms), in the presence of a base, in an inert solvent, at reaction temperatures in the range of -78 to 200 ° C, and afforded by formula (3) compounds. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) , alkali metal carbonates, alkali metal hydroxides, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Suitable reaction temperatures are 0-100 ° C.

Compounds of formula (3) may be treated with hydrazine hydrate in an inert solvent at a temperature of 0 to 200 ° C, preferably at a temperature of 70 to 150 ° C, to give compounds of formula (4). Inert solvents include, but are not limited to, water, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4- dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Compounds of formula (4) may be treated with compounds of formula (5) (wherein R^c is alkyl (1-6 carbon atoms)) in the presence or absence of an acid in an inert solvent at a temperature in the range of 0 to 200 ° C to give compounds of formula (6). The acids may include, but are not limited to, alkanoic acids having from 2 to 10 carbon atoms (preferably acetic acid), haloalkanoic acids (2-10 carbon atoms, 1-10 halogen atoms such as trifluoroacetic acid), arylsulfonic acids (preferably p-). toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids having from 1 to 10 carbon atoms (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, water, alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), halocarbons having 1 to 6 carbon atoms and 1 to 6 halogen atoms (preferably dichloromethane or chloroform), alkyl alcohols having 1 to 6 carbon atoms. 10 carbon atoms (preferably ethanol), dialkyl ethers (4-12 carbon atoms, preferably diethyl ether or diisopropyl ether) or cyclic ethers such as dioxane or tetrahydrofuran. The most suitable temperature range is from room temperature to 100 ° C.

Compounds of formula (6) can be converted to intermediates of formula (7) by C = Y (R^d)₂ compounds of the formula (wherein Y is O or S and R^d is halogen (preferably chlorine), alkoxy (1-4 carbon atoms) or alkylthio (1-4 carbon atoms), in the presence or absence of a base, in an inert solvent at reaction temperatures ranging from -50 to 200 ° C. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal carbonates, alkali metal hydroxides, trialkylamines (preferably N, N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane). , Ν, Ν-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Suitable reaction temperatures are 0-150 ° C.

Intermediates of formula (7) wherein Z is N may be synthesized according to the methods outlined in Scheme 5.

scheme

ArCH₂CN

R^c'CH₂N₃, base solvent

<img file="LT4680B_D0029.tif" />

NH reducing agent, solvent

<img file="LT4680B_D0030.tif" />

(10)

R¹ (5) OR = +/- acid, solvent

<img file="LT4680B_D0031.tif" />

Y = C (R^d)₂, base, solvent

<img file="LT4680B_D0032.tif" />

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

ArCH₂CN exposed R^qCH₂Compounds of the formula CN (in which R^q is a phenyl group optionally substituted with H, alkyl (1-6 carbon atoms) or alkoxy (1-6 carbon atoms), in the presence or absence of a base, in an inert solvent at a temperature of 0 to 200 ° C to give (9) compounds. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide, sodium ethoxide or potassium t-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonate, alkali metal hydroxides, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Suitable reaction temperatures range from room temperature to 100 ° C.

Compounds of formula (9) may be treated with a reducing agent in an inert solvent at -100 ° C to 100 ° C to give products of formula (10). Reducing agents may include, but are not limited to: (a) hydrogen gas together with noble metal catalysts such as Pd / C, PtO₂, Pt / C, Rh / AI₂O₃or Renee 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 8 carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers. (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Suitable reaction temperatures are from -50 ° C to 60 ° C. The compounds of formula (9) are then converted to the compounds of formula (7) (wherein Z is N) via the intermediates of formula (11) using the reagents and reaction conditions shown in Scheme 4 to convert the compounds of formula (4) to in which Giraffe CR²).

Compounds of formula (1) may also be prepared from compounds of formula (7) (wherein Y is O, S and Z is as described above) according to Scheme 6.

scheme

HN N _K\

Λ, N

R¹

<img file="LT4680B_D0033.tif" />

Z

Ar (7) Y = O, S; Z = N, CR²

R³H, +/- acid, +/- dehydration agent +/- solvent

<img file="LT4680B_D0034.tif" />

Z (1) A = N

Can compounds of formula (7) be exposed to R³Compounds of formula H in the presence of a dehydrating agent in an inert solvent at a temperature in the range of 0 to 250 ° C. Dehydration agents include, but are not limited to, P₂O₅, molecular grids, and inorganic or organic acids. The acids may include, but are not limited to, alkanoic acids having from 2 to 10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids containing from 1 to 10 carbon atoms (preferably methanesulfonic acid), , sulfuric acid or phosphoric acid. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably glim or diglyme), 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), dialkylsulfoxide: (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or halocarbons having from 1 to 10 carbon atoms and from 1 to 10 halogen atoms (preferably chloroform). The preferred temperature range is from room temperature to 150 ° C.

Some compounds of formula (I) (wherein A is N) may also be prepared by the methods shown in Scheme 7:

scheme

<img file="LT4680B_D0035.tif" />

R³C (OR^e)₃, +/- acid, solvent

<img file="LT4680B_D0036.tif" />

Intermediates of formula (14) wherein Z is as defined above may be exposed to R³C (OR^e)₃ compounds of the formula wherein R^e may be alkyl (1-6 carbon atoms), in the presence or absence of an acid, in an inert solvent at a temperature in the range of 0 to 250 ° C. The acids may include, but are not limited to, alkanoic acids having from 2 to 10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids having 1-10 carbon atoms (preferably methanesulfonic acid), , sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents include, but are not limited to, lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides ( preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes containing from 1 to 10 carbon atoms and from 1 to 10 halogen atoms (preferably dichloromethane). The preferred temperature range is from 50 ° C to 150 ° C.

The intermediates of formula (7) may also be synthesized according to the reactions shown in Scheme 8.

scheme

<img file="LT4680B_D0037.tif" />

ArM, + / - catalyst, solvent (15) Y = OH, SH, NR^SR⁷: Z = N, CR²,

X = Br, Cl, I, B {OR;

<img file="LT4680B_D0038.tif" />

Compounds of formula (15) (wherein Y is OH, SH, NR⁶R⁷; Z is as defined above, X is Br, Ci, I, O₃SCF₃ or B (OR "")₂, and R '' is H or alkyl (1-6 carbon atoms)) can be treated with a compound of formula ArM (wherein M is halogen, alkali metal, ZnCl, Znl, MgBr, MgCl, Mgl, CeCl_2lCeBr₂ or copper halides) in the presence or absence of an organometallic catalyst, in the presence or absence of a base, in inert solvents at a temperature in the range of -100 to 200 ° C. It will be apparent to those skilled in the art that ArM reagents may be prepared in situ. Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd (PPh₃)₄), palladium halides or alkanoates (such as PdCI₂(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 trialkylamines (preferably N, N-diisopropyl-N-ethylamine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. The preferred temperature range is -80 ° C to 100 ° C. The choice of M and X is known to those skilled in the art (see Imamoto, T., Organocerium Reagents in Comprehensive Organic Svnthesis, Trost, BM ed., (Elmsford, NY: Pergamon Press, 1991), 1, 231-250; Knochel, P., Organozinc, Organocadmium and Organomercury Reagents in Comprehensive Organic Svnthesis, Trost, BM ed., (Elmsford,

NY: Pergamon Press, 1991), 1, 211-230; Knight, DW, Coupling Reactions between sp² Carbon Centers, in Comprehensive Organic Synthesis, Trost, BM ed., (Elmsford, NY: Pergamon Press, 1991), 3, 481-520.

Compounds of formula (1) may also be prepared using the methods shown in Scheme 9.

scheme

<img file="LT4680B_D0039.tif" />

ArM, +/- catalyst, solvent (16) Y = Br, Cl, I;

B (OR)₂, o₃scf₃

<img file="LT4680B_D0040.tif" />

Compounds of formula (16) wherein A, Z, R¹ and R² are as defined above, and X is Br, Cl, I, O3SCF3 or B (OR^!'') 2 and R '' being H or alkyl (1-6 carbon atoms)) can be treated with a compound of formula ArM (wherein M is halogen, alkali metal, ZnCl, Znl, MgBr, MgCl, Mgl, CeCl₂, CeBr₂ or copper halides) in the presence or absence of an organometallic catalyst, in the presence or absence of a base, in inert solvents at a temperature in the range of -100 to 200 ° C. It will be apparent to those skilled in the art that ArM reagents may be prepared in situ. (see Comprehensive Organic Synthesis references above). Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd (PPh₃)₄), palladium halides or alkanoates (such as PdCI₂(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 trialkylamines (preferably N, N-diisopropyl-Nethylamine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide). ), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. The preferred temperature range is -80 ° C to 100 ° C.

Intermediates of formula (7) (wherein Y is O, S, NH, Z are CR)² o R¹, R² and Ar are described above) can be prepared as shown in Scheme 10.

scheme

<img file="LT4680B_D0041.tif" />

Compounds of formula (3) may be exposed to H₂NNH (C = Y) NH₂ Compounds of formula (I) wherein Y is O, S or NH, in the presence or absence of a base or acid, in an inert solvent at a temperature in the range of 0 to 250 ° C, to afford compounds of formula (17). The acids may include, but are not limited to, alkanoic acids having from 2 to 10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids having from 1 to 10 carbon atoms (preferably methanesulfonic 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 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dicylamides (preferably lithium diisopropylamide) , alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl polyhydric alcohols (1 to 6 carbon atoms), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4). -dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having from 1 to 10 carbon atoms and from 1 to 10 halogen atoms (preferably dichloromethane). Suitable reaction temperatures are in the range of 0-150 ° C.

The compounds of formula (17) may then be exposed to R³C (OR^e)₃ compounds of the formula wherein R^e may be alkyl (1-6 carbon atoms), in the presence or absence of an acid, in an inert solvent at a temperature in the range of 0 to 250 ° C. The acids may include, but are not limited to, alkanoic acids having from 2 to 10 carbon atoms (preferably acetic acid), arylsulfonic acids (preferably ptoluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids having from 1 to 10 carbon atoms (preferably methanesulfonic 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 alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N, N-dialkylformamides ( preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes containing from 1 to 10 carbon atoms and from 1 to 10 halogen atoms (preferably dichloromethane). The preferred temperature range is from 50 ° C to 150 ° C.

Scheme I depicts the procedures that can be used for compounds of formula (1) wherein R³ is a COR⁷, CO2R⁷, NR⁸COR⁷ and CONR⁵R⁷, convert to other compounds of formula (1) wherein R³ is CH (OH) R⁷, CH2OH,

NR⁸CH2R⁷ and CH2NR⁶R⁷, acting as a reducing agent in an inert solvent over a temperature range of -80 to 250 ° C.

scheme

R³

R³

R¹ mN ^N NN

<img file="LT4680B_D0042.tif" />

X reducing agent, solvent (1

R³ = COR⁷, CO., LTD₂R⁷, CONR⁶R⁷

Is (1) R³= C (OH) R⁷, CH₂OH, CH₂NR^sR⁷

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

Scheme I depicts the procedures that can be used for compounds of formula (1) wherein R³ is a COR⁷ a^rba CO2R⁷ to other compounds of formula (I) wherein R³ is CH (OH) {R⁷) 2 while operating at Rs⁷Formula M reagent in an inert solvent at a temperature in the range of -80 to 250 ° C.

scheme

<img file="LT4680B_D0043.tif" />

reducing agent, solvent

<img file="LT4680B_D0044.tif" />

(1) R³ = COR⁷, CO., LTD₂R⁷ (1) R³ = C (OH) (R⁷)₂

M is halogen, alkali metal, ZnCI, Znl, MgBr, MgCl, Mgl, 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). Suitable reaction temperatures are -80 ° C to 100 ° C.

Compounds of formula (1) wherein R³ may be -NR⁸COR⁷, -N (COR⁷) 2, NR⁸CONR⁶R⁷, -NR⁸CO2R¹³, -NR^sR⁷, Scheme 13.

NR⁸SO₂R⁷, can be synthesized by

<img file="LT4680B_D0045.tif" />

<img file="LT4680B_D0046.tif" />

(10) Z = N

<img file="LT4680B_D0047.tif" />

alkylating, sulfonylating or acylating agents +/- base, solvent

<img file="LT4680B_D0048.tif" />

A = CR;

R³ = no⁵r⁷, NR⁸COR⁷,

N (COR⁷) 2 'NR⁸CONR⁶R⁷, NR⁸CO2R¹³ Compounds of formula (18) wherein R and R¹ as described above, reaction with compounds of formula (4) or (10), in the presence or absence of a base, in an inert solvent may yield compounds of formula (19) at a temperature in the range -50 to 250 ° C. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di- isopropylamide), alkali metal carbonates, alkali metal bis (triaxylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulphoxides (preferably dimethyl sulphoxide) or aromatic hydrocarbons (preferably benzene or toluene). Suitable reaction temperatures are 0-100 ° C.

The compounds of formula (19) may then be reacted with alkylating agents, sulfonimine agents or acylating agents, or may be carried out stepwise with or without combinations thereof, in an inert solvent at reaction temperatures in the range of -80 to 250 ° C, and may be obtained (1). ) in which R³ may be -NR⁸COR⁷, -N (COR⁷) 2, NR⁸CONR⁶R⁷, -NR⁸CO2R¹³, -NR⁶R⁷, .- NR⁸SO2R⁷. Alkylating agents may include, but are not limited to, C 1 -C 10 alkyl halides, -tosylates, methanesulfonates or triflates; Ci-C₁₀-haloalkyl (1-10 halogens) -halides,-tosylates, -methanesulfonates or triflates; C₂-C₈-alkoxyalkyl halides, tosylates,

-methanesulfonates or triflates; C3-C₆-cycloalkyl halides, tosylates,

<td>-methanesulfonates</td><td>or</td><td>-triflates;</td><td>C₄-Ci₂-cycloalkylalkyl-halides</td>

<td>tozias,</td><td></td><td></td><td></td>

<td>-methanesulfonates</td><td>or</td><td>-triflates;</td><td>aryl (C₁-C₄-alkyl) -halides,</td>

<td>tozias,</td><td></td><td></td><td></td>

<td>-methanesulfonates</td><td>or</td><td>-triflates;</td><td>heteroaryl (C 1 -C 6)₄-alkyl) -halides,</td>

tozias,

-methanesulfonates or triflates; or heterocyclyl (C 1 -C₄-alkyl) -halogenides, thiosiates, -methanesulfonates or triflates. Acylating agents may include, but are not limited to, Ci-Ci₀-alkanoyl halides or anhydrides, C1-C₁₀haloalkanoyl halides or anhydrides with 1 to 10 halogen atoms, C₂-C₈alkoxyalkanoyl halides or anhydrides, C3-C₆-cycloalkanoyl halides or anhydrides, C₄-Ci₂-cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl (C 1 -C₄) alkanoyl halides or anhydrides, heteroaryl halides or anhydrides, heteroaryl (CiC)₄) alkanoyl halides or anhydrides, halides or anhydrides of heterocyclylcarboxylic acids or heterocyclyl (C1-C)₄) alkanoyl halides or anhydrides. Sulfonylating agents include, but are not limited to, C 1 -C 10 alkylsulfonyl halides or anhydrides, C 1 -C 10 haloalkylsulfonyl halides or anhydrides with 1 to 10 halogen atoms, C₂-C₈-alkoxyalkylsulfonyl halides or anhydrides, C3-C₆-cycloalkylsulfonyl halides or anhydrides, C₄-Ci₂cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl (C, -C₄) alkyl-, heteroarylsulphonyl halides or anhydrides, heteroarylC 1 -C 6 -alkylsulphonyl halides or anhydrides, heterocyclylsulphonyl halides or anhydrides or heterocyclyl (C 1 -C 8)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 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide) , alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran) or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Suitable reaction temperatures are 0-100 ° C.

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

scheme

<img file="LT4680B_D0049.tif" />

(20) +/- base, solvent

<img file="LT4680B_D0050.tif" />

A

<img file="LT4680B_D0051.tif" />

(4) Z = CR₂(10) Z = N

<img file="LT4680B_D0052.tif" />

R³H, +/- base, +/- solvent

<img file="LT4680B_D0053.tif" />

halogenating agent or sulfonylating agent +/- base, +/- solvent

<img file="LT4680B_D0054.tif" />

Compounds of formula (4) or (10) may be treated with compounds of formula (20) wherein R¹ and R³ are as described above, in the presence or absence of a base, in an inert solvent at a temperature in the range of 0 to 250 ° C to give compounds of formula (I) 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 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di- isopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pyridine). inert solvents include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Suitable reaction temperatures are 0-100 ° C. Alternatively, compounds of formula (1) wherein A is CR and R is as described above may be synthesized via intermediates (22) and (23).

Compounds of formula (4) or (10) may be treated with compounds of formula (21) wherein R¹ is as described above, and R® is alkyl (1-6 carbon atoms), in the presence or absence of a base, in an inert solvent at a temperature in the range of 0-250 ° C to afford compounds of formula (1) wherein A is CR and R is as described above. . The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di- isopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Suitable reaction temperatures are 0-100 ° C. Compounds of formula (22) may be treated with a halogenating or sulfonylating agent, in the presence or absence of a base, in an inert solvent or solvent-free at a temperature range of -80 to 250 ° C to afford products of formula 23 (wherein X is halogen, alkanesulfonyloxy, or halosulfonyloxy). Halogenating agents include, but are not limited to, SOCI₂, POCI₃, PCI₃, 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 anhydride. The bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di- isopropylamide), alkali metal carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably NN-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, ialdialkylformamides (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 containing from 1 to 10 carbon atoms and from 1 to 10 halogen atoms (preferably dichloromethane). Suitable reaction temperatures are -20 to 100 ° C. Compounds of formula (23) may be exposed to R³Compounds of formula H (wherein R³ is as described above except that R³ cannot be SH, COR⁷, CO., LTD₂R⁷, aryl or heteroaryl) in the presence or absence of a base in an inert solvent or solvent at a temperature of -80 to 250 ° C to give 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 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di- isopropylamide), alkali metal carbonates, alkali metal acid carbonates, alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably diisopropylethylamine) or aromatic amines (preferably pyridine). inert solvents include, but are not limited to, alkyl alcohols (1 to 8 carbon atoms, preferably methanol or ethanol), lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides (preferably dimethylformamide), Ν, Ν-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkyl sulfoxides (preferably dimethyl sulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes having from 1 to 10 carbon atoms and from 1 to 10 halogen atoms (preferably dichloromethane). Suitable reaction temperatures are 0-140 ° C.

Some of the compounds of formula (I) may also be prepared by the methods shown in Scheme 15.

scheme

<img file="LT4680B_D0055.tif" />

Compound of Formula (24) (R^c is a lower alkyl group, and Ar is as described above) may be treated with hydrazine in an inert solvent or solvent free to give an intermediate of formula (25) wherein Ar is as described above Using similar reaction conditions as in Scheme 4 (4) for the preparation of an intermediate of the compound of formula (3). Compounds of formula (25) wherein A is N may be exposed to R¹C (= NH) OR^ewith the reagents of the formula wherein R¹ is described above while R⁹ is a lower alkyl group, in the presence or absence of an acid, in an inert solvent and then subjected to Y = C (R^a)₂ of the formula wherein Y is O or S and R 'is halogen (preferably chlorine), alkoxy (1-4 carbon atoms) or alkylthio (1-4 carbon atoms), in the presence or absence of a base, in an inert solvent and afforded (27). ) (wherein A is N and Y is O, S).

These transformations use the same conditions as for converting the compound of formula (4) shown in Scheme 4 to the compound of formula (7).

Alternatively, compounds of formula (25) wherein A is CR may be exposed to R¹(C = O) CHR (C = Y) OR^C compounds of the formula (wherein R¹ and R are as described above and R^c is a lower alkyl group) to give compounds of formula (27) (wherein A is CR) using similar reaction conditions as in Scheme 14 to convert compounds of formula (21) to compounds of formula (22). The intermediates of formula (27) (wherein Y is O) may be reacted with a halogenating agent or a sulfonylating agent, in the presence or absence of a base, in an inert solvent, and then exposed to R³H or R²H, in the presence or absence of a base, in an inert solvent to give compounds of formula (1) (wherein Z is CR²).

The skilled artisan will appreciate that various halogenating, sulfonylating agents, R³H or R²H combinations in various order of reaction sequences. For example, in some cases it may be desirable to effect the compounds of formula (1) on stoichiometric amounts of halogenating or sulfonylating agents,²H (or R³H), then repeat the reaction with halogenating agents or sulfonylating agents and act on R³H (or R²H). Reaction conditions and reagents to effect these conversions are similar to those used in Scheme 14 for converting intermediates of formula (22) to compounds of formula (23), followed by compounds of formula (1) (when A is CR), or those used in Scheme 1. converting intermediates of formula (7) into compounds of formula (8) followed by compounds of formula (I) (when A is N).

Alternatively, compounds of formula (27) (wherein Y is S) may be converted to compounds of formula (I) shown in Scheme 15. Intermediates of formula (27) may be alkylated with R^fX (where R^f is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent (which may then be oxidized by an oxidizing agent in an inert solvent), and then exposed to R³H, in the presence or absence of a base, in an inert solvent to give compounds of formula (1). The conditions and reagents used are similar to those of Scheme 2 for the conversion of intermediates of formula (7) to compounds of formula (12) (or j 13), followed by conversion to compounds of formula (1).

Compounds of formula (1) may be prepared from compounds of formula (24) using another route shown in Scheme 15. Compounds of formula (24) can be converted to compounds of formula (27) by interaction with NH₂NH (C = NH) NH₂compounds of formula I, in the presence or absence of an acid, in an inert solvent, followed by treatment with R¹C (OR^c)₃ compounds of the formula (wherein R^c is lower alkyl, and R¹ is as described above) using the same conditions as in Scheme 10 for converting compounds of formula (3) into compounds of formula (17) followed by conversion to compounds of formula (7).

Some of the compounds of formula (2) may be prepared by the methods outlined in Scheme 16.

scheme

<img file="LT4680B_D0056.tif" />

<img file="LT4680B_D0057.tif" />

see text

<img file="LT4680B_D0058.tif" />

(1) Z = COH

T

<img file="LT4680B_D0059.tif" />

Compounds of formula (27b) may be exposed to various alkylating agents

R¹⁴X (where R¹⁴ is as defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to give compounds of formula (28). The compounds of formula (28) (Y = O) can then be converted to the compounds of formula (2) by treatment with halogenating or sulfonylating agents, in the presence or absence of a base, in an inert solvent, and then R³H, in the presence or absence of a base, in an inert solvent to give compounds of formula (2). The reaction conditions used in these conversions are similar to those used in Scheme 1 for the conversion of intermediates (22) into j (23) followed by j (1) (when A is CR), or the conditions used in Scheme 1 for the conversion of intermediates (7) into (8) then to (1) (when A is N), Alternatively, compounds of formula (28) (Y is S) may be alkylated with R^fX (where R^f is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent (then oxidized, if necessary, with an oxidizing agent in an inert solvent), and then exposed to R³H, in the presence or absence of a base, in an inert solvent to give compounds of formula (1). The reaction conditions and reagents are similar to the conditions and reagents used in Scheme 2 for converting intermediates of formula (7) into (12) (or into (13)) followed by compounds of formula (1).

Compounds of formula (1) wherein Z is COH can be converted to compounds of formula (2) as shown in Scheme 16. By the action of various alkylating agents R¹⁴X (where R¹⁴ is as described above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to give compounds of formula (2). It will be apparent to those skilled in the art that the methods used in Scheme 16 may also be used for compounds wherein Z is COR⁷, get it.

the terms base and inert solvent used in the scheme 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 carbon atoms) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di) -isopropylamide), alkali metal bis (trialkylsilyl) amides (preferably sodium bis (trimethylsilyl) amide), trialkylamines (preferably N, N-diisopropyl-N-ethylamine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanonitriles (1 to 6 carbon atoms, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), Ν, Ν-dialkylformamides ( preferably dimethylformamide), N, N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxide! (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes containing from 1 to 10 carbon atoms and from 1 to 10 halogen atoms (preferably dichloromethane). Suitable reaction temperatures are in the range of -20 to 100 ° C.

EXAMPLES

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

Reagents were obtained from commercial sources and, if necessary, purified prior to use according to Conventional Methods described by D. Perrin and WLF Armarego, Purification of Laboratory Chemicals, 3rd ed. (New York: Pergamon Press, 1988). Chromatography was performed on silica gel using the following solvent systems. Volume ratios given for solvent mixtures. Alternatively, the parts or percentages are by weight or percent by weight.

The following examples are intended to illustrate the invention in more detail. The following examples, which illustrate the best embodiment of the invention, are provided by way of illustration and are not intended to limit the invention.

example

Preparation of 2,7-Dimethyl-8- (2,4-dimethylphenyl) [1,5-a] -pyrazolo- [1,3,5] -triazin-4 (3H) -one Formula f7 wherein Y is O, R¹ is CH₃, Z is C-CH₃, Is 2,4-dimethylphenyl)

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

Sodium beads (9.8 g, 0.43 mol) were added portionwise to a solution of 2,4-dimethylphenylacetonitrile (48 g, 0.33 mol) in ethyl acetate (150 mL) at room temperature. The reaction mixture was refluxed and stirred for 16 hours. The resulting suspension is cooled to room temperature and filtered. The collected precipitate is washed with a large amount of ether and air dried. This solid was dissolved in water and treated with 1N HCl solution to pH = 5-6. The mixture was extracted with ethyl acetate (3 x 200 mL): the combined organic layers were dried over MgSO 4₄ and filtered off. Evaporation of the solvents in vacuo afforded a white solid (45.7 g, 74% yield): NMR (CDCl3, 300 MHz):

: CI-MS: 188 (M + H).

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

1-Cyano-1- (2,4-dimethylphenyl) propan-2-one (43.8 g, 0.23 mol), hydrazine hydrate (22 mL, 0.46 mol), glacial acetic acid (45 mL, 0, 78 mol) and toluene (500 ml) were stirred and refluxed for 18 hours. in a device with a Dino-Stark trap. The reaction mixture was cooled to room temperature and the solvent was evaporated in vacuo. The residue is dissolved in 6N HCl and the resulting solution is extracted three times with ether. Concentrated ammonium hydroxide was added to the aqueous layer until pH = 11. The resulting semi-solution was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO 4₄ and filtered off. The solvent was evaporated in vacuo to give a light brown viscous oil (34.6 g, 75% yield): NMR (CDCl₃, 300 MHz): 7.10 (s, 1H), 7.05 (d, 2H, J = 1), 2.37 (s, 3H), 2.10 (s, 3H); CI-MS: 202 (M + H).

C. Acetic acid salt of 5-acetamidino-4- (2,4-dimethylphenyl) -3-methylpyrazole

Ethylacetamidate hydrochloride (60 g, 0.48 mol) was added to a rapidly stirred 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 MgSO 4₄ and filtered off. The solvent is usually distilled off and the remaining flask residue (clear yellow liquid) (35.0 g) is used without further purification.

Glacial acetic acid was added to a stirred mixture of 5-amino-4- (2,4-dimethylphenyl) -3-methylpyrazole (34 g, 0.17 mol), ethyl acetate (22 g, 0.25 mL) and acetonitrile (500 mL). (9.7 mL, 0.17 mol). The resulting reaction mixture was stirred at room temperature for 3 days, then concentrated in vacuo to about one third of its initial volume. The resulting suspension is filtered and the collected solid is washed with a large amount of ether. The white solid was dried in vacuo (31.4 g, 61% yield): NMR (DMSO-dg, 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) - 1,5,5-α1-pyrazolo-n, 3,51-triazin-4 (3H) -one

Sodium beads (23 g, 1 mol) were added portionwise to ethanol (500 mL) with vigorous stirring. When all the sodium has reacted, 5-acetamidine-4- (2,4-dimethylphenyl) -3-methylpyrazole is added. ' acetic acid salts (31.2 g, 0.1 mol) and diethyl carbonate (97 ml, 0.8 mol). The resulting reaction mixture was refluxed and stirred for 18 hours. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. The residue was dissolved in water, and 1N HCl solution was added slowly to pH = 5-6. The aqueous layer was extracted with ethyl acetate three times; the combined organic layers were dried over MgSO4₄ and filtered off. Evaporation of the solvents in vacuo gave a tan solid (26 g, 98% yield): NMR (CDCl_3l 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

Preparation of 5-Methyl-3- (2,4,6-trimethylphenyl) [1,5-a] - [1,2,3] -triazolo [1,3,5] triazin-7 (6H) -one ( Formula 7 wherein Y is O, R¹ 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 room temperature for 2.5 days. The resulting suspension was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO 4₄ and filtered off. Evaporation of the solvent in vacuo gives a brown oil. Trituration with ether and filtration gave a yellow solid (1.12 g, 61% yield): NMR (GDCI₃, 300 MHz): 7.607.30 (m, 5H), 7.30-7.20 (m, 2H), 5.50 (s, 2H), 3.18 (s, 2H), 2.30 (s, 3H),

2.10 (s, 6H); CI-MS: 293 (M + H) @ +.

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

To a stirred mixture of liquid ammonia (30 mL) and 1-phenylmethyl-4- (2,4,6-trimethylphenyl) -5-aminotriazole (1.1 g, 3.8 mmol) was added sodium (500 mg, 22 mmol). The reaction mixture is stirred until dark green. Ammonium chloride solution was added and the mixture was stirred at room temperature for 16 hours. The residue is taken up in 1M HCl solution and filtered. The aqueous layer was basified with concentrated ammonium hydroxide solution (pH = 9), then extracted three times with ethyl acetate. The combined organic layers were dried over MgSO 4₄ and filtered off. Evaporation of the solvent in vacuo gave a yellow solid (520 mg) which was homogeneous by TLC (ethyl acetate); NMR (CDCl₃, 300 MHz): 6.97 (s, 2H), 3.68-3.50 (ss, 2H), 2.32 (s, 3H), 2.10 (s, 6H); CI-MS: 203 (M + H).

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

A mixture of 4- (2,4,6-trimethylphenyl) -5-aminotriazole (400 mg, 1.98 mmol), ethyl acetate (261 mg, 3 mmol) and glacial acetic acid (0.1 mL, 1.98 mmol) in acetonitrile (6 mL) was stirred at room temperature for 4 h. The resulting suspension is filtered and the collected solid is washed with a large amount of ether. Vacuum drying afforded a white solid (490 mg, 82% yield): NMR (DMSO-d₆, 300 MHz): 7.90-7.70 (ss, 0.5H), 7.50-7.20 (ss, 0.5H), 6.90 (s, 2H), 3, 50-3.10 (m.s, 3H), 2.30-2.20 (m.s, 3H), 2.05 (d, 1H, J = 7), 1.96 (s, 6H) 1.87 (s, 6H); CI-MS: 244 (M + H) @ +.

D. 5-Methyl-3- (2,4,6-trimethylphenyl) r, 5-a1-r1, 2,31-triazolo- [1,3,51-triazin-7 (4H) -one

Sodium (368 mg, 16.2 mmol) was added to ethanol (10 mL) with stirring at room temperature. When the sodium reacts, 4- (2,4,6-trimethylphenyl) 5-acetamidinotriazole acetic acid salt (490 mg, 1.6 mmol) and diethyl carbonate (1.6 mL, 13 mmol) are added. The reaction mixture was refluxed and stirred for 5 hours and then cooled to room temperature. The mixture was diluted with water, made up to pH 5-6 with 1N HCl and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO 4₄ and filtered off. Evaporation of the solvent in vacuo gives a yellow residue. Trituration with ether and filtration afforded a yellow solid (300 mg, 69% yield): NMR (CDCl3, 300 MHz): 6.98 (s, 2H), 2.55 (s, 3H), 2.35 (s) , 3H), 2.10 (s, 6H); CI-MS: 270 (M + H).

example

Preparation of 4- (Di (carbomethoxy) methyl) -2,7-dimethyl-8- (2,4-dimethylphenyl) [1,5-a] -pyrazolo-1,3,5-triazine (Formula 1 wherein P³ is CH (CHCO2CH3) 2, P¹ is CH 3, Z is C-CH₃, Is 2,4-dimethylphenyl)

A. 4-Chloro-2,7-dimethyl-8- (2,4-dichlorophenyl) F1,5-al-pyrazolotriazine

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) A mixture of N, N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) was stirred and refluxed for 48 h. Excess phosphorus oxychloride is removed in vacuo. The residue is taken up in an ice-water mixture, stirred briefly and extracted three times with ethyl acetate. The combined organic layers were washed with ice water and then dried over MgSO4₄ and filtered off. Evaporation of the solvent in vacuo yields a brown oil. Flash column chromatography (ethyl acetate: hexanes - 1: 4) yields one fraction (R_f = 0.5). Evaporation of the solvents in vacuo gave 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-al-pyrazolo-1,3,5-triazine

Sodium hydride (60% in oil, 80 mg, 2 mmol) was washed twice with hexanes, decanted after each wash and added to anhydrous tetrahydrofuran (THF, 1 mL). A solution of diethyl malonate (0.32 g, 2 mmol) in THF (2 mL) was added dropwise over 5 minutes; there is a significant difference in gas during drip. 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 stirred. stirred under nitrogen for 48 hours. The resulting suspension is poured into water and extracted three times with ethyl acetate. The combined organic layers were washed once with saturated NaCl solution, dried over MgSO4₄ and filtered off. Evaporation of the solvent in vacuo gives a brown oil. Column chromatography (ethyl acetate: hexanes = 1: 9) and evaporation of the solvent in vacuo gave a yellowish solid (Rf = 0.2, 250 mg, 35% yield): m.p. mp: 50-52 ° C; NMR (CDCl₃, 300 MHz): 12.35 (ss, 1H), 7.15-7.00 (m, 3H), 4.40 (kv,

2H, J = 7), 4.30 (s, 2H, J = 7), 2.4, 2.35, 2.3, 2.2, 2.1 (5s, 12H), 1.4 (t , 3H, J = 7), 1.35-1.25 (m, 3H); CI-ASGMS: Calculated: 411.2032; found: 411.2023.

example

Preparation of 4- (1,3-dimethoxy-2-propylamino) -2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] pyrazole-1,3,5-triazine (Formula 1, in which R³ are NHCHjChhOCHs) ?, R¹ is CH₃, Z is C-CH₃, Is 2,4-dichlorophenyl)

A. 4-Chloro-2,7-dimethyl-8- (2,4-dichlorophenyl) ri, 5-al-pyrazolotriazine

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) A mixture of N, N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) was stirred and refluxed for 48 h. Excess phosphorus oxychloride is removed in vacuo. The residue is taken up in an ice-water mixture, stirred briefly and extracted three times with ethyl acetate. The combined organic layers were washed with ice water and then dried over MgSO4₄ and filtered off. Evaporation of the solvent in vacuo gives a brown oil. Flash column chromatography (ethyl acetate: hexanes - 1: 4) yields one fraction (R_f = 0.5). Evaporation of the solvent in vacuo gave 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) n, 5-alpha-pyrazolo-1,3,5-triazine

4-Chloro-2,7-dimethyl-8- (2,4-dichlorophenyl) [1,5-a] -pyrazolo-1,3,5-triazine (Part A, 570 mg, 1.74 mmol), A mixture of 3-dimethoxypropyl-2-aminopropane (25 mg, 2.08 mmol) and ethanol (10 mL) was stirred at room temperature for 18 h. The reaction mixture was poured into water (25 mL) and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO 4₄ and filtered off. The solvent is evaporated off under vacuum. Column chromatography (CH₂CI₂: CH3OH 50: 1) yields one fraction. Evaporation of the solvent in vacuo afforded a solid (250 mg, 35% yield): m.p. m.p. 118-120 ° C; NMR (CDCl 3, 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-ASDMS: Calc'd: 409.1072; found: 409.1085. Analysis: Calculated by

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

The examples in Table 1 may be prepared by the methods described in Examples 1, 2, 3 or 6. Commonly used abbreviations are: Ph - phenyl, Pr - propyl, Me - methyl, Ethyl - ethyl, Bu - butyl, e.g. - an example.

table

R³

<img file="LT4680B_D0060.tif" />

Ar

N

<td>For example,</td><td>Z</td><td>Ra</td><td>Ar</td><td>Lyd.</td>

<td>No.</td><td></td><td></td><td></td><td>temp.</td>

<td></td><td></td><td></td><td></td><td>(° C)</td>

<td> 6^a</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4-CI₂-Ph</td><td> 118-120</td>

<td> 7^b</td><td>C-Me</td><td>NHCHPr₂</td><td>2,4-Ci₂-Ph</td><td> 114-116</td>

<td> 8^C</td><td>C-Me</td><td>NEtBu</td><td>2,4-CI₂-Ph</td><td>oil</td>

<td> 9^d</td><td>C-Me</td><td>NPr (CH₂-cC₃H₅)</td><td>2,4-Cl / Ph</td><td>oil</td>

<td> 10^e</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-CI₂-Ph</td><td>oil</td>

<td> 11'</td><td>C-Me</td><td>Β-3-heptyl</td><td>2,4-CI₂-Ph</td><td> 90-92</td>

<td> 12⁹</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2,4-CI₂-Ph</td><td> 179-181</td>

<td> 13^h</td><td>C-Me</td><td>NEt₂</td><td>2,4-CI₂-Ph</td><td> 133-134</td>

<td> 14'</td><td>C-Me</td><td>NHCH (CH₂OEt)₂</td><td>2,4-CI₂-Ph</td><td>oil</td>

<td> 15'</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2,4-CI₂-Ph</td><td> 139-140</td>

<td> 16^k</td><td>C-Me</td><td>NMePh</td><td>2,4-CI₂-Ph</td><td> 60-62</td>

<td> 17'</td><td>C-Me</td><td>NPr₂</td><td>2,4-CI₂-Ph</td><td>oil</td>

<td> 18^m</td><td>C-Me</td><td>ΝΗ-3-hexyl</td><td>2,4-CI₂-Ph</td><td> 130-132</td>

<td> 19</td><td>C-Me</td><td>morpholine residue</td><td>2,4-CI₂-Ph</td><td></td>

<td>C-Me</td><td>N (CH₂Ph) CH₂CH₂OMe</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>NHCH (CH₂Ph) CH₂OMe</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>ΝΗ-4-Tetrahydropyranyl</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>NH-cyclopentyl</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>1,2,3,4-Tetrahydroisoquinoline Las</td><td>2,4-Cla-Ph</td>

<td>C-Me</td><td>CH₂- (1,2,3,4-Tetrahydroisoquinoline Las)</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>Oh no</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>OCH (Et) CH₂OMe</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>OCH₂Ph</td><td>2,4-Cb-Ph</td>

<td>C-Me</td><td>Ο-3-pentyl</td><td>2,4-Cb-Ph</td>

<td>C-Me</td><td>SEt</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>S (O) Et</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>SO₂No.</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>CH (CO₂No)₂</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>C (Et) (CO₂No)₂</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>CH (Et) CH₂OH</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>CH (Et) CH₂OMe</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>CONMe₂</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>COCH₃</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>CH (OH) CH₃</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>C (OH) Ph-3-pyridyl</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>Ph</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>2-CF₃-Ph</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>2-Ph-Ph</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>3-pentyl</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>cyclobutyl</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>3-pyridyl</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>CH (Et) CH₂CONMe₂</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>CH (Et) CH₂CH₂NMe₂</td><td>2,4-CI₂-Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4,6-Me₃-Ph</td>

<td>C-Me</td><td>NHCHPr₂</td><td>2,4,6-Me₃-Ph</td>

141-143

125-127

<td> 51</td><td>C-Me</td><td>NEtBu</td><td colspan="2">2,4,6-Me₃-Ph</td>

<td> 52</td><td>C-Me</td><td>NPr (CH₂-cC₃H₅)</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 53^as</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4,6-Me₃-Ph</td><td> 123-124</td>

<td> 54</td><td>C-Me</td><td>Β-3-heptyl</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 55^ac</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2,4,6-Me₃-Ph</td><td> 145-146</td>

<td> 56^ah</td><td>C-Me</td><td>NEt₂</td><td>2,4,6-Me₃-Ph</td><td> 88-90</td>

<td> 57^al</td><td>C-Me</td><td>NHCH (CH₂OEt)₂</td><td>2,4,6-Me₃-Ph</td><td> 132-134</td>

<td> 58^ad</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2,4,6-Me₃-Ph</td><td> 134-135</td>

<td> 59</td><td>C-Me</td><td>NMePh</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 60</td><td>C-Me</td><td>NPr₂</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 61</td><td>C-Me</td><td>ΝΗ-3-hexyl</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 62</td><td>C-Me</td><td>morpholine residue</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 63</td><td>C-Me</td><td>N (CH₂Ph) CH₂CH₂OMe</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 64</td><td>C-Me</td><td>NHCH (CH₂Ph) CH₂OMe</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 65</td><td>C-Me</td><td>ΝΗ-4-Tetrahydropyranyl</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 66</td><td>C-Me</td><td>NH-cyclopentyl</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 67</td><td>C-Me</td><td>1,2,3,4-Tetrahydroisoquinolinyl</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 68</td><td>C-Me</td><td>CH₂- (1,2,3,4-Tetrahydroisoquinolinyl)</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 69</td><td>C-Me</td><td>OEt</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 70</td><td>C-Me</td><td>OCH (Et) CH₂OMe</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 71</td><td>C-Me</td><td>OCH₂Ph</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 72</td><td>C-Me</td><td>Ο-3-pentyl</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 73</td><td>C-Me</td><td>S No</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 74</td><td>C-Me</td><td>S (O) Et</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 75</td><td>C-Me</td><td>SO₂No.</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 76</td><td>C-Me</td><td>CH (CO₂No)₂</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 77</td><td>C-Me</td><td>C (Et) (CO₂No)₂</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 78</td><td>C-Me</td><td>CH (Et) CH₂OH</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 79</td><td>C-Me</td><td>CH (Et) CH₂OMe</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 80</td><td>C-Me</td><td>CONMe₂</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 81</td><td>C-Me</td><td>COCH₃</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 82</td><td>C-Me</td><td>CH (OH) CH₃</td><td colspan="2">2,4,6-Me₃-Ph</td>

<td> 83</td><td>C-Me</td><td>C (OH) Ph-3-pyridyl</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 84</td><td>C-Me</td><td>Ph</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 85</td><td>C-Me</td><td>2-CF₃-Ph</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 86</td><td>C-Me</td><td>2-Ph-Ph</td><td> 2_t4,6-Me₃-Ph</td><td></td>

<td> 87</td><td>C-Me</td><td>3-pentyl</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 88</td><td>C-Me</td><td>cyclobutyl</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 89</td><td>C-Me</td><td>3-pyridyl</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 90</td><td>C-Me</td><td>CH (Et) CH₂CONMe₂</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 91</td><td>C-Me</td><td>CH (Et) CH₂CH₂NMe₂</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 92^p</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4-Me₂-Ph</td><td> 44-45</td>

<td> 93^q</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 94^r</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2,4-Me₂-Ph</td><td> 102-104</td>

<td> 95^s</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2,4-Me₂-Ph</td><td> 102-104</td>

<td> 96¹</td><td>C-Me</td><td>NEt₂</td><td> 2_t4-Me₂-Ph</td><td>oil</td>

<td> 97^u</td><td>C-Me</td><td>N (CH₂CN)₂</td><td>2,4-Me₂-Ph</td><td> 148-150</td>

<td> 98^v</td><td>C-Me</td><td>NHCH (Me) CH₂OMe</td><td>2,4-Me₂-Ph</td><td> 102-104</td>

<td> 99^w</td><td>C-Me</td><td>OCH (Et) CH₂OMe</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 100*</td><td>C-Me</td><td>NPr-cC₃H₅</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 101^y</td><td>C-Me</td><td>NHCH (Me) CH₂NMe₂</td><td>2,4-Me₂-Ph</td><td> 47-48</td>

<td> 102^z</td><td>C-Me</td><td>N (cC₃H₅) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td><td> 117-118</td>

<td> 103^aa</td><td>C-Me</td><td>N (Pr) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 104^ab</td><td>C-Me</td><td>N (Bu) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 105</td><td>C-Me</td><td>NHCHPr₂</td><td>2,4-Me₂-Ph</td><td></td>

<td> 106</td><td>C-Me</td><td>NEtBu</td><td>2,4-Me₂-Ph</td><td></td>

<td> 107</td><td>C-Me</td><td>NPr (CH₂-cC₃H₅) ’</td><td>2,4-Me₂-Ph</td><td></td>

<td> 108</td><td>C-Me</td><td>Β-3-heptyl</td><td>2,4-Me₂-Ph</td><td></td>

<td> 109</td><td>C-Me</td><td>N No₂</td><td>2,4-Me₂-Ph</td><td></td>

<td> 110</td><td>C-Me</td><td>NHCH (CH₂OEt)₂</td><td>2,4-Me₂-Ph</td><td></td>

<td> 111</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2,4-Me₂-Ph</td><td></td>

<td> 112</td><td>C-Me</td><td>NMePh</td><td>2,4-Me₂-Ph</td><td></td>

<td> 113</td><td>C-Me</td><td>NPr₂</td><td>2,4-Me₂-Ph</td><td></td>

<td>C-Me</td><td>ΝΗ-3-hexyl</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>morpholine residue</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>N (CH₂Ph) CH₂CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>NHCH (CH₂Ph) CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>ΝΗ-4-Tetrahydropyranyl</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>NH-cyclopentyl</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>1,2,3,4-Tetrahydroisoquinolinyl</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>CH₂- (1,2,3,4-Tetrahydroisoquinoline Las)</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>Oh no</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>OCH (Et) CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>OCH₂Ph</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>Ο-3-pentyl</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>SEt</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>S (O) Et</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>SO₂No.</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>CH (CO₂No)₂</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>C (Et) (CO₂No)₂</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>CH (Et) CH₂OH</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>CH (Et) CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>CH (Et) CH₂OEt</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>CONMe₂</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>COCH₃</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>CH (OH) CH₃</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>C (OH) Ph-3-pyridyl</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>Ph</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>2-CF₃-Ph</td><td>2.4-Me₂-Ph</td>

<td>C-Me</td><td>2-Ph-Ph</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>3-pentyl</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>cyclobutyl</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>3-pyridyl</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>CH (Et) CH₂CONMe₂</td><td>2,4-Me₂-Ph</td>

50-52

<td> 144</td><td>C-Me</td><td>CH (Et) CH₂CH₂NMe₂</td><td colspan="2">2,4-Me₂-Ph</td>

<td> 145^bc</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4-MeO-Ph</td><td> 45-46</td>

<td> 146^bd</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4-MeO-Ph</td><td>oil</td>

<td> 147^without</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Me-4-MeO-Ph</td><td> 86-88</td>

<td> 148^bf</td><td>C-Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Me-4-MeO-Ph</td><td>oil</td>

<td> 149</td><td>C-Me</td><td>OCH (Et) CH₂OMe</td><td>2-Me-4-MeO-Ph</td><td></td>

<td> 150^af</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-MeO-Ph</td><td> 88-90</td>

<td> 151^al</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-MeO-Ph</td><td>oil</td>

<td> 152^ag</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4-MeO-Ph</td><td> 95-97</td>

<td> 153</td><td>C-Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Br-4-MeO-Ph</td><td></td>

<td> 154</td><td>C-Me</td><td>OCH (Et) CH₂OMe</td><td>2-3r-4-MeO-Ph</td><td></td>

<td> 155</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4-NMe₂-Ph</td><td></td>

<td> 156</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4-NMe₂-Ph</td><td>oil</td>

<td> 157</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Me-4-NMe₂-Ph</td><td></td>

<td> 158</td><td>C-Me</td><td>N (PijCH₂CH₂CN</td><td>2-Me-4-NMe₂-Ph</td><td></td>

<td> 159</td><td>C-Me</td><td>OCH (Et) CH₂OMe</td><td>2-Me-4-NMe₂-Ph</td><td></td>

<td> 160</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-NMe₂-Ph</td><td></td>

<td> 161</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-NMe₂-Ph</td><td></td>

<td> 162</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4-NMe₂-Ph</td><td></td>

<td> 163</td><td>C-Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Br-4-NMe₂-Ph</td><td></td>

<td> 164</td><td>C-Me</td><td>OCH (Et) CH₂OMe</td><td>2-Br-4-NMe₂-Ph</td><td></td>

<td> 165</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-i-Pr-Ph</td><td></td>

<td> 166</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-i-Pr-Ph</td><td></td>

<td> 167</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4-i-Pr-Ph</td><td></td>

<td> 168</td><td>C-Me</td><td>N (Pr) CH₂CH₂CN;</td><td>2-Br-4-i-Pr-Ph</td><td></td>

<td> 169</td><td>C-Me</td><td>OCH (Et) CH₂OMe</td><td>2-Br-4-i-Pr-Ph</td><td></td>

<td> 170</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-Me-Ph</td><td></td>

<td> 171</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-Me-Ph</td><td></td>

<td> 172</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4-Me-Ph</td><td></td>

<td> 173</td><td>C-Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Br-4-Me-Ph</td><td></td>

<td> 173</td><td>C-Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Br-4-Me-Ph</td><td></td>

<td> 174</td><td>C-Me</td><td>OCH (Et) CH₂OMe</td><td>2-Br-4-Me-Ph</td><td></td>

<td> 175^with</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4-Br-Ph</td>

<td> 176</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4-Br-Ph</td>

<td> 177</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Me-4-Br-Ph</td>

<td> 178</td><td>C-Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Me-4-Br-Ph</td>

<td> 179</td><td>C-Me</td><td>OCH (Et) CH₂OMe</td><td>2-Me-4-Br-Ph</td>

<td> 180</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4,6-Me₂-Ph</td>

<td> 181</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4,6-Me₂-Ph</td>

<td> 182</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>4-Br-2,6- (Me)₂-Ph</td>

<td> 183</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-Br-2,6- (Me)₂-Ph</td>

<td> 184</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td> 185</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td> 186</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-CF₃-Ph</td>

<td> 187</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-CF₃-Ph</td>

<td> 188</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4,6- (MeO)₂-Ph</td>

<td> 189</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4,6- (MeO)₂-Ph</td>

<td> 190</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4,6- (MeO)₂-Ph</td>

<td> 191</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4,6- (MeO)₂-Ph</td>

<td> 192</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2.6- (Me)₂-4-SMe-Ph</td>

<td> 193</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2.6- (Me)₂-4-SMe-Ph</td>

<td> 194</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>4- (COMe) -2-Br-Ph</td>

<td> 195</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>4- (COMe) -2-Br-Ph</td>

<td> 196</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td> 2,4_t6-Me₃-pyrid-3-yl</td>

<td> 197</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4,6-Me₃-pirid-3-i! as</td>

<td> 198</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4- (Br)₂-Ph</td>

<td> 199</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4- (Br)₂-Ph</td>

<td> 200</td><td>C-Me</td><td>NHCH (CH₂O'Me)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td> 201</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td> 202</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>4-i-Pr-2-SO₂Me-Ph</td>

<td> 203</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-i-Pr-2-SO₂Me-Ph</td>

<td> 204</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2.6- (Me)₂-4-SMe-Ph</td>

<td> 205</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2.6- (Me)₂-4-SMe-Ph</td>

<td> 206</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2.6- (Me)₂-4-SO₂Me-Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2.6- (Me)₂-4-SO₂Me-Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-l-4-i-Pr-Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-l-4-i-Pr-Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-N (Me)₂-6-MeO- Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-N (Me)₂-6-MeO- Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4- [SMe]₂-Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4- [SMe]₂-Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4- [SO₂Me]₂-Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4- [SO₂Me]₂-Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>4-i-Pr-2-SO₂Me-Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-i-Pr-2-SO₂Me-Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-N (Me)₂-4-Me-Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-N (Me)₂-4-Me-Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-MeS-4,6- (Me)₂-Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeS-4,6- (Me)₂-Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2- (CH₃CO) -4,6- (Me)₂- Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2- (CH₃CO) -4,6- (Me)₂- Ph</td>

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

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

<td>cf₃</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

<td>CF.₃</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

<td>N</td><td>NHCH (CH₂OMe)₂·</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>NHCHPr₂</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>NEtBu</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>NPr (CH₂-cC₃H₅)</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>N (CH₂CH₂OMe)₂</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>Β-3-heptyl</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>NHCH (Et) CH₂OMe</td><td> 2_t4,6-Me₃-Ph</td>

<td>N</td><td>NEt₂</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>NHCH (CH₂OEt)₂</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>ΝΗ-3-pentyl</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>NMePh</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>NPr₂</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>ΝΗ-3-hexyl</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>morpholine residue</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>N (CH₂Ph) CH₂CH₂OMe</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>NHCH (CH₂Ph) CH₂OMe</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>Α-4-tetrahydropyranyl</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>NH-cyclopentyl</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>1,2,3,4-Tetrahydroisoquinolinyl</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>CH₂- (1,2,3,4-Tetrahydroisoquinolinyl)</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>OEt</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>OCH (Et) CH₂OMe</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>OCH₂Ph</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>Ο-3-pentyl</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>SEt</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>S (O) Et</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>SO₂No.</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>CH (CO₂No)₂</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>C (Et) (CO₂No)₂</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>CH (Et) CH₂OH</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>CH (Et) CH₂OMe</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>CONMe₂</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>COCH₃</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>CH (OH) CH₃</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>C (OH) Ph-3-pyridyl</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>Ph</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>2-CF₃-Ph</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>2-Ph-Ph</td><td>2,4,6-Me₃-Ph</td>

<td>N</td><td>3-pentyl</td><td>2,4,6-Me₃-Ph</td>

<td> 269</td><td>N</td><td>cyclobutyl</td><td>2,4,6-Me₃-Ph</td>

<td> 270</td><td>N</td><td>3-pyridyl</td><td>2,4,6-Me₃-Ph</td>

<td> 271</td><td>N</td><td>CH (Et) CH₂CONMe₂</td><td>2,4,6-Me₃-Ph</td>

<td> 272</td><td>N</td><td>CH (Et) CH₂CH₂NMe₂</td><td>2,4,6-Me₃-Ph</td>

<td> 273</td><td>N</td><td>NHCH (CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

<td> 274</td><td>N</td><td>NHCHPr₂</td><td>2,4-Me₂-Ph</td>

<td> 275</td><td>N</td><td>NEtBu</td><td>2,4-Me₂-Ph</td>

<td> 276</td><td>N</td><td>NPr (CH₂-cC₃H₅)</td><td>2,4-Me₂-Ph</td>

<td> 277</td><td>N</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

<td> 278</td><td>N</td><td>Β-3-heptyl</td><td>2,4-Me₂-Ph</td>

<td> 279</td><td>N</td><td>NHCH (Et) CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td> 280</td><td>N</td><td>NEt₂</td><td>2,4-Me₂-Ph</td>

<td> 281</td><td>N</td><td>NHCH (CH₂OEt)₂</td><td>2,4-Me₂-Ph</td>

<td> 282</td><td>N</td><td>ΝΗ-3-pentyl</td><td>2,4-Me₂-Ph</td>

<td> 283</td><td>N</td><td>NMePh</td><td>2,4-Me₂-Ph</td>

<td> 284</td><td>N</td><td>NPr₂</td><td>2,4-Me₂-Ph</td>

<td> 285</td><td>N</td><td>ΝΗ-3-hexyl</td><td>2.4-Me₂-Ph</td>

<td> 286</td><td>N</td><td>morpholine residue</td><td>2.4-Me₂-Ph</td>

<td> 287</td><td>N</td><td>N (CH₂Ph) CH₂CH₂OMe</td><td>2 4-Me₂-Ph</td>

<td> 288</td><td>N</td><td>NHCH (CH₂Ph) CH₂CH₂O Me</td><td>2.4-Me₂-Ph</td>

<td> 289</td><td>N</td><td>NH -4-tetrahydropyran I as</td><td>2.4-Me₂-Ph</td>

<td> 290</td><td>N</td><td>NH-cyclopentyl</td><td>2,4-Me₂-Ph</td>

<td> 291</td><td>N</td><td>1,2,3,4-Tetrahydroisoquinolinyl</td><td>2,4-Me₂-Ph</td>

<td> 292</td><td>N</td><td>CH₂- (1,2,3,4-Tetrahydroisoquinolinyl)</td><td>2,4-Me₂-Ph</td>

<td> 293</td><td>N</td><td>OEt</td><td>2,4-Me₂-Ph</td>

<td> 294</td><td>N</td><td>OCH (Et) CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td> 295</td><td>N</td><td>OCH₂Ph</td><td>2,4-Me₂-Ph</td>

<td> 296</td><td>N</td><td>Ο-3-pentyl</td><td>2,4-Me₂-Ph</td>

<td> 297</td><td>N</td><td>S No</td><td>2,4-Me₂-Ph</td>

<td> 298</td><td>N</td><td>S (O) Et</td><td>2,4-Me₂-Ph</td>

<td> 299</td><td>N</td><td>SO₂No.</td><td>2,4-Me₂-Ph</td>

<td> 300</td><td>N</td><td>CH (CO₂No)₂</td><td colspan="2">2,4-Me₂-Ph</td>

<td> 301</td><td>N</td><td>C (Et) (CO₂No)₂</td><td>2,4-Me₂-Ph</td><td></td>

<td> 302</td><td>N</td><td>CH (Et) CH₂OH</td><td>2,4-Me₂-Ph</td><td></td>

<td> 303</td><td>N</td><td>CH (Et) CH₂OMe</td><td>2,4-Me₂-Ph</td><td></td>

<td> 304</td><td>N</td><td>CONMe₂</td><td>2,4-Me₂-Ph</td><td></td>

<td> 305</td><td>N</td><td>COCH₃</td><td>2,4-Me₂-Ph</td><td></td>

<td> 306</td><td>N</td><td>CH (OH) CH₃</td><td>2,4-Me₂-Ph</td><td></td>

<td> 307</td><td>N</td><td>C (OH) Ph-3-pyridyl</td><td>2,4-Me₂-Ph</td><td></td>

<td> 308</td><td>N</td><td>Ph</td><td>2,4-Me₂-Ph</td><td></td>

<td> 309</td><td>N</td><td>2-CF₃-Ph</td><td>2,4-Me₂-Ph</td><td></td>

<td> 310</td><td>N</td><td>2-Ph-Ph</td><td>2,4-Me₂-Ph</td><td></td>

<td> 311</td><td>N</td><td>3-pentyl</td><td>2,4-Me₂-Ph</td><td></td>

<td> 312</td><td>N</td><td>cyclobutyl</td><td>2,4-Me₂-Ph</td><td></td>

<td> 313</td><td>N</td><td>3-pyridyl</td><td>2,4-Me₂-Ph</td><td></td>

<td> 314</td><td>N</td><td>CH (Et) CH₂CONMe₂</td><td>2,4-Me₂-Ph</td><td></td>

<td> 315</td><td>N</td><td>CH (Et) CH₂CH₂NMe₂</td><td>2,4-Me₂-Ph</td><td></td>

<td> 316^an</td><td>C-Me</td><td>ΝΕΐ₂</td><td>2-Br-4-MeO-Ph</td><td>oil</td>

<td> 317^am</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-Br-4-MeO-Ph</td><td>oil</td>

<td> 318^aj</td><td>C-Me</td><td>NHCH (CH₂CH₂OMe) CH₂OMe</td><td>2,4,6-Me₃-Ph</td><td> 101-103</td>

<td> 319^ao</td><td>C-Me</td><td>NH (cC₃H₅)</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 320^ak</td><td>C-Me</td><td>morpholine residue</td><td>2,4,6-Me₃-Ph</td><td> 139-141</td>

<td> 321^ap</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CN-4-Me-Ph</td><td> 152-153</td>

<td> 322^aq</td><td>C-Me</td><td>N (cC₃H₅) CH₂CH₂CN</td><td>2,4,6-Mea-Ph</td><td> 149-151</td>

<td> 324^as</td><td>C-Me</td><td>NHCH (CH₂CH₂OMe) CH₂OMe</td><td>2-Me-4-Br-Ph</td><td> 115-117</td>

<td> 325^at</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2.5-Me₂-4-MeO-Ph</td><td> 55-57</td>

<td> 326^hi</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2.5-Me₂-4-MeO-Ph</td><td> 72</td>

<td> 327^av</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2.5-Me₂-4-MeO-Ph</td><td> 45-47</td>

<td> 328^{s, v}</td><td>C-Me</td><td>NEt₂</td><td>2.5-Me₂-4-MeO-Ph</td><td>oil</td>

<td> 329«</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4-Me-Ph</td><td> 80-81</td>

<td> 330^ay</td><td>C-Me</td><td>NCH ​​(Et) CH₂OMe</td><td>2-CI-4-Me-Ph</td><td> 77-79</td>

<td> 331^that</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4-Me-Ph</td><td>oil</td>

<td> 332^ba</td><td>C-Me</td><td>fS) -</td><td>2-CI-4-Me-Ph</td><td> 139-140</td>

NHCH (CH₂CH₂OMe) CH₂

OMe

<td> 333^bb</td><td>C-Me</td><td>N (cC₃H₅) CH₂CH₂CN</td><td>2.5-Me₂-4-MeO-Ph</td><td> 120-122</td>

<td> 334^bg</td><td>C-Me</td><td>NEt₂</td><td>2-Me-4-MeO-Ph</td><td>oil</td>

<td> 335^bh</td><td>C-Me</td><td>OEt</td><td>2-Me-4-MeO-Ph</td><td>oil</td>

<td> 336^bi</td><td>C-Me</td><td>(S) - NHCH (CH₂CH₂OMe) CH₂OMe</td><td>2-Me-4-MeO-Ph</td><td>oil</td>

<td> 337^b'</td><td>C-Me</td><td>N (cC₃H₅) CH₂CH₂CN</td><td>2-Me-4-MeO-Ph</td><td> 129</td>

<td> 338^bk</td><td>C-Me</td><td>NHCH (CH₂CH₂OEt)₂</td><td>2-Me-4-MeO-Ph</td><td>amorphous.</td>

<td> 339</td><td>C-Me</td><td>N (cC₃H5) CH₂CH₂CN</td><td>2,4-CI₂-Pn</td><td> 109-110</td>

<td> 340</td><td>C-Me</td><td>(S) - NHCH (CH₂CH₂OMe) CH₂OMe</td><td>2,4-CI₂-Ph</td><td> 93-94</td>

<td> 341</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-Me-4-Br-Ph</td><td> 118-119</td>

<td> 342</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4-Br-Ph</td><td>oil</td>

<td> 343</td><td>C-Me</td><td>NHCH (CH₂-iPr) CH₂OMe</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 344</td><td>C-Me</td><td>NHCH (Pr) CH₂OMe</td><td>2,4-Me₂-Ph</td><td> 94-95</td>

<td> 345</td><td>C-Me</td><td>NHCH (Et) CH₂OEt</td><td>2,4-Me₂-Ph</td><td> 76-77</td>

<td> 346</td><td>C-Me</td><td>NHCH (CH₂OMe) CH₂CH₂OMe</td><td>2-Me-4-Me₂NPh</td><td>oil</td>

<td> 347</td><td>C-Me</td><td>NEt₂</td><td>2-Me-4-CI-Ph</td><td>oil</td>

<td> 348</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-Me-4-C 1 -Pn</td><td> 122-124</td>

<td> 349</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4-CI-Ph</td><td>oil</td>

<td> 350</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4-CI-Ph</td><td> 122-123</td>

<td> 351</td><td>C-Me</td><td>NEt₂</td><td>2-Me-4-CI-Ph</td><td>oil</td>

<td> 352</td><td>C-Me</td><td>NEt₂</td><td>2-CI-4-Me-Ph</td><td>oil</td>

<td> 353</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-CI-4-Me-Ph</td><td> 120-121</td>

<td> 354</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4-MeO-Ph</td><td></td>

<td> 355^bl</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-C 1-4 -MeO-Ph</td><td>oil</td>

<td> 356^bm</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-CI-4-MeO-Ph</td><td> 108-110</td>

<td> 357^bn</td><td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI-4-MeO-Ph</td><td> 127-129</td>

<td> 358^b0</td><td>C-Me</td><td>NEt₂</td><td>2-CI-4-MeO-Pn</td><td>oil</td>

<td> 359^bp</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-Ci-4-MeO-Ph</td><td> 77-79</td>

<td> 360</td><td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-CI-4-MeO-Ph</td><td></td>

<td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td colspan="2">2-CI-4-MeO-Ph</td>

<td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Br-4-MeO-Ph</td><td></td>

<td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Br-4-MeO-Ph</td><td></td>

<td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4-MeO-Ph</td><td></td>

<td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Me-4-MeO-Ph</td><td></td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-C14 -5,5 (MeO)₂Ph</td><td></td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4,5- (MeO)₂Ph</td><td></td>

<td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-C14 -5,5 (MeO)₂Ph</td><td></td>

<td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI-4,5- (MeO)₂Ph</td><td></td>

<td>C-Me</td><td>N No₂</td><td>2-CI-4,5- (MeO)₂Ph</td><td></td>

<td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-CI-4,5- (MeO)₂Ph</td><td></td>

<td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-CI-4,5- (MeO)₂Ph</td><td></td>

<td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-CI-4,5- (MeO)₂Ph</td><td></td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4,5- (MeO)₂Ph</td><td> 137-138</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4,5- (MeO)₂Ph</td><td></td>

<td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4,5- (MeO)₂Ph</td><td> 147-148</td>

<td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Br-4,5- (MeO)₂Ph</td><td></td>

<td>C-Me</td><td>NEt₂</td><td>2-Br-4,5- (MeO)₂Ph</td><td> 52-58</td>

<td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-Br-4,5- (MeO)₂Ph</td><td></td>

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

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

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4,6- (MeO)₂Ph</td><td></td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Ci-4,6- (MeO)₂Ph</td><td></td>

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

<td>C-Me</td><td>N (c-PijCH₂CH₂CN</td><td>2-CI-4,6- (MeO)₂Ph</td><td></td>

<td>C-Me</td><td>NEt₂</td><td>2-CI-4,6- (MeO)₂Ph</td><td></td>

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

<td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-CI-4,6- (MeO)₂Ph</td><td></td>

<td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-CI-4,6- (MeO)₂Ph</td><td></td>

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

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

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

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

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

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

<td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4,6- (MeO)₂Ph</td>

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

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

<td>C-Me</td><td>N No₂</td><td>2-Br-4,6- (MeO)₂Ph</td>

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

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

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

<td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4-MeO-Ph</td>

<td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Me-4-MeO-Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>NEt₂</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>NEt₂</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4-Me-Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4-CI-Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-CI-Ph</td>

<td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4-CI-Ph</td>

<td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4-CI-Ph</td>

oil

<td> 427</td><td>C-Me</td><td>NEt₂</td><td>2-MeO-4-Ci-Ph</td>

<td> 428</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4-CI-Ph</td>

<td> 429</td><td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4-Ci-Ph</td>

<td> 430</td><td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4-CI-Ph</td>

Notes to Table 1:

(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; Ci, 17.50.

b) CI-ASGMS: Calc'd: 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-ASGMS: Calc'd: 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 (s, J = 8, 2H), 1.65 -1.85 (m, 2H), 2.30 (s, 3H), 2.40 (s, 3H), 3.85-4.20 (m, 4H), 7.30 (s, 2H), 7.50 (s, 1H).

d) CI-ASGMS: Calc'd: 404.1409; found: 404.1408 (M + H);

NMR (CDCl 3, 300 MHz): 0.35-0.45 (m, 2H), 0.52-0.62 (m, 2H), 0.98 (t, J = 8, 3H), 1.70 -1.90 (m, 2H), 2.30 (s, 3H), 2.40 (s, 3H), 3.85-4.20 (m, 2H), 4.02-4.20 (m , 2H), 7.30 (s, 2H), 7.50 (s, 1H).

e) CI-ASGMS: Calculated: 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-ASGMS: Calc'd: 406.1565; found: 406.1578 (M + H);

NMR (CDCl3, 300 MHz): 0.90 (t, J = 8, 3H), 1.0 (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-ASGMS: calculated: 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 (o.s, 1H),

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

h) CI-ASGMS: calculated: 364.1096; Found: 364.1093 (M + H);

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

NMR (CDCl3, 300 MHz): 1.35 (t, J = 8, 6H), 2.30 (s, 3H), 2.40 (s, 3H),

3.95 - 4.15 (m, 4H), 7.30 (s, 2H), 7.50 (d, J = 1, 1H),

i) CI-ASGMS: Calc'd: 438.1464; found: 438.1454 (M + H);

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

3.39 (sq, J = 8, 4H), 3.65 (dd, J = 8, 1.2H), 3.73 (dd, J = 8, 1.2H), 4.554.65 (m, 1H ), 6.75 (d, J = 8, 1H), 7.30 (d, J = 1.2H), 7.50 (s, 1H).

j) CI-ASGMS: Calcd .: 378.1252; found: 378.1249 (M + H);

Analysis: Calculated: C, 57.15; H, 5.61; N, 18.51; C18.74; Found: C, 57.56; H, 5.65; N, 18.35; Cl, 18.45;

100

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-ASGMS: Calc'd: 398.0939; found: 398.0922 (M + H);

Analysis: Calculated: C, 60.31; H, 4.30; N, 17.58; Cl, 17.80; found: C

60.29; H, 4.59; N, 17.09; Cl, 17.57;

NMR (CDCl 3, 300 MHz): 2.05 (s, 3H), 2.50 (s, 3H), 3.78 (s, 3H), 7.207.45 (m, 7H), 7.50 (d, J = 1, 1H).

l) CI-ASGMS: Calc'd: 392.1409; found: 392.1391 (M + H);

NMR (CDCl 3, 300 MHz): 0.98 (t, J = 8, 6H), 1.70-1.85 (m, 4H), 2.30 (s, 3H). 2.40 (s, 3H), 3.80-4.10 (m, 4H), 7.30 (s, 2H), 7.50 (d, J = 1, 1H).

m) CI-ASGMS: Calc'd: 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 (CDCl 3, 300 MHz): 0.90-1.05 (m, 6H), 1.35-1.55 (m, 2H), 1,551.85 (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-ASGMS: Calc'd: 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 (s, J = 8, 2H) ), 7.30 (d, J = 8, 1H), 7.35 (dd, J = 8, 1, 1H), 7.55 (d, J = 1, 1H).

o) CI-ASGMS: Calc'd: 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), 4,604.70 (m, 1H), 6.70 (d, J = 8, 1H), 6.94 (s, 2H).

p) CI-ASGMS: Calcd .: 370.2243; Found: 370.2246 (M + H);

Analysis: Calculated: C, 65.02; H, 7.38; N, 18.96; Found: C, 65.22; H, 7.39;

N, 18.71;

NMR (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, 1H),

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

q) CI-ASGMS: Calculated: 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, 1H).

r) CI-ASGMS: 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;

NMR (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, 1H), 7.04 (d, J = 8, 1H). 7.10 (d,

J = 8, 1H), 7.12 (s, 1H).

s) Ci-ASGMS: Calc'd: 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;

101

NMR (CDCl₃, 300 MHz); 1.00 (t, J = 8, 6H), 1.55-1.70 (m, 2H), 1.70-1.85 (m, 2H), 2.19 (s, 3H), 2, 30 (s, 3H), 2.35 (s, 3H), 2.46 (s, 3H), 4.15-4.26 (m, 1H), 6.17 (d, J = 8, 1H). , 7.06 (d, J = 8. 1H), 7.10 (d, J = 1, 1H), 7.13 (s, 1H).

t) CI-ASGMS; calculated: 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, 1H), 7.07 (s, 1H), 7.10 (d, J = 1, 1H) ).

u) CI-ASGMS: Calc'd: 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), 5.25-5. 35 (m, 4H), 7.08 (s, 2H), 7.15 (s, 1H).

v) CI-ASGMS: Calc'd: 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 = Δ, 1H), 7.00-7.15 (m, 3H).

w) CI-ASGMS: Calcd .: 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) , 5.70-5.80 (m, 1H), 7.00-7.20 (m, 3H).

x) CI-ASGMS: 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), 7.007.15 (m, 3H).

y) CI-ASGMS: Calc'd: 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 (s, 3H), 2 , 60-2.75 (m, 2H), 4.30-4.50 (m, 1H), 6.60-6.70 (m, 1H), 7.00-7.15 (m, 3H). .

z) CI-ASGMS: Calcd .: 361.2140; found: 361.2128 (M + H);

NMR (CDCl₃, 300 MHz): 0.75-0.83 (m, 2H), 1.00-1.10 (m, 2H), 2.17 (s, 3H), 2.30 (s, 3H), 2 , 36 (s, 3H), 2.47 (s, 3H), 2.85 (t, J = 8, 2H), 3.303.40 (m, 1H), 4.40-4.55 (m, 2H), 7.00-7.18 (m, 3H).

aa) CI-ASGMS: Calcd .: 363.2297; Found: 363.2311 (M + H);

NMR (CDC!₃, 300 MHz): 1.01 (t, 3H, J = 8), 1.75-1.90 (m, 2H), 2.15 (s, 3H), 2.19 (s, 3H), 2 , 35 (s, 3H), 2.40 (s, 3H), 2.98 (t, 2H, J = 8), 3,974.15 (m, 2H), 4.15-4.30 (m, 2H). ), 7.03 (d, 1H, 1H), 7.08 (d, 1H, J = 8), 7.10 (s, 1H).

ab) CI-ASGMS: Calcd .: 363.2297; found: 363.2295 (M + H):

NMR (CDCl3₃, 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

102 (m, 2H), 4.95-5.10 (m.p., 2H), 7.05 (d, 1H, J = 8), 7.10 (d, 1H, J = 8),

7.15 (s, 1H).

ac) CI-ASGMS: Calcd .: 368.2450; found: 368.2436;

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

NMR (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) CI-ASGMS: Calcd .: 352.2501; found: 352.2500 (M + H);

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) CI-ASGMS: Calc'd: 398.2556; found: 398.2551 (M + H);

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

N, 17.70;

NMR (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-ASGMS: Calc'd: 450.1141; found: 450.1133 (M + H);

Analysis: Calculated: C, 50.67; H, 5.37; N, 15.55; Br, 17.74; found: C

52,36;

H, 5.84; N, 14.90; Br, 17.44;

NMR (CDCl3, 300 MHz): 2.32 (s, 3H), 2.57 (s, 3H), 3.42 (s, 6H), 3.60 (s, J = 8, 2H), 3, 69 (s, J = 8, 2H), 3.82 (s, 3H), 4.60-4.70 (m, 1H), 6.73 (d, J = 8, 1H), 6.93 ( dd, J = 8, 1H, 7.22 (d, J = 8, 1H).

ag) CI-ASGMS: Calc'd: 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, 1H), 6.92 (dd, J = 8, 1.1, 1H), 7.20-7.30 (m, 2H).

ah) CI-ASGMS: Calc'd: 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), &lt;07 (sq, J = 8, 4H), 6.93 (s, 2H).

ai) CI-ASGMS: 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; N17.13;

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 (sq, J = 8, 4H), 3.66 (dd, J = 8, 3, 2H), 3.75 (dd, J = 8, 3, 2H), 4.55-4.65 (m, 1H) 6.75 (d, J = 8, 1H), 6.95 (s,

2H).

aj) CI-ASGMS: Calc'd: 398.2556; found: 398.2545 (M + H);

103

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

NMR (CDCl 3, 300 MHz): 1.95-2.10 (m, 8H), 2.20 (s, 3H), 2.32 (s, 3H), 2.44 (S, 3H), 3, 38 (s, 3H), 3.42 (s, 3H), 3.50-3.70 (m, 4H), 4.58-4.70 (m, 1H), 6.87 (d, J = Δ (1H), 6.95 (s, 2H).

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

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

NMR (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).

ai) CI-ASGMS: calculated: 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 = 8, 1, 1H).

am) CI-ASGMS: Calc'd: 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 = S, 1H), 6.93 (dd, J = 8 , 1H, 7.21-7.30 (m, 2H).

an) CI-ASGMS: Calc'd: 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, 1H), 7.20-7.25 (m, 2H) ).

ao) CI-ASGMS: 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), 6.506.55 (m, 1H), 7.00-7.15 ( m, 3H).

ap) CI-ASGMS: Calc'd: 397.1988; found: 397.1984 (M + H);

NMR (CDCl_3l 300 MHz): 2.43 (s, 3H), 2.50 (s, 3H), 3.43 (s, 3H), 3.61 (dd, J = 8, 8, 2H), 3.69 ( dd, J = 8.8, 2H), 3.88 (s, 3H), 4.58-4.70 (m,

1H), 6.75 (d, J = 8, 1H), 7.20 (dd, J = 8, 1, 1H), 7.25 (d, J = 1, 1H), 7.40 (s,

1H).

aq) CI-ASGMS: 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), 3.303.40 (m, 1H), 4.50 (t, J = Δ, 2Η), 6.95 (s, 2H).

ar) CI-ASGMS: Calc'd: 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;

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, 1H), 7.08 (d, J = 8, 1H), 7.37 (dd, J = 8, 1, 1H), 7.45 (d, J = 1) , 1H).

as) CI-ASGMS: Calc'd: 448.1348; found: 448.1332 (M + H);

Analysis: Calculated: C, 53.58; H, 5.85; N, 16.62; Br, 17.82; found: C

53.68; H, 5.74; N, 15.52; Br, 13.03;

104

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 = Δ, 1H), 7.05 (d, J = 8, 1H), 7.35 (dd, J = 8, 1, 1H), 7.47 (d, J = 1, 1H).

at) CI-ASGMS: Calculated: 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;

N17.14;

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

au) CI-ASGMS: Calc'd: 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-ASGMS: Calcd .: 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 = Δ, 1H), 6.78 (s, 1H), 6.98 (s, 1H).

aw) CI-ASGMS: Calc'd: 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) -ASGMS: Calcd .: 390.1697; found: 390.1688 (M + H);

Analysis: Calculated: C, 58.53; H, 6.20; N, 17.96; Cl, 9.09; Found: C, 58.95; H, 6.28; N17.73; Cl, 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, 1H),

6.72 (d, J = 8, 1H), 7.12 (d, J = 8, 1H), 7.23 (d, J = 8, 1H), 7.32 (s, 1H), ay) CI-ASGMS: Calcd .: 374.1748: Found: 374.1735 (M + H);

Analysis: Calculated: C, 61.04; H, 6.47; N, 18.73; Cl, 9.48; Found: C, 61.47; H, 6.54; N18.23; 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, 1H), 7.12 (d, J = 8, 1H), 7.07 (d,

J = 8, 1H), 7.12 (s, 1H).

az) CI-ASGMS: calculated: 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, 1H), 7.22 (d,

J = 8, 1H), 7.31 (s, 1H), ba) CI-ASGMS: Calc'd: 404.1853; Found: 404.1859 (M + H);

Analysis: Calculated: C, 59.47; H, 6.50; N, 17.34; C 8.79; Found: C, 59.73; H, 6.46; N17.10; 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 = S. 1H), 7.12 (d, J = 8, 1H), 7.45 (d, J = 8, 1H), 7.32 (s, 1H).

bb) CI-ASGMS: Calc'd: 391.2246; found: 391.2258 (M + H);

105

Analysis: Calculated: C, 67.67; H, 6.71; N, 21.52; Found: C, 67.93; H, 6.70; N21.48;

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).

be) CI-ASGMS: Calcd .: 386.2196; 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,

H, J = 8, 1), 6.7 (pi.d, 1H, J = 8), 4.7 - 4.6 (m, 1H), 3.85 (s, 3H), 3,703.55 (m, 4H), 3.45 (s, 6H), 2.5 (s, 3H), 2.3 (s, 3H), 2.15 (s, 3H).

bd) CI-ASGMS: Calculated: 400.2349; found: 400.2336 (M + H);

NMR (CDCl_a, 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 (ss, 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-ASGMS: Calcd .: 370.2243; Found: 370.2247 (M + H);

Analysis: Calculated: C, 65.02; H, 7.38; N, 18.96; Found: C, 65.28; H, 7.27;

N1S.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 , Δ (ppm, 1H, J = 1), 4.5-4.3 (m, 1H), 3.85 (s, 3H), 3,653.5 (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-ASGMS: Calc'd: 379.2246; Found: 379.2248 (M + H);

NMR (CDCl3, 300 MHz): 7.1 (d, 1H, J = 8). 6.85 (d, 1H, J = 1). 6.8 (dd, 1H, J = 8, 1), 4.3-4.0 (m, 4H), 3.85 (s, 3H), 3.0 (t, 2H, J = 7), 2.45 (s,

3H), 2.3 (s, 3H), 2.2 (s, 3H), 1.9-1.8 (m, 2H), 1.0 (t, 3H, J = 7).

bg) CI-ASGMS: Calc'd: 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 (pi, 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-ASGMS: Calc'd: 313.1665; found: 313.6664 (M + H).

bi) CI-ASGMS: Calc'd: 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, Δ (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-ASGMS: Calcd .: 377.2090; Found: 377.2092 (M + H);

Analysis: 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-ASGMS: Calc'd: 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 (kv, 4H, J = 7), 2.5 (s, 3H) ), 2.3 (s, 3H), 2.2 (s, 3H), 1.25 (t, 6H, J = 7).

bl) CI-ASGMS: Calc'd: 420.1802; found: 420.1825 (M + H);

bm) CI-ASGMS: Calc'd: 390.1697; found: 390.1707 (M + H);

106 bn) CI-ASGMS: Calc'd: 397.1465: Found: 397.1462 (M + H);

bo) CI-ASGMS: Calc'd: 360.1513; found: 360.1514 (M + H);

bp) CI-ASGMS: Calcd .: 374.1748; Found: 374.1737 (M + H);

bq) CI-ASGMS: Calcd: 479.1155; found: 479.1154 (M + H);

br) CI-ASGMS: Calc'd: 463.1219; found: 463.1211 (M + H);

Analysis: Calculated: C, 51.96; H, 5.23; N, 15.15; Br, 17.28; Found: C, 52.29; H, 5.62; N14.79; Br, 17.47.

bs) CI-ASGMS: Calc'd: 433.1113; found: 433.1114 (M,⁷⁹Br);

bt) NH₃-Cl MS: Calcd .: 406; found: 406 (M + H)⁺;

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

431 example

Preparation of 2,4,7-Dimethyl-8- (4-methoxy-2-methylphenyl) [1,5-a] -pyrazolo-1,3,5-triazine (Formula 1 wherein F!³ is CH 3, R¹ is CH 3, Z is C-CH₃, Is 2,4-dimethylphenyl)

5-Acetamidino-4- (4-methoxy-2-methylphenyl) -3-methylpyrazole acetic acid salt (602 mg, 2 mmol) was stirred with saturated NaHCO₃ solution (10 mL). The aqueous mixture was extracted with EtOAc three times. The combined organic layers were dried over MgSO 4₄, filtered and concentrated in vacuo. The residue was mixed with toluene (10 mL) and trimethylorthoacetate (0.36 g, 3 mmol) was added to the suspension. The reaction mixture was refluxed under nitrogen and stirred for 16 h. After cooling to room temperature, the reaction mixture is concentrated in vacuo to give an oily solid. After column chromatography (CHCI₃: MeOH - 9: 1) and evaporation of the solvent in vacuo gave a yellow viscous oil (R_f = 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), 2.95 (s, 3H), 2.65 (s, 3H), 2.4 (s, 3H), 2.15 (s, 3H); CI-ASGMS: Calc'd: 283.1559, Found: 283.1554 (M + H).

432 example

Preparation of 7-Hydroxy-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine

107 (Formula 1 wherein A is CH, R¹ is Me, R³ is OH, Z is C-Me, Ar is 2-chloro-4-methylphenyl)

5-Amino-4- (2-chloro-4-methylphenyl) -3-methylpyrazole (1.86 g, 8.4 mmol) was dissolved in glacial acetic acid (30 mL) with stirring. Ethyl acetate (1.18 mL, 9.2 mmol) was added dropwise to the resulting solution. The reaction mixture was then refluxed and stirred for 16 hours and cooled to room temperature. Ether (100 mL) was added and the resulting precipitate was filtered off. Drying in vacuo afforded a white solid (1.0 g, 42% yield): NMR (CDCl₃,

300 MHz): 8.70 (ss, 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) @ +.

433 example

Preparation of 7-Chloro-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] -pyrimidine (Formula 1 wherein A is CH, R¹ is Me, R³ is Cl, Z is C-Me, Ar is 2-Chloro-4-methylphenyl)

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, A mixture of 64 ml, 17.4 mmol), N, N-diethylaniline (0.63 g, 0.7 ml, 4.2 mmol) and toluene (20 ml) was stirred and refluxed for 3 hours, then cooled to room temperature. Volatiles are evaporated in vacuo. Flash chromatography of the residue (EtOAc: hexane - 1: 2) affords 7-chloro-5-methyl-3- (2-chloro-4-methylphenyl) -pyrazolo [1,5-a] pyrimidine (900 mg, 84% yield). is a yellow oil; NMR (CDCl₃, 300 MHz): 7.35 (s, 1H), 7.28-7.26 (m, 1H), 7.16 (d, 1H, J = 7), 6.80 (s, 1H), 2 , 55 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H); CI-MS: 306 (M + H).

434 example

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

108

A solution of 3-pentylamine (394 mg, 6.5 mmol) and 7-chloro-5-methyl-3- (2-chloro-4-methylphenyl) pyrazolo [1,5-a] pyrimidine (200 mg, 0.65 mmol) in dimethyl sulfoxide (DMSO, 10 mL) was stirred at 150 ° C for 2 h; then cooled to room temperature. The reaction mixture is then poured onto water (100 mL) and stirred. After three extractions with dichloromethane, washing the combined organic layers with a saturated NaCl solution, drying over MgSO4, filtration and evaporation in vacuo, a yellow solid was obtained. Flash chromatography (EtOAc: hexanes 1: 4) gave a white solid (140 mg, 60% yield); melt temp. 139-141 ° C; NMR (CDCl3, 300 MHz): 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 (ΐ, 6H, J = 8); analysis subtracted from C₂₀H₂₅CIN4 ·. 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 in Table 1 can be prepared by the methods described in Examples 1A, 1B, 432, 433, 434. Commonly used abbreviations are: Ph - phenyl, Pr - propyl, Me - methyl, Et - ethyl, Bu - butyl, e.g. example, EtOAc - ethyl acetate.

table

R³

<img file="LT4680B_D0061.tif" />

Ar

<td>For example,</td><td>Z</td><td>R³</td><td>Ar</td><td>Lyd. temp</td>

<td>No.</td><td></td><td></td><td></td><td>(= C)</td>

<td> 435^b</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-CI₂-Ph</td><td> 71-73</td>

<td> 436^c</td><td>C-Me</td><td>N (Bu) Et</td><td>2,4-CI₂-Ph</td><td> 86-87</td>

<td> 437^d</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2,4-Cb-Ph</td><td> 110-111</td>

<td> 438®</td><td>C-Me</td><td>N (Pr) CH₂CH₂CN</td><td>2,4-Cb-Ph</td><td> 83-85</td>

109

<td> 439</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2,4-CI₂-Ph</td><td> 175-176</td>

<td> 440⁹</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4-CI₂-Ph</td><td> 107</td>

<td> 441^h</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 442'</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4-Me₂-Ph</td><td> 103-105</td>

<td> 443'</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-Me₂-Ph</td><td> 87-89</td>

<td> 444^k</td><td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td><td>133 (splits)</td>

<td> 445'</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI, 4-MePh</td><td> 77-78</td>

<td> 446^m</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI, 4-MePh</td><td> 131-133</td>

<td> 447ⁿ</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2-CI, 4-MePh</td><td> 139-141</td>

<td> 448°</td><td>C-Me</td><td>NEt₂</td><td>2,4-Me₂-Ph</td><td> 92-94</td>

<td> 449^p</td><td>C-Me</td><td>N (Pr) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td><td> 143-144</td>

<td> 450^q</td><td>C-Me</td><td>N (Bu) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td><td> 115-117</td>

<td> 451^r</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 452^s</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2-Me, 4-MeOPh</td><td> 104-106</td>

<td> 453'</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me, 4-MeOPh</td><td> 115-116</td>

<td> 454^u</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me, 4-MeOPh</td><td>oil</td>

<td> 455^v</td><td>C-Me</td><td>fSJ- NHCH (CH₂CH₂OMe) - (CH₂OMe)</td><td>2-Me, 4-MeOPh</td><td>oil</td>

<td> 456^w</td><td>C-Me</td><td>(S) - NHCH (CH₂CH₂OMe) - (CH₂OMe)</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 457*</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me, 4-CIPh</td><td>oil</td>

<td> 458^y</td><td>C-Me</td><td>ΝΗΕΐ</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 459^z</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2-Me, 4-CIPh</td><td> 94-96</td>

<td> 460^aa</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me, 4-CIPn</td><td> 113-114</td>

<td> 461^ab</td><td>C-Me</td><td>N (Ac) Et</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 462^ac</td><td>C-Me</td><td>fSj- NHCH (CH₂CH₂OMe) - (CH₂OMe)</td><td>2-Me, 4-CIPh</td><td>oil</td>

<td> 463^ad</td><td>C-Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Me, 4-MeOPh</td><td> 118-119</td>

<td> 464^ae</td><td>C-Me</td><td>NEt₂</td><td>2-Me, 4-MeOPh</td><td> 97-99</td>

<td> 465^af</td><td>C-Me</td><td>(S) - NHCH (CH₂CH₂OMe) - (CH₂OMe)</td><td>2-CI, 4-MePh</td><td> 101-103</td>

<td> 466^ag</td><td>C-Me</td><td>NEt₂</td><td>2-CI, 4-MePh</td><td> 129-130</td>

110

<td> 467^ah</td><td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Me, 4-MeOPh</td><td> 177-178</td>

<td> 468^a'</td><td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI, 4-MePh</td><td> 162-163</td>

<td> 469^aj</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Me, 4-MeOPh</td><td>oil</td>

<td> 470^ak</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-CI, 4-MePh</td><td> 111-113</td>

<td> 471</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4-MeOPh</td><td></td>

<td> 472</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4-MeOPh</td><td></td>

<td> 473</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-CI-4-MeOPh</td><td></td>

<td> 474</td><td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI-4-MeOPh</td><td></td>

<td> 475</td><td>C-Me</td><td>N No₂</td><td>2-CI-4-MeOPh</td><td></td>

<td> 476</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-CI-4-MeOPh</td><td></td>

<td> 477</td><td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Ci-4-MeOPh</td><td></td>

<td> 478</td><td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-CI-4-MeOPh</td><td></td>

<td> 479</td><td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Br-4-MeOPh</td><td></td>

<td> 480</td><td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Br-4-MeOPh</td><td></td>

<td> 481</td><td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4-MeOPh</td><td></td>

<td> 482</td><td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Me-4-MeOPh</td><td></td>

<td> 483</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4,5- (MeO)₂Ph</td><td></td>

<td> 484</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Ci-4,5- (MeO)₂Ph</td><td></td>

<td> 485</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-CI-4,5- (MeO)₂Ph</td><td></td>

<td> 486</td><td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI-4,5- (MeO)₂Ph</td><td></td>

<td> 487</td><td>C-Me</td><td>NEt₂</td><td>2-CI-4,5- (MeO)₂Ph</td><td> 99-101</td>

<td> 488</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-CI-4,5- (MeO)₂Ph</td><td> 169-170</td>

<td> 489</td><td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-CI-4,5- (MeO)₂Ph</td><td></td>

<td> 490</td><td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-CI-4,5- (MeO)₂Ph</td><td></td>

<td> 491</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4,5- (MeO)₂Ph</td><td> 90-93</td>

<td> 492</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4,5- (MeO)₂Ph</td><td> 110</td>

<td> 493</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4,5- (MeO)₂Ph</td><td></td>

<td> 494</td><td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Br-4,5- (MeO)₂Ph</td><td></td>

<td> 495</td><td>C-Me</td><td>NEt₂</td><td>2-Br-4,5- (MeO)₂Ph</td><td></td>

<td> 496</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-Br-4,5- (MeO)₂Ph</td><td></td>

<td> 497</td><td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Br-4,5- (MeO)₂Ph</td><td></td>

<td> 498</td><td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Br-4,5- (MeO)₂Ph</td><td></td>

111

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-0-4.6- (MeO)₂Ph</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4,6- (MeO)₂Ph</td>

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

<td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-0-4.6- (MeO)₂Ph</td>

<td>C-Me</td><td>NEt₂</td><td>2-CI-4,6- (MeO)₂Ph</td>

<td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-0-4.6- (MeO)₂Ph</td>

<td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-0-4.6- (MeO)₂Ph</td>

<td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-0-4.6- (MeO)₂Ph</td>

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

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

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

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

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

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

<td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4,6- (MeO)₂Ph</td>

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

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

<td>C-Me</td><td>N No₂</td><td>2-Br-4,6- (MeO)₂Ph</td>

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

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

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

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

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

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4-MePh</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-MePh</td>

<td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4-MePh</td>

<td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4-MePh</td>

<td>C-Me</td><td>N No₂</td><td>2-MeO-4-MePh</td>

<td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4-MePh</td>

<td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4-MePh</td>

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

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4-MePh</td>

112

<td> 531</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-MePh</td>

<td> 532</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4-MePh</td>

<td> 533</td><td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4-MePh</td>

<td> 534</td><td>C-Me</td><td>NEt₂</td><td>2-MeO-4-MePh</td>

<td> 535</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4-MePh</td>

<td> 536</td><td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4-MePh</td>

<td> 537</td><td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4-MePh</td>

<td> 538</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4-C! Ph</td>

<td> 539</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-CIPh</td>

<td> 540</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4-CIPh</td>

<td> 541</td><td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4-CIPh</td>

<td> 542</td><td>C-Me</td><td>NEt₂</td><td>2-MeO-4-CIPh</td>

<td> 543</td><td>C-Me</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4-CIPh</td>

<td> 544</td><td>C-Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4-CIPh</td>

<td> 545</td><td>C-Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4-CIPh</td>

Notes to Table 2:

b)

c)

d)

e)

f)

h)

i)

7,49

i)

7,83

k)

D

m)

n)

o)

CI-ASGMS: Calc'd: 423.1355; found: 423.1337 (M + H);

Analysis: Calculated: C, 61.38; H, 6.18; N, 14.32; Found: C, 61.54; H, 6.12; N, 14.37;

Analysis: Calculated: C, 58.02; H, 5.65; N, 14.24; Found: C, 58.11; H, 5.52; N, 14.26;

Analysis: Calculated: C, 59.71; H, 5.26; N, 14.85; Found: C, 59.94; H, 5.09; N, 17.23;

Analysis: Calculated: C, 60.48; H, 5.89; N, 14.85; Found: C, 60.62; H, 5.88; N, 14.82;

CI-ASGMS: Calc'd: 337.2388; found: 337.2392 (M + H);

Analysis: Calculated: C, 68.45; H 7.669: N 15.21; Found: C, 68.35; HN, 14.91;

Analysis: Calculated: C, 69.08; H, 7.915; N, 14.65; Found: C, 68.85; HN, 14.54;

Analysis: Calculated: C, 73.51; H, 7.01; N, 19.48; Found: C, 71.57; H, 7.15; N, 19.12;

CI-ASGMS: Calcd .: 403.1899; Found: 403.1901 (M + H);

Analysis: Calculated: C, 61.77; H, 6.49; N, 14.41; Cl, 9.13; Found: C, 61.90; H, 6.66; N, 13.62; Cl, 9.25;

Analysis: Calculated: C, 67.31; H, 7.06; N, 15.70; Cl, 9.93; Found: C, 67.32; H, 6.95; N, 15.50; Cl, 9.93;

Analysis: Calculated: C, 74.50; H, 8.14; N, 17.38. Found: C, 74.43; H, 7.59; N, 17.16;

113

P)

P)

r)

s)

t)

u)

v)

w)

x)

y)

z) aa) ab) ac) ad) ae) aq) ah) ai) aj) ak)

Analysis: Calculated: C, 73.10; H, 7.54; N, 19.37; found; C, 73.18; H, 7.59; N, 18.81;

Analysis: Calculated: C, 73.57; H, 7.78; N, 18.65; Found: C, 73.55; H, 7.79; N, 18.64;

CI-ASGMS: Calcd .: 353.2333; Found: 353.2341 (M + H);

Analysis: Calculated: C, 71.56; H, 8.02; N, 15.90; Found: C, 71.45; H, 7.99; N, 15.88;

Analysis: Calculated: C, 65.60; H, 7.34; N, 14.57; Found: C, 65.42; H, 7.24;

N, 14.37;

CI-ASGMS: Calc'd: 399.2398; CI-ASGMS: Calc'd: 399.2398; CI-ASGMS: Calcd .: 383.2450; CI-ASGMS: Calcd .: 403.1887; CI-ASGMS: Calcd .: 295.1919; Analysis: Calculated: C, 67.31; H 7, (found: 399.2396 (M + H); found: 399.2396 (M + H); found: 383.2447 (M + H); found: 403.1901 (M + H); found: 295.1923 (M + H);

) 6; N, 15.70; Found: C, 67.12; H, 6.86;

N, 15.53;

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;

CI-ASGMS: Calcd .: 337.2017; Found: 337.2028 (M + H); CI-ASGMS: Calcd .: 403.1893; Found: 403.1901 (M + H);

Analysis: Calculated: C, 70.00; H, 7.22; N, 18.55; Found: C, 70.05; H, 7.22; N, 18.36.

Analysis: Calculated: C, 70.98; H, 7.74; N, 16.55; Found: C, 71.15; H, 7.46;

N, 16.56.

Analysis: Calculated: C, 66.59; H, 6.76; N, 16.34; Found: C, 66.69; H, 6.82; N, 16.20;

Analysis: Calculated: C, 70.38; H, 6.71; N, 18.65; Found: C, 70.35; H, 6.82;

N, 18.83;

Analysis: Calculated: C, 66.39; H, 5.85; N, 18.44; Cl, 9.33; Found: C, 66.29; H, 5.51; N, 18.36. C 9.31;

CI-ASGMS: Calcd .: 369.2278; Found: 369.2291 (M + H);

Analysis: Calculated: C, 64.42; H, 6.77; N, 15.02; Found: C 64.59: H 6.51: N 14.81;

The examples in Table 1 may be prepared by the methods described in Examples 1, 2, 3 or 6. Commonly used abbreviations are: Ph - phenyl, Pr - propyl, Me - methyl, Et - ethyl, Bu - butyl, e.g. - example, table

<img file="LT4680B_D0062.tif" />

Ar

114

For example, Lyd.

<td>No.</td><td>Z</td><td>r₃</td><td>Ar</td><td>temp. (° C)</td>

<td> 546^a</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2-Me-4-Me₂N-Ph</td><td> 164-166</td>

<td> 547^b</td><td>C-Me</td><td>(S) -NHCH (CH₂CH₂OMe) - CH₂OMe</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 548</td><td>C-Me</td><td>fS) -NHCH (CH₂CH₂OMe) - CH₂OMe</td><td>2-Me-4-CI-Ph</td><td>oil</td>

<td> 549^d</td><td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Me-4-CI-Ph</td><td> 115-116</td>

<td> 550®</td><td>C-Me</td><td>NHCH (Et) CH₂CN</td><td>2-Me-4-CI-Ph</td><td> 131-132</td>

<td> 551’</td><td>C-Me</td><td>N (Et)₂</td><td>2,3-Me₂-4-OMe-Ph</td><td>oil</td>

<td> 552³</td><td>C-Me</td><td rowspan="2">N (CH₂CH₂OMe) CH₂CH₂O H N (CH₂CH₂OMe)₂</td><td>2,4-CI₂-Ph</td><td>oil</td>

<td> 553^h</td><td>C-Me</td><td>2,3-Me₂-4-OMe-Ph</td><td>oil</td>

<td> 554ⁱ</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2,3-Me₂-4-OMePh</td><td> 123-124</td>

<td> 555^J</td><td>C-Me</td><td>N (CH₂-c-Pr) Pr</td><td>2-Me-4-CI-Ph</td><td>oil</td>

<td> 556^k</td><td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2,3-Me₂-4-OMePh</td><td> 158-160</td>

<td> 557</td><td>C-Me</td><td>N (c-Pr) Et</td><td>2-CI-4-OMePh</td><td></td>

<td> 558</td><td>C-Me</td><td>N (c-Pr) Me</td><td>2-CI-4-OMePh</td><td></td>

<td> 559</td><td>C-Me</td><td>N (c-Pr) Pr</td><td>2-CI-4-OMePh</td><td></td>

<td> 560</td><td>C-Me</td><td>N (c-Pr) Bu</td><td>2-CI-4-OMePh</td><td></td>

<td> 561'</td><td>C-Me</td><td>N (Et)₂</td><td>2-CI-4-CN-Ph</td><td> 115-117</td>

<td> 562</td><td>C-Me</td><td>N (c-Pr)₂</td><td>2-CI-4-OMe</td><td> 127-129</td>

<td> 563 ^m</td><td>C-Me</td><td>NHCH (CH₂OH)₂</td><td>2,4-CI₂-Ph</td><td> 128-129</td>

<td> 564</td><td>C-Me</td><td>N (c-Pr) Et</td><td>2-Br-4,5- (MeO)₂Ph</td><td></td>

<td> 565</td><td>C-Me</td><td>N (c-Pr) Me</td><td>2-Br-4,5- (MeO)₂Ph</td><td></td>

<td> 566</td><td>C-Me</td><td>NH-c-Pr</td><td>2-Me-4-MeOPh</td><td> 126-128</td>

<td> 567</td><td>C-Me</td><td>NHCH (Et) CH₂OH</td><td>2-Me-4-MeOPh</td><td> 60-62</td>

<td> 568</td><td>C-Me</td><td>NMe₂</td><td>2-Br-4,5- (MeO)₂Ph</td><td></td>

<td> 569</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2-Me-4-MeOPh</td><td> 103-105</td>

<td> 570</td><td>C-Me</td><td>N (c-Pr) Et</td><td>2-Me-4-MeOPh</td><td> 173-174</td>

<td> 571</td><td>C-Me</td><td>ΝΗ-2-pentyl</td><td>2,4-Cb-Ph</td><td> 118-120</td>

<td> 572</td><td>C-Me</td><td>NHCH (Et) CH₂CN</td><td>2,4-CI₂-Ph</td><td> 141-142</td>

<td> 573</td><td>C-Me</td><td>NHCH (Pr) CH₂OMe</td><td>2,4-Cb-Ph</td><td> 87-88</td>

115

<td> 574</td><td>C-Me</td><td>NHCH (CH₂-iPr) CH₂OMe</td><td>2,4-CI₂-Ph</td><td>amorphous.</td>

<td> 575</td><td>C-Me</td><td>ΝΗ-2-Butyl</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 576</td><td>C-Me</td><td>ΝΗ-2-pentyl</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 577</td><td>C-Me</td><td>ΝΗ-2-hexyl</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 578</td><td>C-Me</td><td>NHCH (i-Pr) Me</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 579</td><td>C-Me</td><td>NHCH (Me) CH₂-iPr</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 580</td><td>C-Me</td><td>NHCH (Me) -CC₆Hn</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 581</td><td>C-Me</td><td>ΝΗ-2-Indanyl</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 582</td><td>C-Me</td><td>ΝΗ-1-Indanyl</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 583</td><td>C-Me</td><td>NHCH (Me) Ph</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 584</td><td>C-Me</td><td>NHCH (Me) CH₂- (4-CIPh)</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 585</td><td>C-Me</td><td>NHCH (Me) CH₂COCH₃</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 586</td><td>C-Me</td><td>NHCH (Ph) CH₂Ph</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 587</td><td>C-Me</td><td>NHCH (Me) (CH₂)₃NEt₂</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 588</td><td>C-Me</td><td>NH- (2-Ph-cC.)₃H₄)</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 589</td><td>C-Me</td><td>NHCH (Et) CH₂CN</td><td>2,4-Me₂-Ph</td><td> 119-120</td>

<td> 590</td><td>C-Me</td><td>ΝΗ-3-hexyl</td><td>2,4-Me₂-Ph</td><td>oil</td>

<td> 591ⁿ</td><td>C-Me</td><td>NEt₂</td><td>2-MeO-4-CIPh</td><td>oil</td>

<td> 592°</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2-MeO-4-CIPh</td><td>oil</td>

<td> 593^p</td><td>C-Me</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4-CIPh</td><td>oil</td>

<td> 594</td><td>C-Me</td><td>NMe₂</td><td>2-MeO-4-CIPh</td><td>oil</td>

<td> 595^q</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2-OMe-4-MePh</td><td>oil</td>

<td> 596^r</td><td>C-Me</td><td>NEt₂</td><td>2-OMe-4-MePh</td><td>oil</td>

<td> 597^s</td><td>Cc-Pr</td><td>NHCH (CH₂OMe)₂</td><td>2,4-CI₂-Ph</td><td>oil</td>

<td> 598</td><td>C-Me</td><td>N (c-Pr) Et</td><td>2,4-Me₂-Ph</td><td></td>

<td> 599</td><td>C-Me</td><td>N (c-Pr) Et</td><td>2,4-CI₂-Ph</td><td></td>

<td> 600</td><td>C-Me</td><td>N (c-Pr) Et</td><td>2,4,6-Me₃-Ph</td><td></td>

<td> 601</td><td>C-Me</td><td>N (c-Pr) Et</td><td>2-Me-4-CI-Ph</td><td></td>

<td> 602</td><td>C-Me</td><td>N (c-Pr) Et</td><td>2-CI-4-Me-Ph</td><td></td>

<td> 603</td><td>C-Me</td><td>NHCH (c-Pr)₂</td><td>2,4-CI₂-Ph</td><td></td>

<td> 604</td><td>C-Me</td><td>NHCH (c-Pr)₂</td><td>2,4-Me₂-Ph</td><td></td>

<td> 605</td><td>C-Me</td><td>NHCH (c-Pr)₂</td><td>2-Me-4-CI-Ph</td><td></td>

116

<td> 606</td><td>C-Me</td><td>NHCH (c-Pr)₂</td><td>2-CI-4-Me-Ph</td>

<td> 607</td><td>C-Me</td><td>NHCH (c-Pr)₂</td><td>2-Me-4-OMe-Ph</td>

<td> 608</td><td>C-Me</td><td>NHCH (c-Pr)₂</td><td>2-CI-4-OMe-Ph</td>

<td> 609</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-5-F-OMePh</td>

<td> 610</td><td>C-Me</td><td>N No₂</td><td>2-CI-5-F-OMePh</td>

<td> 611</td><td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI-5-F-OMePh</td>

<td> 612</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2-CI-5-F-OMePh</td>

<td> 613</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-5-F-OMePh</td>

<td> 614</td><td>C-Me</td><td>Not this</td><td>2,6-Me₂-pyridyl-3-yl</td>

<td> 615</td><td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2,6-Me₂-pyridyl-3-i! as</td>

<td> 616</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2,6-Me₂-pyridii-3-yl</td>

<td> 617</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,6-Me₂-pyridyl-3-yl</td>

<td> 618</td><td>C-OH</td><td>NHCH (CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

<td> 619</td><td>C-OH</td><td>NEt₂</td><td>2,4-Me₂-Ph</td>

<td> 620</td><td>C-OH</td><td>N (c-Pr) OH₂OH₂ON</td><td>2,4-Me₂-Ph</td>

<td> 620</td><td>C-OH</td><td>N (c-Pr) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td>

<td> 621</td><td>C-OH</td><td>NHCH (Et)₂</td><td>2,4-Me₂-Ph</td>

<td> 623</td><td>C-OH</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

<td> 624</td><td>C-NEtg</td><td>NHCH (CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

<td> 625</td><td>C-NEt₂</td><td>N No₂</td><td>2,4-Me₂-Ph</td>

<td> 626</td><td>C-NEts</td><td>N (c-Pr) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td>

<td> 627</td><td>C-NEt₂</td><td>NHCH (Et)₂</td><td>2,4-Me₂-Ph</td>

<td> 628</td><td>C-NEt₂</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

<td> 629</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2-Me-4-CN-Ph</td>

<td> 630</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4-CN-Ph</td>

Notes to Table 3:

a) CI-ASGMS: Calculated: 367.2610; Found: 367.2607 (M + H);

b) CI-ASGMS: Calculated: 384.2400; Found: 384.2393 (M + H);

c) CI-ASGMS: Calc'd: 404.1853; Found: 404.1844 (M + H);

d) CI-ASGMS: Calc'd: 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-ASGMS: Calcd .: 369.1594; Found: 369.1576 (M + H);

f) CI-ASGMS: Calc'd: 354.2216; Found: 354.2211 (M + H);

117

g) CI-ASGMS: Calcd: 410.1072: Found: 410.1075 (M + H):

h) CI-ASGMS: Calc'd: 414.2427; found: 414.2427 (M + H);

i) CI-ASGMS: Calcd .: 368.2372; Found: 368.2372 (M + H);

j) CI-ASGMS: Calc'd: 384.1955; Found: 384.1947 (M + H);

k) CI-ASGMS: Calc'd: 391.2168; found: 391.2160 (M + H);

l) CI-ASGMS: Calc'd: 335.1984; Found: 335.1961 (M + H);

m) CI-ASGMS: Calc'd: 382.0759; Found: 382.0765 (M + H);

n) NH₃-Cl MS: Calcd .: 360; found: 360 (M + H) +;

o) NH3-CI MS: Calcd .: 374; found: 374 (M + H) +;

NMR (CDCl3, 300 MHz): δ 7.29 (d, J = 8.4Hz, 1H), 7.04 (dd, J = 1.8, 8Hz, 1H), 6.96 (d, J = 1) , 8Hz, 1H), 6.15 (d, J = 10, 1H), 4.19 (m, 1H), 3.81 (s,

3H), 2.47 (s, 3H), 2.32 (s, 3H), 1.65 (m, 4H), 0.99 (t, J = 7.32Hz, 6H).

p) NH 3 -Cl MS: Calcd .: 390; found: 390 (M + H) +;

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

7.32 Hz, 3H).

q) CI-ASGMS: Calcd .: 354.2294; found: 354.2279 (M + H) +;

r) CI-ASGMS: Calc'd: 340.2137; found: 340.2138 (M + H) +;

s) CI-ASGMS: Calc'd: 436.1307; found: 436.1296 (M + H) +.

The examples in Table 1 can be prepared by the methods described in Examples 1A, 1B, 432, 433, 434. Commonly used abbreviations are: Ph - phenyl, Pr - propyl, Me - methyl, Et - ethyl, Bu - butyl, Eg, example, EtOAc - ethyl acetate.

R³

<img file="LT4680B_D0063.tif" />

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

<td>For example, No.</td><td>Z</td><td>R³</td><td>Ar</td>

<td> 631</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2-Br-4,5- (MeO)</td>

<td> 632</td><td>C-Me</td><td>NHCH (Et)₂</td><td>2-Br-4-MeOPh</td>

<td> 633</td><td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-MeOPh</td>

<td> 634</td><td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-MeOPh</td>

<td> 635</td><td>C-Me</td><td>N (Et)₂</td><td>2-Me-4-CIPh</td>

table

Lyd.

temp.

(° C)

160-161

110-111

74-76

128-130

113-114

118

<td>C-Me</td><td>N (c-Pr) Et</td><td>2,4-CI₂Ph</td>

<td>C-Me</td><td>N (c-Pr) Et</td><td>2,4-Me₂Ph</td>

<td>C-Me</td><td>N (c-Pr) Et</td><td>2,4,6-Me₃Ph</td>

<td>C-Me</td><td>N (c-Pr) Et</td><td>2-Me-4-MeOPh</td>

<td>C-Me</td><td>N (c-Pr) Et</td><td>2-CI-4-MeOPh</td>

<td>C-Me</td><td>N (c-Pr) Et</td><td>2-CI-4-MePh</td>

<td>C-Me</td><td>N (c-Pr) Et</td><td>2-Me-4-CIPh</td>

<td>C-Me</td><td>NHCH (c-Pr)₂</td><td>2,4-Cb-Ph</td>

<td>C-Me</td><td>NHCH (c-Pr)₂</td><td>2,4-Me₂-Ph</td>

<td>C-Me</td><td>NHCH (c-Pr)₂</td><td>2-Me-4-Ci-Ph</td>

<td>C-Me</td><td>NHCH (c-Pr)₂</td><td>2-CI-4-Me-Ph</td>

<td>C-Me</td><td>NHCH (c-Pr)₂</td><td>2-Me-4-OMe-Ph</td>

<td>C-Me</td><td>NHCH (c-Pr)₂</td><td>2-Ci-4-OMe-Ph</td>

<td>C-Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-5-F-OMePh</td>

<td>C-Me</td><td>NEt₂</td><td>2-CI-5-F-OMePh</td>

<td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI-5-F-OMePh</td>

<td>C-Me</td><td>NHCH (Et)₂</td><td>2-CI-5-F-OMePh</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-5-F-OMePh</td>

<td>C-Me</td><td>N No₂</td><td>2,6-Me₂-pyrid-3-! las</td>

<td>C-Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2,6-Me₂-pyrid-3-yl</td>

<td>C-Me</td><td>NHCH (Et)₂</td><td>2,6-Me₂-pyrid-3-yl</td>

<td>C-Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,6-Me₂-pyrid-3-yl</td>

<td>C-OH</td><td>NHCH (CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

<td>C-OH</td><td>NEt₂</td><td>2,4-Me₂-Ph</td>

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

<td>C-OH</td><td>NHCH (Et)₂</td><td>2,4-Me₂-Ph</td>

<td>C-OH</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

<td>C-NEt₂</td><td>NHCH (CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

<td>C-NEt₂</td><td>NEt₂</td><td>2,4-Me₂-Ph</td>

<td>C-NEt₂</td><td>N (c-Pr) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td>

<td>C-NEt₂</td><td>NHCH (Et)₂</td><td>2,4-Me₂-Ph</td>

<td>C-NEt₂</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-Me₂-Ph</td>

119

668

669

C-Me NHCH (Et)₂C-Me N (CH₂CH₂OMe)₂

2-Me-4-CN-Ph

2-Me-4-CN-Ph or the examples in Table 6 may be prepared by the methods described in Examples 1A, 1B, 2, 3, 6, 431, 432, 433, 434 or by appropriate combinations thereof. Commonly used abbreviations are: Ph - phenyl, Pr - propyl, Me - methyl, Ethyl - ethyl, Bu - butyl, e.g. - an example.

table

R³

<img file="LT4680B_D0064.tif" />

Ar

<td>For example, No.</td><td>R14</td><td>Ra</td><td></td>

<td> 670</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4-CI₂-Ph</td>

<td> 671</td><td>Me</td><td>NHCHPr₂</td><td>2,4-CI₂-Ph</td>

<td> 672</td><td>Me</td><td>NEtBu</td><td>2,4-CI₂-Ph</td>

<td> 673</td><td>Me</td><td>NPr (CH₂-cC₃H₅)</td><td>2,4-CI₂-Ph</td>

<td> 674</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4-CI₂-Ph</td>

<td> 675</td><td>Me</td><td>Β-3-heptyl</td><td>2,4-CI₂-Ph</td>

<td> 676</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2,4-CI₂-Ph</td>

<td> 677</td><td>Me</td><td>NEt₂</td><td>2,4-CI₂-Ph</td>

<td> 678</td><td>Me</td><td>NHCH (CH₂OEt)₂</td><td>2,4-CI₂-Ph</td>

<td> 679</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2,4-CI₂-Ph</td>

<td> 680</td><td>Me</td><td>NMePh</td><td>2,4-CI₂-Ph</td>

<td> 681</td><td>Me</td><td>NPr₂</td><td>2,4-CI₂-Ph</td>

<td> 682</td><td>Me</td><td>ΝΗ-3-hexyl</td><td>2,4-CI₂-Ph</td>

<td> 683</td><td>Me</td><td>morpholine residue</td><td>2,4-CI₂-Ph</td>

<td> 684</td><td>Me</td><td>N (CH₂Ph) CH₂CH₂OMe</td><td>2,4-CI₂-Ph</td>

<td> 685</td><td>Me</td><td>NHCH (CH₂Ph) CH₂OMe</td><td>2,4-CI₂-Ph</td>

<td> 686</td><td>Me</td><td>ΝΗ-4-Tetrahydropyranyl</td><td>2,4-CI₂-Ph</td>

<td> 687</td><td>Me</td><td>NH-cyclopentyl</td><td>2,4-CI₂-Ph</td>

120

<td> 688</td><td>Me</td><td>OEt</td><td>2,4-CI₂-Ph</td>

<td> 689</td><td>Me</td><td>OCH (Et) CH₂OMe</td><td>2,4-CI₂-Ph</td>

<td> 690</td><td>Me</td><td>OCH₂Ph</td><td>2,4-CI₂-Ph</td>

<td> 691</td><td>Me</td><td>Ο-3-pentyl</td><td>2,4-CI₂-Ph</td>

<td> 692</td><td>Me</td><td>S No</td><td>2,4-CI₂-Ph</td>

<td> 693</td><td>Me</td><td>S (O) Et</td><td>2,4-Cb-Ph</td>

<td> 694</td><td>Me</td><td>SO₂No.</td><td>2,4-CI₂-Ph</td>

<td> 695</td><td>Me</td><td>Ph</td><td>2,4-CI₂-Ph</td>

<td> 696</td><td>Me</td><td>2-CF₃-Ph</td><td>2,4-Cb-Ph</td>

<td> 697</td><td>Me</td><td>2-Ph-Ph</td><td>2,4-Cb-Ph</td>

<td> 698</td><td>Me</td><td>3-pentyl</td><td>2,4-CI₂-Ph</td>

<td> 699</td><td>Me</td><td>cyclobutyl</td><td>2,4-CI₂-Ph</td>

<td> 700</td><td>Me</td><td>3-pyridyl</td><td>2,4-CI₂-Ph</td>

<td> 701</td><td>Me</td><td>CH (Et) CH₂CONMe₂</td><td>2,4-CI₂-Ph</td>

<td> 702</td><td>Me</td><td>CH (Et) CH₂CH₂NMe₂</td><td>2,4-CI₂-Ph</td>

<td> 703</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4,6-Me₃-Ph</td>

<td> 704</td><td>Me</td><td>NHCHPr₂</td><td>2,4,6-Me₃-Ph</td>

<td> 705</td><td>Me</td><td>NEtBu</td><td>2,4,6-Me₃-Ph</td>

<td> 706</td><td>Me</td><td>NPr (CH₂-cC₃H₅)</td><td>2,4,6-Me₃-Ph</td>

<td> 707</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4,6-Me₃-Ph</td>

<td> 708</td><td>Me</td><td>Β-3-heptyl</td><td>2,4,6-Me₃-Ph</td>

<td> 709</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2,4,6-Me₃-Ph</td>

<td> 710</td><td>Me</td><td>NEt₂</td><td>2,4,6-Me₃-Ph</td>

<td> 711</td><td>Me</td><td>NHCH (CH₂OEt)₂</td><td>2,4,6-Me₃-Ph</td>

<td> 712</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2,4,6-Me₃-Ph</td>

<td> 713</td><td>Me</td><td>NMePh</td><td>2,4,6-Me₃-Ph</td>

<td> 714</td><td>Me</td><td>NPr₂</td><td>2,4,6-Me₃-Ph</td>

<td> 715</td><td>Me</td><td>ΝΗ-3-hexyl</td><td>2,4,6-Me₃-Ph</td>

<td> 716</td><td>Me</td><td>morpholine residue</td><td>2,4,6-Me₃-Ph</td>

<td> 717</td><td>Me</td><td>N (CH₂Ph) CH₂CH₂OMe</td><td>2,4,6-Me₃-Ph</td>

<td> 718</td><td>Me</td><td>NHCH (CH₂Ph) CH₂OMe</td><td>2,4,6-Me₃-Ph</td>

<td> 719</td><td>Me</td><td>ΝΗ-4-Tetrahydropyranyl</td><td>2,4,6-Me₃-Ph</td>

121

<td>Me</td><td>NH-cyclopentyl</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>OEt</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>OCH (Et) CH₂OMe</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>OCH₂Ph</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>Ο-3-pentyl</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>S No</td><td>2,4,6-Me₃-Ph</td>

<td>M e</td><td>S (O) Et</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>SO₂No.</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CH (CO₂No)₂</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>C (Et) (CO₂No)₂</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CH (Et) CH₂OH</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CH (Et) CH₂OMe</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CONMe₂</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>COCH₃</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CH (OH) CH₃</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>C (OH) Ph-3-pyridyl</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>Ph</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>2-Ph-Ph</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>3-pentyl</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>cyclobutyl</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>3-pyridyl</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CH (Et) CH₂CONMe₂</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CH (Et) CH₂CH₂NMe₂</td><td>2,4,6-Me₃-Ph</td>

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

<td>Me</td><td>N (CH₂CH₂OM)₂</td><td>2,4-Me₂-Ph</td>

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

<td>Me</td><td>ΝΗ-3-pentyl</td><td>2,4-Me₂-Ph</td>

<td>Me</td><td>NEt₂</td><td>2,4-Me₂-Ph</td>

<td>Me</td><td>N (CH₂CN)₂</td><td>2,4-Me₂-Ph</td>

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

<td>Me</td><td>OCH (Et) CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td>Me</td><td>NPr-cC₃H₅</td><td>2,4-Me₂-Ph</td>

122

<td> 752</td><td>Me</td><td>NHCH (Me) CH₂NMe₂</td><td>2,4-Me₂-Ph</td>

<td> 753</td><td>Me</td><td>N (cC₃H₅) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td>

<td> 754</td><td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td>

<td> 755</td><td>Me</td><td>N (Bu) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td>

<td> 756</td><td>Me</td><td>NHCHPr₂</td><td>2,4-Me₂-Ph</td>

<td> 757</td><td>Me</td><td>NEtBu</td><td>2,4-Me₂-Ph</td>

<td> 758</td><td>Me</td><td>NPr (CH₂-cC₃H₅)</td><td>2,4-Me₂-Ph</td>

<td> 759</td><td>Me</td><td>Β-3-heptyl</td><td>2,4-Me₂-Ph</td>

<td> 760</td><td>Me</td><td>NEt₂</td><td>2,4-Me₂-Ph</td>

<td> 761</td><td>Me</td><td>NHCH (CH₂OEt)₂</td><td>2,4-Me₂-Ph</td>

<td> 762</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2,4-Me₂-Ph</td>

<td> 763</td><td>Me</td><td>NMePh</td><td>2,4-Me₂-Ph</td>

<td> 764</td><td>Me</td><td>NPr₂</td><td>2,4-Me₂-Ph</td>

<td> 765</td><td>Me</td><td>ΝΗ-3-hexyl</td><td>2,4-Me₂-Ph</td>

<td> 766</td><td>Me</td><td>morpholine residue</td><td>2,4-Me₂-Ph</td>

<td> 767</td><td>Me</td><td>N (CH₂Ph) CH₂CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td> 768</td><td>Me</td><td>NHCH (CH₂Ph) CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td> 769</td><td>Me</td><td>ΝΗ-4-Tetrahydropyranyl</td><td>2,4-Me₂-Pn</td>

<td> 770</td><td>Me</td><td>NH-cyclopentyl</td><td>2,4-Me₂-Ph</td>

<td> 771</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4-MeO-Ph</td>

<td> 772</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4-MeO-Ph</td>

<td> 773</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Me-4-MeO-Ph</td>

<td> 774</td><td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Me-4-MeO-Ph</td>

<td> 775</td><td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Me-4-MeO-Ph</td>

<td> 776</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-MeO-Ph</td>

<td> 777</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-MeO-Ph</td>

<td> 778</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4-MeO-Ph</td>

<td> 779</td><td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Br-4-MeO-Ph</td>

<td> 780</td><td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Br-4-MeO-Ph</td>

<td> 781</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4-NMe₂-Ph</td>

<td> 782</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4-NMe₂-Ph</td>

<td> 783</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Me-4-NMe₂-Ph</td>

123

<td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Me-4-NMe₂-Ph</td>

<td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Me-4-NMe₂-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-NMe₂-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-NMe₂-Ph</td>

<td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4-NMe₂-Ph</td>

<td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Br-4-NMe₂-Ph</td>

<td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Br-4-NMe₂-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-i-Pr-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-i-Pr-Ph</td>

<td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4-i-Pr-Ph</td>

<td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Br-4-i-Pr-Ph</td>

<td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Br-4-i-Pr-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-Me-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-Me-Ph</td>

<td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4-Me-Ph</td>

<td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Br-4-Me-Ph</td>

<td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Br-4-Me-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4-Br-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4-Br-Ph</td>

<td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Me-4-Br-Ph</td>

<td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Me-4-Br-Ph</td>

<td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Me-4-Br-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4,6-Me₂-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4,6-Me₂-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>4-Br-2,6- (Me)₂-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-Br-2,6- (Me)₂-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-CF₃-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-CF₃-Ph</td>

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

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

124

<td> 816</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4,6- (MeO)₂-Ph</td>

<td> 817</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4,6- (MeO)₂-Ph</td>

<td> 818</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2.6- (Me)₂-4-SMe-Ph</td>

<td> 819</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2.6- (Me)₂-4-SMe-Ph</td>

<td> 820</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>4- (COMe) -2-Br-Ph</td>

<td> 821</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>4- (COMe) -2-Br-Ph</td>

<td> 822</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4,6-Me₃-pyrid-3-yl</td>

<td> 823</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4,6-Me₃-pyrid-3-yl</td>

<td> 824</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4- (Br)₂-Ph</td>

<td> 825</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4- (Br)₂-Ph</td>

<td> 826</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td> 827</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td> 828</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>4-i-Pr-2-SO₂Me-Ph</td>

<td> 829</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-i-Pr-2-SO₂Me-Ph</td>

<td> 830</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2.6- (Me)₂-4-SMe-Ph</td>

<td> 831</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2.6- (Me)₂-4-SMe-Ph</td>

<td> 832</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2.6- (Me)₂-4-SO₂Me-Ph</td>

<td> 833</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2.6- (Me)₂-4-SO₂Me-Ph</td>

<td> 834</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-l-4-i-Pr-Ph</td>

<td> 835</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-l-4-i-Pr-Ph</td>

<td> 836</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-N (Me)₂-6-MeO-Ph</td>

<td> 837</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-N (Me)₂-6-MeO-Ph</td>

<td> 838</td><td>Me</td><td>NEt₂</td><td>2-Br-4-MeO-Ph</td>

<td> 839</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-Br-4-MeO-Ph</td>

<td> 840</td><td>Me</td><td>NHCH (CH₂OMe)₂..</td><td>2-CN-4-Me-Ph</td>

<td> 841</td><td>Me</td><td>N (cC₃H₅) CH₂CH₂CN</td><td>2,4,6-Me₃-Ph</td>

<td> 842</td><td>Me</td><td>NHCH (CH₂CH₂OMe) CH₂OMe</td><td>2-Me-4-Br-Ph</td>

<td> 843</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2.5-Me₂-4-MeO-Ph</td>

<td> 844</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2.5-Me₂-4-MeO-Ph</td>

<td> 845</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2.5-Me₂-4-MeO-Ph</td>

<td> 846</td><td>Me</td><td>NEt₂</td><td>2.5-Me₂-4-MeO-Ph</td>

<td> 847</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4-MePh</td>

125

<td>Me</td><td>NCH ​​(Et) CH₂OMe</td><td>2-CI-4-MePh</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4-MePh</td>

<td>Me</td><td>(SJ-NHCH (CH₂CH₂OMe) CH₂OMe</td><td>2-CI-4-MePh</td>

<td>Me</td><td>N (cC₃H₅) CH₂CH₂CN</td><td>2.5-Me₂-4-MeOPh</td>

<td>Me</td><td>NEt₂</td><td>2-Me-4-MeOPh</td>

<td>Me</td><td>OEt</td><td>2-Me-4-MeOPh</td>

<td>Me</td><td>(SJ-NHCH (CH₂CH₂OMe) CH₂OMe</td><td>2-Me-4-MeOPh</td>

<td>Me</td><td>N (cC₃H₅) CH₂CH₂CN</td><td>2-Me-4-MeOPh</td>

<td>Me</td><td>NHCH (CH₂CH₂OEt)₂</td><td>2-Me-4-MeOPh</td>

<td>Me</td><td>N (cC₃H₅) CH₂CH₂CN</td><td>2,4-CI₂-Ph</td>

<td>Me</td><td>NEt₂</td><td>2-Me-4-CIPh</td>

<td>Me</td><td>ΝΗ-3-pentyl</td><td>2-Me-4-CiPh</td>

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

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

<td>Me</td><td>NEt₂</td><td>2-Me-4-CIPh</td>

<td>Me</td><td>N No₂</td><td>2-CI-4-MePh</td>

<td>Me</td><td>ΝΗ-3-pentyl</td><td>2-CI-4-MePh</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4-MeOPh</td>

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

<td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-CI-4-MeOPh</td>

<td>Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI-4-MeOPh</td>

<td>Me</td><td>N No₂</td><td>2-CI-4-MeOPh</td>

<td>Me</td><td>ΝΗ-3-pentyl</td><td>2-CI-4-MeOPh</td>

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

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

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

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

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

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

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-CI-4,5- (MeO)₂Ph</td>

126

<td> 880</td><td>Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td> 881</td><td>Me</td><td>NEt₂</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td> 882</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td> 883</td><td>Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td> 884</td><td>Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td> 885</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 886</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 887</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 888</td><td>Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 889</td><td>Me</td><td>NEt₂</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 890</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 891</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4,6- (MeO)₂Ph</td>

<td> 892</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4,6- (MeO)₂Ph</td>

<td> 893</td><td>Me</td><td>NEt₂</td><td>2-CI-4,6- (MeO)₂Ph</td>

<td> 894</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-CI-4,6- (MeO)₂Ph</td>

<td> 895</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 896</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 897</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 898</td><td>Me</td><td>NEt₂</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 899</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 900</td><td>Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4-MeOPh</td>

<td> 901</td><td>Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Me-4-MeOPh</td>

<td> 902</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4-MePh</td>

<td> 903</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-MePh</td>

<td> 904</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4-MePh</td>

<td> 905</td><td>Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4-MePh</td>

<td> 906</td><td>Me</td><td>NEt₂</td><td>2-MeO-4-MePh</td>

<td> 907</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4-MePh</td>

<td> 908</td><td>Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4-MePh</td>

<td> 909</td><td>Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4-MePh</td>

<td> 910</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4-MePh</td>

<td> 911</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-MePh</td>

127

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

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

<td>Me</td><td>NEt₂</td><td>2-MeO-4-MePh</td>

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

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4-CIPh</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-CIPh</td>

<td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4-CIPh</td>

<td>Me</td><td>NEt₂</td><td>2-MeO-4-CIPh</td>

<td>Me</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4-CIPh</td>

table

<img file="LT4680B_D0065.tif" />

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

<td>Me</td><td>NHCHPr₂</td><td>2,4-CI₂-Ph</td>

<td>Me</td><td>NEtBu</td><td>2,4-CI₂-Ph</td>

<td>Me</td><td>NPr (CH₂-cC₃H₅)</td><td>2,4-CI₂-Ph</td>

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

<td>Me</td><td>Β-3-heptyl</td><td>2,4-CI₂-Ph</td>

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

<td>Me</td><td>NEt₂</td><td>2,4-CI₂-Ph</td>

<td>Me</td><td>NHCH (CH₂OEt)₂</td><td>2,4-CI₂-Ph</td>

<td>Me</td><td>ΝΗ-3-pentyl</td><td>2,4-Ci₂-Ph</td>

<td>Me</td><td>NMePh</td><td>2,4-Ci₂-Ph</td>

<td>Me</td><td>NPr₂</td><td>2,4-CI₂-Ph</td>

<td>Me</td><td>ΝΗ-3-hexyl</td><td>2,4-CI₂-Ph</td>

<td>Me</td><td>morpholine residue</td><td>2,4-CI₂-Ph</td>

<td>Me</td><td>N (CH₂Ph) CH₂CH₂OMe</td><td>2,4-CI₂-Ph</td>

128

<td> 936</td><td>Me</td><td>NHCH (CH₂Ph) CH₂OMe</td><td>2,4-CI₂-Ph</td>

<td> 937</td><td>Me</td><td>ΝΗ-4-Tetrahydropyranyl</td><td>2,4-CI₂-Ph</td>

<td> 938</td><td>Me</td><td>NH-cyclopentyl</td><td>2,4-Cb-Ph</td>

<td> 939</td><td>Me</td><td>OEt</td><td>2,4-CI₂-Ph</td>

<td> 940</td><td>Me</td><td>OCH (Et) CH₂OMe</td><td>2,4-CI₂-Ph</td>

<td> 941</td><td>Me</td><td>OCH₂Ph</td><td>2,4-CI₂-Ph</td>

<td> 942</td><td>Me</td><td>Ο-3-pentyl</td><td>2,4-CI₂-Ph</td>

<td> 943</td><td>Me</td><td>S No</td><td>2,4-Cb-Ph</td>

<td> 944</td><td>Me</td><td>S (O) Et</td><td>2,4-CI₂-Ph</td>

<td> 945</td><td>Me</td><td>SO₂No.</td><td>2,4-CI₂-Ph</td>

<td> 946</td><td>Me</td><td>Ph</td><td>2,4-CI₂-Ph</td>

<td> 947</td><td>Me</td><td>2-CF₃-Ph</td><td>2,4-CI₂-Ph</td>

<td> 948</td><td>Me</td><td>2-Ph-Ph</td><td>2,4-CI₂-Ph</td>

<td> 949</td><td>Me</td><td>3-pentyl</td><td>2,4-Cb-Ph</td>

<td> 950</td><td>Me</td><td>cyclobutyl</td><td>2,4-CI₂-Ph</td>

<td> 951</td><td>Me</td><td>3-pyridyl</td><td>2,4-CI₂-Ph</td>

<td> 952</td><td>Me</td><td>CH (Et) CH₂CONMe₂</td><td>2,4-CI₂-Ph</td>

<td> 953</td><td>Me</td><td>CH (Et) CH₂CH₂NMe₂</td><td>2,4-CI₂-Ph</td>

<td> 954</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4,6-Me₃-Ph</td>

<td> 955</td><td>Me</td><td>NHCHPr₂</td><td>2,4,6-Me₃-Ph</td>

<td> 956</td><td>Me</td><td>NEtBu</td><td>2,4,6-Me₃-Ph</td>

<td> 957</td><td>Me</td><td>NPr (CH₂-cC₃H₅)</td><td>2,4,6-Me₃-Ph</td>

<td> 958</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4,6-Me₃-Ph</td>

<td> 959</td><td>Me</td><td>Β-3-heptyl</td><td>2,4,6-Me₃-Ph</td>

<td> 960</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2,4,6-Me3-Ph</td>

<td> 961</td><td>Me</td><td>NEt₂</td><td>2,4,6-Me₃-Ph</td>

<td> 962</td><td>Me</td><td>NHCH (CH₂OEt)₂</td><td>2,4,6-Me₃-Ph</td>

<td> 963</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2,4,6-Me₃-Ph</td>

<td> 964</td><td>Me</td><td>NMePh</td><td>2,4,6-Me₃-Ph</td>

<td> 965</td><td>Me</td><td>NPr₂</td><td>2,4,6-Me₃-Ph</td>

<td> 966</td><td>Me</td><td>ΝΗ-3-hexyl</td><td>2,4,6-Me₃-Ph</td>

<td> 967</td><td>Me</td><td>morpholine residue</td><td>2,4,6-Me₃-Ph</td>

129

<td>Me</td><td>N (CH₂Ph) CH₂CH₂OMe</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>NHCH (CH₂Ph) CH₂OMe</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>ΝΗ-4-Tetrahydropyranyl</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>NH-cyclopentyl</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>OEt</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>OCH (Et) CH₂OMe</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>OCH₂Ph</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>Ο-3-pentyl</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>S No</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>S (O) Et</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>SO₂No.</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CH (CO₂No)₂</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>C (Et) (CO₂No)₂</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CH (Et) CH₂OH</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CH (Et) CH₂OMe</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CONMe₂</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>COCH₃</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CH (OH) CH₃</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>C (OH) Ph-3-pyridyl</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>Ph</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>2-P'n-Ph</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>3-pentyl</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>cyclobutyl</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>3-pyridyl</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CH (Et) CH₂CONMe₂</td><td>2,4,6-Me₃-Ph</td>

<td>Me</td><td>CH (Et) CH₂CH₂NMe₂</td><td>2,4,6-Me₃-Ph</td>

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

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

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

<td>Me</td><td>ΝΗ-3-pentyl</td><td>2,4-Me₂-Ph</td>

<td>Me</td><td>NEt₂</td><td>2,4-Me₂-Ph</td>

<td>Me</td><td>N (CH₂CN)₂</td><td>2,4-Me₂-Ph</td>

130

<td> 1000</td><td>Me</td><td>NHCH (Me) CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td> 1001</td><td>Me</td><td>OCH (Et) CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td> 1002</td><td>Me</td><td>NPr-cC₃H_s</td><td>2,4-Me₂-Ph</td>

<td> 1003</td><td>Me</td><td>NHCH (Me) CH₂NMe₂</td><td>2,4-Me₂-Ph</td>

<td> 1004</td><td>Me</td><td>N (cC₃H₅) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td>

<td> 1005</td><td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td>

<td> 1006</td><td>Me</td><td>N (Bu) CH₂CH₂CN</td><td>2,4-Me₂-Ph</td>

<td> 1007</td><td>Me</td><td>NHCHPr₂</td><td>2,4-Me₂-Ph</td>

<td> 1008</td><td>Me</td><td>NEtBu</td><td>2,4-Me₂-Ph</td>

<td> 1009</td><td>Me</td><td>NPr (CH₂-cC₃H₅)</td><td>2,4-Me₂-Ph</td>

<td> 1010</td><td>Me</td><td>Β-3-heptyl</td><td>2,4-Me₂-Ph</td>

<td> 1011</td><td>Me</td><td>NEt₂</td><td>2,4-Me₂-Ph</td>

<td> 1012</td><td>Me</td><td>NHCH (CH₂OEt)₂</td><td>2,4-Me₂-Ph</td>

<td> 1013</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2,4-Me₂-Ph</td>

<td> 1014</td><td>Me</td><td>NMePh</td><td>2,4-Me₂-Ph</td>

<td> 1015</td><td>Me</td><td>NPr₂</td><td>2,4-Me₂-Ph</td>

<td> 1016</td><td>Me</td><td>ΝΗ-3-hexyl</td><td>2,4-Me₂-Ph</td>

<td> 1017</td><td>Me</td><td>morpholine residue</td><td>2,4-Me₂-Ph</td>

<td> 1018</td><td>Me</td><td>N (CH₂Ph) CH₂CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td> 1019</td><td>Me</td><td>NHCH (CH₂Ph) CH₂OMe</td><td>2,4-Me₂-Ph</td>

<td> 1020</td><td>Me</td><td>NH-4-tetrahydropyranyl</td><td>2,4-Me₂-Ph</td>

<td> 1021</td><td>Me</td><td>NH-cyclopentyl</td><td>2,4-Me₂-Ph</td>

<td> 1022</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4-MeO-Ph</td>

<td> 1023</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4-MeO-Ph</td>

<td> 1024</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Me-4-MeO-Ph</td>

<td> 1025</td><td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Me-4-MeO-Ph</td>

<td> 1026</td><td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Me-4-MeO-Ph</td>

<td> 1027</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-MeO-Ph</td>

<td> 1028</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-MeO-Ph</td>

<td> 1029</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4-MeO-Ph</td>

<td> 1030</td><td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Br-4-MeO-Ph</td>

<td> 1031</td><td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Br-4-MeO-Ph</td>

131

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4-NMe₂-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4-NMe₂-Ph</td>

<td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Me-4-NMe₂-Ph</td>

<td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Me-4-NMe₂-Ph</td>

<td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Me-4-NMe₂-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-NMe₂-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-NMe₂-Ph</td>

<td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4-NMe₂-Ph</td>

<td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Br-4-NMe₂-Ph</td>

<td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Br-4-NMe₂-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-i-Pr-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-i-Pr-Ph</td>

<td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4-i-Pr-Ph</td>

<td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Br-4-i-Pr-Ph</td>

<td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Br-4-i-Pr-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-Me-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-Me-Ph</td>

<td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4-Me-Ph</td>

<td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Br-4-Me-Fh</td>

<td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Br-4-Me-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4-Br-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4-Br-Ph</td>

<td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Me-4-Br-Fri</td>

<td>Me</td><td>N (Pr) CH₂CH₂CN</td><td>2-Me-4-Br-Ph</td>

<td>Me</td><td>OCH (Et) CH₂OMe</td><td>2-Me-4-Br-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Ci-4,6-Me₂-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4,6-Me₂-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>4-Br-2,6- (Me)₂-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-Br-2,6- (Me)₂-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-CF₃-Ph</td>

132

<td> 1064</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4-CF₃-Ph</td>

<td> 1065</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4,6- (MeO)₂-Ph</td>

<td> 1066</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Br-4,6- (MeO)₂-Ph</td>

<td> 1067</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4,6- (MeO)₂-Ph</td>

<td> 1068</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4,6- (MeO)₂-Ph</td>

<td> 1069</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2.6- (Me)₂-4-SMe-Ph</td>

<td> 1070</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2.6- (Me)₂-4-SMe-Ph</td>

<td> 1071</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>4- (COMe) -2-Br-Ph</td>

<td> 1072</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>4- (COMe) -2-Br-Ph</td>

<td> 1073</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4,6-Me₃-pyrid-3-yl</td>

<td> 1074</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4,6-Me₃-pyrid-3-yl</td>

<td> 1075</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2,4- (Br)₂-Ph</td>

<td> 1076</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2,4- (Br)₂-Ph</td>

<td> 1077</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td> 1078</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-i-Pr-2-SMe-Ph</td>

<td> 1079</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>4-i-Pr-2-SO₂Me-Ph</td>

<td> 1080</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>4-i-Pr-2-SO₂Me-Ph</td>

<td> 1081</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2.6- (Me)₂-4-SMe-Ph</td>

<td> 1082</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2.6- (Me)₂-4-SMe-Ph</td>

<td> 1083</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2.6- (Me)₂-4-SO₂Me-Ph</td>

<td> 1084</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2.6- (Me)₂-4-SO₂Me-Ph</td>

<td> 1085</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-l-4-i-Pr-Ph</td>

<td> 1086</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-l-4-i-Pr-Ph</td>

<td> 1087</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4-N (Me)₂-6-MeO-Ph</td>

<td> 1088</td><td>Me</td><td>N (CH₂CH₂OMe)₂·</td><td>2-Br-4-N (Me)₂-6-MeO-Ph</td>

<td> 1089</td><td>Me</td><td>NEt₂</td><td>2-Br-4-MeO-Ph</td>

<td> 1090</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-Br-4-MeO-Ph</td>

<td> 1091</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CN-4-Me-Ph</td>

<td> 1092</td><td>Me</td><td>N (cC₃H5) CH₂CH₂CN</td><td>2,4,6-Me₃-Ph</td>

<td> 1093</td><td>Me</td><td>NHCH (CH₂CH₂OMe) CH₂OMe</td><td>2-Me-4-Br-Ph</td>

<td> 1094</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2.5-Me₂-4-MeO-Ph</td>

<td> 1095</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2.5-Me₂-4-MeO-Ph</td>

133

<td>Me</td><td>ΝΗ-3-pentyl</td><td>2.5-Me₂-4-MeO-Ph</td>

<td>Me</td><td>NEt₂</td><td>2.5-Me₂-4-MeO-Ph</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4-MePh</td>

<td>Me</td><td>NCH ​​(Et) CH₂OMe</td><td>2-CI-4-MePh</td>

<td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4-MePh</td>

<td>Me</td><td>fS; -NHCH (CH₂CH₂OMe) CH₂OMe</td><td>2-CI-4-MePh</td>

<td>Me</td><td>N (cC₃H₅) CH₂CH₂CN</td><td>2.5-Me₂-4-MeOPh</td>

<td>Me</td><td>NEt₂</td><td>2-Me-4-MeOPh</td>

<td>Me</td><td>OEt</td><td>2-Me-4-MeOPh</td>

<td>Me</td><td>fS / -NHCH (CH₂CH₂OMe) CH₂OMe</td><td>2-Me-4-MeOPh</td>

<td>Me</td><td>N (cC₃H₅) CH₂CH₂CN</td><td>2-Me-4-MeOPh</td>

<td>Me</td><td>NHCH (CH₂CH₂OEt)₂</td><td>2-Me-4-MeOPh</td>

<td>Me</td><td>N (cC₃H₅) CH₂CH₂CN</td><td>2,4-CI₂-Ph</td>

<td>Me</td><td>NEt₂</td><td>2-Me-4-CIPh</td>

<td>Me</td><td>ΝΗ-3-pentyl</td><td>2-Me-4-CIPh</td>

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

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

<td>Me</td><td>N No₂</td><td>2-Me-4-CIPh</td>

<td>Me</td><td>NEt₂</td><td>2-CI-4-MePh</td>

<td>Me</td><td>ΝΗ-3-pence</td><td>2-CI-4-MePh</td>

<td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4-MeOPh</td>

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

<td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-CI-4-MeOPh</td>

<td>Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI-4-MeOPh</td>

<td>Me</td><td>NEt₂</td><td>2-CI-4-MeOPh</td>

<td>Me</td><td>ΝΗ-3-pentil '</td><td>2-CI-4-MeOPh</td>

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

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

<td>Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Br-4-MeOPn</td>

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

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

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

134

<td> 1129</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td> 1130</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Cf-4,5- (MeO)₂Ph</td>

<td> 1131</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td> 1132</td><td>Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td> 1133</td><td>Me</td><td>NEt₂</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td> 1134</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td> 1135</td><td>Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td> 1136</td><td>Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-CI-4,5- (MeO)₂Ph</td>

<td> 1137</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 1138</td><td>Me</td><td>N (CH₂CH₂OMe}₂</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 1139</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 1140</td><td>Me</td><td>N (c-Pr) CH₂CH₂ON</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 1141</td><td>Me</td><td>NEt₂</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 1142</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-Br-4,5- (MeO)₂Ph</td>

<td> 1143</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-CI-4,6- (MeO)₂Ph</td>

<td> 1144</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-CI-4,6- (MeO)₂Ph</td>

<td> 1145</td><td>Me</td><td>NEt₂</td><td>2-CI-4,6- (MeO)₂Ph</td>

<td> 1146</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-CI-4,6- (MeO)₂Ph</td>

<td> 1147</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 1148</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 1149</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 1150</td><td>Me</td><td>N No₂</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 1151</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-Me-4,6- (MeO)₂Ph</td>

<td> 1152</td><td>Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-Me-4-MeOPh</td>

<td> 1153</td><td>Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-Me-4-MeOPh</td>

<td> 1154</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4-MePh</td>

<td> 1155</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-MePh</td>

<td> 1156</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4-MePh</td>

<td> 1157</td><td>Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4-MePh</td>

<td> 1158</td><td>Me</td><td>N No₂</td><td>2-MeO-4-MePh</td>

<td> 1159</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4-MePh</td>

<td> 1160</td><td>Me</td><td>NHCH (Et) CH₂CH₂OMe</td><td>2-MeO-4-MePh</td>

135

<td> 1161</td><td>Me</td><td>NHCH (Me) CH₂CH₂OMe</td><td>2-MeO-4-MePh</td>

<td> 1162</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4-MePh</td>

<td> 1163</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-MePh</td>

<td> 1164</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4-MePh</td>

<td> 1165</td><td>Me</td><td>N (c-Pr) CH₂CH₂CN</td><td>2-MeO-4-MePh</td>

<td> 1166</td><td>Me</td><td>N No₂</td><td>2-MeO-4-MePh</td>

<td> 1167</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4-MePh</td>

<td> 1168</td><td>Me</td><td>NHCH (CH₂OMe)₂</td><td>2-MeO-4-CIPh</td>

<td> 1169</td><td>Me</td><td>N (CH₂CH₂OMe)₂</td><td>2-MeO-4-CIPh</td>

<td> 1170</td><td>Me</td><td>NHCH (Et) CH₂OMe</td><td>2-MeO-4-CIPh</td>

<td> 1171</td><td>Me</td><td>N No₂</td><td>2-MeO-4-CIPh</td>

<td> 1172</td><td>Me</td><td>ΝΗ-3-pentyl</td><td>2-MeO-4-CIPh</td>

USE OF COMPOUNDS

CRF-R1 receptor binding assay for evaluation of biological activity

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

The informational RNA was isolated from the human hippocampus. This iRNA was reverse transcribed using oligo (dt) 12-18, and the coding region was amplified by PCR from start to stop codon. The resulting PCR fragment was cloned into the pREMV EcoRV site from which the inserted fragment was excised with Xhol + Xbal and cloned into the j pm3ar vector (which contains the CMV promoter, SV40 "t" maturation and early polyA signaling, Epstein-Barr virus replication). and hygromycin resistance marker) Xhol + Xbal sites. The resulting expression vector, named phchCRFR, was transfected in 293EBNA cells, and retaining episome cells in the presence of 400 μΜ hygromycin were selected. Cells surviving hygromycin 4 weeks of selection were mixed, adapted for growth in suspension, and used

136 generating membranes for the assay described below. After that, individual portions containing about 1 χ 10⁸ suspended cells were centrifuged to obtain a cell pellet and this pellet was frozen,

For the binding assay, frozen pellets containing 293EBNA cells transfected with hCRFFH receptors as described above are homogenized in 10 ml of ice-cooled tissue buffer (50 mM HEPES buffer, pH 7.0 containing 10 mM MgCl 2).₂, 2 mM EGTA, 1 µg / l aprotinin, 1 µg / l leupeptin and 1 µg / l pepstatin). This homogenate is centrifuged at 40,000 xg for 12 min and the resulting pellet is rehomogenized in 10 mL of tissue buffer. After another 12 min. After centrifugation at 40,000 xg, the pellet is resuspended to a protein concentration of 360 µg / ml and this homogenate is used in the assay.

The binding test is carried out in 96-well plates with a capacity of 300 μΙ per well. To each well, add 50 μΙ of a given concentration of test drug solution (final drug concentrations are 10 '¹° to W⁵ M limits), 100 μΙ ¹²⁵1-sheep CRF (¹²⁵lo-CRF) (final concentration 150 pM) and 150 μΙ of the cell homogenate described above. The plates are then incubated at room temperature for 2 hours, and the incubate is filtered through GF / F filters (pre-soaked in 0.3% polyethylene) using an appropriate cell harvester. The filters are washed twice with ice-cooled test buffer, then the individual filters are removed and their radioactivity is measured on a gamma counter.

¹²⁵Inhibition curves for lo-CRF binding to cell membranes at various dilutions of the test drug are analyzed by the LIGAND iterative curve approximation program [PJ Munson and D. Rodbard, Ann. Biochem. 107: 220 (1980)], which gives the inhibition K values ​​used for the evaluation of biological activity.

A compound is considered to be active if its CRF inhibition K value is less than 10,000 nM.

Inhibition of CRF-stimulated adenincyclase activity

137

Inhibition of CRF-stimulated adenincyclase activity was performed as described by G.Battaglia et al. Synapse 1: 572 (1987). Briefly, the tests were performed at 37 ° C for 10 min. 200 ml buffer containing 100 mM Tris-HCl (pH 7.4 at 37 ° C), 10 mM MgCl₂, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (ΙΒΜΧ), 250 units / ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine-5'-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10 ')⁹-10'⁶ M) and 0.8 mg wet weight of starting tissue (about 40-60 mg protein). Reactions were initiated by addition of 1 mM ATP /³²P] ATP (about 2-4 mCi / tube) and stopped by addition of 100 mL of 50 mM Tris-HCl, 45 mM ATP and 2% sodium dodecyl sulfate. To control cAMP regeneration, 1 μΙ was added to each tube prior to separation [³H] cAMP (about 40,000 dpm). [³²P] cAMP was distinguished from [³²P] ATP, eluting first through Dowex and then through alumina columns.

In vivo bioassays

The activity of the compounds of the present invention can be determined in vivo using any of the biological assays accepted and available to those skilled in the art. Illustrations of such tests include the "acoustic fright test", the "stair climb test" and the "chronic use test". These and other models suitable for testing compounds of the present invention are described in CW Berridge and AJ Dunn Brain Research Reviews 15:71 (1990). The compounds may be tested in a variety of rodent or small mammalian species.

The compounds of the present invention are useful in the treatment of disorders associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective psychosis and / or anxiety.

The compounds of the present invention can be used in the treatment of such disorders by any means that enables the active agent to come into contact with the site of action of the agent in a mammal. The compounds may be administered by any conventional route of administration, either as a single therapeutic agent or in combination of therapeutic agents. They can be used alone, but usually they are used

138 with a pharmaceutical carrier selected on the basis of the desired mode of administration and standard pharmaceutical practice.

Dosages used may vary depending on the use and known factors such as the pharmacodynamic profile of the particular agent and the route of administration, age, weight and health of the recipient, nature and degree of symptoms, type of combination treatment, frequency of treatment and desired effect. When used in the treatment of the above diseases or conditions, the compounds of the present invention can be administered orally daily in a dosage of 0.002 to 200 mg of active ingredient per kilogram of body weight. Generally, a dose of 0.01-10 mg / kg, divided into 1 to 4 times a day, or sustained release dosage forms, is effective and produces the desired pharmacological effect.

Suitable dosage forms (compositions) contain from 1 mg to 100 mg of active ingredient per unit dosage form. These pharmaceutical compositions contain from about 0.5% to about 95% by weight of the active ingredient, based on the total weight of the composition.

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

Gelatin capsules containing the active ingredient and a suitable carrier such as, but not limited to, lactose, starch, magnesium stearate, stearic acid, or cellulose may be used. Similar diluents may also be used to make compressed tablets. Both tablets and capsules may be manufactured as sustained release products to provide continuous release over time. Compressed tablets may be sugar or film coated to mask the unpleasant taste or to protect the active ingredients from the atmosphere, or to obtain selective gastrointestinal disintegration.

Liquid oral dosage forms may contain coloring and flavoring agents to make them more acceptable to the patient.

139

Generally, suitable carriers for parenteral solutions include water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose) and related sugars, and glycols such as propylene glycol or polyethylene glycol. Preferably, the parenteral solution contains a water-soluble salt of the active ingredient, a suitable stabilizing agent and, if necessary, buffering agents. Suitable stabilizing agents include antioxidants such as sodium hydrogen sulfite, sodium sulfite, or ascorbic acid, either alone or in admixture. Citric acid and its salts and EDTA are also used. In addition, parenteral solutions may contain safeners such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.

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

Pharmaceutical dosage forms suitable for use in the compounds of the present invention are illustrated by the following examples:

Capsules

Many capsules are made from two-part hard gelatin capsules, each containing 100 mg of the active ingredient powder, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatine capsules

The active ingredient is prepared in a blend of edible oils, such as soybean, cottonseed or olive oil, and pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. Capsules.washed and dried,

Pills

Many tablets are formulated in a conventional manner so that the unit dose contains 100 mg of the 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. The required coatings can be applied to give a pleasant taste or delayed adsorption.

140

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

While the present invention has been described with reference to certain embodiments and examples, other embodiments will be apparent to those skilled in the art. Therefore, the present invention is not limited to the specific embodiments described and illustrated by way of example, but various modifications or variations thereof are possible without departing from the spirit and scope of the invention, the full scope of which is set forth in the appended claims.