AU2002300983B2

AU2002300983B2 - Azolo Triazines And Pyrimidines

Info

Publication number: AU2002300983B2
Application number: AU2002300983A
Authority: AU
Inventors: Argyrios Georgios Arvanitis; Robert Chorvat; Paul Gilligan; Liqi He
Original assignee: DuPont Merck Pharmaceutical Co
Current assignee: Bristol Myers Squibb Pharma Co
Priority date: 1998-01-28
Filing date: 2002-09-11
Publication date: 2005-06-09
Anticipated expiration: 2019-01-28

Description

P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A DIVISIONAL PATENT

ORIGINAL

TO BE COMPLETED BY APPLICANT Name of Applicant: Actual Inventor(s): DU PONT PHARMACEUTICALS COMPANY Liqi HE, Paul GILLIGAN, Robert CHORVAT, Argyrios Georgios

ARVANITIS

Address for Service: Invention Title: CALLINAN LAWRIE, 711 High Street, Kew, Victoria 3101, Australia AZOLO TRIAZINES AND PYRIMIDINES The following statement is a full description of this invention, including the best method of performing it known to us:- To: The Commissioner of Patents 11/09/02.sw12915.3

TITLE

AZOLO TRIAZINES AND PYRIMIDINES FIELD OF THE INVENTION This invention relates a treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heartrelated diseases and colonic hypersensitivity associated with psychopathological disturbance and stress, by administration of certain and pyrimidines.

BACKGROUND OF THE INVENTION Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC) -derived peptide secretion from the anterior pituitary gland 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 at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G.F. Koob, Persp. Behav. Med. 2:39 (1985); E.B. De Souza et al., J. Neurosci. 5:3189 (1985)].

There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors Blalock, Physiological Reviews 69:1 (1989); J.E. Morley, Life Sci. 41:527 (1987)].

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

In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals Nemeroff et al., Science 226:1342 (1984); C.M. Banki et al., Am. J. Psychiatry 144:873 (1987); R.D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v.

administered) observed in depressed patients [P.W.

Gold et al., Am J. Psychiatry 141:619 (1984); F.

Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P.W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine nonbenzodiazepie anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models Britton et al., Life Sci. 31:363 (1982); C.W. Berridge and A.J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines Berridge and A.J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders.

Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test Britton et al., Psychopharmacology 86:170 (1985); K.T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Rol5-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF Britton et al., Psychopharmacology 94:306 (1988)].

The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders.

Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (a-helical CRF9- 4 1) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to the benzodiazepines [for review see G.F.

Koob and K.T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E.B. De Souza and C.B. Nemeroff eds., CRC Press p221 (1990)].

Several publications describe corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT application US94/11050 Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and Pfizer EP 0778 277 Al.

Insofar as is known, 1,3,5-triazines, and have not been previously reported as corticotropin releasing factor antagonist compounds useful in the treatment of psychiatric disorders and neurological diseases. However, there have been publications which teach some of these compounds for other uses.

For instance, EP 0 269 859 (Ostuka, 1988) discloses pyrazolotriazine compounds of the formula 1 R2- N

R

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

EP 0 594 149 (Ostuka, 1994) discloses pyrazolotriazine and pyrazolopyrimidine compounds of the formula A N (R2 R3 where A is CH or N, RO and R 3 are H or alkyl, and RI and R 2 are H, alkyl, alkoxyl, alkyithio, nitro, etc., and states that the compounds inhibit androgen -and are useful in treatment of benign prostatic hypertrophy and prostatic carcinoma.

US 3, 910, 907 (ICI, 1975) discloses pyrazolotria'zines of the formula: z x where R1 is CH 3

C

2

H

5 or C 6

H

5 X is H, C 6

H

5 m-CH 3

C

6

H

4 CN, COOEt, Cl, I or Br, Y is H, C 6 Hs, o-CH 3

C

6

H

4 or p-

CH

3

C

6

H

4 and Z is OH, H, CH 3

C

2 H5, C 6

H

5 n-C 3

H

7 i-C 3

H

7 SH, SCH 3

NI{C

4

H

9 or N(C 2 H5)2, and states that the compounds are c-AMP phosphodiesterase inhibitors useful as bronchodilators.

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

NR

2

R

3 N N- N

RANN

R

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

US 5,137,887 discloses pyrazolotriazines of the formula

OH

RN IN N (O)n

N

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

US 4,892,576 discloses pyrazolotriazines of the formula x

R

7 N S- N- Ar

II

Re N O R

R

9 where X is O or S, Ar is a phenyl, naphthyl, pyridyl or thienyl group, R 6

-R

8 are H, alkyl, etc., and R 9 is H, alkyl, phenyl, etc. The patent states that the compounds are useful as herbicides and plant growth regulants.

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

A

R-

R

B

where A can be N, B can be CR 3

R

3 can be phenyl or substituted phenyl, etc., R is -N(R 4 )S0 2

R

5 or S0 2

N(R

6

)R

7 and RI and R 2 can be taken together to form z Y z Y x D or Cwhere X, Y and Z are H, alkyl, acyl, etc. and D is O or

S.

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

N

where Z is H, OH, CH 3

C

2

H

5

C

6

H

5 n-C 3

H

7 iso-C 3

H

7

SH,

SCH

3 NH(n-C 4

H

9 or N(C 2

H

5 2 R is H or CH 3 and RI is

CH

3 or C 2 Hs. The reference lists eight therapeutic areas where inhibitors of cAMP phosphodiesterase could have utility: asthma, diabetes mellitus, female fertility control, male infertility, psoriasis, thrombosis, anxiety, and hypertension.

W095/35298 (Otsuka, 1995) discloses pyrazolopyrimidines and states that they are useful as analgesics. The compounds are represented by the formula R6 (NH) A--R2

RR

4 where Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond, alkylene or alkenylene, R 1 is H, alkyl, etc., R 2 is naphthyl, cycloalkyl, heteroaryl, substituted phenyl or phenoxy, R 3 is H, alkyl or phenyl, R 4 is H, alkyl, alkoxycarbonyl, phenylalkyl, optionally phenylthio-substituted phenyl, or halogen,

R

5 and R 6 are H or alkyl.

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

R

1

N

R2 N

R

3 where RI, R 2

R

3 and R 4 are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl, or phenyl, RS is SR 6 or NR 7 Re, R 6 is pyridyl or optionally substituted phenyl, and R 7 and R 8 are H or optionally substituted phenyl.

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

OH

HO N

R

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

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

N

where R 1 is CF 3

C

2

F

5 or C 6

H

4 F, and R 2 is CH 3

C

2

H

5

CF

3 or C 6 Ii 4

F.

Maquestiau et al., Bull. Soc. Belg., vol.101, no. 2, 1992, pages 131-136 discloses a alpyrimidine of the formula

C

6

H

Ibrahimn et al., Arch. Pharm. (weinheim) 320, 487-491 (1987) discloses pyrazolo[1,5-alpyrimidines of the formula CH3

N

CH3 N Ar where R is NH2 or OH and Ar is 4-phenyl-3-cyano-2aminopyrid-2-yl.

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

SUMMARY OF THE INVENTION In accordance with one aspect, the present -12invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessivecompulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of -13inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hear related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction-related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in a mammal.

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

-14- According to another aspect, the present invention provides novel compounds described below which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing such compounds of Formulae and and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders.

According to yet another aspect of the invention, the compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.

DETAILED DESCRIPTION OF INVENTION The present invention provides compounds of Formula 11/09/02,swl 2915spa, FORMULA and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof selected from the group: a compound of Formula (70) wherein R is Cl, R 3 is -NHCH(n-Pr)2, R 4 a is Me, R 4 b is H,

R

4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is -NHCH(CH20Me)2, R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is -N(CH2CH20Me)2, R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; -16- 11/09/02.swl2915spa.doc,1 6 a compound of Formula (70) wherein R is Cl, R 3 is -N(C- Pr) (CH 2 CH2CN), R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- N(CH2CH2DMe)2,

R

4 a is Cl, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl,,R 3 is- NHCH(CH2OMe)2,

R

4 a is Cl, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula .(70).wherein R is Cl, R 3 is- NIICH(Et)2, R 4 a is Cl-, R 4 b is H, R 4 c is Me', R 4 d is H and R.is H; a c ompound of Formula (70) wherein R is Cl, R 3 is- N(Et)2, R 4 a is Me, Rb is H, R 4 c is Me, Rd is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is -N(n- Pr) (CH2CH2CN), R 4 a is Me, Rb is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is -N(n- Bu) (CH2CH2CN), R 4 a is Me, ROb-is H, R 4 c is Me, R4d is Hand R 4 e is H; a compound of Formula (70) wherein R 'is Cl, R 3 is- N'tCH(n-Pr) (CH2OMe) R 4 a is Me, R 4 b is H, R 4 c is Me, Rd is Hand R4E is H; a compound of Formula (70) wherein R is Cl, R 3 is- NHCH(Et)2, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- NHCH(CH2OMe)2, R 4 a is Me, R 4 b is H, R 4 c is OMe,

R

4 d is Hand R 4 e is H.

a compound of Formula (70) wherein R is Cl, R 3 is' 17- 11 /09/02,docuinentl 3,17 in-NHCH(CH2CH2OMe)(CH2OMe), Rais Me, ROis H, R 4 c is Me, R 4 d is H and

R

4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- NHCH(CH2CH2OMe)(CH2OMe), R 4 a is Me, RO sH is Me, R 4 d is H and (Ni R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- 0(HC2Oe2

R

4 a is Me, R 4 D is H, Rc is Cl, R 4 d is H and R 4 e is H; 0 a compound of Formula (70) wherein R is Cl, R 3 is- NH(Et), Ra is Me, RO is H, Rc is Me, R 4 d is H and Re is H; a compound of Formula (70) wherein R is Cl, R 3 is- NHCH(n-Pr)2, R 4 a is Me, RO sH is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is -NHCH(CH2OMe)2, R a is Me,R is H, R is Ci, Rd is H and Re is H; a compound of Formula (70) wherein R is Cl, R 3 is NHCH(CH2CH2OMe)(CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is Cl, R 4 d is H and

R

4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- NHCH(CH2CH2OMe)(CH2OMe), R 4 a is Me, ROb is H, R 4 c is Cl, R 4 d is H and

R

4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- N(n-Pr)(CH2CH2CN), R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- N(Et)2, R 4 a is Me, ROb is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is NHCH(CH2CH2OMe)(CH2OMe), R 4 a is Cl, ROb is H, R 4 c is Me, R 4 d is H and

R

4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- 19/05/05,at 1291 S.specipgs, 18 18- NHCH(CH2CH2OMe)(CH2OMe), R 4 a is Cl, R 4 b is H sMRdi n

R

4 e is H; Ct a compound of Formula (70) wherein R is Cl, R 3 is- N(Et)2, R 4 a is Cl R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- N(c-Pr)(CH2CH2CN), R 4 a is Me, Rb is H, R 4 C is OMe, Rd is Hand R 4 e isH; a compound of Formula (70) wherein R is Cl, R 3 isci ~~N(c-Pr)(CH2CH2CN), R 4 a is Cl Rb is H, R 4 Ci eRdi n sH CI a compound of Formula (70) wherein R is Cl, R 3 is- NHCH (n-Pr)(CH 2 OMe), R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is

H;

a compound of Formula (70) wherein R is Cl, R 3 is- NHCH (n-Pr)(CH 2 OMe), R 4 a is Cl, R~bi ,R4c iMe 4d iHan 4eisH a compound of Formula (70) wherein R is Cl, R 3 is NHCH(Et)2, R 4 a is Br, R 4 b is H, R 4 c is OMe, R 4 d is OMe and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is NHCH(Et)2, R 4 a is Br, R 4 b is H, R 4 C is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- N(CH2CH2OMe)2, R 4 a is Br, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is NHCH(CH2OMe)2, R 4 a isBROib H R 4 c i eRdis H and Re is H; I 9/OS/OS at 1291 S.specipgs, 19 19a compound of Formula (70) wherein R is C1, R 3 is N(Et)2, R 4 a is Me, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is N(Et)2, R 4 a is Cl, R 4 b is H, R 4 C.is OMe, R 4 d is OMe and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is NHCH(Et)2, R 4 a is Cl, R 4 b is H, R 4 c is OMe, R 4 d is OMe and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is N(CH2CH20Me)2, R 4 a is Cl, R 4 b is H, R 4 c isCl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is NHCH(CH20Me)2, R 4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is N(Pr) (CH2CH2CN), R 4 a is Cl, R 4 b is H, R 4 c is Cl,

R

4d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is N(Bu)(Et), R 4 a is C1, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is NHCH(Et)CH20Me, R 4 a is Cl, R 4 b is H, R 4 c is Cl,

R

4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is NHCH(Et)2, R 4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is NHCH(Et)2, R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is 11 /09/02,documentl 3,20 NHCH(Et)2, R 4 a is Cl, R 4 b is H, R 4 c is Me, R4d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- NHCH(Et)2, R 4 a is Me, R 4 b is H, R 4 c: is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- NEt2, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; and a compound of Formula (70) wherein R is Cl, R 3 is- N(Pr(CHCH2N),R 4 a is Me, Rb is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula wherein R is Me, R 3 is- NHCH(n-Pr)2, R 4 a i s Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H.

a compound of Formula (70) NHCH(CH2OMe)2, R 4 a is is H and R 4 e is H; a compound of Formula (70) N(CH2CH2OMe)2, R 4 a is is Hand Re is H; a compound of Formula (70) Pr) (CH2CH2CN), R 4 a is is Hand Re is H; a compound of Formula (70) N(CH2CH2OMe)2, R 4 a is is H and R 4 e is H; a compound of Formula (70) NHCH(CH2OMe)2, R 4 a is is Hand R 4 e is H; a compound of Formula (70) NHCH(Et)2, R 4 a is Cl.

wherein R is Me, R 3 is- Me, R 4bis H, R 4 c is Me, R 4 d.

whereinR is Me, R 3 is Me, R 4 b is H, R 4 c is Me, R 4 d wherein R is Me R 3 is -N(c- Me, Rb is H, R 4 c is Me, R 4 d wherein R is Me, R 3 is Cl, R 4 b is H, R 4 c is Me, R 4 d wherein R is Me, R 3 is Cl, R 4 b is H, R 4 c is Me, R 4 d wherein R is Me, R 3 is R 4 b is H, R 4 c is Me, R 4 d is 21 I1I /09/02,docmentl 3,2! H and R 4 e is H; C a compound of Formula (70) wherein R is Me, R 3 is N(Et)2, R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is N(n-Pr)(CH2CH2CN), R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; 0 a compound of Formula (70) wherein R is Me, R 3 is N(n-Bu)(CH2CH2CN), R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; 0a compound of Formula (70) wherein R is Me, R 3 is

R

4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NHCH(Et)2, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NHCH(CH20Me)2, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NHCH(CH2CH20Me)(CH20Me), R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and

R

4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NHCH(CH2CH2OMe)(CH20Me), R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and

R

4 e is H; a compound of Formula (70) wherein R is Me, R 3 is N(CH2CH2OMe)2, R 4 a is Me, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NH(Et), R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NHCH(n-Pr)2, R 4 a is Me, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is 19/05/05,atl 2915.specipgs,22 -22- NHCH(CH2OMe)2, R 4 a is Me, RO is H, Rc is Cl, Rd isHan eis; a compound of Formula (70) wherein R is Me, R 3 is NHCH(CH2CH2OMe)(CH2OMe), R 4 a is Me, RO sH is Cl, R 4 d is H and C) 5 R 4 e is H; rn a compound of Formula (70) wherein R is Me, R 3 is 00 NHCH(CH2CH2OMe)(CH2OMe),

R

4 a is Me, ROb is H, R 4 C is Cl, R 4 d is H and

R

4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- (1 ~~N(n-Pr)(CH2CH2CN), R 4 a is Me, Rbis H, R 4 CiO eRdiHadReiH a compound of Formula (70) wherein R is Me, R 3 is N(t)2, Ra is Me, RO is H, Rc is OMe, Rd is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NHCH(CH2CH2OMe)(CH2OMe), R 4 a is Cl, ROb is H, R 4 c is Me, R 4 d is H and

R

4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- NHCH(CH2CH2OMe)(CH2OMe), R 4 a is Cl, ROb is H, R 4 c is Me, R 4 d is H and

R

4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- N(Et)2, R 4 a is Cl, ROb is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is N(c-Pr)(CH2CH2CN), R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is -N(c- 19/OS/05,atlI 2915.specipgs.23 23 Pr) (CH 2 CH2CN), R 4 a is Cl, R 4bis H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is -NIICH (n-Pr) (CH 2 OMe), R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4dis Hand Re is H; a compound of Formula (70) wherein R is Me, R 3 is -NIICH (n-Pr) (CH 2 OMe), R 4 a is Cl, R 4 b is H, R 4 c is Me, R~dis H and Re is H; a compound of.Formula (70) wherein R is Me, R 3 is- NHCH (Et) 2, R 4 a is Br, R 4 b is H, R 4 c is OMe, R 4 d is OMe and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- NHCH(Et)2, R 4 a is Br, R 4 b is H, R 4 c is OMe, R 4 d is H and Re is H; a compound of Formula (70) wherein R is Me, R 3 is- *N(CH2CH2OMe) 2, 'R 4 a is Br, Rb is H, R 4 c is OMe, is H and Re is H; a compound of Formula (70) wherein R is Me, R 3 isbHCH (CH2OMe) 2, R 4 a is Br, R 4 b is H, R 4 c is OMe, Rd is Hand Re is H; a compound of Formula (70) wherein R is Me, R 3 is- N(Et)2, R 4 a is Me, Rb is H, R 4 c is Cl, Rd is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- N (Et) 2, R 4 a is Cl, R 4 b is H, R 4 c is OMe, R 4 d -is OMe and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- NHCH(Et)2, R 4 a is Cl R 4 b is H, R 4 c is O~e R 4 d is OMe and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 i's- N(CH2CH2OMe)2,

R

4 a is Cl R 4 b is H, R 4 c is Cl, R4d 24 1I It 9fOcdoet ,uotI 3,24 is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NHCH (CH2OMe) 2, R 4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is Hand R 4 e is H; a compound of Formula (70) wherein R i's Me, R 3 is- N(Pr) (CH 2 CH2CN) R 4 a is Cl, R 4 b is H, R 4 c is Cl, Rd is Hand Re is H a compound of Formula. w herein R is Me, R 3 is- N (Bu) (Et) R 4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NHCH(Et)CH2OMe, R 4 a is .Cl, R 4 b is H, R 4 c is Cl, R~d is H and R 4 is H; a compound of Formula (70) wherein R is Me, R 3 is- NIICH(Et)2, R 4 a. is Cl, R 4 b is-H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NHCH(Et)2, R 4 a is Me, R 4 b is H, R 4 C is Me, R 4 d is H and R 4 e Iis H; a compound of Formula (70) wherein R is Me, R 3 is- NHCH (Et) 2, R 4 a is Cl, R 4 b is H, R 4 c is -Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- NI{CH (Et) 2, R 4 a is Me, R 4 b is H, R 4 c is Cl, R 4 d is H and Re is H; a compound of Formula (70) wherein R is Me, R 3 is- NEt2, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; and a compound of Formula (70) wherein R is Me, R 3 is- N(Pr) (CH2CH2CN) R 4 a is Me, R 4 b is H, R 4 c is OMe, R4d is Hand R 4 e is H; 25 11 /(l9/C)2,docunt 1 3.25 a compound of Formula (70) wherein R is F, R 3 is'- NHCH(n-Pr)2, R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is .H and R 4 e is H; a compound of Formula (70) NHCH (CH2 OMe) 2, Ra is H and R 4 e is H; a compound of Formula (70) N(CH2CH2OMe)2, R 4 a is is Hand R 4 e is H; a compound of Formula (70) Pr) (CH2CH2CN), R 4 a. is is H and R 4 eisH a compound of Formula (70) N(CH2CH2OMe)2, R 4 a is is Hand R 4 e is H; a compound of Formula (70) NHCH(CH2OMe)2, R 4 a is is Hand R 4 e is H; a compound of Formula (70) NHCH(Et)2, R 4 a is Cl, H and R 4 e is H; wherein R is F, R 3 is Me, R 4bis-H, R 4Cis Me, R 4 d wherein R is F, R 3 is- Me, R 4 b is H, R 4 C is Me, R 4 d wherein R is F, R 3 is -N(c- Me, R 4bis H, R 4 c is-Me, R 4 d wherein R is F, R 3 is Cl, R 4bis H, R 4cis Me, R 4 d wherein R is F, R 3 is Cl, R 4 b is H, R 4 c is Me, R 4 d wherein R is F, R 3 is-

R

4 b is H, R 4 c is Me;- R 4 'd -I s a compound of Formula (70) wherein R is F, R 3 is- N(Et)2, R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is -M(n- Pr) (CH2CH2CN) R 4 a is Me, R 4 b is H, R 4 c is Me, R 4d is Hand R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is -N(n- Bu) (CH 2 CH2CN), R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is Hand.R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- 26 11 /09/02,docurnt 3.26 NHCH(n-Pr)(CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NHHEt2 R 4 a is Me, RO is R is OMe, R 4 d is Hand R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- NHCH(CH2OMe)2, R 4 a is Me, ROb is H, R 4 c is OMe, R 4 d is H and R 4 e is H; 00 a compound of Formula (70) wherein R is F, R 3 is NHCLI(CH2CH2OMe)(CH2OMe), R 4 a is Me, R is H, Rc is M, is H and ROe is H; NI a compound of Formula (70) wherein R is F, R 3 is- NHCH(CH2CH2OMe)(CH2OMe), R 4 a is Me, ROb is H, R 4 c is Me, R 4 d is H and

R

4 e is H; a compound of Formula (70) wherein R is F, R 3 is N(CH2CH2OMe)2, R 4 a is Me, ROb is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NH(Et), R 4 a is Me, ROb is H, ROc is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(n-Pr)2, R 4 a is Me, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- NHCH(CH2OMe)2, R 4 a is Me, ROb is H, R 4 C is Cl R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(CH2CH2OMe)(CH2OMe), R 4 a is Me, RbisH c is Cl, R 4 d is H and

R

4 e is H; a compound of Formula (70) wherein R is F, R 3 is- NHCH(CH2CH2OMe)(CH2OMe), R 4 a is Me, ROb is H, R 4 c is Cl, R 4 d is H and

R

4 e is H; a compound of Formula (70) wherein R is F, R 3 is- I 9/OS/05,at 1291 5. specipgs.27 27 N(n-Pr)(CH2CH2CN), R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- N(Et)2, R 4 a is Me, ROb is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(CH2CH2OMe)(CH2OMe), R 4 a is Cl, ROb is H, R 4 c is Me, R 4 d is H and

R

4 e is H; 00 a compound of Formula (70) wherein R is F, R 3 isciNHCH(CH2CH2OMe)(CH2OMe), Rais Cl, ROis H, R is Me, R 4 d is H and

R

4 e is H; a compound of Formula (70) wherein R is F, R 3 is- N(Et)2, R 4 a is Cl, ROb is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is N(c-Pr)(CH2CH2CN), R 4 a is Me, ROb is H, R 4 c is OMe, R 4 d is Hand R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is N(c-Pr)(CH2CH2CN), R 4 a is Cl, ROb is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NHCH (n-Pr)(CH2OMe), R 4 a is Me, ROb is H, R 4 c is OMe, R 4 d is H and R 4 e is

H;

a compound of Formula (70) wherein R is F, R 3 is- NHCH (n-Pr)(CH 2 OMe), R 4 a is Cl, BY' is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is -NHCH(Et) 2

R

4 a is Br, R 4 b is H, R 4 c is OMe, R 4disOMeand R' is H; 19/O5/05,at 12915. specipgs,28 -28a compound of Formula (70) wherein R is F, R 3 is NHCH(Et)2, R 4 a is Br, R 4 b is H, R 4 c is OMe, R 4 d is H- and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- N(CH2CH2OMe)2, R 4 a is Br, R 4 b is H, R 4 c is OMe, Rd is Hand Re is'H; a compound of Formula (70) wherein R is F, R 3 is- NHCH(CH2OMe)2, R 4 a is Br, R 4 b is H, R 4 c is OMe, Rd is Hand Re is H; a compound of Formula (70) wherein R is F, R 3 is N(Et)2, R 4 a is Me, R 4 b is H, R 4 c is'Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- N(Et)2, R 4 a is Cl, R 4 b is H, R 4 c is OMe, R 4 d is OMe and R 4 e is H; a compound of Formula (70) wherein'R is F, R 3 is- NI{CH(Et)2, R 4 a is Cl, R 4 b is H, R 4 c is OMe, R 4 d is OMe and

R

4 e is H; a compound of Formula (70) wherein R is F, R 3 is- N(CH2CH2OMe)2,

R

4 a is Cl, R 4bis H, R 4 c is Cl, R4 is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- NHCH(CH2OMe)2,

R

4 a is Cl, R 4bis H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- ~N (Pr) (CH2 CH2 CN) R 4 a is Cl, Rb is H, R 4 c is Ci., Rd is H and R 4 e is H; a compound of Formul-a (70) wherein R is F, R 3 is- N(Bu)(Et), R 4 a is Cl, R 4 b is R 4 c is Cl, R 4 d is H and R 4 eisH -29- 09/12 ,doc te l 3,29 a compound of Formula (70) wherein R is F, R 3 is NHCH(Et)CH2OMe, R 4 a is Cl, R 4 b is H, R 4 c is C1,

R

4 d is H and R 4 e is H; a compound of Formula (70) NHCH(Et)2, R 4 a is C1, H and R 4 e is H; a compound of Formula (70) 0 NHCH( Et)2, R 4 a is Me, H .and R 4 e is H; a compound of Formula (70) N'HCH(Et)2, R 4 a is Ci, H and R 4 e is H; a compound of Formula (70) NHCH(Et)2, R 4 a is Me, H and R 4 e is H; wherein R is F, R 3 is

R

4 b is H, R 4 c is Cl, R 4 d is wherein R is F, R 3 is-

R

4 b is H, R 4 c is Me, R 4 d is wherein R is F, R 3 is-

R

4 b is H, R 4 c is Me, .R 4 d is wh erein R is F, R 3 is

R

4 b is H, R 4 c is Cl, R 4 d is a compound of Formula (70) wherein R is F, R 3 is -NEt2,

R

4 a. is Me, Rbis H, R 4cis OMe, R 4 d is H and R 4 is H; and a compound of Formula (70) wherein R is F, R 3 is- N(Pr) (CH2CH2CN), R 4 a is Me, R 4 b is H, R 4 c is OMe,

R

4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, N(Pr) (CH2CH2OMe), R 4 a is Me, R 4 b is H,

R

4 d is H and R 4 e is H; a compound of Formula (70) wherein R is CI, N(Et) (CH2CH2OMe), R 4 a is Me, R 4 b is H,

R

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

a compound of Formula (70) wherein R is Cl, W(Me) (CH2CH2OMe), R 4 a is Me, R 4 b is H,

R

4 d is H and R 4 e is H;

R

3 is

R

4 c is OMe,

R

3 is R 4 c is OMe,

R

3 is

R

4 c is OMe, a compound of Formula (70) wherein R is C1, R 3 is NMeEt, R 4 a. is Me, R 4 b is H, R 4 c is OMe, R 4 d is H 11 /09/02,doctunentl 3,30 and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is NMePr, R 4 a is Me, R 4b is H, R 4c is OMe, R 4d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is NMeBu, R 4a is Me, R 4 b is H, R 4C is OMe, R 4d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is -NH- 2-butyl, R 4 a is Me, R4b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is cyclobutylamino, R 4a is Me, R 4 b is H, R 4 c is OMe,

R

4d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, N(Pr)(CH2CH2OMe), R 4 a is Me, .R 4 b is H, R4d is Me and R 4 e is H; a compound of Formula (70) wherein R is Cl, N(Et) (CH2CH2OMe), R 4 a is Me, R 4 b is H,

R

4 d is Me'and R 4 e is H; a compound of Formula (70) wherein R is Cl, N(Me) (CH2CH2OMe), R 4 a is Me, R 4 b is H,

R

4 d is Me and R 4e is H;

R

3 is

R

4 c is OMe,

R

3 is

R

4 c is OMe,

R

3 is

R

4 c is OMe, a compound of Formula (70) wherein R is Cl, R 3 is NMeEt, R 4 a is Me, R 4 is H, R 4 c is OMe, R 4d is Me and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is NMePr, R 4a is Me, R 4 b is H, R 4 c is OMe, R 4d is Me and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is NMeBu, R 4 a is Me, R 4 is H, R 4c is OMe, R 4d is Me 31- 11 /09/02,documnentl 3.31 and R 4eisH; a compound of Formula (70) wherein R is Cl, R 3 is -NH- 2-butyl, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is cyclobutylamino, R 4 a is Me, R 4 b is H, R 4 c is OMe,

R

4 d is ME and R 4 e is H; a compound of Formula (70) wherein R is.F, R 3 is N(Pr) (CH2CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is

R

4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- N(Et) (CH2CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is Rd is H and Re is H; a compound of Formula (70) wherein R is F, R 3 is- N(Me) (CH2CH2OMe), R 4 a is Me,..R 4 b is H, R 4 c is Rd is H arnd R 4 is H; OMe, OMe, OMe, a compound of Formu~la.(70) wherein R NMeEt, R 4 a is Me, R 4 b is H, R 4 c and R 4 e is H; a compound of Formula (70) wherein R NI~ePr, R 4 a is Me, R 4 b is H, R 4 c and R 4 e is H; a compound of Formula (70) wherein R NI~eBu, R 4 a is Me, R 4 b is H, c and Re is H; a compound of Formula (70) wherein*R butyl, R 4 a is Me, R 4 b is H, c and R 4 e is H; a compound of Formula (70) wherein R cyclobutylamino, R 4 a is Me, R 4 b is F, R 3 is is OMe,

R

4 d is F, R 3 is is, OMe,

R

4 d is F, R 3 is is OMe,

R

4 d is F, R 3 is is OMe,

R

4 d is H is H is H NH -2is H is F, R 3 is is H, R 4 c is OMe, 32 I I /09/02.docunenil 3,32 R 4dis Hand R 4e sH; a compound of Formula (70) wherein R is F, R 3 is N(Pr) (CH 2 CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is*OMe, R4d is Me and R 4e sH; a compound of Fo rmula (70) wherein R is F, R 3 is- N(Et) (CH 2 CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is OMe, Rd is Me and Re isH; a compound of Formula (70) wherein R is F, R 3 is- Nj(Me) (CH 2 CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is OMe,

R

4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is F, F N~et, ~ais Me, R 4 b is H, Rc is OMe, and R 4 e is H; a compound of Formula (70) wherein R is F, N~ePr, R 4 a is Me, R 4 b is H, R 4 c is OMe, and R 4 e is H; a compound of Formula (70) wherein R is F, N~eBu, R 4 a is Me, R 4 b is H, R 4 c is OMe and R 4 e is H; a compound of Formula (70) wherein R is F, butyl, R 4 a is Me, R 4 b is H, R 4 c is OMe and R 4 e is H; a compound of Formula (70) wherein R is F, cyclobutylamino, R 4 a is Me, R 4 b is H,

R

4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is Me, N(Pr) '(CH2CH2OMe), R 4 a is Me, R 4 b.is H, Rd is Hand Re is H; a compound of Formula (70) wherein R is Me, N~(Et) (CH2CH2OMe), R 4 a is Me, R 4 b is H,

R

4 d is Hand R 4 e is H; ~3 is

R

4 d'is Me Z3 is IR 4dis Me 13 is IR 4dis Me

R

3 is -NH-2- I R 4dasMe

R

3 is

R

4 c is OMe,

R

3 is

R

4 c is OMe,

R

3 is

R

4 c is, OMe, 33 I I /09/02,dovwnet 3,33 a compound of Formula (70) wherein R is Me, R 3 is N(Me)(CH2CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is OMe,

R

4 d is Hand R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NMeEt, R 4 a is Me R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- NMePr, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- N~eBu, R 4 a. is Me, Rb is H, R 4 Ci OMe, R~di and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is -NH- 2-butyl, R 4 a is Me, R is H, RC is OMe, Rd is H and R 4 e is H; a compound of Formula'(70) wherein R is Me, R 3 is cyclobutylamino, R 4 a. is Me, R 4 b is H, R 4 c is OMe,

R

4 d is Hand R 4 e is H; a compound of Formula wherein R is Me, N (Pr) (CH2CH2OMe) R 4 a is Me, R 4 b is H,

R

4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is Me, N(Et) (CH2CH2OMe) R 4 a is Me, R 4 b is H,

R

4 d is Me and R 4 e is H; a compoun d of Formula (70) wherein R is Me, N (CH2CH2OMe) R 4 a is Me, R 4 b is H,

R

4 d is Me and R 4 e is H;

R

3 is-

R

4 c is OMe,

R

3 is-

R

4 c is OMe,

R

3 is-

R

4 c is OMe, a compound of Formula (70) wherein R is Me, R 3 is N~eEt, R 4 a. is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; 34-- I1I /09/02,docurnntl 3,34 a compound of Formula (70) wherein R is Me, R 3 is NMePr,

R

4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NMeBu,

R

4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NH-2-butyl,

R

4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; and a compound of Formula (70) wherein R is Me, R 3 is cyclobutylamino

R

4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H.

Specifically preferred compounds of the present invention may include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein said compound is selected from: 7-(diethylamino)-2,5-dimethyl-3-(2-methyl-4-methoxyphenyl-[1,5-a]pyrazolopyrimidine and 7-(N-(3-cyanopropyl)-N-propylamino)-2,5-dimethyl-3-(2,4- The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of the above-described compounds and a pharmaceutically acceptable carrier.

The present invention still further provides methods of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord 11/09/02,swl2915spa,35 traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of the above-described compounds.

The present invention still even further provides the use of the above-described compounds in the preparation of a medicament to treat affective disorder, anxiety depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals.

Many compounds of this invention have one or more asymmetric centers or planes.

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

The term "alkyl" includes both branched and straight-chain alkyl having the specified number of -36- 11/09/02,swl 2915spa,36 carbon atoms. Commonly used abbreviations have the following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl. The prefix means a straight chain alkyl. The prefix means a cycloalkyl. The prefix means the S enantiomer and the prefix means the R enantiomer.

Alkenyl" includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. "Alkynyl" includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.

"Haloalkyl" is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ringgroups, including mono-,bi- or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth.

"Halo" or "halogen" includes fluoro, chloro, bromo, and iodo.

The term "substituted", as used herein, means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto then 2 hydrogens on the atom are replaced.

Combinations of substituents and/or variables -37- 11 /09/02,documentl 3,37 are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.' The term "appropriate amino acid protecting group" means any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. Such amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley Sons, New York (1991) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(pbiphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.

The term "pharmaceutically acceptable salts" includes acid or base salts of the compounds of Formulae and Examples of pharmaceutically -38- 11/09/02,documentl 3,38 acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

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

"Prodrugs". are considered to. be any covalently bonded carriers which release the active parent drug of formula or (II) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formulas and and the like.

The term "therapeutically effective amount" of a compound of this invention means an amount -39- 11/09/02,docunntl 3,39 effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.

Syntheses Some compounds of Formula may be prepared from intermediate compounds of Formula using the procedures outlined in Scheme 1: SCHEME 1 halogenating agent or sulfonylating agent base, solvent H N RN N R1N Z R IN Ar Ar Y 0 (8)

R

3

R

3 H, base, N solvent R N Ar A N Compounds of Formula (where Y is 0) may be treated with a halogenating agent or sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from -80 0 C to 250 0 C to give products of Formula (where X is halogen, alkanesulfonyloxy, 11 /09/02,documenl 3,40 arylsulfonyloxy or haloalkane-sulfonyloxy).

Halogenating agents include, but are not limited to, SOC12, POC1 3 PC1 3 PC1i, POBr 3 PBr 3 or PBrs.

Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides- (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20 0 C to 100°C.

Compounds of Formula may be reacted with compounds of Formula R 3 H (where R 3 is defined as above except R 3 is not SH, COR 7

CO

2

R

7 aryl or heteroaryl) -41- 11 /i9/02,documnlll1 3,11 in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from -80 to 250 0 C to generate compounds of Formula Bases may include, but are not limited to, alkali metal-hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,Ndialkylformamides (preferably dimethylformamide),

N,N-

dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0OC to 140 0

C.

Scheme 2 delineates the procedures for converting intermediate compounds of Formula (where Y is S) to some compounds of Formula -42- 11 /09/02,documentl 3,42 SCHEME 2

Y

R N Ar

SR

13

R

13 X, base, solvent Y S oxidizing agent, solvent (12)

I

R

3 H, base, solvent

R

3 H, base, solvent

PP,

R

3 A N\ NAr Ar (13) A N Compounds of Formula (where Y is S) may be treated with an alkylating agent R 13 X (where R 13 is defined as .above, except R 13 is not aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from -800C to 250 0 C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably -43- 11/09/02,documentl 3,43 sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably N,N-di-isopropyl-N-ethyl amine or triethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -80 0 C to 100 0

C.

Compounds of Formula (12) (Formula where R 3 is

SR

13 may then be reacted with compounds of Formula R 3

H

to give compounds of Formula using the same conditions and reagents as were used for the conversion of compounds of Formula to compounds of Formula (1) as outlined for Scheme 1 above. Alternatively, compounds of Formula (12) (Formula where R 3 is

SR

13 may be oxidized to compounds of Formula (13) (Formula where R 3 is S(O)nR 1 n is 1,2) by treatment with an oxidizing agent in the presence of an inert solvent at temperatures ranging from -80 0 C to 250°C. Oxidizing agents include, but are not limited to, hydrogen peroxide, alkane. or aryl peracids (preferably peracetic acid or m-chloro-perbenzoic acid), dioxirane, oxone, or sodium periodate. Inert solvents may include, but are not limited to, alkanones (3 to 10 carbons, preferably acetone), water, alkyl -44- 11 /09/02,docuincill 3.1 alcohols (1 to 6 carbons), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to carbons and 1 to 10 halogens (preferably dichloromethane) or combinations thereof. The choices of oxidant and solvent are known to those skilled in the art (cf. Uemura, Oxidation of Sulfur, Selenium and Tellurium, in Comprehensive Organic Synthesis, Trost, B.M. ed., (Elmsford, NY: Pergamon Press, 1991), 7, 762-769). Preferred reaction temperatures range from -20 0 C to 100oC. Compounds of Formula (13) (Formula (1) where R 3 is S(O)nR 13 n is 1,2) may then be reacted with compounds of Formula R 3 H to give compounds of Formula using the same conditions and reagents as were used for the conversion of compounds of Formula to compounds of Formula as outlined for Scheme (1) above.

Compounds of Formula where R 3 may be

NR

8

COR

7

-N(COR

7 2

-NR

8

CONR

6

R

7

-NR

8 C02R 1 3

-NR

6

R

7 NR8SO2R 7 may be prepared from compounds of Formula where Y is NH, by the procedures depicted in Scheme 3.

11/09/02,doctunentl 3,45 SCHM 3 V alkylating, sufonyating 3 N or acylating agents MN N I-basesolvent A N R1" N N" ArX Y =NH 1 A =N;

R

3

NR

6

R',NRBCOR

7 N (COR 7 2

NR

9

CONR

6

R

7

NRSCO

2

R

13 Reaction of compounds of Formula where Y is NH, with alkylating agents, sulfonylating agents or acylating agents or sequential reactions with combinations thereof, in the presence or absence of a base in an inert solvent at reaction temperatures ranging from -800C to 250 0 C may afford compounds of Formula where R 3 may be -NR 8

COR

7 -N (COR 7 2

NRSCONR

6

R

7

-NR

8 CO2Rl 3

-NR

6

R

7

-NRBSO

2

R

7 Alkylating agents may include, but are not limited to, Cj-Cj 0 alkyl -halides, -tosylates, -mesylates or -triflates; Cj-Cj 0 haloalkyl(l 10 halogens)-halides, -tosylates, -mesylates or -triflates; C 2

-C

8 alkoxyalkyl-halides, tosylates, -mesylates or -triflates; C 3

-C

6 cycloalkylhalides, -tosylates, -mesylates or -triflates; C 4

C

1 2 cycloalkylalkyl -halides, -tosylates, -mesylates or -triflates; aryl(CI-C 4 *alkyl) -halides, -tosylates,mesylates or -triflates; heteroaryl(Cl-C 4 alkyl)halides, -tosylates, -mesylates or -triflates; or heterocyclyl(Cl-C4 alkyl)-halides, -tosylates,- 46 II /(:9/02,locmfienl 3.46 mesylates or -triflates. Acylating agents may include, but are not limited to, C1-CO10 alkanoyl halides or anhydrides, C1-Co10 haloalkanoyl halides or anhydrides with 1 10 halogens, C2-CB alkoxyalkanoyl halides or anhydrides, C3-C6 cycloalkanoyl halides or anhydrides, C4-C12 cycloalkylalkanoyl.halides or anhydrides, aroyl halides or anhydrides, aryl(C1-C4) alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl(C1-C4) alkanoyl halides or anhydrides, heterocyclylcarboxylic acid halides or anhydrides or heterocyclyl(C1-C4) alkanoyl halides or anhydrides.

Sulfonylating agents include, but are not limited to, C1-CO10 alkylsulfonyl halides or anhydrides, C 1

-C

10 haloalkylsulfonyl halides or anhydrides with 1 halogens, C2-C8 alkoxyalkylsulfonyl halides or anhydrides, C3-C6 cycloalkylsulfonyl halides or anhydrides, C 4 -C12 cycloalkylalky.sulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl(C1-C4 alkyl)-, heteroarylsulfonyl halides or anhydrides, heteroaryl(C1-C4 alkyl)sulfonyl halides or anhydrides, het'erocyclylsulfonyl halides or anhydrides or heterocyclyl(C1-C4 alkyl)sulfonyl halides or anhydrides. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower -47- 11 /09/02,documentl 3,47 alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Nmethylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0 C to 1000C.

Scheme 4 delineates procedures, which may be employed to prepare intermediate compounds of Formula where Y is 0, S and Z is CR 2 -48- 11/09/02,documentl 3,48 SCHEME 4

R

2 CORb, base, solvent ArCH 2 CN

NH

2

NH

2

H

2 0,

R

2 solvent Ar (3)

NH

Ri

ORC

acid, solvent

HMN

R

2

H

2

N

Ar NH HN 2 Ar Y=C(Rd) 2 base, solvent

HN

Z

RAr N Ar Y 0, S; Z CR 2 Compounds of the formula ArCH 2 CN are reacted with compounds of the formula R 2 CORb, where R 2 is defined above and Rb is halogen, cyano, lower alkoxy (1 to 6 carbons) or lower alkanoyloxy (1 to 6 carbons), in the presence of a base in an inert solvent at reaction temperatures ranging from -78 0 C to 200 0 C to afford compounds of Formula Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal -49- I /09/02,documentl 3,49 dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably .acetonitrile), water, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene).

Preferred reaction temperatures range from 0°C to 100 0

C.

Compounds of Formula may be treated with hydrazine-hydrate in the presence of an inert solvent at temperatures ranging from 0°C to 200 0 C, preferably 0 C to 1500C, to produce compounds of Formula Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,Ndialkylformamides (preferably dimethylformamide),

N,N-

dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) Compounds of Formula may be reacted with compounds of Formula (where Rc is alkyl (1-6 carbons)) in the 11 /09/02,docunentl 3.50 presence or absence of an acid in the presence of an inert solvent at temperatures ranging from OoC to 2000C to produce compounds of Formula Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2 10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably.p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid.

Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, water, alkanenitriles (1 to 6 carbons, preferably acetonitrile), halocarbons of 1 to 6 carbons and 1 to 6 halogens (preferably dichloromethane or chloroform), alkyl alcohols of 1 to 10 carbons (preferably ethanol), dialkyl ethers (4 to 12 carbons, preferably diethyl ether or di-isopropylether) or cyclic ethers such as dioxan or tetrahydrofuran.

Preferred temperatures range from ambient temprature to 100 0

C.

Compounds of Formula may be converted to intermediate compounds of Formula by treatment with compounds C=Y(Rd) 2 (where Y is O or S and Rd is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) in the presence or absence of a base in an inert solvent at reaction temperatures from -50 0 C to 200 0 C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkali metal carbonates, alkali metal hydroxides, trialkyl amines (preferably N,N-diisopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may -51- 11/09/02,docwuentl 3.51 include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene).

Preferred temperatures are 0°C to 1500C.

Intermediate compounds of Formula where Z is N, may be synthesized according the methods outlined in Scheme -52- 11 /09/02.docunienl 3.52 SCHEME RqCH 2

N

3 base, solvent ArCH 2

CN

NH

R 5

)O

acid, solvent *reducing agent solvent

A)W

A

NH HN\ Ri)

NN

H

RN

Ar (11) Y=C (Rd) 2 base, solve=,,-

Y

N N Ar Y 0, S Z =N Compounds of ArCH2CN are reacted with compounds of Formula RqCH 2

N

3 (where Rq is a phenyl group optionally substituted by H, alkyl (1 to 6 carbons) or alkoxy (1 to 6 carbons) in the presence or absence of a base in an inert solvent at temperatures ranging from QOC to 200 0 C to generate compounds of Formula Bases may -53 I1I /09/02,docuxnentl 3,53 include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide, sodium ethoxide or potassium t-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide) alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl.alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Nmethylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from ambient temperature to 100 0 C. Compounds of Formula may be treated with a reducing agent in an inert solvent at -100OC to 1000C to afford products of Formula Reducing agents include, but are not limited to, hydrogen gas in combination with noble metal catalysts such as Pd-on-carbon, PtO 2 Pt-oncarbon, Rh-on-alumina or Raney nickel, alkali metals (preferably sodium) in combination with liquid ammonia or ceric ammonium nitrate. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), water, dialkyl ethers (preferably -54- 11 /09/02,docunentl 3,54 diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene) The preferred reaction temperatures are -50 0 C to 600C.

Compounds of Formula are then converted to compounds of Formula (where Z is N) via intermediates of Formula (11) using the reagents and reaction conditions outlined in Scheme 4 for the conversion of compounds of Formula to compounds of Formula (where Z is CR 2 Compounds of Formula may also be prepared from compounds of Formula (where Y is O, S and Z is defined above) as outlined in Scheme 6: SCHEME. 6 Y R 3 H, acid,

R

L dehydrating agent HN N Z -solvent A N RN

R

1

N

Ar Ar Y O, S; Z N, CR 2 A N Compounds of Formula may be reacted with compounds of Formula R 3 H in the presence of a dehydrating agent in an inert solvent at reaction temperatures ranging from 0°C to 2500C. Dehydrating agents include, but are not limited to, P 2 0 5 molecular sieves or inorganic or organic acids. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic S/09/02,docunentl 3.55 acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid.

Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably glyme or diglyme), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide)- N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or halocarbons of 1 to 10 carbons and 1 to 10 halogens (preferably chloroform). Preferred reaction temperatures range from ambient temperature to 150 0

C.

Some compounds of Formula (where A is N) may also be prepared'by the methods shown in Scheme 7: SCHEME 7

R

3 C(ORe),

R

3

_,N

NH HN.. acid, 1Z solvent N R1 N

/Z

(14) Ar A N Intermediate compounds of Formula where Z is defined above, may be reacted with compounds of Formula

R

3 C(ORe)3, where Re may be alkyl (1 to 6 carbons) in the presence or absence of an acid in an inert solvent at temperatures ranging from 0oC to 2500C. Acids may -56- 11 /09/02,documentl 3,56 include, but are not limited to alkanoic acids of 2 to carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Nmethylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).

Preferred reaction temperatures range from 50 0 C to 150oC.

Intermediatecompounds of Formula may also be synthesized by the reactions displayed in Scheme 8.

SCHEME 8

Y

X N_ Y OH, SE NR 6

R

7

A

r Z N, CR 2 A N X Br, Cl, I, B(OR"")2 -57- 1 1109/02,docunenl 3,57 Compounds of Formula (where Y is OH, SH, NR 6

R

7

Z

is defined above, X is Br, Cl, I, 03SCF 3 or B(OR"") 2 and is H or alkyl (1 to 6 carbons)) may be reacted with a compound of Formula ArM (where M is halogen, alkali metal, ZnC1, ZnBr, ZnI, MgBr, MgCl, MgI, CeC1 2 CeBr 2 or copper halides) in the presence or absence of an organometallic catalyst in the presence or absence of a base in an inert solvents at temperatures ranging from -100 0 C to 200 0 C. Those skilled in the art will recognize that the reagents ArM may be generated in situ. Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd(PPh 3 4 palladium halides or alkanoates (such as PdCl 2 (PPh 3 2 or Pd(OAc) 2 or nickel complexes (such as NiCl 2 (PPh 3 2 Bases may include, but are not limited to, alkali metal carbonates or trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Nmethylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. Preferred reaction temperatures range from -800C to 100 0

C.

The choices of M and X are known to those skilled in the art (cf. Imamoto, Organocerium Reagents in Comprehensive Organic Synthesis, Trost, B.M. ed., (Elmsford, NY: Pergamon Press, 1991), 1, 231-250; Knochel, Organozinc, Organocadmium and Organomercury Reagents in Comprehensive Organic Synthesis, Trost, B.M. ed., (Elmsford, NY: Pergamon -58- 11/09/02,documentl 3,58 Press, 1991), 1, 211-230; Knight, Coupling Reactions between sp 2 Carbon Centers, in Comprehensive Organic Synthesis, Trost, B.M. ed., (Elmsford, NY: Pergamon Press, 1991), 3, 481-520).

Compounds of Formula may also be prepared using the methods shown in Scheme 9.

R3 SCHEME 9

SR

3 Ssolvent

Z

RR

1 N

X

Ar (16) X Br, Cl, I, (1) 03SCF3 Compounds of Formula where A, Z, R 1 and R 3 are defined above and X is Br, Cl, I, 03SCF 3 or B(OR"")2 and is H or alkyl (1 to 6 carbons)) may be reacted with a compound of Formula ArM (where M is halogen, alkali metal, ZnCl, ZnBr, ZnI, MgBr, MgCl, MgI, CeC1 2 CeBr 2 or copper halides) in the presence or absence of an organometallic catalyst in the presence or absence of a base in an inert solvents at temperatures ranging from -100 0 C to 200 0 C. Those skilled in the art will recognize that the reagents ArM may be generated in situ (see the above references in Comprehensive Organic Synthesis). Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd(PPh 3 4 palladium halides or alkanoates (such as PdCl 2 (PPh 3 2 or Pd(OAc) 2 or nickel complexes (such as NiC12(PPh 3 2 Bases may include, but are not limited to, alkali metal carbonates or trialkyl amines -59- 11/09/02,documentl 3,59 (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine). Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylfornamides (preferably dimethylformamide), NJ'7-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably 1'methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or water. Preferred reaction temperatures range from -80 0 C to 100 0

C.

Intermediate compounds of Formula (where Y is 0, S, NH, Z is CR 2 and R 1

R

2 and Ar are def ined as above) may be prepared as illustrated in Scheme SCHEME 0 Ar (3) base or acid, solvent

H

2 'N N~ N R 2

H

2

N."

Ax (17) RIC (OR) 3 acid, solvent

Y

EN

Ax Y 0, S, NH; Z CR 2 Compounds of Formula may be reacted with compounds 60 11 /09/02,ciocu~etl 3,60 of Formula H 2

NNH(C=Y)NH

2 where Y is 0, S or NH, in the presence or absence of a base or acid in an inert solvent at temperatures from OOC to 2500C to produce compounds of Formula Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or catalytic amounts of such acids may be used. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert'solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Nmethylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).

Preferred reaction temperatures range from 0 0 C-to 150 0 C. Compounds of Formula (17) may then be reacted with compounds of Formula R3C(ORe)3, where Re may be -61- 1 /09/02,documentl 3,61 alkyl (1 to 6 carbons) in the presence or absence of an acid in an inert solvent at temperatures ranging from 0°C to 250 0 C. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid.

Stoichiometric or catalytic amounts of such acids may be used. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 50 0 C to 1500C.

In Scheme 11, the procedures which may be used to convert compounds of Formula where R 3 is COR 7 C0 2

R

7

NR

8

COR

7 and CONR 6

R

7 to other compounds of Formula where R 3 is CH(OH)R 7 CH20H, NR 8

CH

2

R

7 and

CH

2

NR

6

R

7 by treatment with a reducing agent in an inert solvent at temperatures ranging from -80 0 C to 250 0

C.

-62- 11 /09/02,documentl 3,62 SCHEME 11

R

3 A N' reducing agent, N Z solvent A N

RN

Ar Ar

R

3

COR

7

CO

2

R

7

R

3

C(OH)R

7 CONR6R7

CH

2

NR

6

R

7 Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane, dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides,.or dialkyl aluminum hydrides (such as di-isobutylaluminum hydride). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 6 carbons), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from -80 0 C to 100 0

C.

In Scheme 12, the procedures are shown which may be used to convert compounds of Formula where R 3 is COR 7 or CO 2

R

7 to other compounds of Formula where R 3 is C(OH)(R 7 2 by treatment with a reagent of Formula R 7 M in an inert solvent at temperatures ranging from -80 0 C to 250 0

C.

-63- 11/09/02,documentl 3.63 SCHEME 12 AXreducing agent, A

R

1 N i\ tolvent Nz Ar Ar R 3 C0R 7

CO

2 R 71(1) R 3 C C(OH) (R 7 M is halogen, alkali nietal, ZnCl, ZnBr, ZnI, MgBr,' MgCl, MgI, CeCl 2 CeBr 2 or copper halides. Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from -8OoC to 100 0

C.

Compounds of Formula where R 3 may be

NR

8

COR

7

-N(COR

7 2

-NR

8

CONR

6

R

7

-RCOR,-NR'-

NR

8

SO

2

R

7 may be synthesized as depicted in Scheme 13.

64 1 IM9/02.docuinentl 3.64 SCHEME 13 (18) ]k base, solvent (19) Z CR 2 Z =N alkylating, sulfonylating or acylating agents /-base,solvent A =CR

R

3

=N

6

R

7

NR

8

COR

7 N (COR 7 2 NR,3CONR 6

R

7

NR

6 C0 2

R

13 Reaction of compounds of Formula where R and R 1 are defined above, with compounds of Formula or 5(10) in the presence or absence of base in an inert solvent may produce compounds of Formula (19) at 65 11 I)9IO2,docuinventI 3,65 temperatures ranging from -50 0 C to 250 0 C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene).

Preferred reaction temperatures range from 0°C to 100oC.

Compounds of Formula (19) may then be reacted with alkylating agents, sulfonylating agents or acylating agents or sequential reactions with combinations thereof, in the presence or absence of a base in an inert solvent at reaction temperatures ranging from 0 C to 250 0 C may afford compounds of Formula where R 3 may be -NR 8

COR

7

-N(COR

7 2

-NR

8

CONR

6

R

7

NR

8 CO2R 13

-NR

6

R

7

-NR

8

SO

2

R

7 Alkylating agents may include, but are not limited to, C 1

-C

10 alkyl -halides, -tosylates, -mesylates or -triflates; C1-C10 haloalkyl( 10 halogens)-halides, -tosylates, -66- 11/09/02.documnentl 3,66 mesylates or -triflates; C 2 -C8 alkoxyalkyl-halides, tosylates, -mesylates or -triflates; C3-C6 cycloalkylhalides, -tosylates, -mesylates or -triflates; C 4 C12 cycloalkylalkyl -halides, -tosylates, -mesylates or -triflates; ary l(Cl-C4 alkyl)-halides, -tosylates,mesylates or -triflates; heteroaryl(Cl-C4 alkyl)halides, -tosylates, -iesylates or -triflates; or heterocyclyl (C 1

-C

4 alkyl) -halides, -tosylates, mesylates. or -triflates. Acylating agents may include, but are not limited to, Ci-CjO alkanoyl halides or anhydrides, Ci-ClO haloalkanoyl halides or anhydrides with 1 10 halogens, C 2

-C

8 alkoxyalkanoyl halides or anhydrides, C3-C6 cycloalkanoyl halides or anhydrides, C4-Cl2 cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl(Cl-C4 alkanoyl halides or anhydrides, heteroaroyl halides or'anhydrides, heteroaryl(Cl-C4) alkanoyl halides or anhydrides, he terocyclylcarboxylic acid halides or anhydrides or heterocyclyl(Cl-C4) alkanoyl halides or anhydrides.

Sulfonlylating agents include, but are not limited to, cl-Cl 0 alkylsulfonyl halides or anhydrides, C 1

-C

10 haloalkylsulfonyl halides or anhydrides with 1 halogens, C 2

-C

8 alkoxyalkylsulfonyl halides or anhydrides, C3-C6 cycloalkylsulfonyl halides or anhydrides, C4-Cl2 cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl(Cl-C4 alkyl)-, heteroarylsulfonyl halides or anhydrides, heteroaryl(Cl-C4 alkyl)sulfonyl halides or anhydrides, heterocyclylsulfonyl halides or anhydrides or heterocyclyl(Cl-C4 alkyl)sulfonyl halides or anhydrides. Bases may include, but are not limited. to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably -67- I I/09/02,docu~mentI 3.67 sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or-ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably Nmethylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from OOC to 100 0

C.

Compounds of Formula where A is CR and R is defined above, may be synthesized by the methods depicted in Scheme 14.

-68- 11/09/02,documentl3,68 SCHEME 14

N

H N z

H

2

N."

Ar Z=CR 2 Z =N

R

base, solvent xp.

R

3 z Ar A CR

R

(21) base, solvent

R

3 H, base, solvent x h a l o g n a tit a gN or sulfonylating agent -base, /-solvent

N

Ax Ar (23) (22) Compounds of Formula or (10) may be treated with compounds of Formula where R 1 and R 3 are defined above in the presence or absence of base in an inert solvent at temperatures ranging from 0 0 C to 250 0 C to give compounds of Formula where A is CR and R is, 69 11 /09/02,documentl 3,69 defined above. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,Ndialkylformamides (preferably dimethylformamide),

N,N-

dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene).

Preferred reaction temperatures range from 0 0 C to 100 0 C. Alternatively, compounds of Formula where A is CR and R is defined above, may be synthesized through intermediates (22) and (23).

Compounds of Formula or (10) may be treated with compounds of Formula where R 1 is defined above and Re is alkyl (1 6 carbons), in the presence or absence of base in an inert solvent at temperatures ranging from OOC to 250 0 C to give compounds of Formula where A is CR and R is defined above. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), 11 /09/02,documentl 3,70 alkali metal carbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols-(l to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene).

Preferred reaction temperatures range from 0°C to 100 0 C. Compounds of Formula (22) may be treated with a halogenating agent or sulfonylating agent in the presence or absence of a base in the prebence or absence of an inert solvent at reaction temperatures ranging from -80 0 C to 250 0 C to give products of Formula (23) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkane-sulfonyloxy).

'Halogenating agents include, but are not'limited to, SOC12, POC1 3 PC1 3 PC15, POBr 3 PBr3'or PBr 5 Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as methanesulfonyl chloride or methanesulfonic acid anhydride), arylsulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride) or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium -71- 11 /09/02,docunentl 3,71 ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20 0 C to 100oC.

Compounds of Formula (23) may be reacted with compounds of Formula R 3 H (where R3 is defined as above except R 3 is not SH, COR 7 C0 2

R

7 aryl or heteroaryl) in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from -80 0 C to 250 0 C to generate compounds of Formula Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons) (preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine) or aromatic amines -72l /09/02,documentl 3,72 (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,Ndialkylformamides (preferably dimethylformamide),

N,N-

dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene)' or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from OOC to 140 0

C.

Some compounds of Formula may also be prepared using the methods shown in Scheme -73- 11/09/02,doctu entl 3,73

NH

2

NH

2 acid, solvet SCHE Ar NE 2 NN NH 2 (2 4) AX acid, solvent

H

2

N-O)

1 NN O H 2 N

O

(26)Y =0O, S A For A =N: 1) R IC(=NH)ORO acid, solvent 2) Y=C (Rd) 2 base, solvent For A 1) R 1 ba *olvern C-0) CHR (C-Y)OR, soe or acid, it +/-solvent

R

3

YB

AOH see text R1>%

-OH

Ar (27)Y=O0, S Ar Z C1R 2 A compound of Formula (24) (Rc is a lower alkyl group and Ar is defined as above) may be reacted with hydrazine in the presence or absence of an inert solvent to afford an -intermediate of Formula where Ar is defined as above. The conditions employed are similar to those used for the preparation of intermediate of Formula from compound of Formula in Scheme 4. Compounds of Formula where A~ is N, may be reacted with reagents of the formula 7 4 1 /09/02,doc mr entl 3,74 RIC(=NH)ORe, where R1 is defined above and Re is a lower alkyl group) in the presence or absence of an acid in an inert solvent, followed by reaction with a compound of formula YisC(Rd)2 (where Y is O or S and Rd is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to.4 carbons)) .in the presence or absence of a base in an inert solvent to give compounds of Formula (27) (where A is N and Y is 0, S).

The conditions for these transformations are the same as those employed for the conversions of compound of Formula to compound of Formula in Scheme 4.

Alternatively, compounds of Formula where A is CR, may be reactedwith compounds of the formula

R

1 (C=0)CHR(C=Y)ORc (where R 1 and R are defined as above and Rc is a lower alkyl group) to give a compound of Formula (27) (where A is CR) using conditions similar to those employed for the conversion of compounds of Formula (21) to compounds of Formula (22) in Scheme 14.

Intermediates of Formula (27) (where Y is 0) may be treated with halogenating agents or sulfonylating agents in the presence or absence of a base in an inert solvent, followed by reaction with R 3 H or R 2 H in the presence or absence of a base in an inert solvent to give compounds of Formula (where Z is CR 2 It will be recognized by those skilled in the art that various combinations of halogenating agents, sulfonylating agents, R 3 H or R 2 H may be used in different orders of reaction sequences in Scheme 15 to afford compounds of Formula For example, in some cases, it may be desirable to react compounds with stoichiometric amounts of halogenating agents or sulfonylating agents, react with R 2 H (or R 3 then repeat the reaction with halogenating agents or sulfonylating agents and react with R 3 H (or R 2 H) to 11/09/02,documentl 3,75 give compounds of Formula The reaction conditions and reagents used for these conversions are similar to the ones employed for the conversion of intermediate compounds of Formulae (22) to (23) to in Scheme 14 (for A is CR) or the conversion of intermediate compounds of Formulae to to in Scheme 1 (where A is N).

Alternatively, compounds of Formula (27) (where Y is S) may be converted to compounds of Formula in Scheme 15. Intermediate compounds of Formula (27) may be alkylated with a compound RfX (where R f is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent, (then optionally oxidized with an oxidizing agent in an inert solvent) and then reacted with R 3 H in the presence or absence of a base in an inert solvent to give a compound of Formula The conditions and reagents employed are similar to those used in the conversion of intermediate compounds of Formulae to (12) (or to to compounds of Formula in Scheme 2.

Compounds of'Formula may be prepared from compounds of Formula using an alternate route as depicted in Scheme 15. Compounds of Formula (24) may be converted to compounds of Formula (27) via reaction with compounds of formula NH2NH(C=NH)NH12 in the presence or absence of an acid in an inert solvent, followed by reaction with compounds RIC(ORc) 3 (where Rc is lower alkyl and R 1 is defined as above), using the conditions employed for the conversion of compounds of Formulae to (17) to in Scheme Some compounds of Formula may be prepared by the methods illustrated in Scheme 16.

-76- 1 /09/02,documietl 3,76 SCHEME 16 YH

YH

A R 14 X, base A N NsolventN0 RI N R I

N

Ar Ar 27b) Y O, S 28)Y 0, S see text R3 RRX, R3

R

14 A- N base, N N I solventA

O

R

I

N

Ar Ar Z COH (2) Compounds of Formula (27b) may be treated with various alkylating agents R14X (where R 1 4 is defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to afford structures of Formula Compounds of Formula (28) (Y is 0) may then be converted to compounds of Formula by treatment with halogenating agents or sulfonylating agents in the presence or absence of a base in an inert solvent, followed by reaction with R 3 H in the presence or absence of a base in an inert solvent to give -77- 11/09/02,documentl 3,77 compounds of Formula The reaction conditions used for these conversions are similar to the ones employed for the conversion of intermediate compounds (22) to (23) to in Scheme 14 (for A is CR) or the conversion of intermediate compounds of Formulae to to in Scheme 1 (where A is Alternatively, compounds of Formula (28) (Y is S) may be alkylated with a compound RfX (where R f is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in .an inert solvent, (then optionally oxidized with an oxidizing agent in an inert solvent) and then reacted with R 3 H in the presence or absence of a base in an inert solvent to give a compound of Formula The conditions and reagents employed are similar to those used in the conversion of intermediate compounds of Formulae to (12) (or to to compounds of Formula in Scheme 2.

Compounds of Formula where Z is COH, may be converted to compounds of Formula as illustrated in Scheme 16. Treatment with various alkylating agents

R

14 X (where R 1 4 is defined above and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to afford structures It will be recognized by one skilled in the art that the methods used in Scheme 16 may also be used to prepare compounds of Formula (1) where Z is COR 7 For Scheme 16, the terms "base" and inert solvent" may have the meanings given below. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably -78- 11 /09/02,docuentl 3,78 sodium bis(trimethylsilyl)amide), trialkyl amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine) Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20 0 C to 100 0

C.

EXAMPLES

Analytical data were recorded for the compounds described below'using the following general procedures.

Proton NMR spectra were recorded on an IBM-Bruker FT- .NMR (300 MHz); chemical shifts were recorded in ppm (6) from an internal tetramethysilane standard in deuterochloroform or deuterodimethylsulfoxide as specified below. Mass spectra (MS) or high resolution mass spectra (HRMS) were recorded on a Finnegan MAT 8230 spectrometer (using chemi-ionization (CI) with NH 3 as the carrier gas or gas chromatography (GC) as specified below) or a Hewlett Packard 5988A model spectrometer. Melting points were recorded on a Buchi Model 510 melting point apparatus and are uncorrected.

Boiling points are uncorrected. All pH determinations during workup were made with indicator paper.

Reagents were purchased from commercial sources -79ll /09/02,docunlentl 3,79 and, where necessary, purified prior to use according to the general procedures outlined by D. Perrin and W.L.F. Armarego, Purification of Laboratory Chemicals, 3rd ed., (New York: Pergamon Press, 1988).

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

The following examples are provided to describe the invention in further detail. These examples, which set forth the best mode presently contemplated for carrying out the invention, are intended to illustrate and not to limit the invention.

EXAMPLE 1 Preparation of 2,7-dimethyl-8-(2,4-dimethylphenyl) -pyrazolo-[1,3,5]-triazin-4(3H)-one (Formula 7, where Y is O, R 1 is CH 3 Z is C-CH 3 Ar is 2,4-dimethylphenyl) A. l-Cyano-l-(2,4-dimethylphenyl)propan-2-one Sodium pellets (9.8g, 0.43 mol) were added portionwise to a solution of 2,4dimethylphenylacetonitrile (48 g, 0.33 mol) in ethyl acetate (150 mL) at ambient temperature. The reaction mixture was heated to reflux temperature and stirred for 16 hours. The resulting suspension was cooled to room temperature and filtered. The collected' precipitate was washed with copious amounts of ether and then air-dried. The solid was dissolved in water and a IN HC1 solution was added until the pH 5-6. The mixture was extracted with ethyl acetate (3 X 200 mL); 11/09/02,documentl 3,80 the combined organic layers were dried over MgS0 4 and filtered. Solvent was removed in vacuo to afford a white solid (45.7g, 74% yield): NMR (CDC13,300 MHz):; CI-MS: 188 (M H).

B. 5-Amino-4-(2,4-dimethylphenyl)-3-methylpyrazole A mixture of 1-cyano-l-(2,4-dimethylphenyl)propan- 2-one (43.8g, 0.23 mol), hydrazine-hydrate (22 mL, 0.46 mol), glacial acetic acid (45 mL, 0.78 mol) and toluene (500 mL) were stirred at reflux temperature for 18 hours in an apparatus fitted with a Dean-Stark trap.

The reaction mixture was cooled to ambient temperature and solvent was removed in vacuo. The residue was dissolved in 6N HC1 and the resulting solution was extracted with ether three times. A concentrated ammonium hydroxide solution 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 MgS0 4 and filtered.

Solvent was removed in vacuo to give a pale brown viscous oil (34.6g, 75% yield): NMR (CDC1 3 ,300 MHz): 7.10 1H), 7.05 2H, 2.37 3H), 2.10 (s, 3H); CI-MS: 202 (M H).

C. 5-Acetamidino-4-(2,4-dimethylphenyl)-3methylpyrazole, acetic acid salt Ethyl acetamidate hydrochloride (60g, 0.48 mol) was added quickly to a rapidly stirred mixture of potassium carbonate (69.5g, 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 4 and filtered. Solvent was removed by simple distillation and the pot residue, a -81 ll /l9/0)2.docuienll 3.81 clear pale yellow liquid, (35.0 g) was used without further purification.

Glacial aetic acid (9.7 mL, 0.17 mol) was added to a stirred mixture of 5-amino-4-(2,4-dimethylphenyl)-3methylpyrazole 34g, 0.17 mol), ethyl acetamidate (22g, 0.25 mol) and acetonitrile (500 The resulting reaction mixture was stirred at room temperature for 3 days; at the end of which time, it was concentrated in vacuo to about one-third of its original volume. The resulting suspension was filtered and the collected solid was washed with copious amounts of ether. The white solid was dried in vacuo (31.4g, 61% yield): NMR (DMSO-d 6 ,300 MHz): 7.00 1H), 6.90 (dd, 2H, J=7, 2.28 3H), 2.08 3H), 2.00 (s, 3H), 1.90 3H), 1.81 3H); CI-MS: 243 (M H).

D. 2,7-dimethyl-8-(2,4-dimethylphenyl) pyrazolo-[1,3,5]-triazin-4(3H)-one Sodium pellets (23g, 1 mol) were added portionwise to ethanol (500 mL) with vigorous stirring. After all the sodium reacted, 5-acetamidino-4-(2,4dimethylphenyl)-3-methylpyrazole, acetic acid salt (31.2g, 0.1 mol) and diethyl carbonate 97 mL, 0.8 mol) were added. The resulting reaction mixture was heated to reflux temperature and stirred for 18 hours.

The mix was cooled to room temperature and solvent was removed in vacuo. The residue was dissolved in water and a 1N HC1 solution was added slowly until pH 5-6.

The aqueous layer was extracted with ethyl acetate three times; the combined organic layers were dried over MgS0 4 and filtered. Solvent was removed in vacuo to give a pale tan solid (26g, 98% yield): NMR (CDC13,300 MHz): 7.15(s, 1H), 7.09 2H), 2.45 (s, 3H), 2.39 3H), 2.30 3H); CI-MS: 269 (M H).

-82- 11 /09/02,documentl 3,82 EXAMPLE 2 Preparation of 5-methyl-3-(2,4,6-trimethylphenyl) [1,2,3]-triazolo-[1,3,5]-triazin-7(6H)-one (Formula 7, where Y is O, R 1 is CH 3 Z is N, Ar is 2,4,6-trimethylphenyl) A. 1-Phenylmethyl-4-(2,4,6-trimethylphenyl)-5aminotriazole A mixture of 2,4,6-trimethylbenzyl cyanide 6.3 mmol), benzyl azide (-0.92g, 6.9 mmol) and potassium t-butoxide (0.78g, 6.9 mmol) in tetrahydrofuran was stirred at ambient temperature for 2.5 days. The resulting suspension was diluted with water and extracted three times with ethyl acetate. The combined organic layers were dried over MgS0 4 and filtered.

Solvent was removed in vacuo to give a brown oil.

Trituration with ether and filtration afforded a yellow solid (1.12g, 61% yield): NMR (CDC13,300 MHz):7.60-7.30 5H), 7.30-7.20 2H), 5.50 2H), 3.18 (br s, 2H), 2.30 3H), 2.10 6H); CI-MS: 293 (M H).

B. 4-(2,4,6-Trimethylphenyl)-5-aminotriazole Sodium (500 mg, 22 mmol) was added with stirring to a mixture of liquid ammonia (30 mL) and 1phenylmethyl-4-(2,4,6-trimethylphenyl)-5-aminotriazole (l.lg, 3.8 mmol). The reaction mixture was stirred until a dark green color persisted. An ammonium chloride solution mL) was added and the mixture was stirred while warming to ambient temperature over 16 hours. The residue was treated with a 1M HC1 solution and filtered. The aqueous layer was basified with'a concentrated ammonium hydroxide solution (pH 9) and then extracted with ethyl acetate three times. The -83- 11/09/02,docunentl 3,83 combined organic layers were dried over MgS0 4 and filtered. Solvent was removed in vacuo to give a yellow solid (520 mg), which was homogeneous by thin layer chromatography (ethyl acetate): NMR (CDC1 3 ,300 MHz): 6.97 2H), 3.68-3.50 (br.s, 2H), 2.32 3H), 2.10 6H); CI-MS: 203 (M H).

C. 4-(2,4,6-Trimethylphenyl)-5-acetamidinotriazole, acetic acid salt A mixture of 4-(2,4,6-trimethylphenyl)-5aminotriazole (400 mg, 1.98 mmol), ethyl acetamidate 261 mg, 3 mmol) and glacial acetic acid (0.1 mL, 1.98 mmol) in acetonitrile (6 mL) was stirred at ambient temperature for 4 hours. The resulting suspension was filtered and the collected solid was washed with copious amounts of ether. Drying in vacuo afforded a white solid (490 mg, 82% yield): NMR (DMSO-d 6 ,300 MHz):7.90-7.70 (br s, 0.5H), 7.50-7.20 (br. s, 6.90 2H), 6.90 2H), 3.50-3.10 (br s, 3H), 2.30- 2.20 (br s, 3H), 2.05 1H, J 1.96 6H), 1.87 6H); CI-MS: 244 (M H).

D. 5-methyl-3- (2,4,6-trimethylphenyl) (1,5-a 2,3]-triazolo- 5]-triazin-7 (4H) -one Sodium (368 mg, 16.2 mmol) was added with stirring to ethanol (10 mL) at room temperature. After the sodium had reacted, 4-(2,4,6-trimethylphenyl)-5acetamidino-triazole, acetic acid salt (490 mg, 1.6 mmol) and diethyl carbonate (1.6 mL, 13 mmol) were added. The reaction mixture was stirred at reflux temperature for 5 hours, then cooled to room temperature. The reaction mixture was diluted with water; a 1N HC1 solution was added until pH 5-6 and three extractions with ethyl acetate were performed.

-84- 11/09/02,documentl 3,84 The combined organic layers were dried over MgSO 4 and filtered. Solvent was removed in vacuo to give a yellow residue. Trituration with ether and filtration afforded a yellow solid (300 mg, 69% yield): NMR (CDC1 3 ,300 MHz): 6.98 2H), 2.55 3H), 2.35 (s, 3H), 2.10 6H); CI-MS: 270 (M H).

EXAMPLE 3 Preparation of 4-(di(carbomethoxy)methyl)- 2,7-dimethyl-8-(2,4-dimethylphenyl) 1,3,5-triazine (Formula 1, where R 3 is CH(CHCO 2

CH

3 2

R

1 is CH 3 Z is C-CH3, Ar is 2,4-dimethylphenyl) A. 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl) pyrazolotriazine A mixture of 2,7-dimethyl-8-(2,4- -pyrazolo-1,3,5-triazin-4-one (Example 1, 1.38g, mmol), N,N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) was stirred at reflux temperature for 48 hours. The excess phosphorus oxychloride was removed in vacuo. -The residue was poured onto ice-water, stirred briefly and extracted quickly with ethyl acetate three times. The combined organic layers were washed with ice water, then dried over MgSO 4 and filtered. Solvent was removed in vacuo to give a brown oil. Flash column chromatography (ethyl acetate:hexanes::l:4) gave one fraction (Rf 0.5) Solvent was removed in vacuo to afford a yellow oil (l.0g, 68% yield): NMR (CDC1 3 ,300 MHz): 7.55 (d, 1H, J 7.38 (dd, 1H, J 7,1 7.30 1H, J 2.68 3H), 2.45 3H); CI-MS: 327 (M H).

11 /09/02,docunentl 3,85 B. 4-(di(carbomethoxy)methyl)-2,7-dimethyl-8-(2,4dimethylphenyl) [1,5-a]-pyrazolo-1,3,5-triazine Sodium hydride (60% in oil, 80 mg, 2 mmol) was washed with hexanes twice, decanted after each washing and taken up in anhydrous tetrahydrofuran (THF, 1 mL).

A solution of diethyl malonate (0.32gi 2 mmol) in THF (2 mL) was added dropwise over 5 min, during which time vigorous gas evolution ensued. A solution of 4-chloro- 2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]pyrazolotriazine (0.5g, 1.75 mmol) in THF (2 mL) was added and the reaction mixture was then stirred under a nitrogen atmosphere for 48 hours. The resulting suspension was poured onto water and extracted three times with ethyl acetate. The combined organic layers were washed once with brine, dried over MgSO 4 and filtered. Solvent was removed in vacuo to give a brown oil. Column chromatography (ethyl acetate:hexanes::1:9) afforded, after removal of solvent in vacuo, a pale yellow solid (Rf 0.2, 250 mg, 35% yield): rmp 50-52 0 C; NMR (CDC13, 300 MHz): 12.35 (br.s, 1H, 7.15-7.00 3H), 4.40 2H, J 4.30 2H, J 2.4, 2.35, 2.3, 2.2, 2.1 (5 s, 12H), 1.4 3H, J 1.35-1.25 3H); CI-HRMS: Calcd: 411.2032, Found: 411.2023.

EXAMPLE 6 Preparation of 4-(1,3-dimethoxy-2-propylamino)- 2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo- 1,3,5-triazine (Formula 1, where R 3 is NHCH(CH20CH 3 2 RI is CH 3 Z is

C-CH

3 Ar is 2,4-dichlorophenyl) -86- 11/09/02,documient 13,86 A. 4 -chloro-2,7-dimethyl-8-(2,4-dichlorophenyl) pyrazolotriazine A mixture of 2,7-dimethyl-8-(2,4 dimethylphenyl) [1,5-a]-pyrazolo-1,3,5-triazin-4-one (Example 1, 1.38g, 4.5 mmol), N,N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) was stirred at reflux temperature for 48 hours. The excess phosphorus oxychloride was removed in vacuo. The residue was poured onto ice-water, stirred briefly and extracted quickly with ethyl acetate three times. The combined organic layers were washed with ice water, then dried over MgSO 4 and filtered. Solvent was removed in vacuo to give a brown oil. Flash column chromatography (ethyl acetate:hexanes::1:4) gave one fraction (Rf 0.5) Solvent was removed in vacuo to afford a yellow oil (1.0g, 68% yield): NMR (CDC13,300 MHz): 7.55 1H, J 7.38 (dd, 1H, J 7,1 7.30 1H, J 2.68 3H), 2.45 3H); CI-MS: 327 (M H).

B. 4- (1,3-dimethoxy-2-propylamino)-2,7-dimethyl-8dichlorophenyl) [1,5-a]-pyrazolo-1,3,5-triazine A mixture of 4-chloro-2,7-dimethyl-8-(2,4dichlorophenyl) [1,5-a]-pyrazolo-1,3,5-triazine (Part A, 570 mg, 1.74 mmol), 1,3-dimethoxypropyl-2-aminopropane 2.08 mmol) and ethanol (10 mL) was stirred at ambient temperature for 18 hours. The reaction mixture was poured onto water (25 mL) and extracted three times with ethyl acetate. The combined organic layers were dried over MgSO 4 and filtered. Solvent was removed in vacuo. Column chromatography (CH 2 C12:CH30H::50:1) afforded one fraction. Removal of solvent in vacuo gave a solid (250 mg, 35% yield): mp 118-120OC; NMR (CDC13,300 MHz): 7.50 1H), 7.28 (dd, 2H, J 8,1), -87- 11/09/02,documnentl 3,87 6.75 1H, J 4.70-4.58 1H), 3.70-3.55 (m, 4H), 3.43 6H), 2.50 3H), 2.35 3H); CI-HRMS: Calcd: 409.1072, Found: 409.1085; Analysis Calcd. for

C

18

H

21 C1 2

N

5 0 2 C, 52.69, H, 5.17, N, 17.07, Cl, 17.28; Found: C, 52.82, H, 5.06, N, 16.77, C1, 17.50.

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

The examples delineated in TABLE 1 may be prepared by the methods outlined in Examples 1, 2, 3 or 6.

Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example.

TABLE 1 6 a C-Me

NHCH(CH

2 0Me)2

N(CH

2

CH

2 OMe)2 2,4-C1 2 -Ph 118-120 39 1 bz C-Me 2-Me-4,6-(MeO) 2 Ph oil -88- 11/09/02,documentl 3,88 395 bu C-Me NEt2 2-Me-4,6-(MeO)2Ph 114 396 bv C-Me NH-3-pentyl 2-Me-4,6-(MeO) 2 Ph 145-146 NOTES FOR TABLE 1: a) Analysis Calcd: 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.

bu) Analysis Calcd: C: 65.90, H: 7.72, N, 18.27; Found: C: 65.77, H: 7.62, N: 18.26.

by) Analysis Calcd: C: 65.02, H: 7.38, N, 18.96; Found: C: 65.01, H: 7.43, N: 18.68.

bz) CI-HRMS: Calcd: 430.2454; Found: 430.2468(M H); EXAMPLE 431 Preparation of 2,4,7-dimethyl-8-(4-methoxy-2methylphenyl)[1,5-a]-pyrazolo-1,3,5-triazine (Formula 1, where R 3 is CH 3

R

1 is CH 3 Z is C-CH 3 Ar is 2,4-dimethylphenyl) 5-Acetamidino-4-(4-methoxy-2-methylphenyl)-3methylpyrazole, acetic acid salt 602 mg, 2 mmol) was mixed with a saturated NaHCO3 solution (10 mL). The aqueous mixture was extracted with EtOAc three times.

The combined organic layers were dried over MgS04, filtered and concentrated in vacuo. The residue was taken up in toluene (10 mL) and trimethyl orthoacetate 0.36 g, 3 mmol) was added to the suspension. The reaction mixture was heated to reflux temperature under a nitrogen atmosphere and stirred for 16 hours. 'After being cooled to ambient temperature, the reaction -89- 11/09/02,docunentl 3,89 mixture was concentrated in vacuo to give an oily solid. Column chromatography (CHC13:MeOH::9:1) afforded, after removal of solvent in vacuo, a yellow viscous oil (Rf 0.6, 210 mg, 37% yield): NMR (CDC13, 300 MHz): 7.15 1H, J 6.9 1H, J 6.85 (dd, 1H, J 3.85 3H), 2.95 3H), 2.65 (s, 3H), 2.4 3H), 2.15 3H); CI-HRMS: Calcd: 283.1559, Found: 283.1554 (M EXAMPLE 432 7-hydroxy-5-methyl-3-(2-chloro- 4-methylphenyl)pyrazolo[1,5-a]pyrimidine (Formula 1 where A is CH, R1 is Me, R3 is OH, Z is C-Me, Ar is 2-chloro-4-methylphenyl) 5-Amino-4-(2-chloro-4-methylphenyl)-3methylpyrazole (1.86 g, 8.4 mmol) was dissolved in glacial acetic acid (30 mL) with stirring. Ethyl acetoacetate (1.18 mL, 9.2 mmol) was then added dropwise to the resulting solution. The reaction mixture was then heated to reflux temperature and stirred for 16 hours, then cooled to room temperature.

Ether (100 mL) was added and the resulting precipitate was collected by filtration. Drying in vacuo afforded a white solid 1.0 g, 42% yield): NMR (CDC13, 300Hz): 8.70 (br.s 1H), 7.29 s, 1H), 7.21-7.09 m, 2H), 5.62 1H), 2.35 6H), 2.29 3H); CI-MS: 288 EXAMPLE 433 7-chloro-5-methyl-3-(2-chloro- 4-methylphenyl)pyrazolo[1,5-a]pyrimidine 11/09/02,documentl 3,90 (Formula 1 where A is CH, R1 is Me, R3 is Cl, Z is C-Me, Ar is 2-chloro-4-methylphenyl) A mixture of 7-hydroxy-5-methyl-3-(2-chloro-4methylphenyl)-pyrazolo[1,5-a]pyrimidine (1.0 g, mmol), phosphorus oxychloride (2.7 g, 1.64 mL, 17.4 mmol), N,N-diethylaniline (0.63 g, 0.7 mL, 4.2 mmol) and toluene (20 mL) was stirred at reflux temperature for 3 hours, then it was cooled to ambient temperature.

The volatiles were removed in vacuo. Flash chromatography (EtOAc:hexane::l:2) on the residue gave 7-chloro-5-methyl-3-(2-chloro-4-methylphenyl)- (900 mg, 84% yield) as a yellow oil: NMR (CDC1 3 300Hz): 7.35 1H), 7.28- 7.26 1H), 71.6 d, 1H, J 6.80 1H), 2.55 3H), 2.45 3H), 2.40 3H); CI- MS: 306 EXAMPLE 434 7-(pentyl-3-amino)-5-methyl-3-(2-chloro- (Formula 1 where A is CH, R1 is Me, R3 is pentyl-3amino, Z is C-Me, Ar is 2-chloro-4-methylphenyl) A solution of 3-pentylamine (394mg, 6.5 mmol) and 7-chloro-5-methyl-3-(2-chloro-4- (200 mg, 0.65 mmol) in dimethylsulfoxide (DMSO, 10 mL) was stirred at 150oC for 2 hours; then it was cooled to ambient temperature. The reaction mixture was then poured onto water (100 mL) and mixed. Three extractions with dichloromethane, washing the combined organic layers with brine, drying over MgSO 4 filtration and removal of solvent in vacuo produced a yellow solid. Flash chromatography (EtOAc:hexanes::l:4) afforded a white -91- 11/09/02,docunentl 3,91 solid (140 mg, 60% yield) mp 139-141 0 C; NMR (CDC13, 300Hz) :7.32 1H) 7.27 1H, J 7.12 1H, J 6. 02 1H, J 5.78 s, 1H) 3.50-3.39 (in, 1H) 2.45 3H) 2.36 6H) 1.82-1.60 (in, 4H) 1.01 6H, J Analysis Calcd for 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 delineated in Table 7 may be prepared by the methods outlined in Examples 1, 2, 3 or 6.

Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is'ethyl, Bu is butyl, Ex. is Example.

Table 7 R~ 3

NN

Ar Ex. Z R3 Ar MT) (2a 1200a C-Me 2-ethylpiperidyl 2-Me-4-OMePh58- 59.5 12Ol1b C-Me cyclobutylamino 2-Me-4-OMePh94.5- 96 1202c C-Me N (Me) CH 2

CH=CH

2 2-Me-4-OMePh oil 1203d C-Me N (CH 2

CH=CH

2 2 2-Me-4-OMePh oil 92 11 /09102,documentl 3,92 1204 1205e C-Me N(Et)CH 2 C-Pr C-Me NI{CH 2 -2-tetrahydrofuryl 2-Me-4 -OMePh 2 -Me-4 -OMePh amorphous 1206ay. C-Me 1207az C-Me 1208f C-Me 12099 C-Me 1210h C-Me 12111 C-Me 1212i C-Me 1.213k C-Me 1214 C-Me 1215 C-Me 1216 C-Me 1217m C-Me 1218 C-Me 1219n C-Me 12200 C-Me 1221P C-Me N.

amorphous 12229 C-Me 1223 C-Me 1224 C-Me 1225 C-Me 1226 .C-Me 1227 C-Me 1228 C-Me 1229 C-Me N (Pr) CH 2 C- Pr N (Me) Pr N (Me) Et N (Me) Bu N (Me) propargyl NH (CH (CH 3 CH (CH 3

CH

3 N (CH 2

CH

2 OMe) CH 2

CH=CH

2 N (CH 2

CH

2 OMe) Me N (CH 2

CH

2 OMe) Et N (CH 2

CH

2 OMe) Pr N (CH 2

CH

2 OMe) CH 2 C-Pr NHl (CH (CH 3

CH

2

CH

3 NHCH(c- Pr) 2 NH-2-hexy.

NI{-2 -propyl

HCH

2 tetrahydrofuryl NEt (cyclohexyl) 2 -ethylpiperidyl cyclobutylamino N (Me) CH 2

CH=CH

2 N(Et)CH 2 C-Pr N (Pr) CH 2 C- Pr N (Me) Pr N(Me)Et 2 -Me-4 -OMePh 2 -Me-4 -OMePh 2 -Me-4 -OMePh 2-Me-4-OMePh 2 -Me-4 -OMePh 2 -Me-4 -OMePh 2 -Me-4 -OMePh 2 -Me-4 -OMePh 2 -Me-4 -OMePh 2-Me-4 -OMePh 2-Me-4-QMePh 2 -Me-4 -OMePh 2 -Me-4 -OMePh 2 -Me-4 -OMePh 2-Me-4 -OMePh 2-Me-4-OMePh 2 -Me-4 -OMePh 2, 5-Me 2 -4-OMePh 2,5-Me 2 -4-OMePh 2, 5-Me 2 -4-OMePh 2, S-Me 2 -4-OMePh 2, 5-Me 2 -4 -OMePh 2, 5-Me 2 -4-OMePh 2, 5-Me 2 -4-OMePh oil oil oil oil oil oil oil oil oil oil1 oil oil 93 I1I /09/02,docuxnentl 3,93 1230 1231 1232 1233 1234 1235 1236 1237 1238 1239 1240 1241 1245 125 5 r 65.6 1256 1257 1258 1259 1260 1261 1262 1263 1264 1265 1266 1267 12688 138.3 1269 C-Me C-Me C -Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C -Me C-Me C -Me C-Me C-Me C-Me C-Me N (Me) Bu N (Me) propargyl NH (CH (CH 3 CH (CH 3

CH

3 N (CH 2

CH

2 OMe) CH 2

CH=CH

2 N (CH 2

CH

2 OMe) Me N (CH 2

CH

2 OMe) Et N (CH 2

CH

2 OMe) Pr N (CH 2

CH

2 OMe) CH 2 C Pr NH (CH (CH 3

CH

2

CH

3 NHCH(c-Pr) 2 2- ethylpiperidyl cyclobutylamino N (Me) CH 2

CH=CH

2

N(CH

2

CH=CH

2 2 N (Et) CH 2 C-Pr N (Pr) CH 2 C- Pr N(Me)Pr N(Me)Et N (Me) Bu N (Me) propargyl NI-{(CH (CH 3 CH (CH 3

CH

3 N (CH 2

CH

2 OMe) CH 2

CH=CH

2 N (CH 2

CH

2 OMe) Me

"N(CH

2

CH

2 OMe) Et

"N(CH

2

CH

2 OMe) Pr N (CH 2

CH

2 OMe) CH 2 C- Pr

NH(CH(CH

3

)CH

2

CH

3 NHCH(c-Pr) 2 2, 5-Me 2 -4-OMePh 2, 5-Me 2 -4-QMePh 2, 5-Me 2 -4-OMePh 2, 5-Me 2 -4-OMePh 2, 5-Me 2 -4-OMePh 2, 5-Me 2 -4-OMePh 2, 5-Me 2 -4-OMePh 2, 5-Me 2 -4-OMePh 2, 5-Me 2 -4-OMePh 2, 5-Me 2 -4-OMePh 2,4- (OM e) 2 Ph 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph64.8- 2, 4- (OMe) 2 Ph 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph137.8- 2,4- (OMe) 2 Ph 94 I I ,:9i:2-cocumentl 3.91 1270t 1271u 129.4 1272 1273v 1274 1275 1276 1277 1278 1279 1280 1281 1282 1283 1284 1285 1286 1287 1288 1289 1290 1291 1292 1293 1294 1295 1296 1297 1298 C -Me C -Me C -Me C-Me C -Me C-Me C -Me C -Me C -Me C -Me C -Me C -Me C-.Me C -Me C -Me C-Me C-Me C-Me C-Me C -Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C -Me N (CH 2

CH

2 OMe) 2 NHCH (Et) 2 "N(Et) 2 N (Pr) 2.

2- ethylpiperidyl cyclobutylamino N (Me) CH 2

CH=CH

2 N(Et) CH 2 c-Pr N (Pr) CH 2 C- Pr N (Me) Pr N (Me) Et N (Me) Eu N (Me) propargyl NH (CR(CR 3

CH(CH

3

CR

3 N (CH 2

.CH

2 OMe) CH 2

CH=CH:

N (CH 2 CHQMe) Me

N(CH

2

CH

2 OMe)Et N (CH 2

CH

2 OMe) Pr N (CH 2

CH

2 OMe) CH 2 C- Pr NH (CH ("CR 3

CH

2

CH

3 NHCH (c-Pr) 2 N (CH 2

CH

2 OMe) 2 NHCH (Et) 2 N(Et) 2 2 -ethylpiperidyl cyclobutzylamino N (Me) CH 2

CH=CH

2 N (Et) CH 2 C-Pr N (Pr) CH 2 C Pr 2,4- (OMe) 2 Ph 2,4- (OMe) 2 Ph228- 2, 4- (OMe) 2 Ph 2, 4- (OMe) 2 Ph 2,4 (OMe) 2 2,4- (OMe) 2 2,4- (OMe) 2 2,4- (OMe) 2 2, 4- (OMe) 2 2,4- (OMe) 2 2,4- (OMe) 2 2,4- (OMe) 2 2,4- (OMe) 2 2,4- (OMe) 2 22,4- (OMe) 2 2,4- (OMe) 2 (OMe) 2 5- Me Ph 2,4- (OMe) 2 2,4- (OMe) 2 2,4- (OMe) 2 2,4- (OMe) 2 2, 4- (OMe) 2 2,4- (OMe) 2 2,4- (OMe) 2 2,4- (OMe) 2 -5-C1Ph 2,4- (OMe) 2 2,4- (OMe) 2 2,4- (OMe) 2 -5-C1Ph 2,4- (OMe) 2 oil 95 11 /09/02,docwnentl 3,95 1299 1300 1301 1302 1303 1304 1305 1306 1307 1308 1309 1310 1311 1312 1313 1314Y C -Me C -Me C -Me C -Me C -Me C-Me C -Me C -Me C-Me C-Me C-Me C-Me C-Me C -Me C -Me C -Me N (Me) Pr "N(Me) Et N (Me) Bu N (Me) propargyl

NH(CH(CH

3

CH(CH

3 )CH3) N (CH 2

CH

2 QMe) CH 2

CH=CH

N (CH 2

CH

2 OMe) Me N (CH 2

CH

2 OMe) Et N (CH 2

CH

2 OMe) Pr N (CH 2

CH

2 OMe) CH 2 C-Pr NiH (CH (CH 3

CH

2

CH

3 NHCH (c-Pr) 2 N (CH 2

CH

2 OMe) 2 NIICH (Et) 2 N(Et) 2 2 -ethylpiperidyl cyclobutylano 2,4- (OMe) 2 -5-C1Ph 2,4- (OMe) 2 -5-C1Ph 2,4- (OMe) 2 -5-C1Ph 2, 4- (OMe) 2 5- C1 Ph 2,4- (OMe) 2 -5-C1Ph (OMe) 2 -5-C1Ph 2,4- (OMe) 2 -5-C1Ph 2,4- (OMe) 2 2,4- (OMe) 2 -5-C1Ph 2,4- (OMe) 2 -5-C1Ph 2,4- (OMe) 2 -S-ClPh 2,4- (OMe) 2 -5-C1Ph 2,4- (OMe) 2 -5-C1Ph 2,4- (OMe) 2 -5-C1Ph 2,4- (OMe) 2 2-Me-4,6- (OMe) 2 Ph 2-Me-4,6- (OMe) 2 Ph 2-Me-4,6- (OMe) 2 Ph 2-Me-4,6- (OMe) 2 Ph 2-Me-4, 6- (OMe) 2 Ph 1315z C-Me 1 3 1 6 aa C-Me N (Me) CH 2

CHI=CH

2 N(Et) CH 2 C-Pr N (Pr) CH 2 C -Pr 145- 149 131- 133 oil oil 1317 1318 ab C -Me C -Me 1 3 1 9 ac C-Me 1 3 2 0 ad C-Me 13 2 1 ae C-Me N (Me) Pr N (Me) Et (Me) Bu 2-Me-4, 6- (OMe) 2 Ph 2-Me-4,6- (OMe) 2 Ph 2 -Me-4, 6- (OMe) 2 Ph oil oil oil 96 I1I /09/02documentl 3,96 1322 1323 1324 1325 1 3 2 6 af 1327 1 3 2 8 ag C-Me C-Me C -Me C-Me C-Me C-Me C-Me 1 3 2 9 ax C-Me 1330 133 1 w 1332 1333 1 3 3 4 x 1335 1336 1337 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 N(Me)propargyl 2-Me-4,6- (OMe) 2 Ph NH(CH(CHi 3

)CH(CH

3

)CH

3 )2-Me-4,6-(OMe)2Ph

N(CH

2

CH

2 OMe) CH 2

CH=CH

2 2-Me-4, 6- (OMe) 2 Ph C-Me C-Me C-Me C-Me C-Me C-Me C -Me C-Me C -Me C-Me C -Me C -Me C -Me C-Me C -Me C -Me C -Me C -Me C -Me N (CH 2

CH

2 OMe) Me N (CH 2

CH

2 OMe) Et N (CH 2

CH

2 OMe) Pr

N.(CH

2

CH

2 OMe) CH 2 C-Pr NH (CH (CH 3

CH

2

CH

3 NHCH (c-Pr) 2 N (CH 2

CH

2 OMe)2 NHCH(Et) 2 N(Et) 2 NEt (fu) 2 -ethylpiperidyl cyclobutylamilo, N(Me)CH 2 CH=CH2 N (Et) CH 2 C- Pr N (Pr) CH 2 C-Pr N (Me) Pr N (Me) Et N (Me)Bfu N (Me) propargyl 2 -Me 6 (OMe) 2 Ph 2 -Me-4, 6- (OMe) 2 Ph 2 -Me-4, 6- (OMe) 2 Ph 2-Me-4,6- (OMe) 2 Ph 2-Me-4,6- (OMe) 2 Ph 2 -C1 6- (OMe) 2 Ph 2 -C1 6- (OMe) 2 Ph 2 -C1 6- (OMe) 2 Ph 2 -C1 6- (OMe) 2 Ph 2 -C1 6- (OMe) 2 Ph 2-Cl-4,6- (OMe) 2 Ph 2 -C1 6- (OMe) 2 Ph 2 -C1 6- (OMe) 2 Ph 2 -C1 6- (OMe) 2 Ph 2-Me-4,6- (OMe) 2 Ph 2-Me-4,6- (OMe) 2 Ph oil 2-Me-4,6- (OMe) 2 Ph 2 -Me-4, 6 -(OMe) 2 Ph oil 2 -Me-4, 6 (OMe) 2 Ph 107 -110 oil

NH(CH(CH

3

)CH(CH

3

)CH

3 2-C1 6 -(OMe) 2Ph N (CH 2 CH2OMe) CH 2 CH=CH2 2-Cl 6 -(OMe) 2 ph

N(CH

2

CH

2 OMe)Me 2 -C1 6- (OMe) 2 Ph

N(CH

2

CH

2 OMe)Et 2 -C1 6- (OMe) 2 Ph

N(CH

2

CH

2 OMe)Pr 2 -C1 6- (OMe) 2 Ph 97 I1I /09/02,docuentl 3,97 1349 C-Me N(CH 2

CH

2 OMe)CH 2 C-Pr 2-C1-4,6-(OMe) 2 Ph 1350 1351 1352 1353 1354 1355 1356 1357 1358 1359 1360 1361 1362 1363 1364 1365 1366 1367 1368 1369 1370 1371 1372 1373 1374 1375 1376 1377 13'78 1379 C -Me C -Me C -Me C-Me C -Me C -Me C -Me C -Me C -Me C-Me C -Me C-Me C-Me C-Me C -Me C-Me C -Me C-Me C-Me C -Me C -Me C -Me C -Me C -Me C-Me.

C -Me C M C -Me C -Me C -Me NH (CH (CH 3

CH

2

CH

3 NHCH (c-Pr) 2 NHCH (Et) 2 N (Et) 2 2 -ethylpiperidyl cyc lobutylamino N (Me) CH 2

CH=CH

2 N (Et) CH 2 C- Pr N (Pr) CH 2 C- Pr N (Me) Pr N(Me)Et N (Me) Bu N (Me) propargyl NH (CH (CH 3 CH (CH 3

CH

3 N (CH 2

CH

2 OMe) CH 2

CH=CH

2 N (CH 2

CH

2 OMe) Me N (CH 2

CH

2 OMe) Et

"N(CH

2

CH

2 OMe) Pr N (CH 2

CH

2 OMe) CH 2 C-Pr NH (CH (CM 3

CH

2

CH

3 NIICH (c-Pr) 2 2 -ethylpiperidyl cyclobutylamino N (Me) CH 2

CH=CH

2 N (Et) CH 2 C -Pr N (Pr) CH 2 C -Pr N (Me) Pr N(Me)Et N (Me) Bu N (Me) propargyl 2-C1-4,6- (OMe) 2 Ph 2-C1-4,6- (OMe) 2 Ph 2 -C1 6- (OMe) 2 Ph 2-C1-4,6- (OMe) 2 Ph 2-C1-4-OMe-Ph 2-C1-4-OMe-Ph 2-Cl -4-OMe-Ph 2 -C1-4 -OMe-Ph 2-C1-4-OMe-Ph 2-Cl-4-OMe-Ph 2 -C1-4 -OMe-Ph- 2 -Cl-4-OMe-Ph 2-C1-4-OMe-Ph 2-Cl-4-OMe-Ph 2-Cl-4-OMe-Ph 2-C1-4-OMe-Ph 2-Cl-4-OMe-Ph 2-Cl-4-OMe-Ph 2-Cl-4-OMe-Ph 2-C1-4 -OMe-Ph 2-C1-4-QMe-Ph 2 -Me S- (OMe) 2 Ph 2-Me-4,5- (OMe) 2 Ph 2-Me-4,5- (OMe) 2 Ph 2-Me-4,5- (OMe) 2 Ph 2 -Me 5- (OMe) 2 Ph 2 -Me-4, 5- (OMe) 2 Ph 2-Me-4,5- (OMe) 2 Ph 2 -Me -4,5S- (OMe) 2 Ph 2 -Me-4,5- (OMe) 2 Ph 98 I I /(J9/02,documleiitl 3,98 1380 1381 1382 1383 1384 1385 1386 1387 1388 1389 1390 1391 1392 1393 ab C-Me C-Me C -Me C-Me C -Me C-Me C-Me C-Me C-Me C-Me C -Me C -Me C -Me C -Me N (CH 2

CH

2 OMe) Me N (CH 2

CH

2 OMe) Et N (CH 2

CH

2 OMe) Pr N (CH 2

CH

2 OMe) CH 2 C-Pr NH (CH (CH 3

CH

2

CH

3 NHCH (c-Pr) 2 N (CH 2

CH

2 OMe) 2 NHCH (Et) 2 N(Et) 2 NEt (Bu) 2 -ethylpiperidyl cyclobutylamino 2-Me-4, 5- (OMe) 2 Ph 2-Me-4,5- (OMe) 2 Ph 2-Me-4,5- (OMe) 2 Ph 2-Me-4,5- (QMe) 2 Ph 2-Me-4,5- (OMe) 2 Ph 2-Me-4,5- (OMe) 2 Ph 2-Me-4,5- (OMe) 2 Ph 2-Me-4,5- (OMe) 2 Ph 2-Me-4,5- (OMe) 2 Ph 2-Me-4,5- (OMe) 2 Ph 2-C1-4,5- (OMe) 2 Ph 2-C1-4,5- (OMe) 2 Ph 2-C1-4,5- (OMe) 2 Ph 2- C1-4,5- 2 Ph 2-C1-4,5- (OMe) 2 Ph 2-C1-4,5- (OMe) 2 Ph 2-C1-4,5- (OMe) 2 Ph 2-C1-4,5- (OMe) 2 Ph NH (CH (CH 3 CH (CH 3

CH

3 2 -Me 5 -(OMe) 2Ph N (CH 2

CH

2 OMe) CH 2 CH=CH2 2- Me 5- (OMe) 2 Ph 1 3 9 4 ai C-Me N (Me) CH 2

CH=CH

2 N (Et) CH 2 C- Pr N (Pr) CH 2 C- Pr 121- 122 122- 126 1395 1 3 9 6 aj C -Me C -Me oil 1 3 9 7 ak C-Me 1 3 9 8 al C-Me N (Me) Pr N (Me) Et N (Me) Bu 115- 117 115-119 oil 1 3 9 9 am C-Me 1400 1401 C-Me C-Me C -Me C-Me N (Me) propargyl

N}I(CH(CH

3

CH(CH

3

)CH

3 2-C1-4,5- (OMe) 2 Ph 2-C1-4,5- (OMe) 2 Ph 1402 1403 N (CH 2

CH

2 OMe) CH 2

CH=CH

2 2-C 4, 5- (OMe) 2 Ph

N(CH

2

CH

2 OMe)Me 2-C1-4, 5- (OMe) 2 Ph 99 I1I /09/02,docunenl 3,99 1 4 0 4 an C-Me 1405 C-Me 1406 ao C-Me N (CH 2

CH

2 OMe) Et 1407 1408 C -Me C-Me 1 4 0 9 ap C-Me 1 4 1 0 aq C-Me 1 4 1 1 ar C-Me 1 4 1 2 as C-Me 1413 C-Me 1414 C-Me 1415 C-Me 1416 C-Me 1417 C-Me 1418 C-Me 1419 C-Me 1420 C-Me 1421 C-Me N (CH 2

CH

2 OMe) Pr N (CH 2

CH

2 OMe) CH 2 C -Pr NM (CM (CH 3

CH

2

CH

3 NI{CH (c-Pr) 2

N(CH

2

CH

2 OMe) 2 NHCH (Et) 2 N (Et) 2 NEt (Bu) 2 -ethylpiperidYl cyclobutylamilo N (Me) CH 2 CH=CH2 N (Et) CH 2 C-Pr N (Pr) CH 2 C-Pr N(Me) Pr N (Me) Et N (Me) Bu N (Me) propargyl 2-C1-4, 5- (OMe) 2 Ph 2-C1-4, 5- (OMe) 2 Ph 2-C1-4, 5- (OMe) 2 Ph 2-C1-4-OMe-5-MePh 2-C1-4-OMe-5-MePh 2-Cl-4-OMe-5-MePh 2-C1-4-OMe-S-MePh 2-Cl-4-OMe-5-MePh 2-Cl-4-OMe-S-MePh 2-C1-4 2-Cl-4-OMe-5-MePh 2-C1-4 2 -C1-4,5- (OMe) 2 Ph oil 2-C1-4,5- (OMe) 2 Ph 2-C1-4,5- COMe) 2 Ph oil 2-Cl-4, 5- (OMe) 2 2h 2-C1-4, 5- (OMe) 2 Ph 2-C1-4,5-(OMe)2 Ph oil 104-106 oil oil 1422 1423 1424 1425 1426 1427 1428 1429 1430 C-Me C -Me C -Me C -Me C-Me C -Me C -Me C -Me C -Me NH (CH(CH 3

CH(CH

3

CH

3 2C4OMe-5-MePh

N(CH

2

CM

2 OMe)CH 2

CH=CH

2 2C1-4OMe5MePh

N(CH

2

CH

2 OMe) Me 2-C1-4-0Me-5-MePh

N(CH

2

CH

2 OMe)Et 2-Cl-4-OMe-5-MePh N (CH 2

CM

2 OMe) Pr 2-C1-4-OMe-5-MePh

N(CH

2

CH

2 OMe)CH2C-Pr 2-C1-4-OMe-5-MePh NH (CH (CH 3 CH2CH3) 2-C1-4-OMe-5-MePh NHCH(c-Pr)2 2-C1-4-OMe-5-MePh NHCH(Et)2 2-Cl-4-OMe-5-MePh' 100- I I /09/02,docunientI 3,100 1431 1432 1433 1434 1435 1436 1437 1438 1439 1440 1441 1442 1443 1444 1445 1446 1447 1448 1449 .1450 1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C -Me C-Me C-Me C-Me C-Me C-Me C -Me C -Me C-Me C -Me C -Me C -Me N (Et) 2 NEt (Bu) 2 -ethylpiperidyl cyclobutylamilo N (Me) CH 2 CH=CH2 N (Et) CH 2 C-Pr N (Pr) CH 2 C-Pr N (Me) Pr N (Me) Et N (Me) Bu N (Me) propargyl NH (CH (CH 3 CH (CH 3

CH

3 N (CH 2 CHi 2 OMe) CH 2

CH=CH

N (CH 2

CH

2 OMe) Me N (CH 2

CH

2 OMe) Et N (CH 2

CH

2 OMe) Pr N (CH 2

CH

2 QMe) CH 2 C-Py NH (CH (CH 3

CH

2 CH3) NIICH(c-Pr)2 NHCH (Et) 2 N (Et) 2 NEt (Bu) 2 -ethylpiperidyl cyclobutylamiflo N (Me) CH 2 CH=C1 2 N (Et) CH 2 C -Pr N (Pr) CH 2 C -Pr N (Me) Pr N (Me) Et N (Me) Bu N (Me) propargyl 2-C1-4 2-C1-4-OMe-5-MePh 2-C1-6-OMe-4 -MePh 2-C1-6-OMe-4-MePh 2-Cl-6-0Me-4-MePh 2-Cl-6 -OMe-4-MePh 2-Cl-6-OMe-4-MePh 2-C1-6-OMe-4-MePh 2-C1-6-OMe-4 -MePh 2-C1-6-OMe-4-MePh 2 -Cl-6-OMe-4-MePh 2-C1-6-OMe-4-MePh 2 2-C1-6-OMe-4-MePh 2-Cl-6-OMe-4-MePh 2-C1-6-OMe-4-MePh '2-C1-6-OMe-4 -MePh 2-Cl-6-OMe-4-MePh 2-Cl-6-0Me-4-MePh 2'-C1 -6 -OMe-4 -MePh 2-C1-6-OMe-4 -MePh 2-C1-6-OMe-4 -MePh 2-C1-6-OMe-4-MePh 2, 6-Me 2 -4 -OMePh 2, 6-Me 2 -4-OMePh 2, 6-Me 2 -4-OMePh 2, 6-Me 2 -4-OMe Ph 2 ,6-Me 2 -4-OMePh 2, 6-Me 2 -4-OMePh 2, 6 -Me 2 -4 -OMePh 2, 6-Me 2 -4 -OMePh 2, 6-Me 2 -4-OMePh 101 I1I /09/02,documentl 3,101 1462 1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1 4 7 5 be C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me NH (CH (CH 3 CH (CH 3

CH

3 N (CH 2

CH

2 OMe) CH 2 CH=CH2 N (CH 2

CH

2 OMe) Me N (CH 2

CH

2 OMe) Et N (CH 2

CH

2 OMe) Pr N (CH 2

CH

2 OMe) CH 2 C-Pr NHl (CH (CH 3

CH

2

CH

3 NHCH (c-Pr) 2 NHCH (Et) 2 N (Et) 2 NEt (Bu) 2 -ethylpiperidyl cyclobutylamino N(Me) CH 2

CH=CH

2 2, 6-Me 2 -4-OMePh 2, 6-Me 2 -4-OMePh 2, 6-Me 2 -4-OMePh 2, 6-Me 2 -4-OMePh 2, 6-Me 2 -4-OMePh 2,6-M e 2 -4-OMePh 6-Me 2 -4-OMePh 2, 6-Me 2 -4-OMePh 2, 6-Me 2 -4-OMePh 2, 6-Me 2 -4-OMePh 2, 6-Me 2 -4-OMePh 2-C1-4-OMe-5-FPh 2-Cl-4-OMe-5-FPh 2-C1-4-OMe-5-FPh 2-C1-4 -OMe- 2-Cl-4-OMe-5-FPh 2-Cl-4-OMe-5-FPh 2-Cl-4-OMe-S-FPh oil 1476 1478 147 9 bb N (Et) CH 2 C-Pr N (Pr) CH 2 C- Pr N (Me) Pr oil oil 1 4 8 0 bc C-Me N (Me jEt 1481 1482 1483 1484 1485 1486 1487 1488 1 4 8 9 bd C-Me C-Me C-Me C-Me C-Me C-Me C-Me C -Me C-Me N (Me) Bu N(Me) propargyl NH (CH (CH 3 CH (CH 3

CH

3 N (CH 2

CH

2 OMe) CH 2

CH=CH

2 N (CH 2

CH

2 OMe) Me N (CH 2

CH

2 OMe) Et N (CH 2

CH

2 OMe) Pr N (CH 2

CH

2 OMe) CH 2 C-Pr NH (CH (CH 3

CH

2 CH3) 2-C1-4-OMe-5-FPh 2 -Cl-4-OMe 2-C1-4-OMe-5-FPh 2-C1-4-OMe-5-FPh 2-Cl-4-OMe-5-FPh 2-C1-4-OMe-5-FPh 2-C1-4-OMe-5-FPh 2-C1-4-OMe-5-FPh 2-C1-4-OMe-5-FPh solid 102 I1I /09/02,docuxenltl 3,102 1490 C-Me 1 4 9 1 be C-Me 1492 bf C-Me NHl-CH (c-Pr) 2 NHCH (Et) 2 2 -Cl-4-OMe-S-FPh 2 -C1-4-0Me-5-FPh 2 oil N (Et) 2 96-98 oil 1493 bg 1494 1495 1496 1497 1498 1499 1500 1501 1502 1503 1504 1505 1506 1507 1508 1509 1510 1511 1512 1513 1514 C-Me C-Me C-Me C-Me C-Me C-Me C -Me C -Me C-Me C-Me C -Me C-Me C -Me C -Me C-Me C-Me C-Me C-Me C-Me C -Me C-Me C-Me NEt (Bu) 2-Cl-4-0Me-5-FPh 2-ethylpiperidyl 2-Clr4-0Me-6-MePh cyclobutylamilo 2rCl-4-Me6MePh N (Me) CH 2 CH=CH2 2-C1-4-Me6MePh N(Et)CH2 C-Pr 2-C1-4-OMe-6-MePh N(Pr)CH2 c-Pr 2-C1-4-OMe6MePh N(Me) Pr 2-C1-4-OMe-6-MePh N(Me)Et 2-Cl-4-OMe-6-MePh N(Me)Bu 2-Cl-4-OMe-6-Meph N(Me)propargyl 2-Cl-4-OMe-6-MePh NHL (CH (CH 3 CH (C{ 3

CH

3 2 -C1-4 -OMe- 6-MePh N (CH 2

CH

2 OMe) CH 2

CH=CH

2 2C-4OMe6MePh N (CH 2

CH

2 OMe) Me N (CH 2

CH

2 OMe) EL N (CH 2

CH

2 OMe) Pr N (CH 2

CH

2 OMe) CH 2 C-Pr NH (CH (CH 3 CH2CH3) NHCH (c-Pr) 2 NHCH(Et)2 N(Et) 2 NEt (Bu) 2 -ethylpiperidyl cyclobutylamiflo 2-Cl-4-OMe-6-MePh 2-C1-4-OMe-6-MePh 2 C1-4-OMe-6-MePh 2-C1-4-OMe-6-MePh 2-Cl-4-0Me-6-MePh 2.C1-4-OMe-6-MePh 2-C1-4-OMe-6-Me.Ph 2-Cl-4-OMe-6-MePh 2-C1-4-OMe-6-MePh 6-Me 2 N-4 -Mepyrid-3-yl 6-Me 2 N-4-Mepyrid-3 -yl 6-Me 2 N-4 -Mepyrid- 3-yl 1515 C-Me 1516 C-Me N (Me) CH 2

CH=CH

2 103 11 I 0902,documentl 3,103 1517 C-Me 1518 C-Me 1519 C-Me 1520 C-Me 1521 C-Me 1522 C-Me 1523 C-Me 1524 C-Me 1525 C-Me 1 5 2 6 at C-Me 1527 C-Me 1528 C-Me 1529 C-Me 1530 C-Me 1 5 3 1 au C-Me N (Et) CH 2 c -Pr N (Pr) CH 2 C-Pr N (Me) Pr N (Me) Et N (Me) Bu N (Me) propargyl NH (CH (CH 3 CH (CH 3

CH

3 N (CH 2

CH

2 OMe) CH 2

CH=CH

2 N (CH 2

CH

2 OMe) Me N (CH 2

CH

2 OMe) Et N (CH 2

CH

2 OMe) Pr N (CH 2

CH

2 OMe) CH 2 C-Pr NH (CH(CH 3

CH

2

CH

3 NHCH(c-Pr) 2

N(CH

2

CH

2 OMe) 2 6-Me 2 N-4 -Mepyrid-3-yl 6-Me 2 N-4 -Mepyrid-3-yl 6-Me 2 N-4-Mepyrid-3-yl 6 -Me 2 N-4 -Mepyrid- 3-yl 6-Me 2 N-4-Mepyrid- 3-yl 6-Me 2 N-4-Mepyrid-3-yl 6-Me 2 N-4 -Mepyrid- 3-yl 6-Me 2 N-4 -Mepyrid-3-yl 6-Me 2 N-4 -Mepyrid-3-yl 6 -Me 2 N-4 -Mepyrid-3 -yl 6-Me 2 N-4 -Mepyrid-3 -yl 6-Me 2 N-4 -Mepyrid-3-yl 6-Me 2 N-4 -Mepyrid-3-yl 6-Me 2 N-4 -Mepyrid-3-yl 6-Me 2 N-4-Mepyrid-3-yl 6-Me 2 N-4 -Meoil 103-104 1 5 3 2 av C-Me NHiCH (Et) 2 -104- 11 /09/02,documentl 3,104 1 5 3 3 aw C-Me N (Et) 2 1534 1535 1536 1537 1538 1539 1540 1541 1542 1543 1544 1545 1546 1547 C -Me C -Me C -Me C -Me C -Me C Me C -Me C -Me C -Me C -Me C -Me C -Me C -Me C -Me 2 -ethylpiperidyl cycl1obutyl amino N (Me) CH 2

CH=CH

2 N(Et) CH 2 C-Pr N (Pr) CH 2 C-Pr N(Me) Pr N (Me) Et N(Me)Bu N (Me) propargyl NH (CH (CH 3 CH (CH 3

CM

3 N (CH 2

CH

2 OMe) CH 2

CH=CH

2 N (CH 2

CH

2 OMe) Me N (CH 2

CH

2 OMe) Et N (CH 2

CH

2 OMe) Pr pyrid-3-yl 6-Me 2 N-4-Mepyrid- 3-yl 6-MeO-4-Mepyrid- 3-yl 6-MeO-4 -Mepyrid-3-yl 6 -MeO-4 -Me pyrid-3 -yl 6-MeO4 -Mepyrid-3 -yl 6-MeO-4-Mepyrid- 3-yl 6-MeO-4-Mepyrid-3-yl 6-MeO-4--Mepyrid-3-yl 6-MeO-4-Me- -pyrid-3-yl 6-MeO-4-Mepyrid-3-yl 6-MeO-4-Mepyrid- 3-yl 6-MeO-4-Mepyrid-3-yl 6-MeO-4-Mepyrid-3-yl 6-MeO-4-Mepyrid-3-yl 6 -MeO-4 -Mepyrid-3-yl 153- 154 117- 118 105- I] I 09/02,docurnentl 3,105 1548 1549 1550 1551 1552 1553 1554 1555 1556 1557 1558 1559 1560 1561 1562 1563 C-Me C-Me C-Me C-Me C-Me C-Me C-Me C -Me C-Me C-Me C-Me C-Me C-Me C -Me C-Me C-Me N (CH 2

CH

2 OMe) CH 2 C- Pr N'H(CH (CH 3

CH

2

CH

3 NHCH(c-Pr)2 N (CH 2

CH

2 OMe) 2 NHCH (Et) 2 N (Et) 2 2 -ethylpiperidyl cyclobutylamino N (Me) CH 2

CH=CH

2 N (Et) CH 2 C- Pr N(Pr) CH 2 C-Pr N (Me) Pr N(Me) Et N (Me) Bu N (Me) propargyl NH (CH (CH 3 CH (CH 3

CH

3 6-MeO-4 -Mepyrid- 3-yl 6-MeO-4-Mepyrid-3 -yl 6-MeO-4 -Mepyrid-3-yl 6.-MeO-4-Mepyrid-3-yl 6-MeO-4-Mepyrid-3-yl 6-MeO-4 -Mepyrid-3-yl 4,6-Me 2 pyrid- 3-yl 4,6-Me 2 pyrid-3 -yl 4,6-Me 2 pyrid-3 -yl 4,6-Me 2 pyrid-3-yl 4,6-Me 2 pyrid- 3-yl 4,6-Me 2 pyrid-3-yl 4,6-Me 2 pyrid-3 -yl 4,6-Me 2 pyrid-3-y.

4,6-Me 2 pyrid-3 -yl 4,6-Me 2 pyrid- 3-yl 106- I1I /09/02,docwiieitl 3,106 1564 1565 1566 1567 1568 1569 1570 1571.

1572 1573 1574 1575 1576 1577 1578 1579 C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C -Me C -Me C-Me C-Me C-Me N (CH 2

CH

2 OMe) CH 2 CH=CH2 N (CH 2

CH

2 OMe) Me N (CH 2

CH-

2 OMe) Et N (CH 2

CH

2 OMe) Pr

N(CH

2

CH

2 OMe) CH 2 C-Pr NH- (CH (CH 3

CH

2

CH

3 NHCH (c-Pr) 2 N (CH 2

CH

2 OMe) 2 NHCH-(Et) 2 N(Et) 2 2 -ethylpiperidyl cyclobutylamino N (Me) CH 2

CH=CH

2 N(Et) CH 2 C-Pr N (Pr) CH 2 C-Pr.

N(Me) Pr 4, 6-Me 2 pyrid-3-yl 4, 6 -Me2 pyrid-3-yl 4, 6-Me 2 pyrid-3-yl 4, 6-Me 2 pyrid-3-yl 4, 6-Me 2 pyrid-3-yl 4,6-Me 2 pyrid- 3-yl 4, 6-Me 2 pyrid- 3 -yl 4, 6-Me 2 pyrid- 3-yl 4, 6-Me 2 pyrid-3-yl 4, 6-Me 2 pyrid-3-yl 2, 6-Me 2 pyrid- 3-yl 2, 6 -Me2 pyrid-3 -yl 2, 6-Me 2 pyrid- 3 -yl 2, 6-Me 2 pyrid- 3 -y1 2, 6-Me 2 pyrid-3-yl 2, 6-Me 2 pyrid-3-yl 107 I I /09!O02,documentl 3,1097 1580 1581 1582 1583 1584 1585 1586 1587 1588 1589 1590 1591 1592 1593 1594 1595 1596 C-Me C -Me C-Me C -Me C-Me C-Me C-Me C-Me C-Me C -Me C -Me C-Me C -Me C -Me C -Me C -Me C -Me "N(Me) Et N (Me) Bu N (Me) propargyl NH (CH (CH 3 CH (CH 3

CH

3 N (CH 2

CH

2 OMe) CH 2 CH=CH2 N (CH 2

CH

2 OMe) Me N (CH 2

CH

2 OMe) Et N (CH 2

CH

2 OMe) Pr N (CH 2

CH

2 OMe) CH 2 C-Pr NH (CH (CH 3

CII

2

CH

3 NHCH(c-Pr) 2 N (CH 2

CH

2 OMe) 2 NHCH (Et) 2 N(Et) 2 2 -ethylpiperidYl cycl1obutyl amino N (Me) CH 2

CH=CH

2 2, 6-Me 2 pyrid-3-yl 2, 6-Me 2 pyrid-3-yl 2, 6-Me 2 pyrid-3 -yl 2, 6-Me 2 pyrid-3 -yl 2,6-Me 2 pyrid-3-yl 2, 6-Me 2 pyrid-3 -yl 2, 6-Me 2 pyrid-3 -yl 2,6-Me 2 pyrid-3-yl 2,6-Me 2 pyrid-3 -yl 2,6-Me 2 pyrid-3 -yl 2, 6-Me 2 pyrid-3-yl 2,6-Me 2 pyrid-3 -yl 2,6-Me 2 pyrid- 3-yl 2,6-Me 2 pyrid- 3-yl 4-MeO-6-Mepyrid-3-yl 4-MeO-6-Mepyrid-3 -yl 4-MeO-6-Me- 108 11 /09102,doctunentl 3,108 1597 1598 1599 1600 1601 1602.

1603 1604 1605 1606 1607 1608 1609 1610 1611 1612 C -Me C-Me C -Me C -Me C-Me C-Me C-Me C-Me C-Me C -Me C-Me C-Me C -Me C-Me C-Me C -Me N (Et) CH 2 C- Pr N (Pr) CH 2 C- Pr N (Me) Pr N (Me) Et N (Me) Bu N (Me) propargyl NH(CH (CH 3

CH(CH

3

CH

3 N (CH 2

CH

2 OMe) CH 2

CH=CH

2 N (CH 2

CH

2 OMe) Me N (CH- 2

CH

2 OMe) Et

N(CH

2

CH

2 OMe) Pr

N(CH

2

CH

2 OMe) CH 2 C-Pr NH (CH (CH 3

CH

2

CH

3 NHCH (c-Pr) 2 N (CH 2

CH

2 OMe) 2 NHCH (EL) 2 pyrid- 3-yl 4 -MeO-6 -Mepyrid-3-yl 4 -MeO-6-Mepyrid- 3-yl 4 -MeO-6-Mepyrid- 3-yl 4-MeO-6-Mepyrid-3 -yl 4 -MeO-6 -Mepyrid-3 -yl 4 -MeO-.6-Mepyrid-3 -yl 4 -MeO-6 -Mepyrid- 3-yl 4-MeO-6-Mepyrid- 3-yl 4-MeO-6-Mepyrid-3 -yl 4 -MeO-6 -Mepyrid- 3-yl 4 -MeO-6 -Mepyrid- 3-yl 4-MeO-6-Mepyrid-3-yl 4 -MeO-6-Mepyrid-3 -yl 4-MeO-6-Mepyrid- 3-yl 4 -MeO-6-Mepyrid- 3-yl 4 -MeO-6-Mepyrid- 3-yl 109 I I /09/02,documenti 3,109 1613 C-Me 1614 1615 1616 1617 1618 1619 1620 1621 l1522 1623 1624 1625 1626 1627 1628 1629 1630 1631.

1632 1633 1634 Notes a) b) c d) f g) C-Me C -Me C -Me C-Me C -Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C-Me C -Me C-Me C -Me C-Me C-Me C-Me C-Me N(Et) 2 4-MeO-6-Mepyrid-3-yl 2-ethylpiperidyl 2-Br-4, 5- (OMe) 2 Ph cyclobutylamir'o 2-Br-4,5- (OMe) 2 Ph N(Me)CH 2 CH=CH2 2-Br-4,5- (OMe) 2 Ph N (Et) CH 2 C -Pr 2-Br-4,S- (OMe) 2 Ph N(Pr)CH 2 C-Pr 2-Br-4,5- (OMe) 2 Ph N(Me)Pr 2-Br-4,5-(OMe) 2 Ph N (Me) Et 2-Br-4,S- (OMe) 2 Ph N(Me)Bu 2-BSr-4,5- (OMe) 2 Ph N (me) propatgyl 2-Br-4,.5- (OMe) 2 Ph NH(CH (CH 3 CH (CH 3

CH

3 2-Br-4, 5 -(OMe) 2Ph N (CH 2

CH

2 OMe) CH 2

CH=CH

2 2-Br-4, 5 (OMe) 2 Ph N (CH 2

CH

2 OMe) Me 2-Br-4,5- (OMe) 2 Ph

N(CH

2

CH

2 OMe)Et 2-Br-4,5- (OMe) 2 Ph N (CH 2

CH

2 OMe) Pr 2-Br-4,5- (OMe) 2 Ph N (CH 2

CH

2 OMe) CH 2 C-Pr 2-Br-4, 5- (OMe) 2 Ph NH (CH (CH 3

CH-

2

CH

3 2-Br-4,5- (OMe) 2 Ph NH-CH(c-Pr) 2 2-Br-4,5-(OMe) 2 Ph

N(CH

2

CH

2 OMe) 2 2-Br-4,5- (QMe) 2 Ph NHiCH(Et) 2 2-Br-4,5-(OMe)2Ph N (Et) 2 2-Br-4,5-(OMe)2Ph NEt(Bu) 2-Br -4,S-(OMe) 2 Ph for Table 7: CI-MS: 330 (M CI-MS: 338 (M CI-MS: 338 (M CI-MS: 400 (M CI-MS: 326 (1M CI-MS: 354 (M H) I+ H) -110- I I /09/02,docuinentl 3,110 h) i) j) k) m) n) o)

P)

q) r) s) t) u) v) w) x) y) z) aa) ab) ac) ad) ae) af) ag) ah) ai) aj) ak) al) am) an) CI-MS: 336 (M CI-MS: 354 (M CI-MS: 378 (M H) 4 CI-HRMS: Calcd 356.2087 (M H) Found: 356.2071: CI-MS: 340 (M CI-MS: 368 (M CI-MS: 326 (M CI-MS: 368 (M CI-MS: 394 (M CI-HRMS: Calcd CI-HRMS: Calcd CI-HRMS: Calcd CI-HRMS: Calcd CI-HRMS: Calcd CI-HRMS: Calcd CI-HRMS: Calcd CI-HRMS: Calcd CI-HRMS: Calcd CI-HRMS: Calcd CI-MS 410 (M CI-HRMS: Calcd CI-HRMS: Calcd CI-MS 384 (M CI-MS 400 (M CI-MS 426 (M CI-HRMS: Calcd CI-HRMS: Calcd CI-HRMS: Calcd CI-HRMS: Calcd CI-HRMS: Calcd CI-HRMS: Calcd CI-HRMS: Calcd 380.2087 (M H) Found: 380.2078; 356.2008 416.2220 370.2243 380.2400 429.2376 397.2478 410.5438 368.4625 368.2090 370.4785 356.4514 388.1553 388.1540 430.2005 390.1683 376.1554 404.1853 420.1810

H)

H),

H)

H)P,

H) Found: Found: Found: Found: Found: Found: Found: Found: Found: Found: Found: Found: Found: Found: Found: Found: Found: Found: 356.1997; 416.2005; 370.2246; 384.2382; 429.2358; 397.2484; 410.2558; 368.2100; 368.4625; 370.2246; 356.2086; 388.1554; 358.1546; 430.2006; 390.1682; 376.1548; 404.1850; 420.1809;

H)

H),

H)

-111- Sl/09/02,documentl3,l I1 ao) ap) aq) ar) as) at) au) av) aw) ax) ay) az) ba) bb) bc) bd) be) bf) bg) CI-HRMS: Calcd 446.1946 CI-HRMS: Calcd 450.1917 CI-HRMS: Calcd 404.1839 CI-HRMS: Calcd 390.1678 CI-HRMS: Calcd 418.2010 CI-HRMS: Calcd 384.2512 CI-HRMS: Calcd 414.2617 CI-HRMS: Calcd 367.2484 CI-HRMS: Calcd 354.2406 CI-MS 370 (M CI-MS 380 (M CI-MS 340 (M CI-HRMS: Calcd 376.1340 CI-HRMS: Calcd 378.1497 CI-HRMS: Calcd 364.1340 CI-HRMS: Calcd 378.1593 CI-HRMS: Calcd 392.1653 CI-HRMS: Calcd 378.1497 CI-HRMS: Calcd 406.1810 Found: Found: Found: Found: Found: Found: Found: Found: Found: 446.1949; 450.1913; 404.1846; 390.1680; 418.2012; 384.2506; 414.2600; 367.2477; 354.2388; 376.1347; 378.1495; 364.1333; 378.1498; 392.1649; 378.1489; 406.1819;

H),

H)

Found: Found: Found: Found: Found: Found: Found: The examples delineated in TABLE 8 may be prepared by the methods outlined in Examples 1A, 1B, 432, 433, 434.

Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, cPr is cyclopropyl, Ex is Example, EtOAc is ethyl acetate.

TABLE 8 -112- 11 1/09/02.documentl 3.112 R 3 R

~N,.N

CH

3

H

3 C N Ar R3A 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 116' 2020 N (CH 2

CH

2 OMe) 2 N(Bu)Et _NICH (Et) CH 2 OMe N (Pr) CH 2 CH2CN NI{-3 -pentyl NHCH (CH 2 OMe) 2 NHCH (Et) 2 NHICH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 N (c-Pr) CM 2

CH

2

CN

N (CH 2

CH

2 OMe) 2 NHCH (CH 2 OMe) 2 NI{CH(Et) 2 NEt 2 N(Pr) CH 2

CH

2

CN

N (Eu) CH2CH2CN NHCH (Et) CH 2 OMe NHCH (Et) 2 NHCH (CH2OMe) 2 N (CM 2

CH

2 OMe) 2 CS) -NICH(CH 2 CH2OMe) 2,4-C! 2 -Ph 2, 4-C1 2 -Ph 2,4-C1 2 -Ph 2, 4 -C1 2 -Ph 2,4-C1 2 -Ph 2, 4 -C1 2 -Ph 2, 4-Me 2 -Ph 2, 4-Me 2 -Ph 2, 4-Me 2 -Ph 2, 4-Me 2 -Ph 2-Cl, 4-MePh 2-C1,4-MePh 2-Cl, 4-MePh 2, 4 -Me2 -Ph 2, 4-Me 2 -Ph 2 ,4-Me 2 -Ph 2,4-Me 2 -Ph 2-Me, 4-MeOPh 2-Me, 4-MeOPh 2-Me, 2-Me, 4-MeOPh 113 I I /09/02,documentl 3,1 13 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040 2041 2042 2043 2044 2045 2046 2047 2048 2049 2050 2051 2052

(CH

2 OMe) -NHCH (CH 2 CH2OMe)

(CH

2 OMe) N (CH 2

CH

2 OMe) 2 mHt NHCH(Et) 2 NHCH (CH 2 oMe) 2 N(Ac)Et

-NHCH(CH

2 CH2OMe)

(CH

2 0Me) N (Pr) CH 2

CH

2

CN

NEt2 -NHCH (CH 2

CH

2 OMe)

(CH

2 OMe) NEt2 N (c -Pr) CH 2 C42 CN N (c-Pr) CH 2

CH

2

CN

NHCH (Et) CH2OMe NHCH(Et)CH2OMe NH{CH (CH 2 OMe) 2 N (CH 2 CH2OMe) 2 NHCH (Et) CH2OMe N (c-Pr) CH 2

CH

2

CN

NEt 2 NH- 3-pentyl NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH 2

CH

2 OMe NHCH(Et) CH 2

CH

2 oMe NHCH (Me) CH 2 CH2OMe UHCH(Et) CH 2

CH

2 OMe NHCH(Me) CH 2

CH

2 oMe NHCH(CH2OMe) 2 2, 4 -Me 2 -Ph 2-Me, 4-CiPh Z, 4 -Me2 -Ph 2-Me,4-ClPh 2-Me,4-C1Ph 2,4-Me2-Ph 2-Me .4-CIPh 2-Me,4-MeOPh 2-Me,4-MeOPh 2-Cl, 4-MePh 2-Cl, 4-MePh 2-Me, 4-MeOPh 2-Cl, 4-MePh 2-Me, 4-MeOPh 2-Cl,4-MePh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2 -C1-4 -MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-C1-4-MeOPh 2-Cl-4 -MeOPh 2-Cl-4 -MeOPh 2-Br-4 -MeOPh 2-Br-4-MeOPh 2-Me-4 -MeOPh 2-Me-4 -MeOPh 2-Cl-4,S- (MeO) 2 Ph 114- I I /09/02,docurnentl 3,I 14 2053 2054 2055 2056 2057 2058 2059 2060 2061 2062.

2063 2064 2065 2066 20U67 2068 2069 2070 2071 2072 2073 2074 2075 2076 2077 2078 2079 2080 2081 N (CH 2 CH2OMe) 2 NHCH (Et) CH 2 OMe N (c-Pr) CH 2

CH

2

CN

NEt 2 NH-3 -pentyl NHCH (Et) CH 2

CH

2 oMe NHCH (Me) CH 2

CH

2 OMe NHCH (CH2OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (Et) CH 2 OMe N (c-Pr) CH 2

CH

2

CN

NEt2 NH-3 -pentyl NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH 2

CH

2 OMe NHCH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH(Et) CH2OMe N (c-Pr) CH 2

CH

2

CN

NEt 2 NH-3 -pentyl NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH 2

CH

2 OMe NHCH (CH 2 OMe) 2 N (CH2CH2OMe) 2 NHCH (Et) CH2OMe N (c-Pr) CH 2

CH

2

CN

NEt 2 KH-3 -pentyl NMCM (Et) CH 2

CH

2 OMe NHCH (Me) CH 2

CH

2 OMe N (c-Pr) CH 2

CH

2

CN

2-Cl-4,5- (MeO) 2 Ph 2-C1-4,5- (MeO) 2 Ph 2-C1-4, 5- (MeO) 2 Ph 2-Cl-4.5- (MeO) 2 Ph 2-Cl-4,5- (MeO) 2 Ph 2-Cl-4,5- (MeO) 2 Ph 2-Cl-4,5- (MeO) 2 Ph 2-Br-4,5- (MeO) 2 Ph 2-Br-4,5- (MeO) 2 Ph 2-Br-4,5- (MeO) 2 Ph 2-Br-4,5- (MeO) 2 Ph 2-Br-4,5- (MeO) 2 Ph 2-Br-4,5- (MeO) 2 Ph 2-Br-4,5- (Meo) 2 Ph 2-Er-4,5- (Meo) 2 Ph 2-C1-4,6- (MeO) 2 Ph 2-Cl-4, 6- (MeO) 2 Ph 2-CJ.-4, 6- (MeO) 2 Ph 2 -C1-4, 6- (MeO) 2 Ph 2-Cl-4,6- (MeO) 2 Ph 2-C1-4,6- (MeO) 2 Ph 2-C1-4,6- (MeO) 2 Ph 2-Cl-4,6- (MeO) 2 Ph 2-Me-4,6- (MeO) 2 Ph 2-Me-4,6- (Meo) 2 Ph 2-Me-4,6- (MeO) 2 Ph 2-Me-4,6- (MeO) 2 Ph 2-Me-4, 6- (MeO) 2 Ph 2-Me-4, 6- (Meo) 2 Ph 2-Me-4,6- (MeO) 2 Ph 2-Me-4,6- (MeO) 2 Ph 2-Br-4,6- (MeO) 2 Ph 2082 2083 2084 115 I I /09/02,documentl 3,11I5 2085 2086 2087 2088 2089 2090 2091 2092 2093 2094 2095 2096 2097 2098 2099 2100 2101 2102 2103 2104 2105 2106 2107 2108 2109 2110 2111 2112 2113 2114 2115 2116 me me Me Me Me Me Me Me Me Me Me Me Me Me me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Cl Cl NEt2 N1H-3 -pentyl NHCH (Et) CH 2 CH2OMe NHCH (Me) CH 2 CH2oMe NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH 2 CH2OMe NHCH (CH 2 OMe) 2 N (CH 2 CH2OMe) 2 NIICH (Et) CH 2 OMe N (c-Pr) CH 2 CH2CN NEt 2 NH-3-pentyl NHCH (Et) CH 2 CH2OMe NIICH (Me) CH 2

CH

2 OMe NHCH (CH 2 OMe) 2 N (CH 2 CH2OMe) 2 NHCH (Et) CH 2 OMe N(c-Pr) CH 2 CH2CN NEt 2 N-H-3-pefltyl 1'IICH (Et) CH 2 CH2OMe NHCH-(Me) CH 2 CH2OMe NHiCH(CH2oMe) 2 N (CI- 2

CH

2 OMe) 2 NH-CH (Et)CH 2 OMe N(c-Pr) CH 2

CH

2

CN

NEt 2 N1I-3 -pentyl NHCH (Et) CH 2 CH2OMe N]ICH (Me)CH 2 CH2oMe N (CH 2

CH

2 OMe) 2 N (Bu) Et 2-Br-4,6- (MeO) 2 Ph 2-Br-4 (MeO) 2 Ph 2-Br-4,6- (MeO)2Ph 2-Br-4,6- (MeO) 2 Ph 2-Me-4-MeOPh 2 -Me-4 -MeOPh 2-MeO-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh 2 -MeO-4 -MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-MeO-4 -MePh 2-MeO-4 -MePh 2 -MeO-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-Me 0-4-MePh 2-MeO-4-MePh 2-MeO-4-ClPh 2-MeO-4-ClPh- 2-MeO-4-ClPh 2-Meo-4-C1Ph 2-MeO-4-C1Ph 2 -MeO-4 -CiPh 2-MeO-4-C1Ph 2-MeO-4 -ClPh 2,4-C1 2 -Ph 2, 4-C1 2 -Ph 116- I1 I 09/02,docuinentl 3,116 2117 2118 2119 2120 2121 2122 2123 2124 2125 2126 2127 2128 2129 2130 2131 2132 2133 2134 2135 2136 2137 2138 2139 2140 2141 2142 2143 2144 2145 2146 2147 Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl c~l Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl NITCH (Et) CH 2 OMe N (Pr) CH 2

CH

2

CN

NH-3-pentyl NHCM (CH 2 oMe) 2 NHCH (tt) 2 NHCH (CH 2 OM6) 2 N (CH 2

CH

2 OMe) 2 N (c -Pr) CH 2

CH

2

CN

N(CH

2 CR2OMe) 2 NTHCH (CH 2 OMe) 2 NHCH (Et) 2 NEt2 N(Pr) CH 2

CH

2

CN

N (Bu) CH 2

CH

2

CN

NHCH (Et) CH 2 OMe NIICH (Et) 2 NHCH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 'CS) -NHCH(CH 2 CH2OMe)

(CH

2 OMe)

-NHCH(CH

2 CH2OMe)

(CH

2 OMe) N (CH 2

CH

2 OMe) 2 NHEt NHCH (Et) 2 HCH (CH2OMe) 2 N (Ac) Et

-NHCH(CH

2 CH2OMe)

(CH

2 OMe) N(CPr) CH2 CH 2

CN

NEt 2 2, 4-C1 2 Ph 2, 4-C1 2 -Ph 2, 4-C1 2 -Ph 2,4-C1 2 -Ph 2,4 -Me2 -Ph 2,4 -Me 2 -Ph 2,4 -Me 2 -Ph 2,4 -Me 2 -Ph 2-Cl, 4-MePh 2-Cl, 4-MePh 2-Cl,.4-MePh 2,4-Me2-Ph 2,4-Me 2 -Ph 2,4-Me 2 -Ph 2,4-Me 2 -Ph 2-Me,4-MeOPh 2-Me, 4-MeOPh 2-Me, 4-MeOPh 2-Me,4-MeOPh 2,4-Me 2 -Ph 2-Me,4-ClPh 2, 4-Me 2 -Ph 2-Me, 4-ClPh 2-Me, 4-ClPh 2, 4-Me 2 -Ph 2-Me, 4-ClPh 2-Me, 4-MeOPh 2-Me, 4-MeOPh 74-76 b -117- I I1/09/02,doctuiietitl3,1 17 2148 2149 2150 2151 2152 2153 2154 2155 2156 2157 2158 2159 2160 2161 2162 2163 2164 2165 2166 2167 2168 2169 2170 2171 2172 2173 2174 2175 2176

-NHCH(CH

2

CH

2 OMe) (CH2OMe) NEt 2 N (c-Pr) CH 2

CH

2

CN

N (c -Pr) CH 2

QH

2

CN

NHCH (Et) CH2OMe NHCH(Et) CH 2 OMe NHCH (CH20Me) 2

N(CH

2

CH

2 OMe) 2 NHCH(Et) CH2OMe N (c -Pr) CH2 CH 2

CN

NEt 2 NH-3 -pentyl NHCH (Et) CH2CH2OMe NHCHN(Me) CH2CH 2 OMe NHCH (Et) CH2CH 2 OMe NHCH (Me) CH 2

CH

2 OMe NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH 2

CH

2 OMe

NHCH(CH

2 OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (Et) CH2OMe N (c-Pr) CH 2

CH

2

CN

NEt 2 KH-3-pentyl NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH 2

CH

2 OMe

NHCH(CH

2 OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH(Et) CH2OMe N (c-Pr) CH 2

CH

2

CN

NEt 2 2-Cl, 4-MePh 2-Cl, 4-MePh 2-Me,4-MeOPh -Cl,4-MePh 2-Me,4-MeOPh 2-C1,4-MePh 2-01-4 -MeOPh 2-C1-4-MeOPh 2-C1-4-MeOPh 2-C1-4-MeOPh 2 -01-4 -MeOPh 2 -01-4 -MeOPh 2-C1-4-MeOPh 2-C1-4-MeOPh 2-Br-4-MeOPh 2 -Br-4 -MeOPh 2-Me-4 -MeOPh 2 -Me-4 -MeOPh 2-C1-4, 5- (MeO) 2 Ph 2-01-4,5- (MeO) 2 Ph 2-01-4,5- (MeO) 2 Ph 2-C1-4,5- (MeO) 2 Ph 2-01-4,5- (MeO) 2 Ph 2-C1-4,S- (MeO) 2 Ph 2-C1-4,5- (MeO) 2 Ph 2-01-4,5- (MeO) 2 Ph 2-Br-4, 5- (MeO) 2 Ph 2-Br-4, 5- (MeO) 2 Ph 2-Br-4, 5- (MeO) 2 Ph 2-Br-4,5- (MeO) 2 Ph 2 -Br-4, S- (MeO) 2 Ph 2177 2178 2179 118- I 1/09/02,docutren 13,118 2180 2181 2182 2183 2184 2185 2186 2187 2 18'8 2189, 2190 2191 2192 2193 2194 2195 2196 2197 2198 2199 2200 2201 2202 2203 2204 2205 2206 2207 2208 2209 2210 2211 Cl Cl Cl cl Cl Cl Cl Cl Cl Cl cl Cl Cl Cl Cl Cl cl Cl Cl Cl Cl Cl Cl cl Cl Cl Cl Cl Cl Cl Cl Cl NI{-3 -pentyl NHCH (Et) CH2CH 2 OMe NHCH (Me) CH2CH 2 OMe NHCH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (Et) CH 2 OMe N (c -Pr) CH 2

CH

2

CN

NEt 2 NII-3 -pentyl NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH2CH 2 OMe NHCH (CH 2 OMe) 2 N (CH2CH 2 OMe) 2 NHCH (Et) CH 2 OMe N (c -Pr) CH 2

CH

2

CN.

NEt 2 NH--3-pentyl NHCH (Et) CH2CH 2 OMe NHCH (Me) CH2CH 2 OMe N (c-Pr) CH2CH 2

CN

NEt 2 NI{-3 -perityl NHCH (Et) CH2CH 2 OMe NHCH (Me) CH2CH2OMe NHCR (Et) CH 2

CH

2 OMe NHCH (Me) CH2CH 2 OMe N'HCH (CH 2 OMe) 2 N (CH2CH 2 OMe) 2 NIICH (Et) CH 2 OMe N(c-Pr) CH 2

CH

2

CN

NEt 2 NH-3-pentyl 2-Br-4, 5- (MeO) 2 Ph 2-Br-4,5- (MeO) 2 Ph 2-Br-4,5- (MeO) 2 Ph 2-Cl-4,6- (MeO) 2 Ph 2 -C 4, 6- (MeO) 2 Ph 2-Cl-4,6- (MeO) 2 Ph 2-Cl-4,6- (MeO) 2 Ph 2-Cl-4,6- (MeO) 2 Ph 2-Cl-4,6- (Meo) 2 Ph 2-Cl-4, 6- (MeO) 2Ph 2-C1-4,6- (MeO) 2 Ph 2-Me-4,6- (MeO) 2 Ph 2-Me-4,6- (MeO) 2 Ph 2-Me-4,6- (MeO) 2 Ph 2-Me-4, 6- (MeO) 2Ph 2-Me-4, 6- (MeO) 2 Ph 2-Me-4,6- (Meo) 2 Ph 2-Me-4, 6- (MeO) 2 Ph 2-Me-4, 6- (MeO) 2Ph 2-Br-4 (Meo) 2 Ph 2-Br-4,6- (MeC) 2 Ph 2-Br-4, 6- (MeO) 2 Ph 2-Br-4, 6- (Meo) 2 Ph 2-Br-4,6- (MeO) 2 Ph 2 -Me-4 -MeOPh 2 -Me-4 -MeOPh 2.-MeO-4-MePh 2 -MeO-4 -MePh 2-MeO-4-MePh 2-MeO-4 -MePh 2 -MeO-4 -MePh 2-MeO-4 -MePh -119- I I /09M0,doctnientl 3.1 19 2212 2213 2214 2215 D 2216 2217 2218 2219 2220 2221 2222 2223 2224 2225 2226 2227 2228 2229 2230 2231 2232 2233 2234 2235 2236 2237 2238 2239 2240 2241 2242 2243 cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl

F

NICR (Et) CH 2 cH 2 oMe NHCH (Me) CH 2 CH2OMe NHCH (CH 2 OMe) 2 N (CR2 CH 2 oMe) 2 NHCH (Et) CH 2 oMe N(c-Pr) CH 2 CH2CN NEt2 NI{-3 -pentyl NHCR (Et) CH 2 CH2oMe NHCH (Me) CH 2 CH2OMe NHCH(CH2OMe) 2 N (CH 2

CH

2 oMe) 2 NHCH (Et) CH 2 OMe N (c-Pr) CH 2 CH2CN NEt2 NH-3-pefltyl NHCH (Et) CH 2 CH2OMe NHCH (Me) CH 2

CH

2 OMe N (CH 2

CH

2 OMe) 2 N (Bu) Et NHCH (Et) CH 2 oMe N (Pr) CH 2 CH2CN NH-3 -pentyl NHCH (CH 2 OMe) 2 NHCH(Et) 2 NH{CH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 N (c-Pr) CH 2 CH2CN N (CH 2

CH

2 OMe) 2

NIICH(CH

2 oMe) 2 NHCH(Et) 2 flEt 2 2-MeO-4 -MePh 2-Me0-4-MePh 2-Me0-4-MePh 2 -MeO-4-MePh 2-Me 0-4- mePh 2 -MeO-4 -MePh 2-*Me0-4-MePh 2-Me0-4-MePh 2Me0-4-MePh 2 -MeO-4 -MePh 2 -MeO-4 -CiPh 2 -MeO-4-ClPh 2-MeO-4-ClPh 2Me0-4-ClPh 2-Me0-4-ClPh 2MeO-4-ClPh 2-MeO-4-ClPh 2-MeO-4 -CiPh 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2, 4-C1 2 -Ph 2, 4-C1 2 -Ph 2,4-C12 -Ph 2,4-Cl 2 -Ph 2,4-Me2-Ph 2,4-Me 2 -Ph 2,4-Me 2 -Ph 2,4-Me2-Ph 2-Cl, 4-MePh 2-C1,4-MePh 2-Cl,4-MePh 2,4-Me 2 -Ph 120 11 /09/02,doctunentl3,1 2244 2245 2246 2247 2248 2249 2250 2251 2252 2253 2254 2255 2256 2257 2258 2259 2260 2261 2262 2263 2264 2265 2266 2267 2268 2269 2270 2271 2272 2273 2274 2275

F

F.

F

N(Pr) CH 2 CH2CN N (Bu) CH 2 CH2CN NHCH (Et) CH 2 OMe NHCH (Et) 2 NHCH (CH 2 oMe) 2 N (CH 2 CH2oMe) 2 NHCH (CH2CH2oMe)-

(CH

2 OMe) -N1ICH (CH 2 CH2OMe)

(CH

2 OMe) N (CH 2

CH

2 oMe) 2 NI[Et NHCH(Et)2 NHCH (CH 2 OMe) 2 N(AC)Et -N-HCH (CH 2 CH2oMe)-

(CH

2 OMe) N (Pr) CH 2

CH

2

CN

NEt 2 -N-HCH (CH 2 CH2oMe)-

(CH

2 OMe) NEt 2 N (c -Pr) CH 2

CH

2

CN

N (c -Pr) CI{ 2

CH

2

CN

NHCH (Et) CH 2 oMe NHCH (Et) CH 2 OMe N'HCH (CH 2 OMe) 2 N (CH 2

CH

2 oMe) 2 NHCH (Et) CH 2 OMe N (c Pr) CH 2 CH2 CN NEt 2 NH-3 -pentyl 2, 4 -Me 2 -Ph 2.,4-Me 2 -Ph 2, 4 -Me 2 -Ph 2 -Me-4 -MeOPh 2-Me-4 -MeOPh 2- Me-4 -MeOPh 2 -Me-4 -MeOPh 2,4-me2-Ph 2-Me ,4-ClPh 2,4-Me 2 -Ph 2-Me,4-ClPh 2-Me,4-ClPh 2,4-Me 2 -Ph 2-Me,4-ClPh 2-Me, 4-MeOPh 2-Me, 4-MeOPh 2-Cl ,4 -MePh 2-Cl, 4-MePh 2-Me,4-MeOPh 2-Cl, 4-MePh 2-Me,4-MeOPh 2-Cl, 4-MePh 2-Cl-4 -MeOPh 2-Cl-4-meOPh 2-Cl-4 -MeOPh 2-Cl-4-MeOPh 2-Cl-4 -MeOPh' 2-Cl-4-MeOPh 121 11 /09/02,documentl 3,121 2 27 6 2277 2278 2279 2280 2281 2282 2283 2284 2285 2286 2287 2288 2289 2290 2291 2292 2293 2294 2295 2296 2297 2298 2299 NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH 2 CH2OMe NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH 2 CH2OMe NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH 2 CH2OMe NHCH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH{(Et) CH20Me N (c-Pr) CH 2 CH2CN NEt2 NH- 3-pentyl NHCH (Et) CH 2 CH2OMe N-HCH (Me) CH 2

CI{

2 OMe NHCH (CH 2 OMe) 2 N (CM2 CI 2 OMe) 2 NHCH (Et) CH 2 OMe N (c -Pr) CH 2

CH

2

CN

NEt2 NH-3 -pentyl NI{CH(Et) CH 2 CH2OMe NHCH (Me) CH 2

CH

2 OMe NHCH(CH7 2 OMe) 2

N(CH

2 CH2OMe) 2 NHICH (Et) CH 2 OMe N (c-Pr) CH 2

CH

2

CN

NEt 2 NH-3 -pentyl NHCH (Et)CH 2 CH2OMe NHCH (Me) CH2CH2OMe NHCI (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 2-Cl-4-MeOPh 2-C1-4-MeOPh 2 -Br-4 -MeOPh 2-Br- 4-MeOPh 2 -Me-4-MeOPh 2-1Ne-4 -MeOPh 2-Cl-4,5- (MeO) 2 Ph 2-C1-4, 5- (MeO) 2 Ph 2-Cl-4, 5- (MeO) 2 Ph 2-C1-4,5- (MeO)2Ph 2-C1-4, 5- (MeO) 2 Ph 2-C1-4,5- (MeO).2Ph 2-C1-4, 5- (MeO) 2 Ph 2-C1-4. 5- (MeO) 2 Ph 2-r45- (MeO) 2 Ph 2-Br-4,5- (MeO)2Ph 2-Br-4, 5- (MeO) 2 Ph 2-Br-4,5- (MeO) 2 Ph 2-Br-4 (MeD) 2 Ph 2-Br-4, 5- (MeO) 2 Ph 2-Br-4, 5- (MeO) 2 Ph 2-Er-4, 5- (MeO) 2 Ph 2-C1-4,6- (MeO)2Ph 2-C1-4, 6- (MeO) 2 Ph 2-Cl-4,6- (MeC) 2 Ph 2-C1-4,*6- (MeC) 2 Ph 2-CI-4,6- (MeC)2Ph 2-C1-4, 6- (MeC) 2 Ph 2-C1-4,6- (MeC) 2 Ph 2-C1-4,*6- (MeO) 2 Ph' 2-Me-4 (MeC) 2 Ph.

2-Me-4,6- (MeO)2Ph 2300 2301 2302 2303 2304 2305 2306 2307 122 I I/09/02,documentl 3,122 2308 2309 2310 2311 2312 2313 2314 2315 .23 16 2317 2318 2319 2320 2321 2322 2323 2324 2325 2326 2327 2328 2329 2330 2331 2332 2333 2334 2335 2336 2337 2338 2339 NHCH (Et) CH 2 OMe N (c-Pr) CH 2

CH

2

CN

NEt 2 NH- 3-pentyl NHCH (Et) CH 2 CH2OMe NHCH (Me) CH 2 CH2OMe N (c-Pr) CH 2

CH

2

CN

NEt 2 NH-3 -pentyl NHCH-1(Et) CH 2

CH

2 OMe- NHCH (Me) CH 2 CH2OMe NHCH (Et) CH 2 CH2OMe NHCH (Me) CH 2 CH2OMe NHCH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (Et) CH 2 OMe N Cc-Pr) CH 2

CH

2

CN

NEt2 NH-3-pentyl NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH 2

CH

2 OMe NHCH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (Et) CH 2 OMe N Pr) CH 2 CH2CN NEt 2 NH-3 -pentyl NHCH (Et) CH 2 CH2OMe NHCH(Me) CH 2 CH2OMe NHCH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH(Et) CH 2 OMe 2 -Me (MeO) 2 Ph 2-Me-4,6- (MeO) 2 Ph 6- (MeO) 2 Ph 2 -Me-4,6- (MeO) 2 Ph 2-Me-4,6- (MeO) 2 Ph 2-Me-4,6- (MeO) 2 Ph 2-Br-4,6- (MeO) 2 Ph 2-Br-4,6- (MeO) 2 Ph 2-Br-4, 6- (MeO) 2 Ph 2-B4r-4,6- (MeO) 2 Ph 2-Br-4,6- (MeO) 2 Ph 2-Me-4 -MeOPh 2-Me-4-MeOPh 2-MeO-4 -MePh 2-MeO-4 -MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-MeO-4 -MePh 2-MeO-4 -MePh 2-MeO-4 -MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-Meo-4-MePh 2-MeO-4-MePh 2-Meo-4-MePh 2 -MeO-4-MePh 2-MeO-4-C1Ph 2-Meo-4-C1Ph 2-MeO-4-CIPh 123 I1I /09/02,docimentl 3,123 2340 2341 2342 2343 2344 2345 2346 2347 2348 2349 2350 2351 2352 2353 2354 2355 2356 2357 2358 2359 2360 2361 2362 2363 2364 2365 2366 2367 2368 2360 2370 2371 2372

F

Me Me Me Me me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me N (c-Pr) CH 2

CH

2

CN

NEt2 NH-3 -pentyl NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH 2

CH

2 OMe N~e (CH 2

CH

2 OMe) NEt (CH 2 CH2OMe) NPr (CH 2

CH

2 OMe) Nli-2-butyl cyc lobutylamiflo 2 -ethylpiperidilyl l'Me (propargyl) Nit (propargyl) NEtMe NEt Pr NMeBu NMe (CH 2 cPr) NEt (CH 2 cPr) NPr (CH2cPr) N~e (CH 2

CH

2 OMe) NEt (CH 2

CH

2 OMe) NPr (CH 2

CH

2 OMe) NH-2 -butyl cyclobutylamilo 2 -ethylpiperidill NMe (propargyl) NEt (propargyl) NEtMe NEt Pr NMeBu NMe (CH 2 cPr) NEt (CH 2 cPr) NPr (CH 2 cPr) 2-MeO-4 -ClPh 2-MeO-4 -CiPh 2-Me 0-4-ClPh 2-MeO-4 -CiPh 2-MeO-4-ClPh 2,4-Cl 2 -Ph 2, 4-Cl 2 -Ph 2,4-Cl 2 -Ph 2,4-C1 2 -Ph 2, 4-Cl 2 -Ph 2, 4-C1 2 -Ph 2,4-C1 2 -Ph 2, 4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-Cl 2 -Ph 2,4-C1 2 -Ph 2-Me-4 -MeOPh 2 -Me-4 -MeOPh 2:Me-4-MeOPh 2-Me-4-MeOPh 2-Me-4-MeOPh 2-Me-4 -MeOPh 2-Me-4 -MeOPh 2 -Me-4 -MeOPh 2-Me--4-MeOPh 2-Me-4 -MeOPh 2-Me-4-MeOPh 2-Me-4-MeOPh 2 -Me-4 -MeOPh 2-Me-4-MeOPh 124 I1I /09/02,documenti 3,124 2373 2374 2375 2376 2377 2378 2379 2380 2381 2382 2383 2384 2385, 2386 2387 2388 2389 2390 2391 2392 2393 2394 2395 2396 2 397 2398 2399 2400 2401 2402 2403 2404 Me Me Me me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me me Me Me Me Me Me Me Me Me me -NMe (CH 2

CH

2 OMe) NEt (CH 2

CH

2 OMe) NPr (CH 2

CH

2 OMe) NH-2-butyl cyc lobutylamilo 2 -ethylpiperidill N?4e (propargyl) NEt (propargyl) NEtMe NEt Pr NM eB u NMe (CH 2 cPr) NEt (CH 2 cPr) NPr (CH 2 cPr) NMe (CH 2 CH2OMe) NEt (CH 2

CH

2 oMe) NPr (CH 2

CH

2 OMe) NI{-2 -butyl cyclobutylamnio 2 -ethylpipeidill NMe (propargyl) NEt (propargyl) NEtMe NEt Pr N~eBu NMe (CH 2 cPr) NEt (CH 2 cPr) NPr (CH 2 cPr) NMe (CH 2

CH

2 OMe) NEt (CH 2 CH2OMe), NPr (CH 2

CII

2 oMe) UH-2 -butyl 2, 4 Me 2 -Ph 2, 4 me 2 -Ph 2, 4 -Me 2 -Ph 2,4-Me 2 -Ph 2, 4 -Me 2 -Ph 2,4-Me 2 -Ph 2, 4 -Me 2 -Ph 2,4-Me 2 -Ph 2,4-M6 2 -Ph 2, 4-Me 2 -Ph 2, 4-Me 2 -Ph 2, 4 -Me 2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me 2 -Ph 2-C1-4-MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-C1-4-MeOPh 2-Cl -4 -MeOPh 2-Cl -4 -MeOPh 2-C1-4-MeOPh 2-C1-4-MeOPh 2-C1-4-MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeoPh 2-Cl-4 -MeOPh 2, 5-Me 2 -4-MeOPh 2, 5-Me2-4 -MeOPh 2,5 -Me2 -4 -MeOPh 2, 5-Me2-4 -MeOPh 125 I I 09/02,docuineilil 3.125 2405 2406 2407 2408 2409 2410 2411 2412 2413 2414 2415 2416 2417 2418 2419 2420 2421 2422 2423 2424 2425 2426 2427 2428 2429 2430 2431 2432 2433 2434 2435 2436 cyclobutylarnino 2 -ethylpiperidinyl N~Me (propargyl) NEt (propargyl) NEtMe NEt Pr NMeBu Nle (CH2cPr) NEt (CH2cPr) NPr (CH2cPr) MMe (CH 2

CH

2 OMe) NEt (CH2CH2OMe) NPr (CH 2

CH

2 OMe) UH-2 -butyl cyclobutylamino 2 -ethylpiperidinyl NMe (propargyl) NEt (propargyl) NEtMe NEt Pr NMeBu Nme (CH 2 cPr) NEt (CH 2 cPr) NPr (CH2cPr) Nle (CH 2

CH

2 OMe) NEt (CH 2

CH

2 OMe) NPr (CH 2

CH

2 OMe) NH-2-butyl cyclobutylamino 2 -ethylpiperidinyl Nile (propargyl) NEt (propargyl) 2, 5-Me 2 -4-MeOPh 2, 5-Me 2 -4-MeOPh 2,5-Me 2 -4-MeOPh 2,5-Me 2 -4-MeOPh 2 5-Me2 -4 -MeOPh 2,5-Me 2 -4-MeOPh 2, 5-Me 2 -4 -MeOPh 2, 5-Me2-4-MeOPh 2 ,5 -Me2 -4 -MeOPh 2, 5-Me2 -4 -MeOPh 2 ,47C1 2 -Ph 2, 4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2, 4-C1 2 -Ph 2,4-C1 2 -Ph 2, 4-C1 2 -Ph 2, 4-C1 2 -Ph 2,4-C1 2 -Ph 2, 4-C1 2 -Ph 2, 4-C1 2 -Ph 2, 4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2 -Me-4 -MeOPh 2-Me-4 -MeOPh 2-Me-4 -MeOPh 2 -Me-4 -MeOPh 2 -Me-4 -MeOPh 2-Me-4-lMeOPh 2 -Me-4 -MeOPh 2 -Me-4 -MeOPh 126 I1I /09/02,doicsietl 3,126 f 2437 2438 2439 2440 2441 2442 2443 2444 2445 2446 2447 2448 2449 2450 2451 2452 2453 2454 2455 2456 2457 2458 2459 2460 2461 2462 2463 2464 2465 2466 2467 2468 2469 NEtMe NEt Pr NMeBu NMe (CH 2 cPr) NEt (CH2c Pr) NPr (CH 2 cPr) 1'he (CH 2

CH

2 OMe) NEt (CH 2

CH

2 OMe) NPr (CH 2

CH

2 OMe) NH-2-butyl cyc lobutylamino 2 -ethylpiperidinyl Nme (propargyl) NEt (propargyl) NEtMe NEt Pr NMeBu N'Me (CH 2 cPr) NEt (CH 2 cPr) NPr (CH 2 cPr) N~e (CH 2

CH

2 OMe) NEt (CH 2

CH

2 OMe) NPr (CH 2

CH

2 OMe) NH-2 -butyl cyclobutylarnino 2-ethylpiperidinyl NMe (propargyl) NEt (propargyl) NE tMe NEt Pr NMeBu NMe (CH2cPr) NEt (CH 2 cPr) 2-Me-4-MeOPh 2-Me-4 -MeOPh 2 -Me-4 -MeOPh 2-Me-4 -MeOPh 2-Me-4-MeOPh 2-Me-4 -MeOPh 2,4-Me 2 -Ph 2, 4-Me 2 -Ph 2,4-Me 2 -Ph 2,4-Me 2 -Ph 2, 4-Me 2 -Ph 2, 4-Me 2 -Ph 2,4-Me 2 -Ph 2,4-Me 2 -Ph 2, 4-Me 2 -Ph 2,4-Me 2 -Ph 2,4-Me 2 -Ph 2,4-Me 2 -Ph 2, 4-Me2-Ph 2,4-Me 2 -Ph 2-C1-4-MeOPh 2-Cl-4-MeOPh 2-C1-4-MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2 -C1-4 -MeOPh 2-Cl-4-MeOPh 2-C1-4-MeOPh 2-Cl-4-MeOPh 2-Cl-4 -MeOPh 127 I 1/09/02,documentl 3,127 2470 2471 2472 2473 2474 2475 2476 2477 2478 2479 2480 2481 2482 2483 2484 2485 2486 2487 2488 2489 2490 2491 2492 2493 2494 2495 2496 2497 2498 2499 2500 2501 Cl Cl Cl Cl Cl cl Cl Cl Cl Cl Cl Cl Cl Cl

F

NPr (CH 2 cPr) NMe (CM2 CH 2 oMe) NEt (CH 2

CH

2 OMe) NPr (CH 2

CH

2 OMe) NH-2 -butyl cyclobutylamilo 2 -ethylpiperi dill NMe (propargyl) NEt (propargyl) NEtMe NEt Pr N~leBu NMe (CH 2 cPr) NEt (CH 2 cPr) NPr (CM2 cPr) NI~e(CH 2

CH

2 OMe) NEt (CH 2

CH

2 OMe) NPr (CH 2

CH

2 OMe) NH-2-butyl cyc lobutylano 2 -ethylpiperidill NMe (propargyl) NEt (propargyl) NEtMe NEtPr NMeBu N~e (CH 2 cPr) NEt (CH 2 cPr) NPr (CH 2 cPr) NMe (CH 2 CH2OMe) NEt (CM2 CH 2 oMe) NPr (CH 2 CH2oMe) 2-Cl -4 -MeOPh 2, 5-Me 2 -4-MeOPh 2,5-Me 2 -4-MeOPh 2,5-Me 2 -4-MeOPh 2, 5-Me 2 -4-MeOPh 2,5 -Me2 -4 -MeOPh 2, 5 -Me2 -4 -MeOPh 2, 5-Me2 -4 -MeOPh 2,5-Me 2 -4-MeOPh 2. 5-Me 2 -4-MeOPh 2, 5-Me2 -4 -MeOPh 2, 5-Me2 -4 -MeO~h 2, 5-Me 2 -4-MeOPh 2, 5-Me 2 -4-MeOPh 2, 5-Me 2 -4-MeOPh 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2, 4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-Cl 2 -Ph 2, 4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2,4-C1 2 -Ph 2 -Me-4 -MeOPh 2-Me-4 -MeOPh 2 -Me-4 -MeOPh 128 11 /09/02,docunieitl 3,128 2502 2503 2504 2505 2506 2507 2508 2509 2510 '2511 2512 2513 2514 2515 2516 2517 2518 2519 2520 2521 2522 2523 2524 2525 2S26 2527 2528 2529 2530 2531 2532 2533 2534 NH-2 -butyl cyc lobutylamino 2-ethylpiperidinyl NMe (propargyl) NEt (propargyl) NEtMe NEt Pr NMeBu NMe (CH 2 cPr) NEt (CH2cPr) NPr (CH2cPr) Nme (CH2CH 2 OMe) NEt (CH 2

CH

2 OMe) NPr (CH 2

CH

2 OMe) NH-2 -butyl cyc lobutyl amino 2 -ethylpiperidinyl NMe (propargyl) NEt (propargyl) NEtMe NE tPr NMeBu NMe (CH2cPr) NEt (CH2cPr) NPr (CH 2 cPr) NMe (CH 2

CH

2 OMe) NEt (CH 2

CH

2 OMe) NPr (CH 2 CH2OMe) NH-2 -butyl cyc lobutylamino 2 -ethylpiperidinyl NMe (propargyl) NEt (propargjyl) 2 -Me-4 -MeOPh 2 -Me-4 -MeOPh 2 -Me-4 -MeOPh 2 -Me-4 -MeOPh 2-Me-4-MeOPh 2 -Me-4 -leOPh 2-Me-4 -MeOPh 2-Me-4-MeOPh 2 -Me-4 -MeOPh 2 -Me-4 -MeOPh 2-Me-4 -MeOPh 2, 4-Me 2 -Ph 2, 4-Me 2 -Ph 2,4-Me 2 -Ph 2, 4-Me2-Ph 2, 4-Me 2 -Ph 2,4-Me 2 -Ph 2,4-Me 2 -Ph 2, 4-Me 2 -Ph 2,4-Me 2 -Ph 2, 4-Me 2 -Ph 2, 4-Me 2 -Ph 2. 4-Me2-Ph 2, 4-Me 2 -Ph 2, 4-Me 2 -Ph 2 -C1-4 -MeOPh 2-C1-4-MeOPh 2-Cl-4-MeOPh 2-C1-4-MeOPh 2 -C1-4-MeOPh 2-C1-4-MeOPh 2-C1-4-MeOPh 2 -C1-4-MeOPh 129 i I /O9/02,documcnfl 3,129 2535 2536 2 53~7 2538 2539 2540 2541 2542 2543 2544 2545 2546 2547 2548 2549 2550 2551 2552 2553 2554 NEtMe NEt Pr NMeBu NMe (CH 2 cPr) NEt (CH 2 cPr) NPr (CH 2 cPr) NMe (CH 2

CH

2 Oke) NEt (CH 2

CH

2 OMe) NPr(CH 2 CH20Me)_ NH-2-butyl cyclobutylamino 2 -ethylpiperidifll NMe (propargyl) NMt(propargyl) NEtMe NEt Pr NMeBu NMe (CH 2 cPr) NEt (CH 2 cPr) NPr (CH2cPr) 2-Cl-4-Me0Ph 2-Cl -4 -MeOPh 2-C1-4 -MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-C1-4-MeOPh 2,5'-Me 2 -4-MeOPh 2, 5-Me 2 -4-MeOPh 2, S-Me 2 -4-MeOPh 2, 5-Me 2 -4-MeOPh 2, 5-Me 2 -4-MeOPh 2, 5-Me 2 -4-MeOPh 2, 5-Me 2 -4-MeoPh 2, 5-Me 2 -4-MeOPh 2, 5-Me2 -4 -MeOPh 2, 5-Me 2 -4-MeOPh 2, 5-Me2-4 -MeOPh 2,5-Me 2 -4-MeOPh 2, S-Me2-4 -MeOPh 2, 5-Me 2 -4-MeOPh a) CI -HRMS: b) CI -HRMS: calcd: 367.2498; Found: Calcd: 387.1952; Found: 367.2468 387.1939 (M Hi) (M H) utility CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity The following is a description of the isolation of cell membranes containing cloned human CRF-Rl receptors for use in the standard binding assay 130 11 /09102,docinentl 3,130 as well as a description of the assay itself.

Messenger RNA was isolated from human hippocampus.

The mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from start to stop codons The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from whence the insert was reclaimed using XhoI XbaI and cloned into the XhoI XbaI sites of vector pm3ar (.which contains a CMV promoter, the SV40 splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker). The resulting expression vector, called phchCRFR was transfected in 293EBNA cells and cells retaining the episome were selected in the presence of 400 LM hygromycin. Cells surviving 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for the binding assay described below. Individual aliquots containing approximately 1 x 108 of the suspended cells were then centrifuged to form a pellet and frozen.

For the binding assay a frozen pellet described above containing 293EBNA cells transfected with hCRFR1 receptors is homogenized in 10 ml of ice cold tissue buffer 50 mM HEPES buffer pH 7.0, containing 10 mM MgC12, 2 mM EGTA, 1 gg/l aprotinin, 1 gg/ml leupeptin and 1 gg/ml pepstatin). The homogenate is centrifuged at 40,000 x g for 12 min and the resulting pellet rehomogenized in 10 ml of tissue buffer. After another centrifugation at 40,000 x g for 12 min, the pellet is resuspended to a protein concentration of 360 4g/ml to be used in the assay.

Binding assays are performed in 96 well plates; each well having a 300 pl capacity. To each well is added 50 pl of test drug dilutions (final concentration -131- 11 /09/02,documentl 3,131 of drugs range from 10- 1 0 10- 5 100 1 l of 125Iovine-CRF (125I-o-CRF) (final concentration 150 pM) and 150 pl of the cell homogenate described above. Plates are then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (presoaked with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed 2 times with ice cold assay buffer before removing individual filters and assessing them for radioactivity on a gamma counter.

Curves of the inhibition of 125I-o-CRF binding to cell membranes at various dilutions of test drug are analyzed by the iterative curve fitting program

LIGAND

Munson and D. Rodbard, Anal. Biochem. 107:220 (1980), which provides Ki values for inhibition which are then used to assess biological activity.

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

Inhibition of CRF-Stimulated Adenylate Cyclase Activity Inhibition of CRF-stimulated adenylate cyclase activity can be performed as described by G.

Battaglia et al. Synapse 1:572 (1987). Briefly, assays are carried out at 370 C for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 370 10 mM MgC12, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10-9 to 6m) and 0.8 mg original wet weight tissue -132- 11 /09/02.documentl 3,132 (approximately 40-60 mg protein). Reactions are initiated by the addition of 1 mM ATP/ 32

P]ATP

(approximately 2-4 mCi/tube) and terminated by the addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 Al of 3 H]cAMP (approximately 40:000 dpm) is added to each tube prior to separation. The separation of 32 P]cAMP from 3 2 p]ATP is performed by sequential elution over Dowex and alumina columns.

In vivo Biological Assay The in vivo activity of the compounds of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C.W.

Berridge and A.J. Dunn Brain Research Reviews 15:71 (1990).

Compounds may be tested in any species of rodent or -small mammal.

Compounds of this invention have utility in the treatment of inbalances associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders, and/or anxiety.

Compounds of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent's site of action in the body of a mammal. The compounds can be -133- 11/09/02,documentl 3,133 administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of said diseases or conditions, the compounds of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight.

Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.

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

The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention -134- 11 /09102,docmentl 3,134 can also be administered parenterally in sterile liquid dose formulations.

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

Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time.

Compressed tablets can be sugar-coated or filmcoated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.

Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions.

Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described -135- 11/09/02,docunentl 3,135 in "Remington's Pharmaceutical Sciences", A. Osol, a standard reference in the field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: Capsules A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules were washed and dried.

Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption.

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

-136- 11/09/02,documentl 3,136 Although the present invention has been described and exemplified in terms of certain preferred embodiments, other embodiments will be apparent to those skilled in the art. The invention is, therefore, not limited to the particular embodiments described and exemplified, but is capable of modification or variation without departing from the spirit of the invention, the full scope of which is delineated by the appended claims.

Where the terms "comprise", comprises", comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof This is a divisional of Australian Patent Application No. 748818 the disclosure of which is incorporated herein by way of reference.

137- 11/09/02,sw1291 Sspa, 37

Claims

1. A compound of Formula FORMULA and isomers thereof, stereoisomeric forms thereof or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof selected from the group: a compound of Formula wherein R is Cl, R 3 is NHCH(n-Pr) 2 R 4 a isIMe,R 4 1 is H, R 4 'c iMe 4d is Hand R' is H; a compound of Formula wherein R is Cl, R 3 i S NH-CH(CH 2 OMe) 2 R~ is Me, R' is H, R 4 cis Me, Rd is Hand R 4 is H; a compound of Formula wherein R is Cl, R 3 is N(CH 2 CH 2 OMe) 2 Ra is Me, R is H,R 4cis Me, Rd is H and R 4 is H, a compound of Formula wherein R is Cl, R 3 is N(c-Pr)(CH 2 CH 2 CN), R'ais Me, R 4bisH,R 4cis Me, Rd is Hand R 4,isH;

138- 138-11 /09/02,swl 291 Sspa.I 38 a compound of Formula wherein R is Cl, R 3 is N(CH 2 CH 2 OMe) 2 R 4 a iSCl,RW is H, R 4,isMe, R 4dis Hand R 4 'is H; a compound of Formula wherein R is Cl, R3 is NHICH(CH 2 OMe) 2 RWa isCl, R 4 b is H, WeC is Me, RWd is HandR 4 is H; a compound of Formula wherein R is Cl, R 3 is NIICH(Et) 2 RWais Cl,RWb is H, We is Me, R 4 d is Hand R 4 eisH; a compound of Formula wherein R is Cl, R 3 is N(Et) 2 R aisIMe,R~ is H, RC is Me, R, is H and is H; a compound of Formula wherein R is Cl, R3 is -N(n-Pr)(CH 2 CH 2 CN), R 4 ais Me,RWb is H, Wecis Me, R 4dis H adR4,esH a compound of Formula wherein R is Cl, R3 is -N(n-Bu)(CH 2 CH 2 CN), R 4 ais Me,RWb is H, We is Me, R 4 d is HandWe is H; a compound of Formula wherein R is CI, R 3 is NHCH(n-Pr)(CH 2 OMe), R 4 ais Me,RWb isH, R 4 c is Me, RWd is Hand R 4 ,is H; a compound of Formula wherein R is CI, R3 is NHCH(Et) 2 *R 4 a is Me, Rlb is H R 4 cis OMe, RWd is H and R 4 e is H; a compound of Formula wherein R is Cl, R3 is NHJCH(CH 2 OMe) 2 W'a is Me, R 41is H, R 4 c is OMe, R Qis H and W~e is H; -139- 139 -11 /09/02.,sw 1291 5spa.1 39 a compound of Formula (70) wherein R is Cl, R' is NHCH(CH 2 CH 2 OMe)(CH 2 OMe), R isMe, RWb is H, Rc is Me, Ris H and Re is H; a compound of Formula wherein R is Cl, R 3 i- NHCH(CH 2 CH 2 OMe)(CH 2 OMe), R 4ais Me, R 4bis H, Rc is Me, Rd is H and W~eis H; 00 C*3 a compound of Formula wherein R is Cl, R3 is N(CH 2 CH 2 OMe) 2 Ra is Me, R 4bis H, Rc is Cl, R 4 d is H and RWeis H; a compound of Formula wherein R is Cl, R 3 is NH(Et) a is MeRWb is H R 4 c is Me, Rd is sHand R 4 eis H; a compound of Formula wherein R is Cl, R 3 is NHCH(n-Pr) 2 RWa is Me, RWb is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula wherein R is Cl, R3 is NHCH(CH 2 OMe) 2 R 4 a is Me, RWb is H, R 4 c is Cl, RWd is H and W~e is H; a compound of Formula wherein R is Cl, R 3 is NHCH(CH 2 CH 2 OMe)(CH 2 OMe), R 4 a is Me, RWb is H, Rc is Cl RWd is H and R 4 e is H; a compound of Formula wherein R is Cl, R3 is NHCH(CH 2 CH 2 OMe)(CH 2 OMe), R 4 a is Me, R:b is H, RWe is Cl, RWd is HandRWe is H; a compound of Formula wherein R is Cl, R3 is N(n-Pr)(CH 2 CH 2 CN), RWa is Me, 4b isH 4c is OMe, 4d nd4WeisH a compound of Formula wherein R is Cl, R 3is N(Et) 2 RWa is Me, RWb is H, Rc is OMe, RWd is H and R 4 e is H; 19/05/05,atI291 S.specipgs,140 -140- a compound of Formula wherein R is Cl, R 3 is NHNH(CH 2 CH 2 OMe)(CH 2 OMe), R 4 a is Cl, R 4 is H, R 4 c is Me, Rld is H and R 4 is H; a compound of Formula wherein R is Cl, R 3 is NHNH(CH 2 CH 2 OMe)(CH 2 OMe), R~a is Cl, R 4 is H, R 4 c is Me, R 4 d is H and R 4 is H; a compound of Formula wherein R is Cl, R 3 is N(Et) 2 Ra is Cl, R b is H, Rc is Me, Rl is H and R 4 is H; a compound of Formula wherein R is Cl, R 3 is-N(c-Pr) (CH 2 CH 2 CN), R 4 a is Me, W'b is H, Rc is OMe, Rd is H and R 4 e is H; a compound of Formula wherein R is Cl, R 3 is -N(c- Pr)(CH 2 CH 2 CN), Rja is Cl, R 4 is H, R 4 c is Me, Rld is H and R 4 is H; a compound of Formula wherein R is Cl, R 3 is -NHCH (n-Pr)(CH 2 OMe), Ra is Me, R' is H, Rc is OMe, R 4dis H and R 4 e is H; a compound of Formula wherein R is Cl, R 3 is -NHCH (n-Pr)(CH 2 O0e), R 4 a is Cl, R 4 is H, R 4 c is Me, R 4 dis Hand R 4 e is H; a compound of Formula wherein R is Cl, R 3 is NHCH(Et) 2 R 4 a is Br, R~b is H, Ric is OMe, RWd is OMe and is H; a compound of Formula wherein R is Cl, R 3 is 19/05/05,at 12915 5specipgs, 141 141 N(CH2CH 2 OMe) 2 R 4 a is Br, R 4 b is H, R 4 c i s OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is NHCH(CH 2 OMe) 2 R 4 a is Br, R 4 b is H, R 4 c is OMe, R 4 dis Hand R4e is H; a compound of Formula (70) wherein R i s Cl, R 3 is- N(Et) 2 R 4 a is Me, R 4 b is H, R 4 c is Cl R 4 d is H- and R 4 e isH; a compound of Formula (70) wherein R is Cl, R 3 is- N(Et) 2 R 4 a is Cl, R 4 b is H, R 4 c is OMe, R 4 d is OMe and Re is H; a compound of Formula (70) wherein R is Cl, R 3 is- NHCH(Et) 2 R 4 a is Cl, R 4 b is H, R 4 c is OMe, R 4 d is OMe and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- N(CH2CH 2 OMe) 2 R 4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- NHCH(CH 2 OMe), 2 R 4 a is Cl, R 4 b is'H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- M(Pr) (CH2CH 2 CN), R 4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is N (Bu) (Et) R 4 a, is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- NHCH(Et)CH2OMe, R 4 a is Cl, R 4 b is H, R 4 c is Cl, R4d is Hand R 4 eisH a compound of Formula (70) wherein R is Cl, R 3 is- NHCH(Et)2,, R 4 a is C1, Rbis H, R 4 c is C1, R 4 d is -142- 142 I1I /(:9I(:2docunmit2 142 H and R 4 e is H; a compound of Formula (70) NHCH(Et) 2 R 4 a is Me, H and R 4 e is H; a compound of Formula (70) NHCH(Et) 2 R 4 a is Cl, H and R 4 e is H; a compound of Formula (70) NHCH(Et) 2 R 4 a is Me, H and R 4 e is H; wherein R is Cl, R 3 is R 4 b is H, R 4 c is Me, R 4 d is wherein R is Cl, R 3 is R 4 b is H, R 4 c.i. Me, R 4 d is wherein R is Cl, R 3 is R 4 b is H, R 4 c is Cl, R 4 d is a compound of Formula (70) wherein R is Cl,.R 3 is.- NEt 2 R 4 a is Me, R 4 b and R 4 e is H; and is H, R 4 c is OMe, R 4 d is. H a compound of Formula (70) wherein R is Cl, R 3 is N (Pr) (CH2 CH 2 CN) R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- NHCH(n-Pr) 2 R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- NHCH(CH 2 OMe) 2 R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- N(CH2CH 2 OMe) 2 R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is -N(c- Pr) (CH2CH2CN), R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- N(CH2CH 2 OMe) 2 R 4 a is Cl, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H;

143- 143 I I i0902documiei2, 143 ltr a compound of Formula wherein R is Me, R 3 is 0 NHCH(CH 2 0Me) 2 R 4a is Cl, R 4b is H, R 4c is Me, R 4d is H and R 4e is H; a compound of Formula wherein R is Me, R is NHCH(Et) 2 R 4 a is Cl, R 4 b is H, R 4 c is Me, R 4 d is H and R 4e is H; (N a compound of Formula wherein R is Me, R is 0 O N(Et) 2 R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R 4e is H; a compound of Formula wherein R is Me, R 3 is -N(n-Pr) S(CH 2 CH 2 CN), R 4a is Me, R 4 b is H, R 4c is Me, R 4 d is H and R 4 e is H; a compound of Formula wherein R is Me, R 3 is -N(n-Bu) (CH 2 CH 2 CN), R 4 a is Me, R 4 b is H, R 4 C is Me, R 4 d is H and R 4 e is H; a compound of Formula wherein R is Me, R 3 is R 4a is Me, R 4b is H, R 4 c is Me, R 4d is H and R 4e is H; a compound of Formula wherein R is Me, R 3 is NHCH(Et) 2 R 4a is Me, R 4 b is H, R 4 C is OMe, R 4 d is H and R 4 e is H; a compound of Formula wherein R is Me, R 3 is 2 R 4a is Me R 4b is H, R 4 c is OMe, R 4 d is H and R 4e is H; a compound of Formula wherein R is Me, R 3 is NHCH(CH 2 CH 2 0Me)(CH 2 0Me), R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula wherein R is Me, R 3 is NHCH(CH 2 CH 2 0Me)(CH 2 0Me), R 4 a is Me, R 4b is H, R 4c is Me, R 4 d is H and R 4 e is H; a compound of Formula wherein R is Me, R 3 is N(CH 2 CH 2 OMe) 2 R 4a is Me, R 4 b is H, R 4c is Cl, R 4 d is H and R 4e is H; 19/05/05,at12915.specipgs,144 -144- a compound of formula (70) wherein R is Me, R 3is C] ~~4a 4b 4 d4 NH(Et),R isMe,R isH,RcisMe,R isHandR 'isH; a compound of Formula (70) wherein R is Me, R3 is NHCH(n-Pr) 2 R 4ais Me, R 41is H, R 4 c is Cl, R 4dis H and R 4 e is H; 00 a compound of Formula (70) wherein R is Me, R3 is 4a 4 NHCH(CH 2 OMe) 2 R 4ais Me, R' is H, R 4 c is Cl, R 4 d is H and R 4 is H; a compound of Formula (70) wherein R is Me, R 3 is (S5) NHCH(CH 2 CH 2 OMe)(CH 2 OMe), R 4 a is Me, R' is H, R 4 c is Cl1, Rd is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3is NHCH(CH 2 CH 2 OMe)(CH 2 OMe), R 4 a is Me, ROb is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R3 is N(n-Pr)(CH 2 CH 2 CN), Ra is Me, R 4 is H, R 4 c is OMe, R 4dis H and W~e is H; a compound of Formula (70) wherein R is Me, R3 is N(Et) 2 ,Ra is Me, R is H, R is OMe, R is HandR 4eis H; a compound of Formula (70) wherein R is Me, R 3 is NHCH(CH 2 CH 2 OMe)(CH 2 OMe), Rja is ClI, RWb is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R3 is NHCH(CH 2 CH 2 OMe)(CH 2 OMe), R 4 a is ClI, ROb is H, R 4 c is Me, R 4 d is H and R 4 is H; a compound of Formula (70) wherein R is Me, R3 is N(Et) 2 Ra is C1,RWbis H, R is Me,Rd is H I 9105/05,at 12915 5specipgs. 145 145 and R 4e is H; a compound of Formula (70) wherein R is Me, R 3 is -N(c- Pr).(CH2CH2CN), R 4 a is Me, R 4 b is H, R 4c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is -N(c- Pr)(CH2CH2CN), R 4 a is C1, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is -NHCH R 4 a is Me, R 4 b is H, R 4C is OMe, R 4d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is -NHCH (n-Pr)(CH 2 OMe), R 4 a is Cl, R 4 b is H, R 4 c is Me, R 4d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NHCH(Et)2, R 4a is Br, R 4 b is H, R 4 c is OMe, R 4 d is OMe and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NHCH(Et)2, R 4 a is Br, R 4 b is H, R 4 c is OMe, R 4d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is N(CH2CH2OMe)2, R 4 a is Br, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NHCH(CH20Me)2, R 4 a is Br, R 4 b is H, R 4 c is OMe, R 4d is H and R 4e is H; a compound of Formula (70) wherein R is Me, R 3 is N(Et)2, R 4 a is Me, R 4 b is H, R 4 c is Cl, R 4d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is N(Et)2, R 4 a is Cl, R 4b is H, R 4 c is OMe, R 4 d is OMe and R 4e is H;

146- I/0l9/02,docunment2,146 a compound of Formula (70) wherein R is Me, R 3 is NHCH(Et)2, R 4 a is Cl, R 4 b is H, R 4 c is OMe, R 4d is OMe and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is N(CH2CH2OMe)2, R 4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is 0 NHCH(CH2OMe) 2 R 4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is N(Pr)(CH2CH2CN), R 4a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is N(Bu)(Et), R 4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; i0 a compound of Formula (70) wherein R is Me, R 3 is NHCH(Et)CH 2 0Me, R 4 a is Cl, R 4 b is H, R 4 c is Cl, R 4d is H and R 4e is H; a compound of Formula (70) NHCH(Et) 2 R 4 a is Cl, H and R 4 e is H; a compound of Formula (70) NHCH(Et)2, R 4 a is Me, H and R 4 e is H; a compound of Formula (70) NHCH(Et)2, R 4 a is Cl, H and R 4 e is H; a compound of Formula (70) NHCH(Et)2, R 4 a is Me, H and R 4 e is H; wherein R is Me, R 3 is R 4 b is H, R 4 c is C1, R 4 is wherein R is Me, R 3 is R 4 b is H, R 4 c is Me, R 4 d is wherein R is Me, R 3 is R 4 b is H, R 4 c is Me, R 4 d is wherein R is Me, R 3 is R 4 b is H, R 4 c is Cl, R 4 is a compound of Formula (70) wherein R is Me, R 3 is

147- 1 /1.9/0l12document2,147 NEt 2 R 4 a is Me, R 4 b is H, R 4 c is' OMe, R 4 d is H and R 4e is H; and a compound of Formula (70) wherein R is Me, R 3 is- N(Pr) (CH2CH2CN), R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 dis Hand R 4 is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(n-Pr)2, R 4 a is Me, R 4 b is HR 4 c is Me, R 4 d is H and Reis H; a compound of Formula (70) wherein R is F, R 3 is NH{CH(CH2OMe)2, R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wh erein R is F, R 3 is- NCCH2CH2OMe)2, R 4 a is Me, R is H, R 4 Ci e is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is -Nic- Pr) (CH2CH2CN), R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- N(CH2CH2OMe)2, R 4 a is Cl, R 4 b is H, R 4 c is Me, R4d is H and R 4 e is H; a compound of Formula (70) wherein R is F,-R 3 is- NHCH(CH2OMe)2, R 4 a is Cl, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(Et)2, R 4 a is Cl, R 4 b is H, R 4 C is Me, R 4 d is H and R 4 e is H; a compound'of Formula (70) wherein R is F, R 3 is- NCEt)2, R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is -N(fl- P)(CH 2 CH2CN) Rais Me, Rbis H, R 4 c is Me, -4d -148- 148 ~I 09/(P-2docutimenl 148I nis H and R 4 'is H; a compound of Formula (70) wherein R is F, R 3is- N(n-Bu)(CH 2 CH 2 CN), R 4 a is Me, R 4 is H, R 4 C is Me, RWd is H and R 4 is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(n-Pr)(CH 2 OMe), R 4ais Me, R 4 b is H, R 4cis Me, R 4 d is H and R 4 is H; 00 a compound of Formula (70) wherein R is F, R3 is NHCH(Et) 2 R 4 is Me, R 4 is H, We is OMe, R 4 d is H and WeC is H; a compound of Formula (70) wherein R is F, R 3is- NHCH(CH 2 OMe) 2 R 4 a is Me, RWb is H, R 4 C is OMe, RWd is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(CH 2 CH 2 OMe)(CH 2 OMe), R 4 a is Me, R 4bis H, WeC is Me, Rd is H and RWe is H; a compound of Formnula (70) wherein R is F, R3 is NHCH(CH 2 CH 2 OMe)(CH 2 OMe), R 4 a is Me, ROb is H, We is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3is- N(CH 2 CH 2 OMe) 2 RWa is Me, R 4bis H, Re is Cl, R 4dis H and R 4eis H; a compound of Formula (70) wherein R is F, R3 is NH(Et),Ra is Me, R is H,RW isMe,Rd is Hand R' is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(n-Pr) 2 R 4 a is Me, ROb is H, WeC is Cl, R 4 d is H and W~e is H; a compound of Formula (70) wherein R is F, R3 is NHCH(CH 2 0Me) 2 RWais Me, R 4 b is H, WeC is Cl R 4 d is H and R 4 e is H; 19/05/05,at1291 5.specipgs.149 149 a compound of Formula (70) wherein R is F, R 3 is NHCH(CH 2 CH 2 OMe)(CH 2 OMe), R~ai Me, R 4 is H, RWe is Cl1, Rdis H and R 4 is H; a compound of Formula (70) wherein R is F, R 3 is- NHCH(CH 2 CH 2 OMe)(CH 2 OMe), R 4 a is Me, Rb is H, RWe is Cl R 4 d is H and R 4 is H; a compound of Formula (70) wherein R is F, R3 is 00 N~-Pr)CH2CHCNR 4 a is Me, R 4 b is H, WeC is OMe, R 4 d is H and R 4 is H; a compound of Formula (70) wherein R is F, R 3is- N(Et) 2 R 4 a is Me, R 4 is H, We is OMe, R 4 d is H and R 4 is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(CH 2 CH 2 OMe)(CH 2 OMe), R 4 a is ClI, ROb is H, WeC is Me, R 4 d is H and R 4 is H; a compound of Formula (70) wherein R is F, R 3is- NHCH(CH 2 CH 2 OMe)(CH 2 OMe), Rja is ClI, Rb is H, We is Me, Rd is H and R' is H; a compound of Formula (70) wherein R is F, R 3is N(Et) 2 ,RW is Cl,RW is H,RW is Me, R 4dis Hand R 4 'is H; a compound of Formula (70) wherein R is F, R3 is N(c-Pr)(CH 2 CH 2 CN), R 4 a is Me, R 4 b is H, We is OMe, R 4 d is H and W~e is H; a compound of Formula (70) wherein R is F, R 3 is N(c-Pr)(CH 2 CH 2 CN), R 4 a is CR, b isH, WeC is Me, RWd is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(n-Pr)(CH 2 OMe), Rja is Me, RWb is H, RWe is OMe, led is H and R 4 is H; a compound of Formula (70) wherein R is F, R 3 is-NHCH 1 9/05/05,at1 2915.specipgs,1

150- (n-Pr)(CH 2 OMe), R 4 a is Cl, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(Et) 2 R 4 a is Br, R 4 b is H, R 4 c is OMe, R 4 d is OMe and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(Et) 2 R 4 a is Br, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is N(CH2CH20Me)2, R 4 a is Br, R 4b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(CH 2 0Me) 2 R 4 a is Br, R 4 b is H, R 4 c is OMe, R 4d is H and R 4e is H; a compound of Formula (70) wherein R is F, R 3 is N(Et) 2 R 4 a is Me, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4e is H; a compound of Formula (70) wherein R is F, R 3 is N(Et) 2 R 4 a is Cl, R 4 b is H, R 4 c is OMe, R 4 d is OMe and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(Et) 2 R 4 a is Cl, R 4 b is H, R 4 c is OMe, R 4 d is OMe and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is N(CH2CH20Me)2, R 4 a is Cl, R 4 b is H, R 4 c is C1, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is NHCH(CH 2 OMe) 2 R 4 a is Cl, R 4 b is H, R 4 c is C1, R 4d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is N(Pr)(CH2CH 2 CN), R 4 a is Cl, R 4 b is H, R 4 c is Cl; 151 1/0 9/12.documenl2.151 R 4 d is Hand R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is M(Bu) (Et) R 4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4 eisH a compound of Formula (70) wherein R is F, R 3 is- NHCH (Et) CH2OMe, R 4 a is -Cl, R 4 b is. HI R 4 c is Cl, R 4 d is Hand R 4 e is H; a compound of Formula (70) NHCH (Et) 2 R 4 a is Cl, H'and R 4 e is H; a compound of Formula (70) NHCH(Et)2, R 4 a is Me, H and R 4 eisH a compound of Formula (70) NHCH(Et)2, R 4 a is Cl, H and R 4 e is H; a compound of Formula (70) NHCH(Et)2, R 4 a is Me, H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is R 4 b is H, R 4 c is Cl, R 4 d is wherein R is F, R 3 is- R 4 b is H, R 4 c is Me, R 4 d is wherein R is F, R 3 is- R 4 b is H, R 4 c is Me, R 4 d is wherein R is F, R 3 is- R 4 b is H, R 4 c is Cl, R 4 d is wherein R is F, R 3 is -NEt2, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; and a compound of Formula (70) wherein R is F, R 3 -is N(Pr) (CH2CH2CN), R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Hand R 4 e is H; a compound of Formula (70) wherein R is Cl, N(Pr) (CH 2 CH2OMe), R 4 a is Me, R 4 b is H, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, N(Et) (CH2CH2OMe), 4 a is Me R 4 b is H, R 4 d is Hand R 4 e isH; R 3 is R 4 c is OMe, R 3 is R 4 c is OMe, -152- 152 I11/091:2docunient2,1 52 a compound of Formula (70) wherein R is Cl, R 3 is N(Me) (CH2CH2OMe), R 4 a is Me, R 4 b is H, Ric is OMe, Rid is H and R 4 e is H; a compound of Formula (70) wherein R is CI, R 3 is- N~eEt 'R 4 a is Me, Rib is H R 4c is OMe, R 4 d is H and R 4eisH a compound of Formula (70) wherein R is Cl, R 3 is- N~ePr, R 4 a is Me, Rib is H, R 4 c is OMe, Rid is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- NMeBu, R 4 a is Me, R 4 b is H, R 4 c is OMe, Rid is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is -NH- 2-butyl, R 4 a is Me, Ri is H, Ric is OMe, Rid is H and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is cyclobutylamino, R 4 a is Me, R 4 b is H, Ric is OMe, Rid is Hand R 4 e is H; a compound of Formula (70) wherein R is Cl, N(Pr) (CH2CH2OMe), R 4 a is Me, Rib is H, Rid is Me and R 4 e is H; a compound of Formula (70) wherein R is Cl, N(Et) (CH2CH2OMe), R 4 a is Me, R 4 ,b is H, Rid is Me and R 4 e is H; a compound of Formula (70) wherein R is Cl, N(Me) (CH2CH2OMe), R 4 a is Me, Rib is H, Rid is Me and R 4 e is H; R 3 is R 4 c is OMe, R 3 is R 4 c is OMe, R 3 is Ric is OMe, a compound of Formula (70) wherein R is Cl, R 3 is N~eEt, R 4 a is Me, Rib is H, Ric is OMe, Rid is Me and R 4 e is H;I -153 I5 09/02,docujnentr. 153 a compound of Formula (70) wherein R is Cl, R 3 is N~ePr, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is- NMeBu, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is -NH- 2-butyl, R 4 a.is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is Cl, R 3 is cyclobutylamino, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is ME and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- N(Pr) (CH2CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is N(Et) (CH2CH 2 OMe), R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R'is F, R 3 is- N(Me) (CH2CH2OMe) R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- NMeEt, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- NMePr, R 4 a is Mye, R 4 b is H, R 4 c is OMe, R 4 d is H and R~e is H; a compound of Formula (70) wherein R is F, R 3 is- NMeBu, R 4 a is Me, R 4 b is H, R 4 c is O~e, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is -NI{-2-

154- I1I /o(J91,CIocumnft2,l 54 butyl, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4dis H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is cyclobutylamino, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is N(Pr) (CH2CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me arnd R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- N (Et) (CH2CH2OMe) R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is me and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- N(Me) (CH2CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- NMeEt, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is- N~ePr, R 4 a is Me, R 4 b is H, R 4 c j 5 OMe, R 4 d is Me and R 4 e isH; a compound of Formula (70) wherein R is F, R 3 is- N~eBu, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is F, R 3 is -NII-2- butyl, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is F, k 3 is cyclobutylamino, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is -155 1I 09102,docuient 1 N(Pr) (CH2CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- N(Et)(CH2CH2OMe), R 4 a. is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is- N(Me)(CH2CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R NMeEt, R 4 a is me, R 4 b is H, R 4 c and R 4 e is H; a compound of Formula (70) wherein R NMePr, R 4 a is Me, R 4 b is H, R 4 c and R 4 e is H; a compound of Formula (70) wherein R NMeBu. R 4 a is Me, R 4 b is H, R 4 Ic and R 4 e is H; is Me, R 3 is is OMe, R 4 d is H is Me, R 3 is is Oe, 4d i is Me, R is H is OMe, R 4 d is H a compound of Formula (70) wherein R is Me, R 3 is -NH- 2-butyl, Rja is Me, R Ibis H, ROc is OMe, R 4 d is H and R 4 e isH a compound of Formula (70) wherein R is Me, R 3 is cyclobutylamino, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (70) wherein R is Me, N(Pr) (CH2CH2OMe), R 4 a is Me, R 4 b is H, R 4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is Me, N(Et) (CH2CH2OMe), R 4 a is Me, R 4 b is H, Rd is Me and Re is H; a compound of Formula (70) wherein R is Me, R 3 is- R 4 c is OMe, R. 3 is- R 4 c is OMe, R3 is

156- 156-I11 /09/02,document2,1 56 N(Me)(CH 2 CH 2 OMe), R~a is Me, R"b is H, R 4 Cis OMe, R 4d is Me and W'e is H; a compound of Formula (70) wherein R is Me, R 3 is- NMeEt,RWa is Me, Rib is H, R 4 is OMe, Rd is Me and W'e is H; a compound of Formula (70) wherein R is Me, R 3 is NMePr, R 4 a is Me, ROb is H, R 4 C is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (70) wherein R is Me, R 3 is NMeBu, R~ais Me, Rbis H, R 4 c i OMe, R 4 d iMeadR is H; a compound of Formula (70) wherein R is Me, R 3 is NH-2-butyl, R 4 a is Me, R 4 b is H, R 4 c is OMe, R 4 d is Me and R 4 e is H; and a compound of Formula (70) wherein R is Me, R 3 is cyclobutylamino, R~is Me,R~is H, R~is OMe, Rd is Me and R 4 e is H. 19/05/O5,at I291 5specipgs, 144 156a 2. A compound and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein said compound is selected from: 7-(diethylamino)-2, 5-dimethyl-3-(2-methyl-4- and 7-(N-(3-cyanopropyl)-N-propylamino)-2, 5-dimethyl-3-(2,4-dimethylphenyl)-[1,5-a]-pyrazolopyrimidine. 3. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 or claim 2. 4. A method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 or claim 2 or a pharmaceutical composition of claim 3. Use of a compound of claim 1 or claim 2 in the preparation of a medicament to treat affective disorder, anxiety depression, headache, irritable bowel syndrome, post- traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals. 6. A compound of claim 1 or claim 2, substantially as herein described with reference to any one of the Examples.

157- 11/09/02,swl2915spa,157 7. A pharmaceutical composition of claim 3, substantially as herein described with reference to any one of the Examples. 8. A method of claims 4, substantially as herein described with reference to any one of the Examples. 9. Use of claim 5, substantially as herein described with reference to any one of the Examples. Dated this 11 t day of September, 2002 DUPONT PHARMACEUTICALS COMPANY By their Patent Attorneys: CALLINAN LAWRIE /It Vn fV1.,

158- ll/09/02,swl2915spa,158