AU773039B2

AU773039B2 - Azolo triazines and pyrimidines

Info

Publication number: AU773039B2
Application number: AU23236/02A
Authority: AU
Inventors: A.G. Arvanitis; R.J. Chorvat
Original assignee: DuPont Merck Pharmaceutical Co
Current assignee: Bristol Myers Squibb Pharma Co
Priority date: 1996-07-24
Filing date: 2002-03-12
Publication date: 2004-05-13
Anticipated expiration: 2017-07-23
Also published as: AU2323602A; AU773039C

Description

P/00/011 Regulation 3.2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION o 0 FOR A DIVISIONAL PATENT

ORIGINAL

0 .0 0 Name of Applicant: Actual Inventors: Address for Service: Invention Title: TO BE COMPLETED BY APPLICANT DU PONT PHARMACEUTICALS COMPANY ARVANITIS, CHORVAT, R.J.

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 08/03/02,swl2614cover, 1

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 15 stress, by administration of certain pyrazolo-1,3,5-triazines, [1,5-a]-1,2,3-triazolo- S. 1,3,5-triazines, [1,5-a]-pyrazolo-pyrimidines and [1,5-a]-1,2,3-triazolo-pyrimidines.

20 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 25 pituitary gland Rivier et al., Proc. Nat. Acad.

Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)1. 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

(J.E.

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 15 as they relate to the dysfunction of CRF neurons in S: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 S" 25 (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

(R.M.

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 nonbenzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety 15 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 20 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 25 have all demonstrated interactions between CRF and S. 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 dosedependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K.T.

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 o 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 S95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and 25 Pfizer EP 0778 277 Al.

Insofar as is known, 1,3,5-triazines, [1,5-a]-1,2,3-triazolo-1,3,5triazines, [1,5-a -pyrazolo-pyrimidines and 1, 2 3 -triazolo-pyrimidines, 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 -4-

R

2 ~R3 where RI 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.

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

OH

A R 3

N

(Rim 15 wh r A isC.r N O a d R re H o l y a d R n R2 Nr H, alyakxlaklh ito t. n whezre iss Cf ore NfoadrmulaeHo:lyadR n where Ri is CH 3

C

2 H5 or C 6

H

5 X is H, C6H 5 m-CH 3

C

6

H

4 CN, COOEt, Cl, I or Br, Y is H, C0H 5 o-CH 3

C

6

H

4 or p- CH3C 6

H

4 and Z is OH, H, CH 3

C

2

H

5

C

6

H

5 n-C 3 H7, i-C 3

H

7 SH, SCH 3

NHC

4

H

9 or N(C 2

H

5 2 and states that the compounds are c-AMP phosphodiesterase inhibitors useful as bronchodilators.

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

NR

2

R

3 where RI is H or alkyl, R 2 is H cor 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 (0)n whe-re 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 S. N- Ar 0* R7 where X is O or S, Ar is a phenyl, naphthyl, pyridyl or hienyl group, R-R are H, alkyl, etc., and 9 is II US 5,484,760 and WO 92/10098 discloses here X bicidal compositions conta phenyl, naphthyl, pyridyl orngs, a herbicidal compound of the formula, etc, and R 9 is H i 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

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 -SO2N(R 6

)R

7 and R, and R 2 can be taken together to form I_ I 1__ or

C

where X, YI and Z are H, alkyl, acyl, etc. and D is 0 or **10

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 R1 N where Z is H, OH, CH 3

C

2

H

5 C6H5, fl-C3H 7 iso-C 3

H

7

SH,

SCH3, NH (n-C 4

H

9 or N (C 2

H

5 2 R is H or CH 3 and R 1 is

CH

3 or C 2

H

5 The reference lists eight therapeutic areas where inhibitors of cAMP phosphodiesterase could have utility: asthma, diabetes mnellitus, female fertility control, male infertility, psoriasis, thrombosis, anxiety, and hypertension.

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

S.

where Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond, alkylene or alkenylene, RI is H, alkyl, 10 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

S.

S

where R 1

R

2 R3 and R 4 are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl, or phenyl, R is SR 6 or NR7R 8

R

6 is pyridy. or optionally substituted phenyl, and R7 and R8 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 C. C 4 C. CC

C

*C

CCC...

C

where R can be fbhenyl, s'bstituted 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 C0H where R 1 is CFj. C 2

F

5 or C 6

H

4 F, and R 2 is CH 3

C

2

H

5

CE'

3 or C 6

H

4

F.

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

NO

N

C-

6

HS

Ibrahim et al., Arch. Pharn. (weinheim) 320, 487-491 (1987) discloses pyrazolo(1,5-alpyrimidines of the formula 66 e 6666 06 66 6 6 6 66 66 66 66 6 6 66 6 66 66 6 66 66 *466 4 6666 66 66 66 6 6 66 6 6* 66 6 *66666 6 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 (Nissan, 1990), US 4,621,556 (ICN,1997), EP 0 531 901 (Fujisawa, 1993), US 4,567,263 (BASF, 1986), EP 0 662 477 (Isagro, 1995), DE 4 243 279 (Bayer, 1994), US 5,397,774 (Upjohn, 1995), EP 0 521 622 (Upjohn, 1993), WO 94/109017 (Upjohn, 1994), J. Med. Chem., 24, 610-613 (1981), and J. Het. Chem., 22, 601 (1985).

11 SUMMARY OF THE INVENTION In accordance with one aspect, the present invention 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, Al:heimer's disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, Sthe 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, obsessive-compulsive 20 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 25 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; -12stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.r, 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 15 related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral .sclerosis; chemical dependencies and addictions e 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 heartrelated diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in a mammal.

-13- According to another aspect, the present invention provides novel compounds of Formulae (1) and (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 15 invention, the compounds provided by this invention (and especially labelled compounds of this invention) S" 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 -14- The present invention comprises a compound of Formulae or RI1

N

Ax Ar (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein:.

5 A is Nor CR; Z is N or CR; Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydrQ-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with I to 5 R 4 groups and each Ar is attached to an unsaturated carbon atom; is independently selected at each occurrence from H, CI-C 4 alkyl, C 2

-C

4 alkenyl,

C

2

-C

4 alkynyl, C 3

-C

6 cycloalkyl, C 4

-C

7 cycloalkylalkyl, halo, CN, C 1

-C

4 haloalkyl;- R' is independently selected at each occurrence from H, C ,-C 4 alkyl, C 2

-C

4 alkenyl,

:C

2

-C

4 alkynyl, halo, CN, C,-C 4 haloalkyl, C 1

-C,

2 hydroxyalkyl, C 2

.CI

2 alkoxyalkyl, C 2

-CIO

cyanoalkyl, C 3

-C

6 cycloalkyl, C 4 -CIO cycloalkylalkyl, NR 9 R 1 6

CI-C

4 alkyl-NR 9

R'O~,

NR

9

COR'

6 OR", SH or R 2 is selected from H, C 1

-C

4 alkyl, C 2

-C

4 alkenyl, C 2

-C

4 alkynyl, C 3

-C

6 cycloalkyl,

C

4 -CIO cycloalkylalkyl, C 1

-C

4 hydroxyalkyl, halo, CN, -NR6 R 7

NR

9 COR O, -NR S(O)nNR 6 R 7 C I -C 4 haloalkyl, OR 7 SH or -S (O) 1 R' 12;

P.

3 is selected from:

OR

7 SH, S(O)nRl', COR C0 2

R

7

OC(O)R'

3 NR'COR', N(COR 2

NR'CONR

6 R 7, NR. CO 2

R'

3 NR6 R 7, NRa ~R 7 a N(0R 7 )R 6

CONR

6 R 7 aryl, heteroaryl and heterocyclyl, or -C,-Clo alkyl, C 2

-C,

0 alkenyl, C 2 -CIO alkynyl, C 3

-C

8 cycloalkyl, C 5

-C

8 cycloalkenyl, C 4

-C,

2 cycloalkylalkyl or C 6 -CIO cycloalkenylalkyl, each optionally substituted with I to 3 substituents Independently selected at each occurrence from C,-C 6 08/03/02,swl 261 4spc.I alkyl, C 3

-C

6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, SH, 3

COR'

5 C0 2 R 1 5 OC(O)R 1 3

NR

8 COR1 5 N(COR1 5 2

NR

8 CON-RI R 5, NR8CO 2 R 1,N1 CONRI aryl, heteroaryl and heterocyclyl;- R 4 is independently selected at each occurrence from: CI-Cio alkyl, C 2

-C,

0 alkenyl,

C

2 -Cjo alkynyl, C 3

-C

6 cycloalkyl, C 4

-C,

2 cycloalkylalkyl, NO 2 halo, CN, Cl-C 4 haloalkyl, 6 7 CO 7 I\R 2 7 7 or7 7 NR ROR NRC2 COR OR', CONR R, CO(NOR 9 )R C0 2 R rS(O)nR 7 where each such CI-Cio alkyl, C 2 -Cl 0 alkenyl, C 2 -Ci 0 alkynyl, C 3

-C

6 cycloalkyl and C 4

-C

1 2 cycloalkylalkyl are optionally substituted with I to 3 substituents independently selected at each occurrence from C I-C 4 alkyl, NO 2 halo, CN, NR R, NR'COR NR'CO 2 R COR 7 io OR 7

CONRR

7 C0 2

R

7 CO(NOR)R, or R 6and R 7

R

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

-H,

-CI-C

1 0 alkyl, C 3 -Cio alkenyl, C 3 -Clo alkynyl, C,-Clo haloalkyl with 1-10 halogens,

C

2

-C

8 alkoxyalkyl, C 3

-C

6 cycloalkyl, C 4

-CI

2 cycloalkylalkyl, C 5 -CIO cycloalkenyl, or C 6 1~ 5 C 14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently *.:selected at each occurrence from CI-C 6 alkyl, C 3

-C

6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR15 SH, COR 1 5

CO

2

R'

5

OC(O)R

13

NR

8 COR1 5

N(COR'

5 2 **NR 8

CONR

6 R 5, NR8CO 2 R 3, NR 6 R 1 5 CONRH R 15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(CI-C4 alkyl), heteroaryl, heteroaryl(C,-C4 alkyl), heterocyclyl or 2o heterocyclyl(CI-C8 alkyl), alternatively, NRR7 and NR 6 aR 7 are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 CI-C 4 alkyl groups; R 8 is independently selected at each occurrence from H or C I C8 alkyl,

R

9 and R1 0 are independently selected at each occurrence from H, CI-C 4 alkyl, or

C

3

-C

6 cycloalkyl; R"1 is selected from H, CI-C 4 alk yl, C I-C 4 haloalkyl, or C 3

-C

6 cycloalkyl; R 1 2 is CI-C 4 alkyl or C,-C 4 haloalkyl, R 1 3 is selected from CI-C 4 alkyl, C,-C 4 haloalkyl, C 2

-C

4 alkoxyalkyl, C 3

-C

6 cycloalkyl, C 4

-CI

2 cycloalkylalkyl, aryl, aryl(C,-C8 alkyl)-, heteroaryl or heteroaryi(CI-C4 alkyl)-;, R 1 4 is selected from C,-Clo alkyl, C 3 -Clo alkenyl, C 3 -Clo alkynyl, C 3

-C

8 cycloalkyl, or C 4

-C

1 2 cycloalkylalkyl, each optionally substituted with I to 3 substituents independently selected at each occurrence from C,-C 6 alkyl, C 3

-C

6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, OR" SH, S(O)nR' 5

COR'

5 C0 2

R'

5

OC(O)R'

5 NR'COR", ,N(COR 5

V

2 08103/02,,.wI 261 4 spe~l 6

NR

8 CONR1 6

R",NR

8

CO

2 R1 5 NR1 6 R1 5 CONR1 6 and C,-C 6 alkylthio, CI-C 6 alkylsulfinyl and CI-C 6 alkylsulfonyl, R 15and R 16are independently selected at each occurrence from H, C,-C 6 alkyl, C 3 Clo cycloalkyl, C 4

-CI

6 cycloalkylalkyl, except that for RI canobeH aryl is phenyl or naphthyl, each optionally substituted with I to 5 substituents independently selected at each occurrence from C I-C 6 alkyl, C 3

-C

6 cycloalkyl, halo, C I-C 4 haloalkyl, cyano, OR" 5 SH, COR' 5

COR'

5

OC(O)R'

5

NR'COR'

5

N(COR

5 2

NR

8 CONR 16R, NR'CO 2 R NR1 R" ,and CONR1 R' heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuiranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3 -dihydrobenzothienyl or 2,3dihydrobenzofuranyl, each being optionally substituted with I to 5 substituents independently selected at each occurrence from C I-C 6 alkyl, C 3

-C

6 cycloalkyl, halo, C I-C 4 5 85151 15 1 *.:haloalkyl, cyano, OR' 5 SH, COR' 5 C0 2

R'

5

OC(O)R'

5 NR'COR N(COR 5 2 15 RN .U NRN'02 R f, and CONR 6 heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C I-C 6 alkyl, C 3

-C

6 15 15151 *cycloalkyl, halo, CI-C 4 haloalkyl, cyano, SH, 5, COR' 5 C0 2

R'

5

OC(O)R

1 NR'COR 5, N(COR 2 NRCONR1 NR'CO 2 R" ,NR5 R 6, and CONRI R"I n is independently at each occurrence 0, 1 or 2, with the provisos that: *2 2 37 13 7 when AisN, Zis CR ,R is H, R is -OR or -OCOR ,and R is H, then

*R

1 is not H, OHor SH; when Ais N, ZisCR 2, R1 is CH 3 or C 2 H5, R 2is H, and R 3 is OH, H, CH 3

C

2

H

5

C

6

H

5 ni-C 3 H4 7 i-C 3

H

7 SH, SCHJ 3

NI-C

4

H

9 or N(C 2 H5) 2 then Ar is not phenyl or mn-

CH

3 -phenylwhen A is N, Z is CR 2 R 2 is H, and Ar is pyridyl, pyrimidinyl or pyrazinyl, an 3 is N 6 aR 7 a, thn 6 a an 7 are not H or al kyl; when A is N, Z is CR 2 and R 2 is S0 2

NR

6

R

7 then R 3 Is not OH or SH; when A is CR and Z is CR, then R is not .~S0 2

R

7 or when A is N, Z is CR 2 and R 2 is -NR 6 S0 2 R 7 or -SO 2 NR 6 R 7 then R' is not OH or SHK o8/03/02,swi 261 4spej 7 when A is N, Z is CR 2 R' is methyl or ethyl, R 2 is H, and R' is H, OH, CH 3

C

2 Hs, 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 then Ar is not unsubstituted phenyl or m-methylphenyl; when A is CR, Z is CR2, R2 is H, phenyl or alkyl, R 3 is NR 8

COR

7 and Ar is phenyl or phenyl substituted with phenylthio, then R 7 is not aryl, aryl(C 1

-C

4 alkyl), heteroaryl, heteroaryl(CI-C 4 alkyl), heterocyclyl or heterocycly(Ci-C 4 alkyl); when A is CR, Z is CR 2

R

2 is H or alkyl, Ar is phenyl, and R 3 is SR' 3 or

NR

6 aR 7 a, then R' 3 is not aryl or heteroaryl and R 6 a and R 7 a are not H or aryl; or when A is CH, Z is CR 2 R' is OR", R 2 is H, R 3 is OR 7 and R 7 and R" are to both H, then Ar is not phenyl, p-Br-phenyl, p-Cl-phenyl, p-NHCOCH 3 phenyl, p-CH 3 phenyl, pyridyl or naphthyl; (11) when A is CH, Z is CR 2

R

2 is H, ar is unsubstituted phenyl, and Rl is CH 3

C

2 Hs, CF 3 or C 6

H

4 F, then R' is not CF 3 or C2FS; (12) when A is CR, R is H, Z is CR 2 R is OH, and R' and R are H, then Ar is 15 not phenyl; (13) when A is CR, R is H, Z is CR 2

R

2 is OH or NH 2 R' and R3 are CH 3 then Ar is not 4-phenyl-3-cyano-2-aminopyrid-2-yl.

Preferred compounds of the above invention are compounds of Formulae and and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms 20 thereof, and pharmaceutically acceptable salt or pro-drug forms thereof with the additional provisos that: when A is N, R 1 is H, C,-C 4 alkyl, halo, CN, CI-C 12 hydroxyalkyl, C 1

-C

4 *alkoxyalkyl or S0 2

(C

1

-C

4 alkyl), R 3 is NR 6 aR 7 a and R 6 a is unsubstituted C -C 4 alkyl, then

R

7 a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C 3

-C

6 cycloalkyl; and A is N, R' is H, CI-C 4 alkyl, halo, CN, CI-C 12 hydroxyalkyl, C.I-C 4 alkoxyalkyl or S02 (C 1

-C

4 alkyl), R 3 is NR 6 aR 7 and R 7 a is unsubstituted C 1

-C

4 alkyl, then R 6 a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C 3

-C

6 cycloalkyl.

Preferred compounds of the above invention also include compounds of Formulae and and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with I to 4 R 4 substituents.

08/03/02.swl 2614spe,l 8 Preferred compounds of the above invention also include compounds of Formulae and and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is N, Z is CR 2 Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6trimethylphenyl, R' and R 2 are CH 3 and R 3 is NR 6 aR 7 a.

More preferred compounds of the above invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is N.

The present invention further comprises a pharmaceutical composition comprising o0 a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound described above.

More preferred compounds of Formula of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R 4 20 substituents.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R is NRaR 7a or

OR

7 More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R 4 substituents, and R 3 is NR 6 aR 7 a or OR 7 More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Z is CR 2 The present invention also relates to a method for the treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress 12/03/02,swl2614spe, 9 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 a patient/mammal requiring such treatment, which method comprises administering to said patient/mammal an effective amount of a compound of Formulae or

R

3

R

3

R

A N A N A' NR z 0 R* R N o (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein A is N or CR; Z is N or CR 2 Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro benzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R 4 groups and each Ar is attached to an unsaturated carbon atom; R is independently selected at each occurrence from H, CI-C 4 alkyl, C 2

-C

4 alkenyl,

C

2

-C

4 alkynyl, C 3

-C

6 cycloalkyl, C 4

-C

7 cycloalkylalkyl, halo, CN, CI-C 4 haloalkyl; R' is independently selected at each occurrence from H, CI-C 4 alkyl, C 2

-C

4 alkenyl,

C

2

-C

4 alkynyl, halo, CN, Ci-C 4 haloalkyl, CI-C12 hydroxyalkyl, C 2 -C1 2 alkoxyalkyl, C 2

-CIO

cyanoalkyl, C 3

-C

6 cycloalkyl, C 4 -CIo cycloalkylalkyl, NR 9

R'

0 Ci-C 4 alkyl-NRR 9

NR

9

COR

1 9 OR", SH or S(O)nR2; 12/03/02,swl 2614spe,20 R' is selected from H, CI-C 4 alkyl, C 2

-C

4 alkenyl, C 2

-C

4 alkynyl, C 3

-C

6 cycloalkyl,

C

4

-C

10 cycloalkylalkyl, C,-C 4 hydroxyalkyl, halo, CN, ,NR 6

R

7

NR

9

COR'

0

-NR

6 7

S(O).NR

6

R

7 Ci-C 4 haloalkyl, -OR 7 SH or 2 R 3 is selected from: H, OR 7 SH, 3 COR C0 2 R OC(O)R' 3 NR'COR N(COR 2

NR'CONR

6 R 7

NR'CO

2

R'

3 NR6 R7, NP.~ R 7, N(OR 7)R 6, CONR 6

R

7 aryl, heteroaryl and heterocyclyl or

-C

1 -Clo alkyl, C 2 -Cl 0 alkenyl, C 2 -Clo alkynyl, C 3

-C

8 cycloalkyl, C 5

-C

8 cycloalkenyl, C 4

-CI

2 cycloalkylal kyl or C 6

-C

10 cycl oalkenylalkyl, each optionally substituted with I to 3 substituents independently selected at each occurrence from C,-C 6 alkyl, C 3

-C

6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, OR 15 SH, 3

COR'

5 C0 2

R'

5

OC(O)R'

3

NR

8

COR'

5

N(COR

5 2

NR

8

CONRI

6

NR

8

CO

2

R'

3 NR1 6

R'

CONR'

6 aryl, heteroaryl and heterocyclyl; R 4i is independently selected at each occurrence from: CI-Cio alkyl, C 2 0 alkenyl,

C

2 -Cio alkynyl, C 3

-C

6 cycloalkyl, C 4

-C,

2 cycloalkylalkyl, NO 2 halo, CN, C,-C 4 haloalkyl,

NR

6

NR

8 COR', NR 8

CO

2 R 7 COR 7 OR 7

CON-R

6 R 7 CO(NOR')R 7 C0 2 R 7 or (nR7 where each such C,-Cio alkyl, C 2 -Cio alkenyl, C 2 -Clo alkynyl, C 3

-C

6 cycloalkyl and C 4

-C

1 2 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at *each occurrence from CI-C 4 alkyl, NO 2 halo, CN, NR R, NR"COR NR'CO 2 R COR 7 OR, CONR R, C0 2 R 7

CO(NOR

9 )R or (nR a R6 and R 7 R 6 a and R 7 a are independently selected at each occurrence from: -H, :-C,-Clo alkyl, C 3 -Cio alkenyl, C 3 -Clo alkynyl, CI-C 10 haloalkyl with 1-10 halogens,

C

2

-C

8 alkoxyalkyl, C 3

-C

6 cycloalkyl, C 4

-CI

2 cycloalkylalkyl, C 5 -CIO cycloalkenyl, or C 6

C

14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C,-C 6 alkyl, C 3

-C

6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR' 5 SH, S(O)nR' 3

COR'

5

CO

2

R'

5

OC(O)R

3

NR

8

COR'

5

N(COR'

5 2

NR

8

CONR

6 R 1 5

NR

8

CO

2 R 1 3

NR

6 R 1 5 COR1 6 R 1 5 aryl heteroaryl or heterocyclyl, -aryl, aryl(C 1

-C

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

-C

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

R

8 is independently selected at each occurrence from H or CI-C 4 alkyl, 2 1 I 2/03/02,swl 261 4spe,21

R

9 and RIO are independently selected at each occurrence from H, CI-C 4 alkyl,.or

C

3

-C

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

-C

6 cycloalkyl; R 12is C 1

-C

4 alkyl or C,-C 4 haloalkyl; R 1 3 is selected from C,-C 4 alkyl, CI-C 4 haloalkyl, C 2

-C

8 alkoxyalkyl, C 3

-C

6 cycloalkyl, C 4 -C 1 2 cycloalkylalkyl, aryl, aryl(C 1 -C 4 alkyl)-, heteroaryl or heteroaryl(C I-C 4 alkyl)-; R 1 4 is selected from CI-Cio alkyl, C 3 -C~o alkenyl, C 3 -Ci 0 alkynyl, C 3

-C

8 cycloalkyl, or C 4

-CI

2 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents i0 independently selected at each occurrence from C ,-C 6 alkyl, C 3

-C

6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, OR' 5 SH, COR", CO 2

R'

5

OC(O)R'

5

NR'COR'

5

N(COR

5 2

NR

8

CONR'

6

NR

8 C0 2 R'1 5

NR

6 R'1 5

CONR'

6 and C,-C 6 alkylthio, CI-C 6 alkylsulfinyl and C 1

-C

6 alkylsulfonyl; 16 and R' are independently selected at each occurrence from H, CI-C 6 alkyl, C 3 CIO cycloalkyl, C 4

-CI

6 cycloalkylalkyl, except that for R1 5 cannot be H; :aryl is phenyl or naphthyl, each optionally substituted with I to 5 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3

-C

6 cycloalkyl, halo, C,-C 4 **0haloalkyl, cyano, OR' 5 SH, S(O),,R 1

COR'

5 C0 2

R'

5

OC(O)R'

5

NR

8

COR'

5

N(COR

5 2 NIRCO NRC 2

R"

5 RR and CO R'R heteroaryl is pyridyl, pyrymidinyl, triazinyl, furanyl, pyranyl, quinolinyl, S Sisoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, :benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzathienyl or 2,3- 0000.:dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3

-C

6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, SH, S(O).R' 5

-COR'

5 CMAI', OC(O)R' 5

NR'COR'

5 NRCN1 5 W 5 16 15 1OR6

N(COR'

5 2 NRCN R0,NRC 2

R'

5 NR and CO R R heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with I to 5 substituents independently selected at each occurrence from C 1

-C

6 alkyl, C 3

-C

6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, O15, SH, 5

COR'

5

CO

2

R'

5

OC(O)R'

5

NR

8

COR'

5 N(COR 1 5 2

NR

8

CONR'

6

NR'CO

2

R"

5

NR'

5 R1 6 and CONR' 6

R'

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

The present invention also relates to use of a compound of Formulae or I 2/03/02,swi 261 4spe,22

R

3

R

3

R

Z R0 A N A N RI z R7=O Ar Ar (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, in manufacturing pharmaceutical composition for treatment of affective disorder, anxiety, depression, :headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human 10 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, wherein: A is N or CR; 15 Z is N or CR 2 Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro benzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-l,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R 4 groups and each Ar is attached to an unsaturated carbon atom; R is independently selected at each occurrence from H, Ci-C4 alkyl, C 2

-C

4 alkenyl,

C

2

-C

4 alkynyl, C 3

-C

6 cycloalkyl, C 4

-C

4 alkenyl,

C

2

-C

4 alkynyl, halo, CN, CI-C 4 haloalkyl, Ci-Ci 2 hydroxyalkyl, C 2 -Ci 2 alkoxyalkyl, C 2

-C

1 0 cyanoalkyl, C 3

-C

6 cycloalkyl, C 4 -Cio cycloalkylalkyl, NR 9

R

1 0

CI-C

4 alkyl-NR 9

R

19

NR

9

COR

1 9 OR", SH or S(O)nRI2 08/03/02,swl 2614spe,2 3 R 2 is selected from H, CI-C 4 alkyl, C 2

-C

4 alkenyl, C 2

-C

4 alkynyl, C 3

-C

6 cycloalkyl,

C

4

-CI

0 cycloalkylalkyl, C,-C 4 hydroxyalkyl, halo, CN, ,N6R',NRCOR O, -NR 6

S(O),,R

7 S()RR, CI-C 4 haloalkyl, -OR, SH or R 3 is selected from: H, OR 7 SH, COR 7 C0 2 R OC(O)R' 3

NR'COR

7 N(COR 2

NR'CONRR

7

NR'CO

2

R"

3 NR6 NR 6aR 7a,N(OR)R6, CONR6R 7, aryl, heteroaryl and heterocyclyl or -CI-Clo alkyl, C 2

-C

10 alkenyl, C 2 -Cio alkynyl, C 3

-C

8 cycloalkyl, C5-C 8 cycloalkenyl, C 4

-CI

2 cycloalkylalkyl or C 6 -CIO cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C,-C 6 alkyl, C 3

-C

6 cycloalkyl, halo, C 1

-C

4 haloalkyl, cyano, OR" 5 SH, 3

COR'

5 :C0 2

R

15 OC(O)R 1 3

NR'COR'

5 N(COR NR 8 CONR1 R" ,NR'C 2 R 1, NR1 CONR 16R 15, aryl, heteroaryl and heterocyclyl, 1 R4 is independently selected at each occurrence from: CI-Clo alkyl, C 2 -Cio alkenyl,

C

2 -Cio alkynyl, C 3

-C

6 cycloalkyl, C 4

-C

1 2 cycloalkylalkyl, NO 2 halo, CN, C 1

-C

4 haloalkyl, *.*NfR R, NR'COR NR'CO 2 R COR OR 7

CONR

6

R

7

CO(NOR

9 )R C0 2 R or where each such CI-C 10 alkyl, C 2

-C

10 alkenyl, C 2 -Cio alkynyl, C 3

-C

6 cycloalkyl and C 4

-C,

2 cycloalkylalkyl are optionally substituted with I to 3 substituents independently selected at each occurrence from Cl-C 4 alkyl, NO 2 halo, CN, NR 6

R

7 NR'COR 7

NR'CO

2 R 7

COW

7 OR 7

CONR

6

R

7 C0 2 R 7

CO(INOR

9 )R 7 or SOR7 6 7 6a R and R R6a and Ra are independently selected at each occurrence from: -H, -CI-Clo alkyl, C 3 -Clo alkenyl, C 3 -Clo alkynyl, C,-Cio haloalkyl with 1-10 halogens,

C

2

-C

8 alkoxyalkyl, C 3

-C

6 cycloalkyl, C 4

-CI

2 cycloalkylalkyl, C 5 -C ,o cycloalkenyl, or C 6 C1 4 cycloalkenylalkyl, each optionally substituted with I to 3 substituents independently selected at each occurrence from C 1

-C

6 alkyl, C 3

-C

6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, OR' 5 SH, 3

COR'

5

CO

2

R'

5

OC(O)R'

3

NR'COR

5 N(COR' )2, NRCONR6R 5, NR'CO 2 R 1 3 NR1 R 1, CONRI R 15aryl heteroaryl or heterocyclyl, -aryl, aryl(C i-C 4 alkyl), heteroaryl, heteroaryl(C,-C4 alkyl), heterocyclyl or heterocyclyl(CI-C4 alkyl); alternatively, NR 6 R 7 and NR 6 aR 7 are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 CI-C 4 alkyl groups;

R

8 is independently selected at each occurrence from H or C,-C 4 alkyl;- 08 /3/02 ,swI 2614'spe.

24 R 9 and R 1 0 are independently selected at each occurrence from H, C 1

-C

4 alkyl, or

C

3

-C

6 cycloalkyl; R" is selected from H, C 1

-C

4 alkyl, C 1

-C

4 haloalkyl, or C 3

-C

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

-C

4 haloalkyl, C 2

-C

8 alkoxyalkyl, C 3

-C

6 cycloalkyl, C 4 -C1 2 cycloalkylalkyl, aryl, aryl(CI-C 4 alkyl)-, heteroaryl or heteroaryl(CI-C 4 alkyl)-;- R 1 4 is selected from Ci-Cio alkyl, C 3 -Ci 0 alkenyl, C 3 -Clo alkynyl, C 3

-C

8 cycloalkyl, or C 4 -C1 2 cycloalkylalkyl, each optionally substituted with I to 3 substituents io independently selected at each occurrence from C 1

-C

6 alkyl, C 3

-C

6 cycloalkyl, halo, C 1

-C

4 haloalkyl, cyano, OR" 5 SH, S(O)nR' 5

COR'

5

CO

2

R'

5 OC(O)R NR'COR' 5 N(CO 15)2

:::NR

8 CONR'6 NR cO 2 R 5, NR 6 R'1 5 CONR1 R 15, and CI-C 6 alkylthio, C 1

-C

6 alkylsulfinyl and C,-C 6 alkylsulfonyl; R' and R' are independently selected at each occurrence from H, C 1

-C

6 alkyl, C 3 i CIO cycloalkyl, C 4 -C1 6 cycloalkylalkyl, except that for S(O),,Rl R canntb H; :aryl is phenyl or naphthyl, each optionally substituted with I to 5 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3

-C

6 cycloalkyl, halo, C 1

-C

4 haloalkyl, cyano, OR' 5 SH, S(O)nR' 5

COR'

5 C0 2

R'

5 OC(O)R NR'COR' 5

N(COR

5 2 1\RCONRR, NR8CO 2 R 5, NR6R1, and CONRI6R heteroaryl is pyridyl, pyrymidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofttranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzathienyl or 2,3dihydrobenzofuranyl, each being optionally substituted with I to 5 substituents independently selected at each occurrence from C 1

-C

6 alkyl, C 3

-C

6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR SH, -COR' 5 C0 2

R'

5

OC(O)R'

5

NRM

8

COR'

N(COR'

5 2

NR

8

CONR'

6 R1 5 N8CO 2 R 1, R 1 6 R 1 5 and CONR6 R" heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with I to 5 substituents independently selected at each occurrence from C 1

-C

6 alkyl, C 3

-C

6 cycloalkyl, halo, C 1

-C

4 haloalkyl, cyano, OR' 5 SH, 5

COR'

5 C0 2

R'

5

OC(O)R'

8 15 I RS N 16 15, 15 15 1 O p16 NR'COR ,N(COR")2, NRCN RNR 8

CO

2 R. NR R' 6 and CO RR n is independently at each occurrence 0, 1 or 2.

In a further preferred aspect, in the compound of Formulae or A is N, Z is CR 2 Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2, 4, 6-trimethylphenyl,

R

1 and R 2 are CH 3 and R 3 is NR Rk~ 08/03/02 ,swl 261 4spe,2S More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R 4 substituents.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R 3 is NR6aR 7 a or OR 7 More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of 0* 20 stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein

R

6 a is independently selected from:

-H,

-C1-C10 alkyl, C 3 -C10 alkenyl, C3-C10 alkynyl, 25 CI-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4- C12 cycloalkylalkyl, CS-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from CI-C6 alkyl, C3- C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR 1 5 SH, S(O)nR 1 3

COR

15 C02R 1 5

OC(O)R

1 3

NR

8

COR

1 5

N(COR

1 5

NR

8 CONR16R 1 5

NR

8 C02R 1 3

NR

1 6

R

1 5 CONR16R 1 5 aryl, heteroaryl or heterocyclyl, -aryl, aryl(Cl-C 4 alkyl)-, heteroaryl, heteroaryl(Cl- 04 alkyl)-, heterocyclyl or heterocyclyil(0C.

4 alkyl)-; and

R

7 a is independently selected at each occurrence from:

-H,

0 alkyl, 03-C 1 0 alkenyl, 03-ClO alkynyl, Cl-Cl 0 haloalkyl with 1-10 halogens, 02-08 alkoxyalkyl, C3-C 6 cycloalkyl, 04-

C

1 2 cycloalkylalkyl, 05-010 cycloalkenyl, or C6-0l 4 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from 01-06 alkyl, 03- 06 cycloalkyl, halo, 01-04 haloalkyl, cyano,

OR

1 5 SH, S(O)nR 1 3 C0R 1 5 C02R 1 5

OC(O)R

1 3

NR

8 C0R1 5 N(00R 1 5 2 NR8CONRlGR15,

:NR

8 C02Rl 3

NR

1 6 R1 5 C0NR 1 6

R

1 5 aryl, heteroaryl or heterocyclyl, :-aryl, aryl (01-04 alkyl) heteroaryl, heteroaryl

(C

1

-C

4 alkyl) heterocyclyl or heterocyclyl (01-04 alkyl); alternatively,

NR

6

R

7 and NR 6 aR 7 a are independently :piperidine, pyrrolidine, piperazine,

N-

methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 01-04 alkyl groups.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R 6 a and R 7 a are identical and are selected from: -01-04 alkyl or 03-06 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from Cl-C6 alkyl, C3-C 6 cycloalkyl, halo, Cl-C 4 haloalkyl, cyano, OR 1 5 SH, S(O)nR1 3 CO2R1 5

OC(O)R

1 3

NR

8 COR15, N(COR15)2,

NR

8 CONR1 6 R15, NR 8 CO2R1 3 NRl 6 R15, CONRl 6 aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is selected from:

-H,

-Cl-Clo alkyl, C3-ClO alkerIyl, C3-C1O akYny1, :alkoxyalkyl, C3-C6 cycloalkyl, C4- C12 cycloalkylalkyl, CS-CIO cycloalkenyl, :or C6-C1 4 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each :o~ooooccurrence from Cl-C6 alkyl, C3o C6 cycloalkyl, halo, CI-C4 haloalkyl, :cyano, OR1 5 SH, S(O)nR 1 3 C0R 1 5 CO2R1'

OC(O)R

1 3

NR

8 00R 1 5 N(C0R 1 5 2

NR

8

CONR

1 6 Rl 5

NR

8 CO2Rl 3

NR

1 6

R

1 5

CONR

1 6

R

1 5 aryl, heteroaryl or heterocyclyl, -aryl, aryl(Cl-C4 alkyl), heteroaryl, heteroaryl(Cl-C4 alkyl), heterocyclyl. or heterocyclyl(Cl-C4 alkyl); R~a is selected from: -Cl-C 4 alkyl. and each such Cl-C4 alkyl. is substituted with 1-3 substituents independently selected at each occurrence from cl-c 6 alkyl, C 3

-C

6 cycloalkyl, halo, Cj-C 4 haloalkyl, cyano, OR 1 5 SH, S(O)nR' 3

COR

1 5 C02R' 5 OC(O)RlJ,

NR

8 00R15, N(COR15) 2

NR

8 CONR16R15,

NR

8 CO2R13, NR1 6 R15, CONR1 6 aryl, heteroaryl or heterocyclyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereojsomeric forms thereof, or mixtures of stereoisomeric forms thereof, arnd pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R6a and R 7 a is selected from:

-C

3

-C

6 cycloalkyl, each such C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from

C

1

-C

6 alkyl, C 3

-C

6 cycloalkyl, halo, Cl-C 4 *15 haloalkyl, cyano, 0R 1 5 SH, S (0)nR 1 3 CORiS, .:C02R 1 5 OC(0)R 1 3 NRBCOR15, N(COR15) 2

NR

8 CONRl6R15, NR8CO 2 R13, NRl6RI5, CONRl6R15, aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, and the other of R6a and R 7 a is unsubstituted Cl-C 4 alkyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein

R

6 a and R 7 a are independently H or Cj-Cj 0 alkyl, each such Cl-Cl 0 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from Cl-C6 alkyl, C3-C6 cycloalkyl, halo, Cl-C4 haloalkyl, cyano, OR 15 SH, S(O)nR 13 C0R 1 5 C02R' 5

OC(O)R

1 3

NR

8

COR

1 5, N(C0R 1 5 2 R8CONRl6Rl5, NR 8 C02R 1 3

NR

1 6 Rl 5

CONR

1 6

R

1 5 aryl, heteroaryl or heterocyclyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms.-thereof wherein Ar is pnenyl, pyridyl. or 2, 3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R 4 substituents, and R3 is NR6aR 7 a or OR 7 More preferred compounds of the above invention also include compounds and isomers thereof, :15 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically :acceptable salt or pro-drug forms thereof wherein

R

6 a is independently selected from:

-H,

-Ci-CiQ alkyl, 03-ClO alkenyl, C3-Cj0 alkynyl, Cl-Clo haloalkyl. with 1-10 halogens, C2-C8 aikoxyalkyl, C- cycloalkyl, C4- C12 cycloalk .alkyl, C5-Cl0 cycloalkenyl, or 06-014 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from 01-06 alkyl, C3- C6 cycloalkyl, halo, Cl-C4 haloalkyl, cyano, OR1 5 SH, S(O)nR 1 3 COR1 5 C02R 1 5

OC..(O)RI

3

NR

8

COR

1 5 N(C0R 1 5 2

NR

8 CONRl 6

R

1 5

NR

8 C02R1 3

NR'

6 R1' CONR 1 6

R

1 5 aryl, heteroaryl or heterocyclyl, -aryl, aryl(Cl-C4 alkyl)-, heteroaryl, heteroaryl (C1-C4 alkyl) heterocyclyl or heterocyclyl(Cl-C4 alkyl);

R

7 a is independently selected at each occurrence from:

-H,

-C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C 8 alkoxyalkyl, C3-C6 cycloalkyl, C4- C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from Cl-C6 alkyl, C3- C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano,

OR

1 5 SH, S(0)nR 1 3

COR

1 5 C02R 1 5 OC(0)R 1 3

NR

8

COR

1 5

N(COR

15 2

NR

8 CONR16R5, NR8CO2R1 3

NR

16 R1 5

CONR

1 6

R

1 5 aryl, 15 heteroaryl or heterocyclyl, S-aryl, aryl(CI-C4 alkyl), heteroaryl, heteroaryl(Ci-C 4 alkyl), heterocyclyl or heterocyclyl(C-C4 alkyl), alternatively,

NR

6

R

7 and NR6aR 7 a are independently piperidine, pyrrolidine, piperazine,

N-

methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups.

25 More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R 7 a are identical and are selected from: -CI-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from CI-C6 alkyl, C3-C6 cycloalkyl, halo, CI-C4 haloalkyl, cyano, OR15, SH, S(O)nR 13

-COR

15 C02R 15 OC(O)R1 3 NR8COR15, N(COR15)2, NR8CONR1 6

R

1 5

NR

8 CO2R13, NR 1 6

R

1 5 CONR16RI5, aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R 7a are identical and are

-C

1

-C

4 alkyl, each such C 1

-C

4 alkyl optionally substituted with 1 to 3 substituents independently selected at each 15 occurrence from C 1

-C

6 alkyl, C 3

-C

6 cycloalkyl, halo, Ci-C4 haloalkyl, cyano, OR15, SH, S(0)nR 1 3 -COR15, C02R15, OC(O)R13, NR8COR15,

N(COR

1 5)2, NR8CONR16R15, NRSCO2R13, NR16R15,

CONR

1 6R 1 5 aryl, heteroaryl or heterocyclyl.

S*

a* a More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically 25 acceptable salt or pro-drug forms thereof wherein R6a is selected from:

-H,

-C1-C10 alkyl, C3-C 1 0 alkenyl, C3-C10 alkynyl, haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4- C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3- C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano,

OR

1 5 SH-, S(O)nR 1 3 C0R 1 5 C02R 1 5

OC(O)R

1 3

NR

8 COR15, N(C0R 1 5 2

NR

8 CONR1 6

NR

8 CO2Rl 3

NR

1 6

R

1 5, CONR 1 6

RI

5 aryl, heteroaryl or heterocyclyl, -aryl, aryl (Cl-C 4 alkyl) heteroaryl, heteroaryl (Cl-C4 alkyl), heterocyclyl or heterocyclyl (Cl-C 4 alkyl);

R'

7 a is: -Cl-C 4 alkyl and each such Cl-C 4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from Ci-C 6 alkyl, C3-C 6 cycloalkyl, halo, C 1

-C

4 haloalkyl, cyano, 0R 1 5, SHi, S(O)nR13, *C02R15, OCO)1, RC*1,

NR

8 CONRl6R15, NRC2R3 NR6R5 ,1 :aryl, heteroaryl or heterocyclyl.

*:More preferred compounds of the above invention *also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of :R6a and R 7 a is selected from: -C3-C 6 cycloalkyl, each such C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from

C

1

-C

6 alkyl, C 3

-C

6 cycloalkyl, halo, Cl-C 4 haloalkyl, cyano, 0R 1 5, SH, S(O)nRlJ, CORiS, C02R15, OC(O)R 1 3, NR 8

COR

1 5, N(COR1 5 )2,

NR

8 CONR16R15,

NR

8 CO2Rl3, NR 1 6

R

15 CONR1 6

RIS,

aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, and the other of R6a and R 7 a is unsubstituted

C

1

-C

4 alkyl.

More preferred compounds of the above' invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein

R

6 a and R 7 a are independently H or C 1

-C

1 0 alkyl, each such C 1

-C

1 0 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C 1

-C

6 alkyl, C3-C6 cycloalkyl, halo, C 1

-C

4 haloalkyl, cyano, OR 1 5 SH, S(O)nR 1 3

COR

1 5 CO2R 1 5

OC(O)R

13

NR

8

COR

1 5

N(COR

1 5 2

R

8 CONR1 6

R

1 5

NR

8 CO2R 1 3

NR

1 6

R

1 5

CONR

1 6

R

1 5 aryl, heteroaryl or heterocyclyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein -Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R 4 substituents,

-R

3 is NR6aR 7 a or OR 7 and

-R

1 and R 2 are independently selected from H, C 1

-C

4 alkyl, C3-C6 cycloalkyl, C 4

-C

10 cycloalkylalkyl.

R

6 a is independently selected from:

-H,

-Ci-CjO alkyl, C3-CjQ alkenyl, C3-CjO alkynyl, Cl-CjO haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-CE cycloalkyl,

C

4 Cl2 cycloalkylalkyl, C5-C10 cycloalkenyl, or CE-C 14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from Cl-C6 alkyl, C3- C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR 15 SH, S(O)nR 13 COR1 5 CO2R' 5

OC(O)R'

3

NRBCOR

1 5 N(C0R 1 5 2 NRSCO2Rl 3

NR

16

R

15

CONR

16

R

15 aryl, heteroaryl or heterocyclyl, -aryl, aryl(Cl-C 4 alkyl)-, heteroaryl, heteroaryl(C 1 C4 alkyl), heterocyclyl or heterocyclyl(Cl-C 4 alkyl);

R

7 a is independently selected at each occurrence from:

-H,

alkyl, C3-ClO alkenyl, C3-ClO alkynyl, Ci-ClO haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-CE cycloalkyl, C4- C12 cycloalkylalkyl, C5-C1O cycloalkenyl, or C6-Cl4 cycloalkenylalkyl, each optionally substituted with 1 to 3 s.ubstituents independently selected at each occurrence from Cl-C6 alkyl, C3- C6 cycloalkyl, halo, CI-C4 haloalkyl, cyano, OR 15 SH, S(O)nR 13 CaR 15 C02R 15 OC(0)RI 3

NR

8

COR

1 5, N(C0R 1 5 2

NR

8

CONR

1 6

R

1 5 NRBCO2R' 3 NRlERlS, CONR1 6

R

1 5 aryl, heteroaryl or heterocyclyl, -aryl, aryl (Cl-C4 alkyl) heteroaryl, heteroaryl (C1-C4 alkyl) heterocyclyl or heterocyclyl(Cl-C4 alkyl) alternatively, NR 6

R

7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, Nmethylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R 7 a are identical and are selected from:

-C

1

-C

4 alkyl or C 3

-C

6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from 15 CI-C 6 alkyl, C 3

-C

6 cycloalkyl, halo, C 1

-C

4 haloalkyl, cyano, OR 1 5 SH, S(O)n

R

13, -COR 1 5 C02R 1 5

OC(O)R

1 3, NR8COR 1 5

N(COR

1 5 )2,

NR

8

CONR

1 6

R

1 5, NA 8 CO2R 1 3

NR

16

R

1 5

CONR

1 6

R

1 aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R 6 a and R 7 a are identical and are

-CI-C

4 alkyl, each such C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C 1

-C

6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR 1 5

SH,

S(O)nR 13 -COR15, CO2R 1 5

OC(O)R

1 3 NR8COR 1 5

N(COR

1 5

NR

8

CONR

1 6

R

1 5, NR 8 C02R 1 3 NR16R1 5 CONR16R1 5 aryl, heteroaryl or heterocyclyl.

-H,

-Cl-C 10 alkyl, C 3 -Cj 0 alkenyl, C3-ClO alkynyl, Cl-Cj 0 haloalkyl with 1-10 halogens,

C

2

-C

8 alkoxyalkyl, C3-C 6 cycloalkyl,

C

4 C1 cylakyakl C5-C cycloalkenyl, or C--C14cycloalkenvlalkvlec optionally substituted with 1 to 3 substituents independently selected at each :occurrence from C1-C6 alkyl, 03- C6 cycloalkyl, halo, Cl-C 4 haloalkyl, :cyano,

OR

1 5 SH, S(O)nR 1 3

COR

1 5 CO2R' 5

OC(O)R

1 3, NR 8

COR

1 5 N(C0R 1 5 2

NR

8 C0NR1 6

NR

8 CO2Rl 3

NR

16

R

15

CONR

16

R

15 aryl, heteroaryl or heterocyclyl, -aryl, aryl(Cl-C 4 alkyl), heteroaryl, heteroaryl(Cl-C 4 alkyl), heterocyclyl or heterocyclyl (01-04 alkyl);

R

7 a is: -01-04 alkyl and each such 01-04 alkyl is substituted with 1-3 substituents independently selected at each occurrence from 01-06 alkyl, 03-06 cycloalkyl, halo, 01-04 haloalkyl, cyano, 0R 1 3 SH, S(O)nR1 3 CO2R'S, OC(O)R1 3

NR

8 COR15, N(COR1S) 2

NR

8

CONR

1 6R15, NR 8

CO

2 R13, NRlSRI5, CONRl6R1S, aryl, heteroaryl or heterocyclyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one .of

R

6 a and R 7 a is selected from:

-C

3

-C

C

1

-C

6 alkyl, C 3

-C

6 cycloalkyl, halo, C 1

-C

4 haloalkyl, cyano, OR1 5 SH, S(O)nR 1 3

COR

1 5 C02R15, OC(O)R 1 3

NR

8

COR

1 5, N(COR15)2,

NR

8 CONR16R1 5

NR

8 CO2R 1 3

NR

1 6

R

1 5

CONR

1 6 R1 5 aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, .and the other of R6a and R 7 a is unsubstituted C 1

-C

4 alkyl.

R

6 a and R 7 a are independently H or C 1 -C10 alkyl, each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from CI-C6 alkyl, C3-C6 cycloalkyl, halo, C 1 -C4 haloalkyl, cyano, OR 1 5 SH, S(O)nR 1 3

COR

1 5 CO2R 1 5

OC(O)R

1 3

NR

8

COR

1 5

N(COR

1 5 2

R

8

CONR

1 6

R

1 5

NR

8 CO2R 13

NR

16

R

15

CONR

1 6

R

15 aryl, heteroaryl or heterocyclyl.

Specifically preferred compounds of the above invention are compounds of Formula

R

3 N N-N N

IN

4eR R 4 a 4 dR

R

4 b

R

4

C

FORMULA and isomers thereof, stereoisomeric forms thereof, or .mixtures of stereoisomeric forms thereof, and :"pharmaceutically acceptable salt or pro-drug forms thereof, selected from the group consisting of: 10 a compound of Formula (50) wherein R 3 is -NHCH(n-Pr) 2

R

4 a is Cl, R 4 b is H, R 4 c is Cl, R4d is H and R4e is

H;

a compound of Formula (50) wherein R 3 is -N(Et)(n-Bu),

R

4 a is Cl, R 4 b is H, R 4 c is Cl, R4d is H and R4e is

H;

a compound of Formula (50) wherein R 3 is Pr)(CH2cPr),

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 (50) wherein R 3 is -N(CH2CH20Me)2,

R

4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H and R4e is

H;

a compound of Formula (50) wherein R 3 is -NHCH(Et)(n- Bu), 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 (50) wherein R 3 is

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 (50) wherein R 3 is -NHC.H(CH2OMe) 2 R 4 a is Cl, R 4 b is H, R 4 c is Ci, R 4 d is H and R 4 e is

H;

a compound of Formula (50) wherein R 3 is -N(Et)2, R 4 a is Cl, R bis H, R 4 c is Cl, R 4 d is H and R 4e is H; a compound of Formula (50) wherein R 3 is -NHCH(CH 2 OEt) 2 R 4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H andR R 4 e is

H;

a compound of Formula (50) wherein R 3 is -NHCH(Et)2, R 4 a is Cl, R 4 b is H, R 4c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -N(Me) R 4 a 4b4 c 4d 4 is Cl, Rb is H, R is Cl, R is H and Re is H; a compound of Formula (50) wherein R 3 is -N(n-Pr)2, R 4 a :20is Cl, R 4 b is H, R 4c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -NHCH(Et) (n- 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 (50) wherein R 3 is -NHCH(CH2OMe)2, Ra is Me, Rb is H, Rc is Me, Rd is H and R4ei Me; compound of Formula (50) wherein R 3 is -NHCH(CH2OMe)2,

R

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

H;

a compound of Formula (50) wherein R 3 is -N(CH2CH2OMe)2, R 4 a is Me, R 4 b is H, R 4c is Me, R 4d isH and R 4e is

H;

a compound of Formula (50) wherein R 3 is -NHCH(Et)(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 (50) wherein 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 (50) wherein R 3 is -OEt, 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 (50) wherein R 3 is -N(Et)2, R 4 a is Me, R 4 b is H, R 4c is Me, R 4 d is H and R4e is H; a compound of Formula (50) wherein R 3 is -N(CH2CN) 2

R

4 a is Me, R 4 b is H, R4c is Me, R4d is H and R 4 e is H; a compound of Formula (50) wherein 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 (50) wherein R 3 is -OCH(Et)(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; 15 a compound of Formula (50) wherein R 3 is -N(n- Pr) (CH2cPr) R 4a is Me, R 4 b is H, R 4 c is Me, R 4d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -NHCH(Me)(CH2N(Me)2),

R

4 a is Me, R 4b is H, R 4 c is Me, R 4 d is H and R 4e is H; Sa compound of Formula (50) wherein R 3 is -N(cPr)(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 (50) wherein 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 4e is H; a compound of Formula (50) wherein R 3 is -N(n- Bu)(CH2CN), R 4a is Me, R 4 b is H, R 4 c is Me, R 4d is H and R 4 e is H; a compound of Formula (50) wherein 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 Me; a compound of Formula (50) wherein R 3 is -NHCH(Et)2, R 4 a is Me, R 4 b is H, R 4c is Me, R4d is H and R 4 e is Me; a compound of Formula (50) wherein R 3 is -N(CH2CH 2 0Me)2,

R

4 a is Me, R 4b is H, R 4 c is Me, R4d is H and R 4 e is Me; a compound of Formula (50) wherein R 3 is -NHCH(CH2OMe) 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 (50) wherein R 3 is -NHCH(Et) (CH2OMe), 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 (50) wherei-n R 3 is -N(Et)2, R 4 a is Me R~bis H, R 4 c is Me, R 4 d is H and R 4eis Me; a compound of Formula (50) wherein R 3 is -NHCH(CH 2 OEt) 2 R is MRbis HR4cis Me, R 4 d is H and R 4 e is Me; a compound of Formula (50) wherein R 3 is i 4 -NHCH(CH2CH2OMe) (CH20,Me)2, R 4 a. is Me, R 4 b isH, R4 *is Me, Rd is H and Re is Me; :20 a compound of Formula (50) wherein R 3 is morpholino, 4 a is eR 4 b is H, R 4c is Me, R 4d i n sH a compound of Formula (50) wherein R 3 is -N(CH2CH2OMe)2,

R

4 a isBRbis H, R 4 c: is OMe, R 4dis H and R 4 e is H; a compound of Formula (50) wherein R 3 is -NHCH(Et)2, R 4 a is Br, R 4 b is H, R 4cis OMe, R 4 d is H and R 4e is H; a compound of Formula (50) wherein R 3 is -N(Et)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 (50) wherein R 3 is -NH(c-Pr), 'R 4 a is Me, R 4 b is H, R 4cis Me, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -NHCH(CH2OMe)2, R 4a is CN, R 4b is H, R 4 c is OMe, R 4d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -N(c- Pr) (CH2CH2CN), R 4 a is Me, R 4 b is H, R 4cis Me,R R 4 d is H and R 4 e is Me; a compound of Formula (50) wherein R 3 is -NCH(CH2OMe)2, R 4 a is Me, R 4b is H, R 4 c is Br, R 4 d is H and R 4e is

H;

a compound of Formula (50) wherein R 3 is -NHCH(CH2OMe) (CH2CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is Br, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -NHCH(CH 2 OMe) 2

R

4 a is Me, R 4 b is H, R 4c is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (50) wherein R 3 is -N(CH2CH2OMe) 2 R~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 (50) wherein R 3 is -NHCH(Et) 2

R

4 a isM, 4b 4c 4dc 4e 1isMR is H, R is OMe, R~ is Me and R is

H;

a compound of Formula (50) wherein a compound of Formula wherein R 3 is -N(Et)2, R 4 a is Me, R 4 b is H, *20 R 4 c is OMe, R 4 d is Me and R 4 e is H; :a compound of Formula (50) wherein R 3 is -NHCH(CH2OMe) 2 .*Ra is Cl, Rb is HR 4 R is Me, Rd is H anda 4b4Rd 4 e is

H;

a compound of Formula (50) wherein R 3 is -NHCH(Et) (CH2OMe), R 4 a is Cl, R 4b is H, R 4 c is Me,

R

4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -N(CH2CH2OMe)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 (50) wherein R 3 is -NHCH(CH2OMe) (CH2CH2OMe), 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 (50) wherein 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 Me and R 4e is H; a compound of Formula (50) wherein R 3 is -N(c- Pr) (CH2CH2CN), R 4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d.

is H and R 4e is H; a compound of Formula (50) wherein R 3 is

NHCH(CH

2 0Me) (CH2CH2OMe), R~a is Cl, R 4 b is H, R.

4 c is Cl, R 4 d is H and R 4e is H; a compound of Formula (50) wherein R 3 is -NHCH(CH2OMe) (CH2CH2OMe), 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 (50) wherein R 3 is -NHCH(Et)' 2 R 4 a is Me, R 4 b is H, R 4 c is Br, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -N(CH2CH2-OMe)2,

R

4 a is Me, R 4b is H, R 4 c is Br, R 4 d is H and R 4 e is a compound of Formula (50) wherein R 3 is :-NH(CH2OMe) (CH2-iPr), R 4 a is Me, R 4b is H, R 4 c is Me, R is H and R ise H isisH compound of Formula (50) wherein R 3 is -N(CH2CH2OMe)2,

~R

4 a is Me, R 4b is H, R 4 c is R 4d i H and R 4 e i .is H; a compound of Formula. (50) wherein R 3 is-NC2HOe2 4 a is 4b isH 4 c is NeRdi n -NHCH(CH2OMe) R~ai Me, Rb is H, R i Me, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -NHCH(CH2OEt) R 4 a is Me, R 4b is H, R 4 c is Me, R4d isH and R 4e isH; a compound of Formula (50) wherein R 3 is -NHCH(CH2OMe) (CH2CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is NMe2, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -N(Et)2, R 4 a is Me, R bis H, R 4cis Cl, R 4 d is H and R 4 e is H; a compound of-Formula (50) wherein 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 (50) wherein R 3 is -N(CH2CH2QMe) 2 R 4a is Me, R 4b is H, R 4 c is Cl, R 4 d is H and R 4e i

H;

a compound of Formula (50) wherein

R

3 is -NHCH(CH2OMe) 2 R4a is M ,R 4b i HR 4c is Cl, R d is H and R 4e i

H;

a compound of Formula (50) wherein

R

3 is -N(Et)2,

R

4 a is R bis H, R 4cis Br, R 4dis H and Re is H; a compound of Formula (50) wherein

R

3 is -N(Et) 2 R 4 a~s R bis H, R 4 c is Me, R 4 d is H and R 4e is H; a compound of Formula (50) wherein R 3 is -NHCH(Et) 2 R 4 a *is Cl, R 4b is H, IR c is Me, R 4d is H and R 4e is H; a compound of Formula (50) wherein R 3 is -NHCH(Et, 2 R 4 a is Me, R 4 b is H, R 4 c is NMe2, R 4 d is H and Rle is 20

H;

a compound of Formula (50) wherein R 3 is NHCH(CH2OMe) (CH2CH2O.e), R is Me, Rb is H, Rc is Me, R 4 d is H and R 4eis H; a compound of Formula (50) wherein R 3 is -NHCH(CH2OMe) (CH2CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4eis H; 30 a compound of Formula (50) wherein R 3 is NHCH(CH2OMe) (CH2CH2OMe), 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 (50) wherein R 3 is -NHCH(CH2OMe) (CH2CH2OMe), R 4 a is Me, R 4 b is H, R 4 c is Cl, R 4 d is H and R 4e iLs H; a compound of Formula (50) wherein R 3 is -N(c- Pr) (CH2CH2CN), R 4a 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 (50) wherein R 3 is -NH(Et) (CH2CN),

R

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

H;

a compound of Formula (50) wherein R 3 is -N(Et) 2 R4a is Me, R 4 b is Me, R 4c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -N(CH2CH2OMe) (CH2CH2OH), R 4 a is Cl, R 4 b is H, R 4 c is C-l, R dis H and R 4eis H; a compound of Formula (50) wherein R 3 is -N(CH2CH2oMe)2, R 4 a is Me, R 4 b is Me.R4 is OMe, R 4d isH and R4 is H; a compound of Formula (50) wherein R 3 is -NHCH(Etj2, R 4 a is Me, R bis MRcis OMe, R 4dis H and R 4eis

H;

a compound of Formula (50) wherein

R

3 is -N(CH 2 c-Pr) (n- Pr), R 4 a is Me, R 4bis H, 4c isCR4d i n Rl Re is Han is H: nR 4 e is H; 20 a compound of Formula (50) wherein R 3 is -NHC-PrE)2

CHC

2 C) R 4 a is Me, R 4 b is Me, 4 c is OMe, R sHadR 4 e Cl bi ,R4 sOe dis H and R 4e is H; a compound of Formula (50) wherein R 3 is -N(HCH (Et) 2 4 a is Cl, R 4 b is H, 4 c is OMe, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is-NE),Rai 40 :Cl, R 4 b is H, R 4 c is OCe, R 4 d is H and R 4 e is H; compound of Formula (50) wherein R 3 is -N(cH2HOe2 -NHH()(CH2O R 4 a is R 4 b is H, R 4 c is OMe, 4 Ris H and R 4 e is H; 5)whri 3 i NE),Rai a compound of Formula (50) wherein R 3 is -NHCH(CH20H) 2

R

4 a is Cl, R 4 b is H, R 4 c is Cl, R 4 d is H and R4e is H; and a compound of Formula (50) wherein R 3 is N(CH2CH20Me) 2

R

4 a is Me, R 4 b is H, R 4 c is OMe, R4d is H and R 4 e is H.

More specifically preferred is 4-(bis-(2methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4methoxyphenyl)-[1,5-a]-pyrazolo-l,3,5-triazine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and 15 pharmaceutically acceptable salt or pro-drug forms thereof.

*9 4* 0 More specifically preferred is 4-(bis-(2methoxyethyl)amino)-2,7-dimethyl-8- (2,5-dimethyl-4- 20 methoxyphenyl)-(1,5-a]-pyrazolo-1,3, 5-triazine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

More preferred are compounds of the above invention are compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is CR.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisome-ric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R 4 substituents.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R 3 is

NR

6 aR 7 a or OR 7 More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of S.o *stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R 4 substituents, and R 3 is NR6aR 7 a or OR 7 More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Z is

CR

2 More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2 ,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R 4 substituents.

NR

6 aR 7 a or OR 7 More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically 15 acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R 4 substituents, and R 3 is NR6aR 7 a or OR 7 oo More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein

R

6 a and R 7 a are independently H or C 1 -C10 alkyl, and each such CI-C10 alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-

C

6 cycloalkyl, halo, CI-C4 haloalkyl, cyano, OR 1 5 SH, S(O)nR 1 3

COR

1 5 C02R 1 5

OC(O)R

1 3

NR

8

COR

1 5

N(COR

1 5 2

R

8

CONR

1 6

R

1 5 NR8C0 2

R

1 3

NR

1 6

R

1 5

CONR

1 6

R

15 aryl, heteroaryl or heterocyclyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein -Ar is phenyl, pyridyl or 2, 3 -dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R 4 substituents, -R3 is NR6aR 7 a or OR 7 and

-R

1 and R 2 are independently selected from H, C 1

-C

4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.

More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically 15 acceptable salt or pro-drug forms thereof wherein

R

6 a and R 7 a are independently H or C 1 -C10 alkyl, and each such C 1 -C10 alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from Cl-C6 alkyl, C3- 20 C 6 cycloalkyl, halo, CI-C4 haloalkyl, cyano, OR 1 5 SH, S(O)nR 1 3 COR15, CO2R 1 5

OC(O)R

1 3

NR

8 COR1 5

N(COR

1 5 2

R

8

CONR

1 6

R

1 5

NR

8 C02R 1 3

NR

1 6

R

1 5

CONR

1 6

R

15 aryl, heteroaryl or heterocyclyl.

25 Specifically preferred compounds of the above invention are compounds of Formula (51) a 4 dR/ R 4 b

R

4

C

FORMULA (51) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof selected from the group consisting of: 10 a compound of Formula (51) wherein R 3 is -NHCH(n-Pr) 2

R

4a is Me, R 4b is H, R 4c is Me, R 4d is H and R4e is

H;

Sa compound of Formula (51) wherein R 3 is -NHCH(CH 2 OMe) 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 (51) wherein R 3 is -N(CH 2

CH

2 OMe) 2 4a 4b 4c 4d 4e Ra is Me, Rb is H, R c is Me, R is H and Re is 20 H; a compound of Formula (51) wherein R 3 is -N(c- Pr) (CH2CH 2 CN), R 4a is Me, R 4b is H, R 4c is Me, R 4d is H and R4e is H; a compound of Formula (51) wherein R 3 is -N(CH2CH 2 OMe) 2

R

4 a is Cl, R 4b is H, R 4c is Me, R 4d is H and R4e is

H;

a compound of Formula (51) wherein R 3 is -NHCH(CH20Me) 2

R

4 a is Cl, R 4b is H, R 4c is Me, R 4d is H and R4e is

H;

a compound of Formula (51) wherein R 3 is -NHCH(Et)2, R 4 a is Cl, R 4 b is H, R 4cis Me, R 4dis H and R 4 e is H; a compound of Formula (51) wherein R 3 is -N(Et)2, R 4 a is Me, R 4 b is H, R 4 c is Me, R 4d is H and R 4 e is H; a compound of Formula (51) wherein R 3 is -N(n- Pr) (CH 2

CH

2 CN) R 4 a is Me, R 4b i s R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (51) wherein R 3 is -N(n- Bu) (CH 2

CH

2 CN) R ais Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4e is H; a compound of Formula (51) wherein R 3 is -NHCH(n- Pr) (CH 2 OMe) R ais Me bis H, R 4 c is Me, R 4 d is *H and R eis H; *a compound of Formula (51) wherein R 3 is -NHCH(Et)2, Ra 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 (51) wherein R 3 is -NHCH(CH2OMe)2, R R 4 a is Me, R 4b i s R 4c is OMe, R 4 d is H and R 4 e is H; :25 a compound of Formula (51) wherein R 3 is (S)

-NH(CH

2

CH

2 OMe)CH2OMe, R 4 a is Me, R 4 b is H, R 4 c is Me, R dis H and R 4eis H; 0 30 a compound of Formula (51) wherein R 3 i s

-NH(CH

2

CH

2 OMe)CH 2 OMe, R 4 a is Me, R 4 b is H, R 4 c is 0 .0 Me, R 4 d is H and R 4 e is H; a compound of Formula (51) wherein R 3 is -N (CH 2 CH2OMe) 2, R 4a is Me, R 4 b is H, R 4c is Cl, R 4 d is H and R 4 e is

H;

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

H;

a compound of Formula (51) wherein R 3 is -NHCH(CH 2 QMe) 2 R 4a is Me, R 4 b is H, R cis Cl, R 4 d is H and R 4 e is

H;

a compound of Formula (51) wherein R 3 is (S) -NH (CH 2

CH

2 OMe) CH2OMe, R 4 a Cl, R 4 d is H and R 4 e is H, is me, R~b is H, R 4c is a compound of Formula (51) wherein R 3 -NH(CH2CH 2 OMe)CH 2 OMe, R 4 a is Me, Cl, Rdis H and R 4 e is H; a compound of Formula (51) wherein R 3 Pr) (CH2CH 2 CN) R 4 a is Me, R 4 b is is H and RP4 is H; a compound of Formula (51) wherein R 3 Me, Rbis H, R 4c is OMe, R 4d is 20 a compound of Formula (51) wherein R 3

-NH(CH

2

CH

2 OMe)CH 2 OMe, R 4 a is Cl, Me, R 4d is H-and RP4 is H; is R4b is H, is -N (n- H, R 4 C is R 4c is OMe, R4 0* is -N(Et) 2 R 4a. is H and R 4e is H; is (S) R4b is H, R 4c is a compound of Formula (51) wherein R 3 is -NH(CH2CH 2 OMe)CH 2 OMe, R 4 a is Cl, R bis Me, R 4 d is H and R 4 e is H; H, R 4c is a compound of Formula (51) wherein R 3 is -N(Et) 2 R 4a is Cl, Rbis H, Rcis Me, R4d is H and R 4e is H; a compound of Formula (51) wherein R 3 is -N(c- Pr) (CH 2

CH

2 CN) R 4 a is Me, R bis H, R 4c is OMe, R 4 d is H and R 4e is H; a compound of Formula (51) wherein R 3 is -N(c- Pr) (CH2CH 2 CN) Rais Cl, R 4 b is H, R4c is Me, R 4 d is H and R 4e is H; a compound of Formula (51) wherein R 3 is -NHCH (n- Pr) (CH 2 OMe), R4a is Me, R 4 b is H, R cis OMe, d is H and Re is H; a compound of Formula (51) wherein R 3 is -NHCH (n- Pr) (CH 2 OMe), R4a is Cl, R 4 b is H, R 4c is Me, R4.i H and R 4 e is H; a compound of Formula (51) wherein 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 R4e is

H;

a compound of Formula (51) wherein R 3 is -NHCH(Et)2, R 4 a is Br, R 4b is H, R4c is OMe, R 4d is H and R4e is H; a compound of Formula (51) wherein R 3 is -N(CH2CH 2 OMe) 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 (51) wherein R 3 is -NHCH(CH 2 0Me) 2

R

4 a is Br, R 4 b is H, R4c is OMe, R 4 d is and R 4 e is H; a compound of Formula (51) wherein R 3 is -N(Et)2, R 4a 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 (51) wherein R 3 is -N(Et) 2

R

4a is Cl, R 4b is H, R 4 c is OMe, R 4 d is OMe and R4e is H; a compound of Formula (51) wherein R 3 is -NHCH(Et) 2

R

4 a is Cl, R 4b is H, R 4c is OMe, R4d is OMe and R 4 e is

H;

oa compound of Formula (51) wherein 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 (51) wherein 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 (51) wherein R 3 is -N(Pr) (CH 2 CH2CN) R 4a is Cl, R 4 b is H, R 4 c is Cl,

R

4 d is H and R4e is H; a compound of Formula (51) wherein R 3 is 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 (51) wherein R 3 is

R

4 a is Cl, R 4 b is H, R 4c is Cl,

R

4d is H and R 4 e is H; a compound of Formula (51) wherein R 3 is -NHCH(Et) 2

R

4 a is Cl, R 4b is H, R 4 c is Cl, R 4 d is H and R4e is H; a compound of Formula (51) wherein R 3 is -NHCH(Et)2, R4a is Me, R 4 is H, R 4 is Me, Rd is H and R is H; a compound of Formula (51) wherein R 3 is -NHCH(Et)2,

R

4 a is CI, R4b is H, R 4 c is Me, R 4d is H and R 4e is H; a compound of Formula (51) wherein R 3 is -NHCH(Et) 2

R

4 a is Me, R4b is H, R 4 c is Cl, R 4 d is H and R4e is H; a compound of Formula (51) wherein R 3 is -NEt2, R 4 a is A 4b i 4 c 4 d I S Me, R4b is H, R is OMe, R 4 is H and R 4 e is H; and a compound of Formula (51) wherein R 3 is -N(Pr) (CH 2

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.

20 More specifically preferred is 7-(3pentylamino)-2,5-dimethyl-3-(2-methyl-4methoxyphenyl)-[1,5-a)-pyrazolopyrimidine and isomers 25 thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

More specifically preferred is 7 -(Diethylamino)- 30 2,5-dimethyl-3-( 2 -methyl-4-methoxyphenyl-[1, pyrazolopyrimidine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

More specifically preferred is cyanopropyl) -N-propylamino) 5-dimethyl-3- (2,4and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

The present invention also provides pharmaceutical compositions comprising any one of compounds described above and a pharmaceutically acceptable carrier.

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 15 such stable isomers are contemplated in the present invention. The compounds may be isolated in optically e active or racemic forms. It is well known in the art o how to prepare optically .active forms, such as by resolution of racemic forms or by synthesis from 20 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.

25 The term "alkyl" includes both branched and straight-chain alkyl having the specified number of carbon atoms. Commonly used abbreviations have the following meanings: Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl. The prefix 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 carboncarbon 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 ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth.

"Halo" or "halogen" includes fluoro, chloro, bromo, 15 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 20 not exceeded, and that the substitution results in a *e stable compound. When a substitent is keto then 2 hydrogens on the atom are replaced.

Combinations of substituents and/or variables are permissible only if such combinations result in 25 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-(p-biphenyl)-1methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types 15 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.

20 The term "pharmaceutically acceptable salts" includes acid or base salts of the compounds of Formulae and Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such 25 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 15 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.

o 20 The term "therapeutically effective amount" of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.

a Syntheses Some compounds of Formula may be prepared from intermediate compounds of Formula using the procedures outlined in Scheme 1: SCHEME 1 Y halogenating agent or sulfonylating agent N N base, solvent N HN z N N N R N R" N Ar Ar Y 0 (8)

R

3

R

3 S, base, NA N solvent *Ar S(1) A N 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 -800C to 250 0 C to give products of Formula (8) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkane-sulfonyloxy). Halogenating agents include, but are not limited to, SOC1 2

POCI

3 PC1 3 PC15, POBr 3 PBr 3 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 ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), 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) inr.rt 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 15 dimethylacetamide), cyclic amides (preferably Nmethylpyrrolidin-2-one), dialkylsulfoxides (preferably Sdimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane) 20 Preferred reaction temperatures range from -20 0 C to 100 0

C.

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

R

7 aryl or heteroaryl) in S 25 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,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (peferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range 15 from 0 C to 140 0

C.

Scheme 2 delineates the procedures for converting intermediate compounds of Formula (where Y is S) to some compounds of Formula 0* o• 0 bee• SCHEME 2

RI

3 X, base, solvent

SR

1 3 N IN N R N Ar Y S oxidizing agent, solvent S(12)

R

3 H, base, solvent (0)nR 13

R

3 H, base, solvent

R

3

NN

17L N (13) A N Compounds of Formula (where Y is S) may be treated with an alkylating agent R 13 X (where R 1 3 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 2500C. 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 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 Nmethylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons 15 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

1 3 may then be reacted with compounds of Formula R 3

H

20 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 25 may be oxidized to compounds of Formula (13) (Formula where R 3 is S(O)nR 1 3 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 0 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 alcohols (1 to 6 carbons), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane) or combinations thereof.

The choices of oxidant and solvent are known to those skilled in the art (cf. Uemura, Oxidation of Sulfur, Selenium and Tellurium, in Comprehensive OrQanic Syntheis, Trost, B.M. ed., (Elmsford, NY: Pergamon Press, 1991), 7, 762-769). Preferred reaction temperatures range from -20 0 C to 100 0 C. Compounds of Formula (13) (Formula where

R

3 is S(O)nRI3, 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 above.

Compounds of Formula where

R

3 may be -NR 8

COR

7 15 -N(COR) 2

-NR

8

CONR

6 R7, -NR8CO 2 R13, -NR 6

R

7

-NR

8

SO

2 R7 may be prepared from compounds of Formula where Y is NH, by the procedures depicted in Scheme 3.

SCHEME 3

Y

R3 alkylating, sulfonylating HN NN- or acylating agents *N N base, solvent A NN

R

1

N

RNN

Ar Ar Y NH (1) A N;

R

3

NR'R

7 ,NR8COR 7 N (COR 2, NReCONR 6

R

7 NReCO 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 -80 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 C02Rl 3

-NR

6

R

7

-NR

8

SO

2

R

7 Alkylating agents may include, but are-not limited to, Cj-Cj 0 alkyl.

-halides, -tosylates, -mesylates or -triflates; Cl-Cj 0 haloalkyl(l 10 halogens)-halides, -tosylates, -mesylates or -triflates; C2-C 8 alkoxyalkyl-halides, -tosylates, -mesylates or -triflates; C3-C 6 cycloalkylhalides, -tosylates, -mesylates or -triflates; C4- C12 cycloalkylalkyl-hau ides, -tosylates, -mesylates or -triflates; aryl (Cl-C 4 alkyl)-halides, -tosylates, -mesylaces or -triflates; heteroaryl(Cl-C 4 alkyl)halides, -tosylates, -mesylates or -triflates; or :99. heterocyclyl(Cl-C 4 alkyl)-halides, -tosylates, :-mesylates or -triflates. Acylating agents may include, but are not limited to, C 1

-C

1 0 alkanoyl halides or :anhydrides, CI-Clo haloalkanoyl halides or anhydrides with 1 10 halogens, C2-C8 alkoxyalkanoyl halides or anhydrides, C3-C6 cycloalkanoyl halides or anhydrides, :9 C4-C 1 2 cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl(Cl-C 4 alkanoyl. halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl(Cl-C 4 alkanoyl halides or anhydrides, heterocyclylcarboxylic acid halides or anhydrides or heterocyclyl(Cl-C 4 alkanoyl halides or anhydrides.

Sulfonylating agents include, but are not limited to, Cj-Cj 0 alkylsulfonyl. halides or anhydrides, Cj-Cj 0 haloalkylsulfonyl. halides or anhydrides with 1 halogens, C2-CB alkoxyalkylsulfonyl halides or anhydrides, C3-C 6 cycloalkylsulfonyl. halides or anhydrides, C 4 -C1 2 cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl. halides or anhydrides, aryl(Cl-

C

4 alkyl)-, heteroarylsulfonyl halides or anhydrides, heteroaryl(Cl-C 4 alkyl)sulfonyl halides or anhydrides, heterocyclylsulfonyl halides or anhydrides or heterocyclyl(C1-C 4 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 diisopropylamide), 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 15 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 20 (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons o (preferably benzene or toluene). Preferred reaction temperatures range from 0°C to 100 0

C.

Scheme 4 delineates procedures, which may be 25 employed to prepare intermediate compounds of Formula where Y is O, S and Z is CR 2 SCHEME 4 0

R

2 CORb, base, NC 2N2 H 2 0, ArCH 2 CN solvent 2 olvent Ar (3)

NB

RI~ OR N N(5) N R2 acid, R2 solvent Ar Ar 4 (6)

Y=C(R

2 base, HN solvent z

R

I

N

V A Ar Y O, S; Z CR 2 Compounds of the formula ArCH2CN 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 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,Ndialkylformamides (preferably dimethylformamide), N,Ndialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), 15 dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene).

Preferred reaction temperatures range from 0°C to 1000C.

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 70 0

C

to 150 0 C, 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,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). Compounds of Formula may be reacted with compounds of Formula (where Rc is alkyl (1-6 carbons)) in the presence or absence of an acid in the presence of an inert solvent at temperatures ranging from 0°C 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 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 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 15 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 20 compounds C=Y(Rd) 2 (where Y is O or S and R d is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) in the presence or absence of a base in an inert solvent at reaction temperatures from -50 0 C to 200 0 C. Bases may include, but are not 25 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 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 dimet hy lace tamide) cyclic amides (preferably

N-

methylpyrrolidin- 2-one) dialkylsulf oxides (preferably dimethylsulf oxide) or aromatic hydrocarbons (preferably or toluene) Preferred temperatures are 0 0 C to 1500C.

Intermediate compounds of Formula where Z is N, may be synthesized according the methods outlined in Scheme SCHEME RqCS 2

N

3 base, solvent reducing agent, solvent_ ArCH 2

CN

Ar

S

.9~ .5 S S

S

*5

S

*5 *t S S S S S. S V *5

C

S

NH

R

1 acid, solvent

,N

HN

N

H

2

N"

Ar

NH

R 1

N

H

N

(11) S. S S

SS

.56 0 Y=C (Rd) 2 base, solventy HN "kN R 1" z 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 (I to 6 carbons) in the presence or absence of a base in an inert solvent at temperatures ranging from 000 to 200 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, 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 15 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 20 (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 -100 0 C to 100 0 C to afford products of Formula (10) Reducing agents 25 include, but are not limited to, hydrogen gas in combination with noble metal catalysts such as Pd-oncarbon, PtO 2 Pt-on-carbon, 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 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 60 0 C. Compounds of Formula are then converted to compounds of Formula (7) (where Z is N) via intermediates of Formula (11) using the reagents and reaction conditions outlined in Scheme 4 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 3

R

3 acid, R N dehydrating agent HN N solvent A N, 1 1 A

N-

R N Ar Ar Ar Y 0, 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 OOC to 250 0 C. Dehydrating agents include, but are not limited to, P205, molecular sieves or inorganic or organic acids. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid.

Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower 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 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 15 also be prepared by the methods shown in Scheme 7: SSCHEME 7 3 3 SR3C (ORe), R3 NH HN N acid, Z solvent A N N

SRN

Ar (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 0 0 C to 250 0 C. Acids may 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 150 0

C.

15 Intermediate compounds of Formula may also be synthesized by the reactions displayed in Scheme 8.

SSCHEME 8

Y

N|

A N 9 ArM, catalyst, i. Z solvent AN R N

Z

R.N

X R N Y OH, SH NR 6

R

7 Ar Z N, CR 2 A N X Br, Cl, I, B(OR"")2 Compounds of Formula (where Y is OH, SH, NR 6

R

7

Z

is defined above, X is Br, Cl, I, 0 3 SCF3 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, CeCl 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 2000C. 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 PdCl2(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), o cyclic ethers (preferably tetrahydrofuran or 1,4- 15 dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably S. dimethylacetamide), cyclic amides (preferably Nmethylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably 20 benzene or toluene) or water. Preferred reaction temperatures range from -80 0 C to 100 0

C.

S* 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., 25 (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 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.

SCHEME 9

R

3 A NN Z ArM, catalyst, A N-N solvent x RN Ar (16) X Br, Cl, I,

A

r

B(OR"")

2 03SCF 3 Compounds of Formula where A, Z, R 1 and R 3 are defined above and X is Br, Cl, I, 03SCF3 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, ZnCI, ZnBr, ZnI, MgBr, MgCl, MgI, CeC1 2 CeBr2 or copper halides) in the presence or absence of an ee organometallic catalyst in the presence or absence of a S. 10 base in an inert solvents at temperatures ranging from -1000C 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 15 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 NiCl2(PPh 3 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 1,4dioxane), 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 -80 0 C to 100 0

C.

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

R

2 and Ar are defined as above) may be prepared as illustrated in Scheme SCHEME

Y

0 NH 2

NH

2

(C=Y)NH

2

H

2 N N N base or acid, R 2 S2 solvent H

H

2

N

ArAr (17) (17)

I

R1C OR) 3 acid, HN solvent R s R N Ar Y O, S, NH; Z CR 2 Compounds of Formula may be reacted with compounds of Formula H2NNH(C=Y)NH 2 where Y is O, S or NH, in the presence or absence of a base or acid in an inert solvent at temperatures from 0 0 C 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 S. 15 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 carbons and 1 to 10 halogens (preferably dichloromethane Preferred reaction temperatures range from OOC to 150 0 C. Compounds of Formula (17) may then be reacted 25 with compounds of Formula R 3 C(ORe)3, where R e may be alkyl (1 to 6 carbons) in the presence or absence of an acid in an inert solvent at temperatures ranging from 0 0 C to 2500C. 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 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 150 0

C.

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 15 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 2500C.

SCHEME 11

R

3

R

3

N

A N reducing agent,

N

Z solvent A N N R

N

Ar

R

3

COR

7 C0 2

R

7 CONR6 7 R C(OH)R 7

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 1000C.

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

COR

7 or C0 2

R

7 to other compounds of Formula where

R

3 is C(OH)(R7)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.

SCHEME 12

R

3 R*

N

n .RR N 1 R COR C02

R

R3 C (OH) (R)2 M is halogen, alkali metal, ZnCI, ZnBr, ZnI, MgBr, MgCl, MgI, CeCl2, 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 -800C to 1000C.

Compounds of Formula where R 3 may be -NR8COR 7 -N(COR7)2, -NR8CONR6R7, -NR8C2R 13 -NR6R7, -NR8SO2R 7 may be synthesized as depicted in Scheme 13.

may be synthesized as depicted in Scheme 13.

SCEME 13 (18) base, solvent

NH

2

R

z

N

(19) 9.

9.

9* .9 9994 *999 Z= Ca 2 (10) Z =N alkylating, sulf onylating or acylatIng agents /-base,solvent *9 9 .9 9* 9 4**99* 9 A =CR

R

3 =NR R NR COR, N (COR7 )2,

NR

9 CONR R 7

NR

8 C0 2

R

1 3 R~eact ion of compounds of Formula where R and R 1 defined above, with compounds of Formula or in the presence or absence of base in an inert solvent may produce compounds of Formula (19) at 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 15 (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 20 (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0°C to 100 0

C.

Compounds of Formula (19) may then be reacted with alkylating agents, sulfonylating agents or acylating 25 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 1 3

-NR

6

R

7

-NR

8

SO

2

R

7 Alkylating agents may include, but are not limited to, CI-C10 alkyl -halides, -tosylates, -mesylates or -triflates; CI-C10 haloalkyl(l 10 halogens)-halides, -tosylates, -mesylates or -triflates; C2-C8 alkoxyalkyl-halides, -tosylates, -mesylates or -triflates; C3-C6 cycloalkyl-halides, -tosylates, -mesylates or -triflates; C4- C12 cycloalkylalkyl-halides, -tosylates, -mesylates or -triflates; aryl(C1-C4 alkyl)-halides, -tosylates, -mesylates or -triflates; heteroaryl(C 1

-C

4 alkyl)halides, -tosylates, -mesylates or -triflates; or heterocyclyl(C1-C 4 alkyl)-halides, -tosylates, -mesylates or -triflates. Acylating agents may include, but are not limited to, C1-CO10 alkanoyl halides or anhydrides, C1-C10 haloalkanoyl halides or anhydrides with 1 10 halogens, C2-C8 alkoxyalkanoyl halides or anhydrides, C3-C6 cycloalkanoyl halides or anhydrides, C4-C12 cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl(C1-C4) alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl(C1-C4) alkanoyl halides or anhydrides, 15 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, C4-C12 cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl(C1- C4 alkyl)-, heteroarylsulfonyl halides or anhydrides, :i 25 heteroaryl(C1-C4 alkyl)sulfonyl halides or anhydrides, heterocyclylsulfonyl 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 diisopropylamide), 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 (p-eferably 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 where A is CR and R is defined above, may be synthesized by the methods depicted in Scheme 14.

V* SCHEME 14 z

H

2

N-

Z =CR 2 Z =N base, solvent Ar

A=CR

(21) base, solvent

R

3 H, base, /-solvent x halogenating agentN or sulfonylating agent /-base, +/-solventN R1 N-

OR

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 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,N-dialkylformamides 15 (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons S. (preferably benzene or toluene) Preferred reaction 20 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 25 with compounds of Formula where R 1 is defined above and R e is alkyl (1 6 carbons), in the presence or absence of base in an inert solvent at temperatures ranging from 0°C 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), 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 0 C to 100 0 C. Compounds of 15 Formula (22) 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 (23) (where X is halogen, 20 alkanesulfonyloxy, arylsulfonyloxy or haloalkanesulfonyloxy). Halogenating agents include, but are not limited to, SOCl2, POCI3, PC1 3 PC15, POBr 3 PBr3 or PBr 5 Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (such as 25 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 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 -20 0 C to 15 100 0

C.

*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 20 absence of an inert solvent at reaction temperatures ranging from -80 0 C to 2500C to generate compounds of Formula Bases may include, but are not limited to, *o alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably 25 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,N-dialkyiformamides (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 carbons and 1 to 10 halogens (preferably dichioromethane). Preferred reaction temperatures range from 0 0 C to 140 0

C.

Some compounds of Formula may also be pre-pared using the methods shown in Scheme a. 0..

.91 SCREME acid, solvent HN OH

H

2

N

,-Ar CNE

NE

2 (2 4) acid, avent

Y

SOH

H

2

N-

Ar

S

4* 4 *4*4 4* .4 4 4 44 *4 4 4 4* 4 4* 4 4 4* 4* 4 For A -N: 1) RIC OR.

acid, solvent 2) Y-C (Pd) 2 base, solvent For A 1)

RI

ba solven (2 6)Y 0,

=CR:

C=O) CHR(C=Y) ORc as or acid, t R ~C 3 s/-olvent

R

3

YH

OH ~tx Ar Z CR 2 (27)Y 0, S 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 R'C(=NH)ORe, where Rl 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, The ccnditions 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 reacted with compounds of the formula 1 R 1 (C=0)CHR(C=Y)ORc (where R 1 and R are defined as above 15 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 20 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 25 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 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 15 of Formula The conditions and reagents employed are similar to those used in the conversion of intermediate compounds of Formulae to (12) (or to S* to compounds of Formula in Scheme 2.

Compounds of Formula may be prepared from S. 20 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 5 compounds of formula NH2NH(C=NH)NH2 in the presence or absence of an acid in an inert solvent, followed by 25 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 (3) to (17) to in Scheme Some compounds of Formula may be prepared by the methods illustrated in Scheme 16.

SCHEME 16

YH

A' N 0 R1 N 0 Ar 27b) Y 0, S

YH

R

1 4 X, base A N 1 4 solvent 0 R 1 N Ar 28)Y O, S see text

R

1 4

X,

base, solvent Z COB Compounds of Formula (27b) may be treated with various alkylating agents R 1 4 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 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 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 N).

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 15 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, 20 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) oo 25 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 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 Nmethylpyrrolidin-2-one), dialkylsulfoxides (preferably di-iethylsulfoxide) 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.

20 Proton NMR spectra were recorded on an IBM-Bruker FT-NMR (300 MHz); chemical shifts were recorded in ppm from an internal tetramethysilane standard in deuterochloroform or deuterodimethylsulfoxide as specified below. Mass spectra (MS) or high resolution 25 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 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 15 2 ,7-dimethyl-8-(2,4-dimethylphenyl) -pyrazolo-[, 3,5]-triazin-4 (3H)-one (Formula 7, where Y is O, R 1 is CH3, Z is C-CH3, Ar is 2,4-dimethylphenyl) 20 A. 1-Cyano-1-(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 HCI solution was added until the pH 5-6. The mixture was extracted with ethyl acetate (3 X 200 mL); the combined organic layers were dried over MgSO 4 and filtered. Solvent was removed in vacuo to afford a white solid (45.7g, 74% yield): NMR (CDC1 3 ,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 MgSO 4 and filtered. Solvent was removed in vacuo to give a pale brown viscous oil (34.6g, 15 yield) NMR (CDCl 3 ,300 MHz) 7.10 1H) 7.05 2H, 2.37 3H), 2.10 3H) CI-MS: 202 (M H).

C. 5-Acetamidino-4-(2,4-ctimethylphenyl)-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 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 mL). 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, 1), 2.28 3H), 2.08 3H), 2.00 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 15 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 IN HCI solution was added slowly until pH 5-6. The aqueous layer was extracted with ethyl acetate three 20 times; the combined organic layers were dried over MgSO 4 and filtered. Solvent was removed in vacuo to give a pale tan solid (26g, 98% yield): NMR (CDC1 3 ,300 MHz): 7.15(s, 1H), 7.09 2H), 2.45 3H), 2.39 3H), 2.30 3H); CI-MS: 269 (M H).

EXAMPLE 2 Preparation of 5-methyl-3-(2,4,6-trimethylphenyl) 31-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. l-Phenylmethyl-4-(2,4,6-trimethylphenyl)-5aminotriazole A mixture of 2,4,6-trimethylbenzyl cyanide (l.Og, 6.3 mmol), benzyl azide (0.92g, 6.9 mmol) and potassium 100 t-butoxide (0.

7 8g, 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 (CDC1 3 ,300 MHz) :7.60-7.30 (m 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 1-phenylmethyl- 15 4-(2,4,6-trimethylphenyl)-5-aminotriazole (1.1g, 3.8 mmol). The reaction mixture was stirred until a dark green color persisted. An ammonium chloride solution S. :mL) was added and the mixture was stirred while warming to ambient temperature over 16 hours. The residue was treated with a IM HCI 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 combined organic layers were dried over MgSO 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 (CDCl 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, 0.5H), 6.90 (s, 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- 6-trimethylphenyl) [1,2,3]-triazolo-[l 1, 3, 51-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, 6 15 acetamidino-triazole, acetic acid salt (490 mg, 1.6 S' 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.

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 25 a yellow solid (300 mg, 69% yield): NMR (CDC1 3 ,300 MHz): 6.98 2H), 2.55 3H), 2.35 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, (Formula 1, where R 3 is CH(CHCO 2

CH

3 2

R

1 is CH 3 Z is C-

CH

3 Ar is 2,4-dimethylphenyl) A. 4-chloro-2,7-dimethyl-8-(2, 4-dichlorophenyl) 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 icewater, 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 15 acetate:hexanes::1:4) gave one fraction (Rf Solvent was removed in vacuo to afford a yellow oil S" (l.0g, 68% yield) NMR (CDCI3,300 MHz): 7.55 1H, J 7.38 (dd, 1H, J 7,1 7.30 1H, J 2.68 3H), 2.45 CI-MS: 327 (M H) B. 4-(di(carbomethoxy)methyl)-2,7-dimethyl-8-(2,4dimethylphenyl) [1,5-a]-pyrazolo-1,3, 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 (0.32g, 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) 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 vacuc, a pale yellow solid (Rf 0.2, 250 mg, 35% yield) mp 50-52 0

C;

NMR (CDCI3, 300 MHz): 12.35 (br.s, 1H, 7.15-7.00 (in, 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 7), 1.35-1.25 (mn, 3H); CI-HRMS: Calcd: 411.2032, Found: 411.2023.

EXAMPLE 6 Preparation of 3-diinethoxy-2--propylamino)- 2,7-dimethyl-8-(2,4-dichlorophenyl) 15 (Formula 1, where R 3 is NHCH (CH 2

OCH

3 2

R

1 is CH3, Z is

*C-CH

3 Ar is 2,4-dichiorophenyl) A. 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl) pyrazolotriazine A mixture of 2,7-diinethyl-8-(2,4 dimethylphenyl) [1,5-aJ-pyrazolo-l, 3, 5-triazin-4-one (Example 1, 1.38g, 4.5 inmol), N,N-dirnethylaniline (1 mL, 8 inmol) 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= Solvent was removed in vacuo to afford a yellow oil (1.0g, 68% yield): NMR (CDC1 3 ,300 MHz): 7.55 lH, J 1) 7. 38 (dd, IlH, J 1 7. 30 I1H, J 7), 2. 68 3H) 2. 45 3H) C I -MS 3 27 (M H) B. 4 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-l,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 Cl 2 :CH30H: :50:1) afforded one fraction. Removal of solvent in vacuo gave a solid (250 mg, 35% yield): mp 118-120 0 C; NMR (CDC13,300 MHz): 7.50 1H), 7.28 (dd, 2H, J 8,1), P 15 6.75 1H, J 4.70-4.58 1H), 3.70-3.55 (m, o 0 4H), 3.43 6H), 2.50 3H), 2.35 3H); CI-HRMS: Calcd: 409.1072, Found: 409.1085; Analysis Calcd. for

C

1 8

H

2 1 Cl 2

N

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

*oo. 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 R 3 \\z

N)

Ar *o Q. o

S

10 15 20 z 6 a C -Me NHCH(CH2OMe) 2 7* C-Me NHCHPr 2 8cC-Me NEtBu qdC-Me NPr(CH2-c-C3HS) oe C-Me N(CH2CH 2 OMe) 2 lf C-Me NH-3-heptyl 19 C-Me NHCH(Et)-CH 2 OMe 1h C-Me NEt 2 1i C-Me NHCH(CH 2 OEt) 2 15) C-Me NH-3-pentyl 16 k C-Me NMePh 171 C-Me NPr2 18 m C-Me NH-3-hexyl 19 C-Me morpholino 20 C-Me N(CH 2 Ph)CH 2

CH

2 OMe 21 C-Me NHCHCCH2Ph)CH2OMe 22 C-Me NH-4-tetrahydropyranyl 23 C-Me NH-cyclopentyl 24 C-Me 1, 2,3, 4-tet rahydroisoquinolinyl C-Me CH2-(1,2,3,4-tetrahyd roisoquinoliiyl) 26n C-Me QEt 2,4-12P 2, 4-C1 2 -Ph 2, 4-Cl 2 -Ph 2, 4-C12 -Ph 2, 4-Cl 2 -Ph 2, 4-C12-Ph 2, 4-C12-Ph 2, 4-Cl2-Ph 2, 4-C1 2 -Ph 2, 4-C12-Ph 2, 4-Cl2-Ph 2, 4-Cl 2 -Ph 2, 4-Cl 2 -Ph 2, 4-C12-Ph 2, 4-C1 2 -Ph 2, 4-C12-Ph 2, 4-Cl2-Ph 2, 4-C1 2 -Ph 2, 4-Cl 2 -Ph 2, 4-Cl 2 -Ph 2, 4-C1 2 -Ph 2, 4-Cl2-Ph mpL~rC 118 -120 11-116 oil oil oil 9 0-92 179-181 133-134 oil 139-140 6 0-62 oil 130-132 141-143 27 C -Me 0CM (Et)CH2OMe 106 28 29 31 32 33 34 36.

37 38 39 41 42 43 44 46 20 47 48 490 51 52 53 ae 54 5 ac 56a 5 7 ai 58 ad 59 61 62 63 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 C-Me C -Me C -Me C -Me C-Me OCH 2Ph 0-3-pentyl SEt S Et SO2Et CH (CO 2 Et) 2 C (Et) (CO2Et) 2 CH (Et) CH 2

OH

CH (Et) CH 2 OMe CONMe 2 COCH 3 CH COH)CH 3 C (OH) Ph-3-pyriclyl Ph 2-CF 3 -Ph 2-Ph-Ph 3 -pentyl cyclobutyl 3-pyridyl CH (Et) CH 2 CONMe 2 CH (Et) CH 2

CH

2 NMe 2 NHCH (CH 2 OMe) 2 NH-CHPr2 NEtBu NP r (CH2-c-C3H5) N (CH2CH2OMe) 2 NH hept y.I NHCH (Et) CH2OMe NEt 2 NHCH (CH2OEt) 2 NH-3-pentyl NMePh NPr 2 NH-3-hexyl morpholino N (CH2Ph) CH 2

CH

2 oMe 2, 4-C1 2 -Ph 2, 4-C1 2 -Ph 2, 4-C12 -Ph 2, 4-C1 2 -Ph 2, 4 -C 2 -Ph 2, 4-C1 2 -Ph 2, 4-C12 -Ph 2, 4 -C12 -Ph 2, 4-C12-Ph 2, 4 -C 2 -Ph 2, 4 -C 2 -Ph 2, 4 -C 2 -Ph 2, 4-C12-Ph 2, 4-C1 2 -Ph 2, 4-C1 2 -Ph 2, 4-C12-Ph 2, 4-C1 2 -Ph 2, 4 -C12-Ph 2, 4 -C 2 -Ph 2, 4-C1 2 -Ph 2, 4-C12-Ph 2, 4, 6 -Me 3 -Ph 2,4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2f,4, 6-Me 3 -Ph 2, 4,6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2, 4, 6-Me3-Ph 2, 4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2, 4,6-Me 3 -Ph 125-127 123-124 14 5-14 6 8 8-90 132-134 134-135 64 C-Me NHCH (CH 2 Ph)CH2OMe C -Me N H- 4- te tra hydropy ra ny 1 66 C -Me NH-cyclopentyl 67 C-Me 1, 2, 3, 4 -etrahydroisoquinolinyl 68 C-Me CH2-(1,2,3,4-tetrahydroisoquinolinyl) 69 C-Me OEt C-Me OCH (Et) CH 2 OMe 71 C-Me OCH 2 Ph 72 C-Me 0-3-pentyl 73 C-Me SEt 74 C-Me S(O)Et C-Me SO2Et 76 C-Me CH(CO2Et)2 77 C-Me C(Et) (CO2Et)2 78 C-Me CH(Et)CH2OH 79 C-Me CH(Et)GH 2 0Me C-Me CONMe2 20 81 C-Me COCH3 82 C-Me CH(OH-)CH3 83 C-Me C(OH)Ph-3-pyridyl 84 C-Me Ph C-Me 2-CF3-Ph 25 86 C-Me 2 -Ph-Ph 87 C-Me 3-pentyl 88 C-Me cyclobutyl 89 C-Me 3-pyridyl C-Me CH(Et)CH 2 CONMe2 91 C-Me CH (Et) CH 2 CH2NMe 2 92P C-Me NHCH(CH 2 OMe) 2 9 3 q C-Me N(CH2CH 2 OMe) 2 9r C-Me NHCH (Et) CH2OMe C-Me NH-3-pentyl 96t C-Me NEt 2 9u C-Me N(CH2CN)2 2,4, 6-Me 3 -Ph 2,4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2, 4, 6-Me 3 -Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2, 4, 6-Me3-Ph 2 04,,6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2, 4, 6-Me3-Ph 2,4, 6-Me3-Ph 2, 4,6-Me 3 -Ph 2, 4,6-Me3-Ph 2, 4,6-Me3-Ph 2, 4,6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2, 4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me3-Ph 2, 4, 6-Me 3 -Ph 2, 4,6-Me3-Ph 2, 4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-me3-Ph 2,4, 6-Me3-Ph 2, 4-Me2-P~h 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 44-45 oil 102-104 102-104 oil 14 8-150 .t 98

V

99

W

102Ox 105 106.

107 108 109 110 111 112 113 114 115 116 117 118 119 120 25 121 122 123 124 125 126 127 128 3 129 C-Me NHCH (Me) CH2OMe C-Me OCH (Et)CH2oMe C-Me NPr-c-C3H 5 C-Me NHCH (Me) CH2NMe2 C-Me N(c-C3H5)CH2CH2CN C-Me N(Pr)CH2CH2CN C-Me N (Bu) CH2CH2CN C-Me NHCHPr2 C-Me NEtBu C -Me NPr(CH2-c-C3H5) C-Me NH-3-heptyl C-Me NEt2 C-Me NHCH (CH2OEt) 2 C-Me NH-3-perityl C-Me NMePh C-Me NPr2 C-Me NH-3-hexyl C-Me morpho4ino C-Me N(CH2Ph)CH2CH2OMe C-Me NHCH (CH2Ph) CH2OMe C-Me NH-4-tetrahydropyranyl C-Me NH-cyclopentyl C-Me 1, 2,3, 4-tec rahydroisoquinolinyl C-Me CH2-(1,2,3,4-tetrahydroisoquinolinyl) C-Me QEt C-Me OCH (Et) CH2OMe C-Me OCH2Ph C-Me 0-3-pentyl C-Me SEt C-Me S(O)Et C-Me SO2Et C-Me CH(CO2Et) 2 C -Me C (Et) (CO2Et) 2 2, 4 -Me2 -Ph 2, 4-Me2-Ph 2, 4 -Me2-Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2-Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2-Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2-Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me 2-Ph 2, 4-Me2-Ph 2, 4 -Me2 -Ph 2, 4-Me2-Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 102-104 oil oil 47-48 117-118 oil oil 50-52 a.

p.

o 130 131 132 133 134 135 136 137 13S- 139 140 141 142 143 15 144 1 4 6 bd 147 be 1 4 8 bf 149 1 5 0 af 153 25 154 155 156 157 158 159 160 161 162 163 164 165 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 C -Me C -Me C-Me C -Me C -Me Cl-I(Et) CH 2

OH

CH (Et) CH 2 OMe CR (Et) CH 2 OEt CONMe 2 COCH 3 CR (OH) CH3 C (OH) Ph-3-pyridyl Ph 2-CF 3 -Ph 2-Ph-Ph 3-pen tyl cyclobutyl 3-pyridyl CM (Et) CH2CONMe 2 CH (Et CH2CH 2 NMe 2 NHCH (CH2OMe) 2 N (CH-2CH2OMe) 2 NHCH (Et)4CH2OMe N (Pr) CH2CH 2

CN

0CM (Et) CM2OMe NHCH (CH 2 0Me) 2 N (CH2CH 2 OMe) 2 NHCH (Et) CH 2 OMe N (Pr) CM 2

CH

2

CN

OCH (Et) CH2OMe NHCH (CH 2 OMe) 2 N(CH2CH 2 OMe) 2 NH-CH (Et) CH2OMe N (Pr) CH2CH2CN 0CM (Et) CH2OMe NHCH (CH 2 OMe) 2

N(CH

2

CH

2 OMe) 2 NHCH (Et) CH2OMe N (Pr) CH2CH 2

CN

0CM (Et )CH2OMe NHCH (CH2OMe) 2 2, 4-Me2-Ph 2, 4-Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -me2 -Ph 2, 4-Me2 -Ph 2, 4-Me2-Ph 2, 4 -Me2 -Ph 2, 4-Me2 -Ph 2, 4 -Me 2 -Ph 2, 4-Me2-Ph 2, 4 -Me2 -Ph 2, 4-Me2 -Ph 2, -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2-Me-4 -MeO-Ph 2 -Me-4 -MeO-Ph 2 -Me-4 -MeO-Ph 2-Me-4-Mea-Ph 2 -Me-4 -MeO-Ph 2-B r-4-MeO-Ph 2-B r-4-MeO-Ph 2-Br-4 -MeO-Ph 2-B r-4-MeO-Ph 2-Br-4 -MeO-Ph 2-Me-4 -NMe 2 -Ph 2-Me-4-NMe 2 -Ph 2-Me-4-NMe 2 -Ph 2-Me-4 -NMe2-Ph 2-Me-4-NMe 2 -Ph 2-B r-4-NMe2-Ph 2-Br-4 -NMe2-Ph 2-Br-4-NMe 2 -Ph 2-Br-4 -NMe2-Ph 2-Br -4 -NMe 2-Ph 2-Br-4 -i-Pr-Ph 4 5-46 oil 8 6-88 oil 88-90 oil .95-97 oil a. a a S.C a.

.4 166 167 168 169 170 171 172 173 17-4 1 7 5 ar 176 177 178 179 15 180 181 182 183 184 20 185 186 187 188 189 25 190 191 192 193 194 195 196 197 198 199 200 201 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 C -Me C -Me C -Me C -Me C -Me N (CH2CH 2 OMe) 2 NHCH (Et )CH2OMe N (Pr) CH2CH 2

CN

OCH (Et) CH2OMe NHCH (CH2OMe) 2 N (CH2CH-2OMe) 2 NHCH (Et)CH2OMe N (Pr) CH2CH 2

CN

OCH (EU CH2OMe NHCH (CH2OMe) 2 N (CH2CH 2 OMe) 2 NHCH (Et)CH 2 OMe N (Pr) CH2CH 2

CN

OCH (Et) CH2OMe NH-CH (CH2OMe) 2 N (CH2CH 2 QMe) 2 NHCH (CH2OMe) 2 N (CH2CH-2OMe) 2 NHCH (CH-2OMe) 2 N (CH2CH 2 OMe) 2 NHCH (CH2OMe) 2 N (CH2CH 2 OMe) 2 NHCH (CH 2 OMe) 2 N (CH 2

CH

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

CH

2 OMe) 2

NHCH(CH

2 oMe) 2 N (CH2CH 2 oMe) 2 NHCH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (CH2ome) 2 N (CH 2

CH

2 oMe) 2 NHCH (CH2OMe) 2 N (CH2C-2OMe) 2 NHCH(CH2OMe) 2 N (CH 2

CH

2 OMe) 2 2-Br-4 -i-Pr-Ph 2-Br-4-i-Pr-Ph 2-Br-4 -i-Pr-Ph 2-Br-4-i-Pr-Ph 2-B r-4-Me-Ph 2-Br-4 -Me-Ph 2-Br -4-Me -Ph 2-Br-4 -Me-Ph 2-Br-4 -Me-Ph 2-Me-.4-Br-Ph 2-Me-4 -Br-Ph 2-Me-4-Br-Ph 2-Me-4 -Br-Ph 2-Me-4 -Br-Ph 2-C1-4, 6-Me2-Ph 2-C1-4, 6-Me2-Ph 4-Br-2, 6- (Me )2-Ph 4-Br-2, 6- (Me) 2 -Ph 4-i-Pr-2-SMe-Ph 4-i-Pr-2-SMe-Ph 2-B r-4-CF 3 -Ph 2-Br-4-CF 3 -Ph 2-Br-4, 6- (MeO) 2 -Ph 2-Br-4, 6-(MeO) 2 -Ph 2-Cl-4, 6- (MeO) 2 -Ph 2-C1-4, 6- (MeO) 2 -Ph 2,6- (Me) 2-4-SMe-Ph 2,6- (Me) 2-4-SMe-Ph 4- (COMe) -2-Br-Ph 4- (COMe) -2-Br-Ph 4, 6-Me3-pyrid-3-yl 6-Me 3 -pyrid-3-yl 2,4- (Br) 2-Ph 2,4- (Br) 2 -Ph 4-i-P r-2-SMe-Ph 4-i-Pr-2-SMe-Ph 108 -109 C. C

C.

*CCCC.

be 0* C E 202 203 204 205 206 207 208 209 2 1 C- 211 212 213 214 215 15 216 217 218 219 220 20 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 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

H

CF 3 CF 3

N

NHCH (CH 2 OMe) 2 N (CH 2

CH

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

CH

2 OMe) 2 NHCH (CH2OMe) 2 N (CH2CH 2 OMe) 2 NHCH (CH 2 OMi) 2 N (CH2CH2OMe) 2 NHCH (C4 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (CH2OMe) 2 N (CH2CH 2 OMe) 2 NHCH (CH-2OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (CH2OMe) 2 N (CH2CH 2 OMe) 2 NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (CH2OMe) 2

N(C-

2 CH-2OMe) 2 NHCH (CH 2 OMe) 2 N (CH2CH2OMe) 2 NHCH (CH 2 OMe) 2 NHCH (CH 2 OMe) 2 N (CH 2 CH2OMe) 2 N (CH 2 CH2OMe) 2 NHCH (CH 2 OMe) 2 NHCHPr 2 NEtBu NPr (CH 2 -c-C 3

H

5 N (CH2CH2OMe) 2 NH-3-heptyl NHCH (Et) CH 2 Ome NEt 2 4-i -P r-2- SO2Me -Ph 4 -i-P r-2-SO 2 Me-Ph (Me) 2-4-SMe-Ph 2, 6-(Me) 2-4-SMe-Ph 2, 6- (Me) 2-4-SO2Me-Ph 2, 6- (Me) 2-4 -S0 2 Me-Ph 2-I -4-i-Pr-Ph 2-1-4-i-Pr-Ph 2-Br-4-N (Me) 2-6-MeO-Ph 2-Br-4-N (Me) 2-6-MeO-Ph 2, 4- [SMe] 2-Ph 2, 4- [SMe] 2-Ph 1 SO2Me] 2-Ph 2,4- (SO2Me] 2-Ph 4-i-Pr-2-SMe-Ph 4-i-Pr-2-SMe-Ph 4 -i-P r-2-SO2Me-Ph 4-i-P r-2-SO2Me-Ph 2-N(Me) 2-4-Me-Ph 2-N(Me) 2-4-Me-Ph 2-MeS-4, 6- (Me) 2 -Ph 2 -MeS-4, 6- (Me) 2 -Ph 2- (CH3CO) (Me) 2 -Ph 2- (CH 3 CO) (Me) 2 -Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4,6-Me 3 -Ph 2,4, 6-Me3-P~h 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2,4, 6-me 3 -Ph 238 239 240 241 242 243 244 245 24 C' 247 248 249 250 251 252 253 254 20 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 N NHCH(CH 2 OEt) 2 N NH-3-pentyl N NMePh N NPr2 N NH-3-hexyl N morpholino N N(CH2Ph)CH2CH 2 OMe N NHCH (CH 2 Ph) CH2OMe N NH-4 -tet rahydropyrany 1 N NH-cyclopentyl N 1, 2, 3, 4-tet rahydroisoquinolinyl N CH2-(1,2,3,4-tetrahydroisoquinolinyl) N OEt N OCH(Et)CH 2 OMe N OCH2Ph N 0-3-pentyl N SEt N S(O)Et N SO 2 Et N CH(CO2Et)2 C C(Et) (CO2 Et) 2 N CH(Et)CH 2

OH

N CH(Et)CH 2 OMe N CONMe2 N COCH3 N CH(OH)CH 3 NC (OH) Ph-3-pyridyl N Ph '1 2-CF3-Ph 4 2-Ph-Ph 4 3-pentyl 4 cyciobutyl 4 3-pyridyl 4 CH(Et)CH2CONMe 2 2, 4, 6-Me3-Ph 2, 4, 6-Me 3 -Ph 2, 4, 6-Me 3 -Ph 2,4, 6-Me3-Ph 2, 4,6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2, 4, 6-Me 3 -Ph 2, 4,6-Me 3 -Ph 2,4, 6-Me3-Ph 2, 4,6-Me 3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2, 4,6-Me 3 -Ph 2, 4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me3-Ph 2, 4,6-Me3-Ph 2, 4,6-Me 3 -Ph 2,4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2, 4,6-Me 3 -Ph 2, 4,6-Me 3 -Ph 2, 4,6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2, 4,6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 272 273 274 275 276 277 278 279 2 8 281 282 283 284 285 15 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 N CH (Et) CH 2

CH

2 NMe 2 N NHCH (CH 2 OMe) 2 N NHCHPr 2 N NEtBu N NPr (CH 2 -c-CJHi 5 N N (CH2CH 2 OMe) 2 N NH-3-heptyl N NHCH (Et) CH 2 OMe N NEt 2 N NHCH (CH 2 0Et) 2 N NH-3--pentyl N NMePh N NPr 2 N NH-3-hexyi.

N morpholino N N (CH2Ph) CH 2

CH

2 OMe N NHCH (CH2 Ph) CH 2 OMe N NH-4 -tet rahydropyranyl N NH-cyclopentyl N 1 2 3 4-tet rahydroisoquinolinyl N CH2(1, 2, 3, 4-terahydroisoquinolinyl) N OEt N OCH (Et) CH 2 OMe N

OCH

2 Ph N 0-3-pentyl N SEt N S(O)Et N SO2Et N

CH(CO

2 Et) 2 N C(Et) (CO2Et) 2 N CH(Et)CH 2

QH

N CH (Et) CH 2 OMe N CONMe 2 N

COCH

3 2,4, 6-Me3-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me 2 -Ph 2, 4-Me2-Ph 2, 4-Me 2 -Ph 2,4-Me 2 -Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me 2 -Ph 2, 4-Me 2 -Pth 2, 4-Me2-Ph 2, 4-Me 2 -Ph 2, 4-Me2-Ph 2,4-Me 2 -Ph 2, 4-Me2-Ph 2, 4-Me 2 -Ph 2, 4-Me 2 -Ph 2, 4-Me2-Ph 2, 4-me2-Ph 2, 4-Me 2 -Ph 2, 4-Me2-Ph 306 307 308 309 310 311 312 313 3 14 315 3 1 6 an 15 320 ak 3 2 1 ap 322 aq 3 2 6 au 3 2 7 av 328 aw 3 3 1 az 3 3 3 bb 334bg 3 3 5 bh 3 3 6 bi 3 3 8 bk 339 340 341 342

N

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 CM (OH) CH3 C (OH) Ph-3-pyridyl Ph 2-CF 3-Ph 2 -Ph-Ph 3-pentyl cyclobutyl 3-pyridyl CM (Et)CH 2 CONMe 2 CH (Et)CH 2

CH

2 NMe 2 NEt 2 NH-3-pentyl NMCM (CH2CH2OMe)CHL 2 oMe NM (c-C3H 5 rnorpholino NHCH (CMH2OMe) 2 N(c-C3H 5

)CH

2

CH

2

CN

NMCH (CH 2

CH

2 OMe) CH2OMe

NHCH(CH

2 OMe) 2 N(CH2CM2OMe) 2 NH-3-pentyl NEt2 NMCMH(CH2OMe) 2 NCH (Et) CH2OMe N (CH2CM2OMe) 2 -NHCM (CM 2

CH

2 OMe) CH2OMe N (c-C3H 5 CH2CH 2

CN

NEt 2 OE t -NMCH (CH 2

CH

2 OMe) CH2OMe N (c-C3H5) CH2CM 2

CN

NMCM (CH2CH2OEt) 2 N (c-C3H 5

CH

2

CM

2

CN

-NHCM(CM2CH 2 OMe) CH2OMe NM-3-pentyl N (CM2CM2OMe) 2 2, 4 -Me 2 -Ph 2, 4-Me 2 -Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me 2 -Ph 2, 4-Me2 -Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me 2 -Ph 2, 4-_Me 2 -Ph 2-B r-4-MeQ-Ph 2-Br-4 -MeO-Ph 2, 4, 6-Me 3-Ph 2, 4-Me 2 -Ph 2,4, 6-Me3-Ph 2-CN-4-Me-Ph 2,4, 6-Me 3 -Ph 2-Me-4-Br-Ph 2, 5-Me2-4-MeO-Ph 2, 5-Me2)-4 -MeO-Ph 5-Me2-4 -MeO-?h 2, 5-Me2-4-MeO-Ph 2-Cl-4 -MePh 2-Cl-q -MePh 2-Cl-4-MePh 2-CI-4 -MePh 2, 5-Me2-4-MeOPh 2-Me-4 -MeOPh 2-Me-4-MeOPh 2-Me-4-MeOPh 2-Me-4-MeOPh 2Me4 -MeO-Ph 2, 4-C1 2 -Ph 2, e4-1 2 Ph 2 -Me-4 -BrPh oil oil 101-103 oil 139-14 1 152-153 14 9-151 115-117 55-57 72 45-47 oil 80-8 1 77-79 oil 139-140 120-122 oil oil oil 129 amorph.

109-110 93-94 118 -119 oil *0 *4*4 343 344 345 346 347 348 349 350 351 352 353 354 3 5 5 b1 3 5 6 bm 15 3 5 7 bn 3 5 8 bo 360 361 362 363 364 365 366 367 368 369 370 371 372 373 375 377 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 C -Me C -Me C -Me C -Me C -Me NHCH (CH2-iPr)CH 2 OMe NHCH (Pr) CH2OIMe NHCH (Er.)CH2OEt NHCH (CH2OMe) CH 2 CH2OMe, NEt 2 NH-3-penrtyl N (CH2CH2OMe) 2 NHCH (CH2OMe) 2 NEt 2 NEt2 N'H-3-penrtyl NHCH (CH2OMe) 2

N(CH

2 C-2OMe) 2 NHCH (Et.)CH 2 OMe N (c-Pr) CH 2 CH2CN NEt 2 NH-3-pentyl NHCH (Et)Ct1 2

CH

2 OMe NHCH (Me) CI- 2 CH-2OMe NHCH (Er.)CH 2

CH

2 OMe NHCH (Me)CH2CH2OMe NHCH CH 2 CJI2OMe NHCH (Me) CH2CH2OMe NHCH(CH2OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH CH 2 OMe N (c-Pr) CH 2 CH2CN NEt 2 NH-3-pentyl NHCH CH 2

CH

2 OMe NHCH (Me)CH2CH2OMe NHCH (CH 2 OMe) 2 N (CH 2

C-

2 OMe) 2 NH-CH (Er.)CH2OMe N (c -P r) CH 2

CH

2

CN

NEt2 2, 4-Me2 -Ph 2, 4-Me2-Ph 2, 4 -Me2 -Ph 2-Me-4 -Me2NPh 2 -Me-4 -ClPh 2-Me-4-CIPh 2 -Me-4 -CIPh 2-Me-4-CIPh 2-Me-4-ClPh 2-Cl-4-MePh 2-C 1-4-MePh 2-Cl -4-MeOPh 2-C 1-4-MeOPh 2-CI-4-MeOPh 2-CI-4-MeOPh 2-CI-4-MeOPh 2-CI-4-MeOPh 2-C 1-4-MeOPh 2-CI-4-MeOPh 2-B r-4-MeOPh 2-B r-4-MeOPh 2-Me-4-MeOPh 2-Me-4-MeOPh 2-CI-4, 5- (MeO) 2 Ph 2-CI-4, 5- (MeO) 2 Ph 2-CI-4, 5- (MeO) 2 Ph 2-Cl-4, 5- (MeO) 2 Ph 2-Cl-4, 5- (MeO) 2 Ph 2-C1-4, 5- (MeO) 2 Ph 2-CI-4, 5- (MeO) 2 Ph 2-CI-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- (MeG) 2 Ph oil 94-95 76-77 oil oil 122-124 oil 122-123 oil oil 120-121 oil 108-110 127 -12 9 oil 77-7 9 137-138 147 -14 8 52-58 S.

S

S*

S

C,

S

a 5.55.

379 380 381 382 383 384 385 386 38*1 388 389 390 391 392 393 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 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 C -Me C -Me C -Me C-Me C -Me NH-3-pentyl NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH2CH2OMe

NHCH(CCH

2 OMe) 2 N(CH2CH2OMe) 2 NHCH (Et) CH2OMe N (c-Pr) CH2CH2CN NEt2 NH-3-pentyl NHCH (Et) CH2CH2OMe NHCH (Me) CH2CH2OMe NHCH (CH2OMe) 2

N(CH

2

CH

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

CH

2 OMe NHCH (Me) CH2CH2OMe N (c-P r) CH 2

CH

2

CN

NEt 2 NH-3-pentyl NHCH (Et) CH 2 CH2OMe NHCH (Me) CH-2CH 2 OMe NHCH (Et) CH2CH-2OMe 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) CH2CH 2 oMe NEIH(Me) CH 2

CH

2 OMe NHCH (CH 2 OMe) 2

N(CH

2

CH

2 OMe) 2 2-Br-4, 5- (MeO) 2P h 2 -Br-4, 5- (MeO) 2Ph.

2-Br-4, 5- (MeO) 2Ph 2 -CI 6 (MeO) 2Ph 2-CI-4, 6- (MeO) 2Ph 2-Cl-4, 6- (MeO) 2Ph 2-Cl-4, 6- (MeO) 2Ph 2-Cl-4, 6- (MeO) 2Ph 2-CI-4, 6- (MeO) 2 2h 2-CI-4, 6- (MeO) 2 Ph 2-C1-4, 6- (MeO) 2 Ph 2-Me-4, 6- (MeO) 2Ph 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) 2Ph 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) 22h 2-Br-4, 6- (MeO) 2 Ph 2-Br-4, 6- (MeO) 2Ph 2-Br-4, 6- (MeO) 2 2h 2-Br-4, 6- (MeO) 2 2h 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-Me 0-4-MePh 2-Me 0-4-MePh 2-MeO-4-MePh 2 -MeO-4 -MePh 416 417 418 419 420 421 4 2 3 bt 424 425 426 427 428 429 430 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 NHCH (Et) CH2OMe N (c-Pr) CH2CH 2

CN

NEt 2 NH-3-pentyl NHCH (Et) CH2CH 2 OMe NHCH (Me) CH2CH 2 OMe NHCH (CH2OMe) 2 N(CH2CH 2 OMe) 2 NHCH (Et) CH 2 O;Me N (C-Pr) CH2CH2CN NEt2 NH-3-pentyl NHCH (Et) CH2CH2OMe NHCH (Me) CH2CH 2 OMe 2-MeO-4 -MePh 2-MeO-4 -MePh 2 -MeO-4 -MePh 2-meO-4 -MePh 2-MeO-q -MePh 2-MeO-4 -MePh 2-MeO-4 -CIPh 2-MeO-4 -CiPh 2-MeO-4-CiPh 2-MeO-4 -CIPh 2-MeO-4 -CIPh 2-MeO-4 -CiPh 2-MeO-4-ClPh 2-MeO-4-ClPh q NOTES FOR TABLE 1: a) Analysis Calcd: C, 52.6.9, H, 5.17, N, 17.07, Cl, 17.28; Found: C, 52."82, H, 5.06, N, 16.77, Cl, 17.50.

b) CI-HRMS: CalCd: 406.1565, Found: 405.1573 (M H); Analysis CaICd: C: 59.11; H: 6.20; N: 17.23; Cl: 17.45; Found: C: 59.93; H: 6.34; N: 16.50; Cl: 16. NMR (CDCI3, 300 MHz): 0.95 J 8, 4H), 1.30- 25 1.40 Cm, 4H), 1.50-1.75 4H), 2.35 Cs, 3H), 2.48 3H), 4.30-4.45 (in, 1H), 6.15 Cd, J 8, 1H), 7.30 2H), 7.50 1H) C) CI-HRMS: CalCd: 392.1409, Found: 392.1388 (M H); NMR (CDCI 3 300 MHz): 1.00 J 3H), 1.35 (t, J 8, 3H), 1.41 J 2H), 1.65-1.85 (in, 2H), 2.30 3H), 2.40 3H), 3.85-4.20 (mn, 4H), 7.30 2H) 7 .50 1H) d) CI-HRMS: CalCd: 404.1409, Found: 404.1408 (M H); NMR(CDCl3, 300 MHz): 0.35-0.45 Cm, 2H), 6.52-0.62 2H) 0. 98 J 8, 3H) 1 .70-1 .90 Cm, 2H) 2.30 3H), 2.40 3H) 3.85-4.02 2H), 4.02-4.20 2H), 7.30 2H), 7.50 1H) e) CI-HRMS: Calcd: 424.1307, Found: 424.1307 (M H): NMR (CDCI3, 300 MHz): 2.28 3H) 2.40 3H), 3.40 6H), 3.75 J 8, 4H), 4.20-4.45 (m, 4H), 7.30 2H), 7.50 IH).

f) CI-HRMS: Calcd: 406.1565, Found: 406.1578 (M H); NMR (CDC13, 300 MHz): 0.90 J 8, 3H), 1.00 (t, J 8, 3H), 1.28-1.45 4H) 1.50-1.80 4H), 2.35 3H), 2.50 3H) 4.20-4.35 1H), 6.10-6.23 1H), 7.30 2H), 7.50 1H).

g) CI-HRMS: Calcd: 394.1201, Found: 394.1209 (M H); NMR (CDCI3, 300 MHz): 1.02 J 8, 3H), 1.65- 1.90 2H), 2.35 3H), 2.48 3H), 3.40 (s, 3H) 3.50-3.60 2H), 4.35-4.45 (brs, 1H), 6.50- ~6.60 1H), 7.30 2H), 7.50 1H) h) CI-HRMS: Calcd: 364.1096, Found: 364.1093 (M H); Analysis: Calcd: Cr 56.05; H: 5.27; N: 19.23; Cl: 19.46; Found: C 55.96; H: 5.24; N: 18.93; Cl: 20 19.25; NMR (CDC13, 300 MHz) 1.35 J 8, 6H), 2.30 (3, 3H), 2.40 3H), 3.95-4.15 4H), 7.30 2H), 7.50 J 1, 1H).

i) CI-HRMS: Calcd: 438.1464, Found: 438.1454 (M H); 25 NMR (CDCI3, 300 MHz) 1 .22 J 8, 6H), 2.35 (s, 3H), 2.47 3H), 3.39 J 8, 4H), 3.65 (dd, J 8, 1, 2H), 3.73 (dd, J 8, 1, 2H), 4.55-4.65 (m, 1H), 6.75 J 8, 1H), 7.30 J 1, 2H), 7.50 1H).

j) CI-HRMS: Calcd: 378.1252, Found: 378.1249 (M H); Analysis: Calcd: C: 57.15; H: 5.61; N: 18.51; Cl: 18.74; Found: C: 57.56; H: 5.65; N: 18.35; Cl: 18.45; NMR (CDCI3, 300 MHz) 1.00 J 8, 6H), 1.55- 1.70 2H), 1.70-1.85 2H), 2.35 3H), 2.50 3H), 4.15-4.25 IH), 6.18 J 8, 1H), 7.30 2H) 7.50 1H) k) CI-HRMS: Calcd: 398.0939, Found: 398.0922 (M H); Analysis: Calcd: C: 60.31; H: 4.30; N: 17.58; Cl: 17.80; Found: C: 60.29; H: 4.59; N: 17.09; Cl: 17.57; NMR (CDCI 3 300 MHz): 2.05 3H), 2.50 3H), 3.78 3H), 7.20-7.45 7H), 7.50 J 1, 1H).

1) CI-HRMS: Calcd: 392.1409, Found: 392.1391 (M H); NMR (CDC1 3 300 MHz): 0.98 J 8, 1.70- 1.85 4H), 2.30 3H), 2.40 3H), 3.80-4.10 4H), 7.30 2H), 7.50 J 1, 1H) m) CI-HRMS: Calcd: 392.1409, Found: 392.1415 (M H); 15 Analysis: Calcd: C: 58.17; H: 5.92; N: 17.85; Cl: ee 18.07; Found: C: 58.41; H: 5.85: N: 18.10; Cl: 17.75; NMR (CDCI3, 300 MHz).: 0.90-1.05 6H), 1.35-1.55 2H), 1.55-1.85 4H), 2.35 3H), 2.48 (s, 3H), 4.20-4.35 1H), 6.15 J 8, 1H), 7.30 e. 2H), 7.50 J 1, 1H).

n) CI-HRMS: Calcd: 337.0623, Found: 337.0689 (M H); ~Analysis: Calcd: C: 53.43; H: 4.18; N: 16.62; Cl: 21.03, Found: C: 53.56; H: 4.33; N: 16.56; Cl: 25 20.75; NMR (CDCI3, 300 MHz) 1 .60 J 8, 3H), 2.40 (s, 3H), 2.55 3H), 4.80 J 8, 2H), 7.30 J 8, 1H), 7.35 (dd, J 8, 1, 1H), 7.55 J 1, 1H) o) CI-HRMS: Calcd: 383.2321, Found: 383.2309 (M H); NMR (CDCI3, 300 MHz) 2.00 6H), 2.20 3H), 2.30 3H), 2.45 3H), 3.45 6H), 3.61 (dd, J 8, 8, 2H), 3.70 (dd, J 8, 8, 2H), 4.60-4.70 1H), 6.70 J 8, IH) 6.94 2H) p) CI-HRMS: Calcd: 370.2243, Found: 370.2246 (M H); Analysis: Calcd: C: 65.02; H: 7.38; N: 18.96; Found: C: 65.22; H: 7.39; N: 18.71; NMR (CDC13, 300 MHz): 2.18 3H), 2.30 3H), 2.45 3H), 3.45 6H), 3.60 (dd, J 8, 8, 2H), 3.69 (dd, J 8, 8, 2H), 4.60-4.70 IH), 6.70 J 8, IH), 7.05 J 8, IH), 7.07 (d, J 8, IH), 7.10 IH) q) CI-HRMS: Calcd: 384.2400, Found: 384.2393 (M H); NMR (CDCI3, 300 MHz): 2.16 3H), 2.25 3H), 2.35 3H), 2.39 3H), 3.40 6H), 3.77 (t, J 8, 4H), 4.20-4.45 4H), 7.02 J 8, IH) 7.05 IH), 7.10 J 7, IH).

r) CI-HRMS: Calcd: 354.2294, Found: 354.2271 (M H); ,Analysis: Calcd: C: 67.96; H: 7.71; N: 19.81; Found: C: 67.56; H: 7.37; N: 19.60; NMR (CDCI3, 300 MHz): 1.03 J 8, 3H), 1.65- 1.88 2H), 2.17 3H), 2.30 3H), 2.35 (s, 3H), 2.45 3H), 3.40 3H), 3.50-3.62 2H), 4.30-4.45 IH), 6.51 J 8, IH), 7.04 J 20 8, IH), 7.10 J IH), 7.12 1H).

S) CI-HRMS: Calcd: 338.2345, Found: 338.2332 (M H); Analysis: Calcd: C: 71.18; H: 8.06; N: 20.75; ~Found: C: 71.43; H: 7.80; N: 20.70; NMR (CDC13, 300 MHz): 1.00 J 8, 6H), 1.55- :25 1.70 2H), 1.70-1.85 2H), 2.19 3H), 2.30 e 3H), 2.35 3H), 2.46 3H), 4.15-4.26 (m, IH), 6.17 J 8, IH), 7.06 J 8, IH), 7.10 J 1, IH), 7.13 IH).

t) CI-HRMS: Calcd: 324.2188, Found: 324.2188 (M H); NMR (CDC13, 300 MHz): 1.25 J 8, 6H), 2.16 (s, 3H), 2.28 3H), 2.35 3H), 2.40 3H), 3.95-4.20 4H), 7.05 (dd, J 8, 1, IH), 7.07 IH), 7.10 J 1, IH) u) CI-HRMS: Calcd: 346.1780, Found: 346.1785 (M H); Analysis: Calcd: C: 66.07; H: 5.54; N: 28.39; Found:'C: 66.07; H: 5.60; N: 27.81; NMR (CDCI3, 300 MHz): 2.15 Cs, 3H), 2.32 3H) 2 .17 3H) 2 .52 Cs, 3H) 5. 25-5 .35 (in, 4H), 7. 08 2H), 7.15 1H).

v) CI-HRMS: Calcd: 340.2137, Found: 340.2137 (M H); Analysis: Calcd: C: 67 .23; H 7 .42; N: 20.-63; Found:C: 67.11; H: 7.39; N: 20.26; NMR (CDC13, 300 MHz): 1.40 J 8, 3H), 2.16 (s, 3H), 2.32 3H), 2.35 3H), 2.47 3H), 3.42 3H), 3.50-3.60 28), 4.50-4.15 18), 6.56 Cd, J 8, 1H) 7 .00- 7 .15 3H).

w) CI-HRMS: Calcd: 355.2124, Found: 355.2134 (M H); NMR CCDC13, 300 MHz): 1.05 J 8, 3H), 1.85- 2 .00 2H) 2 .17 3H) 2 .36 6H), 2.50 Cs, *3H) 3 .4 1 Cs, 3H) 3. 45 Cdd, J 8, 3, 1H), 3.82 (dci, J 8, 1, 18H), 5.7 0 80 (in, 1H), 7.00-7.20 38).

X) CT-HRMS: Calcd: 364.2501, Found: 364.2501 CM H); NMR (CDC13, 300 MHz)': 0.35-0.43 28), 0.50-0.60 28), 0.98 Ct, J 8, 38), 1.20-1.30 Cm, 18), 1.72-1.90 Cm, 28), 2.18 Cs, 38) 2.28 Cs, 38), 2.35 Cs, 38), 2 .40 Cs, 38) 3 .88-4 .03 Cm, 28) 4 .03-4 Cm, 28), 7 .00-7 .15 Cm, 3H).

y) CI-HRMS: Calcd: 353.2454, Found: 353.2454 CM H); Analysis: Caici: C: 68.15; H: 8.02; N: 23.84; Found: C: 67.43; H: 7.81; N: 23.45; NMR CCDC13, 300 MHz): 1.38 J 8, 38), 2.18 (S, 38), 2.30-2.40 Cm, 128), 2.47 93, 38), 2.60-2.75 (in, 2H) 4 .30-4 .50 Cm, 18) 6. 60-6. 70 Cm, 18) 7. 00-7 .15 Cm, 38).

z) CI-HRMS: Calcd: 361.2140, Found: 361.2123 CM H); NMR CCDC13, 300 MHz): 0.75-0.83 Cm, 28), 1.00-1.10 Cm, 28) 2 .17 Cs, 3H) 2 .30 Cs, 38) 2 .3 6 Cs, 3H), 2.47 Cs, 38), 2.85 Ct, J 8, 28), 3.30-3.40 Cm, 18) 4 .40-4 .55 Cm, 28) 7.00-7 .18 Cm, 38).

aa) CI-HRMS: Calci: 363.2297, Found: 363.2311 CM H); NMR (CDCI3, 300 MHz) 1 .01 3H, J=8) 1. 75- 1.9go 2H) 2. 15 3H) 2. 19 s, 3H) 2 .35 3H)-, 2.40 3H)f, 2.40 3H1), 2.98 2H, J 3.97-4.15 (in, 2H) 4.15-4.30 (in, 2H) 7.03(d, 1H, 1H) 7.08 (di, 1H, J 7 .10 1H) ab) CI-HRMS: Calcci: 363.2297, Found: 363.2295 (M H); NMR (CDC 13, 300 MHz) 1.-01 3H, J 8) 1. 1 .55 (in, 2H) 1 75- 1.90 (in, 2H) 2. 15 3H) 2 3H) 2.-36 3H) 2 .46 3H) 4 .10-4 .30 (mn, 2H) 4 .95-5 .10 (br s, 2H), 7 .05 1H, 1 8), 7. 10 (di, 1H, J 8) 7 .15 3 1H) ac) CI-HRMS: Calcd: 368.2450, Found: 368.2436; Analysis: Calcd: C, 68 .62, H, 7.95, N, 19. 06; **Found: C, 68.73, H, 7.97, N, 19.09; NMR (CDC13, 300 MHz): 1.05 J 3H), 1.70-1.90 (in, 2H), 2.01 J 3, 6H), 2.20 3H) 2 .30 3H) 2 .4 6, *2.465 s, 3H), 3.42, 3.48 s, 3H), 3.53-3.63 2H) 4.35-4 .45 Cm, 1H) 6.73 (di, J 8, 1H), 6.97 2H).

(ad) CI- HRMS: Calcd: 352.2501, Found: 352.2500 (M Analysis: Caici: C: 71.76; H: 8.33; N: 19.92, Found: C: 71.55; H: 8.15; N: 19.28; *NMR (CDCI3, 300 MHz) 1 .01 J 8, 6H) 1. 58 -1 .70 (in, 2H) 1 .70-1 .85 (mn, 2H) 2. 02 6H), 2.19 3H) 2.45 3H), 4 .12-4.28 (mn, 1H) 6.18 J 8, 1H), 6.95 2H).

(ae) CI- HRMS: Calod: 398.2556, Found: 398.2551 (M Analysis: Caicci: C: 66. 47; H: 7 .86; N: 17.62, Found: C: 66.74; H: 7.79; N: 17.70; NMR (CDCl3, 300 MHz) 2.-00 s, 6H) 2 .12 Is, 3H), 2 .30 3H) 2 .37 3H), 3 .40 6H) 3 .78 (t, J 8, 4H) 4. 25-4 .40 (mn, 4H) 6. 93 2H).

(at) CI-HRMS: Caici: 450.1141, Found: 450.1133 (M H); Analysis: Caici: C 50 .67; H: 5. 37; N: 15. 55; Br: 17.74; Found: C: 52.36; H: 5.84; N: 14.90; Br: 17.44; NMR (CDC13, 300 MHz): 2.32 3H), 2.57 3H), 3.42 6H), 3.60 J 8, 2H), 3.69 8, 2H), 3.82 3H), 4.60-4.70 1H), 6.73 J 8, 1H), 6.93 (dd, J 8, 1, 1H), 7.22 J 8, 1H).

ag) CI-HRMS: Calcd: 434.1192, Found: 434.1169 (M H); Analysis: Calcd: C: 52.54; H: 5.58; N: 16.12; Br: 18.40; Found: C: 52.57; H: 5.60; N: 15.98; Br: 18.22; NMR (CDC13, 300 MHz): 1.00-1.07 3H), 1.65-1.85 2H), 2.35 3H), 2.46, 2.47 s, 3H), 3.40, 3.45 s, 3H), 3.83 3H), 4.35-4.45 1H), 6.55 J 8, 1H), 6.92 (dd, J 8, 1, 1H), 7.20- 7.30 2H).

See.

15 ah) CI-HRMS: Calcd: 337.2266, Found: 337.2251 (M H); Analysis: Calcd: C: 70.18; H: 8.06; N: 20.75; Found: C: 70.69; H: 7.66; N: 20.34; NMR (CDC13, 300 MHz) 1.35 J 8, 6H), 2.01 (s, 6H), 2.15 3H), 2.30 3H), 2.38 3H), 4.07 20 J 8, 4H), 6.93 2H) ai) CI-HRMS: Calcd: 412.2713, Found: 412.2687 (M H); Analysis: Calcd: C: 67.13; H: 8.08; N: 17.02; Found C: 67.22; H: 7.85; N: 17.13; NMR (CDC13, 300 MHz):1.24 J 8, 6H), 2.00 (s, 25 6H), 2.20 3H), 2.30 3H), 2.43 3H), 3.60 J 8, 4H), 3.66 (dd, J 8, 3, 2H), 3.75 (dd, J 8, 3, 2H), 4.55-4.65 IH), 6.75 J 8, 1H), 6.95 2H).

aj) CI-HRMS: Calcd: 398.2556, Found: 398.2545 (M H); Analysis: Calcd: C: 66.47; H: 7.86; N: 17.62; Found: C: 66.87; H: 7.62; N: 17.75; NMR (CDC13, 300 MHz): 1.95-2.10 8H), 2.20 (s, 3H), 2.32 3H), 2.44 3H), 3.38 3H), 3.42 3H), 3.50-3.70 4H), 4.58-4.70 IH), 6.87 J 8, 1H), 6.95 2H) ak) CI-HRMS: Calcd: 338.1981, Found: 338.1971 (M H); Analysis: Calcd: C: 67.63; H: 6.87; N: 20.06; Found: C: 67.67; H: 6.82; N: 20.31; NMR (CDCI3, 300 MHz): 2.15 3H), 2.29 3H), 2.35 3H), 2.43 3H), 3.90 J 8, 4H), 4.35-4.45 4H), 7.00-7.15 3H).

al) CI-HRMS: Calcd: 464.1297, Found: 464.1297 (M H); NMR (CDC13, 300 MHz): 2.28 3H), 2.40 3H), 3.40 6H), 3.75 J 8, 4H), 3.83 3H), 4.20-4.50 4H), 6.93 (dd, J 8, 1, 1H), 7.20 1H) 7.24 J 1, 1H) am) CI-HRMS: Calcd: 418.1242, Found: 418.1223 (M H); NMR (CDC13, 300 MHz): 1.00 d, J 8, 1, 6H), 1.55-1.75 4H), 2.34 3H), 2.49 3H), 2.84 3H), 4. 15-4.27 1H), 6. 19 J 8, 1H) Oo* 15 6.93 (dd, J 8, 1, 1H), 7 21-7.30 2H) an) CI-HRMS: Calcd: 404.1086, Found: 404.1079(M H); :NMR (CDC13, 300 MHz) 1.35 J 8, 6H), 2.28 (s, 3H), 2.40 3H), 3.83 3H), 3.90-4.08 2H), 4.08-4.20 2H), 6.92 (dd, J 8, 1, 1H), 7.20- 20 7.25 2H).

ao) CI-HRMS: Calcd: 308.1875, Found: 308.1872 (M H); NMR (CDC13, 300 MHz): 0.75-0.80 2H), 0.93-1.00 2H), 2. 16 3H), 2.28 3H), 2.35 3H), 2.53 3H), 3.00-3.10 1H), 6.50-6.55 1H), 25 7.00-7.15 3H) Sap) CI-HRMS: Calcd: 397.1988, Found: 397.1984 (M H); NMR (CDC13, 300 MHz) 2.43 3H), 2.50 3H), 3.43 3H), 3.61 (dd, J 8, 8, 2H), 3.69 (dd,J 8, 8, 2H), 3.88 3H), 4.58-4.70 1H), 6.75 J 8, 1H), 7.20 (dd, J 8, 1, 1H), 7.25 J 1, 1H) 7.40 1H) aq) CI-HRMS: Calcd: 375.2297, Found: 375.2286 (M H) Analysis: Calcd: C: 70.56; H: 7.01; N: 22.44; Found: C: 70.49; H: 6.99; N: 22.45; NMR (CDC13, 300 MHz) 0.79-0.85 2H), 1.00-1.05 1H) 2.00 6H), 2.19 3H), 2.32 3H) 2 .44 3H) 2 .84 1 8, 2H) 3 .30-3 .40 (m, 18) 4 50 J 8, 2 6. 95 2H).

ar) CI-HRMS: Calcd: 434. 1192, Found: 434.118 9 (m H); Analysis: CalcI: C: 52.54; H: 5.58; N: 16.12; Br: 18.40; Found: C: 52.75; H: 5.59; N: 16.09; Br: 18.67; NMR (CDC13, 300 MHz) 2 .19 3H) 2.30 3H), 2.47 3H), 3.43 6H), 3.60 Cdd, J 8, 8, 2H) 3. 70 Cdd, J 8, 2H) 4 .58-4 .70 Cm, 1,H), 6. 71 J 18H), 7.-0 8 J 18H), 7. 37 (dci, J 8, 1, 1H) 7 .4 5 Cd, J 1, 1H).

as) CI-HRMS: Calcd: 448.1348, Found: 4 48.1332C(M

H);

Analysis: Calcd: C: 53.58; H: 5.85; N: 16.62; Br: 17.82; Found: C: 53.68; H: 5.74; N: 15.52; Br: 13.03; NMR CCDCl3, 300 MHz) 1.95-2.10 Cm, 28), 2.20 Cs, 3 38), 2 30 C s, 3 2. 47 Cs, 38), 3 .38 C s, 38H), 3 .41 3H) 3. 50-3. 67 im, 48), 4 .55-4 .7 0 Cm, 1H), 6.8 9 J 8, 1H), 7.05 Cd, J 1H), 7.35 (dd, J 8, 1, 1H), 7.47 Cd, J 1, 1H).

at) CI-HRMs: Calcd: 400.2349, Found: 400.2348 CM H); Analysis: Calcd: C: C: 63.14; H: 7.32; N: 17.53; Found: C:63.40; H: 7.08; N: 17.14; NMR CCDC1 3 300 MHz) 2 .16 3H), 2.20 Cs, 38), 2.30 38) 2 .46 Cs, 3H), 3.42 Cs, 68) 3.60 (q, i 8, 28), 3.70 Cq, J 8, 2H), 3.85 Cs, 38), 4.59-4.70 (in, 18), 6.70 J 8, 1H), 6.76 Cs, 1H) 6. 96 Cs, 18) au) CI-HRMS: Calcd: 414 .2505, Found: 414 .2493C(M

H);

NMR (CDC1 3 300 MHz) 2 .15 Cs, 3H) 2. 19 3H) 2.25 Cs, 3H) 2.40 Cs, 38) 3.40 Cs; 6H) 3.76 Ct, J 8, 48) 3 .84 Cs, 3H) 4.-20-4 .45 Cm, 48) 6 .77 Cs, 1H), 6.93 Cs, 18).

av) CI-HRMS: Calcd: 368.2450, Found: 368.2447C(M

H);

NMR CCDC13, 300 MHz) 1 .00 J 68) 1. 1.85 Cm, 48), 2.19 Cs, 38), 2.20 Cs, 3H), 2.30 (s, 3M), 2.47 3H), 3.88 3H), 4.10-4.30 Cm, LH), 6. 15 Cd, J 1H) 6. 78 1H), 6. 98 Cs, 1H) aw) CI-HRMS: Calcd: 353.2216, Found: 353.2197 Cm H); NMR (CDC1 3 300 MHz): 1.35 Ct, J 6H), 2.17 (s, 3H), 2.19 3M), 2.28 3H), 2.40 Cs, 3H), 3.85 Cs, 3M), 3.90-4.20 Cm, 48), 6.78 1HI), 6.95 (s, 1H).

ax) CI-HRMS: Calcd: 390.1697, Found: 390.1688C(m H); Analysis: Calcd: C: 58.53; H: 6.20; N: 17.96; Cl: 9.09; Found: C: 58.95; H: 6.28; N: 17.73; Cl: 9.15; NMR (CDC13, 300 MHz): 2.35 Cs, 38), 2.37 -Cs, 3H), 2.48 3H), 3.42 6H), 3.60 (dd, J 8, 8, 2H) 3.68 (dd, J 8, 8, 2H) 4 .59-4.72 Cm, 1H) 6.72 Cd, J 8, 1H), 7.12 J 8, 1H), 7.23 Cd, J= 8, 1H), 7.32 Cs, 1H).

ay) CI-HRMS: Calcd: 374 .1748, Found: 374 .1735 (M H); *Analysis: Calcd: C: 61.04; H: 6.47; N: 18.73; Cl: 9.48; Found: C: 61.47; H: 6.54; N: 18.23; Cl: 9.61; NMR (CDC13, 300 MHz) 1 .01 J 8, 3H) 1. 62- 1 .88 (in, 4H) 2. 35 3M) 2. 37 Cs, 3H) 2 .48 (d, J 1, 3M), 3.40, 3.45 s, aH), 3.50-3.64 Cm, 2 H) 4 .3 8 -4 .47 Cm, 1 H) 6. 53 J 8, 1H) 7 .12 Cd, J 1H), 7.07 Cd, J 1H), 7.12 Cs, IM).

az) CI-MRMS: Calcd: 404 .1853, Found: 404.1839 CM H); NMR CCDC13, 300 MHz): 2.29 3H), 2.38 Cs, 3M), 2.40 Cs, 3H), 3.40 Cs, 6H), 3.76 Ct, J 8, 4H), 4.20-4.45 Cm, 4H), 7.11 Cd, J 8, 1H), 7.22 Cd, J 8, 1H), 7.31 Cs, 1H).

ba) CI-MRMS: Calcd: 404.1853, Found: 404.1859C(M H); Analysis: C: 59.47; H: 6.50; N: 17.34; CI: 8.79; Found: C: 59.73; H: 6.46; N: 17.10; Cl: 8.73; NMR CCDCI3, 300 MHz): 1.95-2.08 Cm, 2H), 2.35 Cs, 3M) 2 .38 Cs, 3M) 2 .46 Cs, 3M) 3 .38 Cs, 3M) 3 .41 Cs, 3H) 3. 50-3 .65 Cm, 4H), 4. 56-4 .70 Cm, 1H) 6 Cd, J 8, 1H), 7.12 Cd, J 1H), 7.45 Cd, J= 8, 1H), 7.32 1H).

bb) CI-HRMS: Calcd: 391.2246, Found: 391.2258 (m H); Analysis: C: 67.67; H; 6.71; N: 21.52; Found: C: 67.93; H: 6.70; N: 21.48; NMR (CDCl 3 300 MHz): 0.76-0.84 Cm, 2H), 0.84-0.5 1 (in, 2H), 1.00-1.08 2H), 2.15 3H), 2.20 (s, 3H), 2.29 3H), 2.45 38), 2.85 j 8, 2H), 3.28-3.30 (mn, 1H), 3.85 3H), 6.78 1H), 6.95 1H).

bc/ CI-HRMS: Calcd: 386.2192, Found: 386.2181 (m 8); Analysis: C: 62.32; H: 7.06; N: 18.17; Found: C: 62.48; H: 6.83; N: 18.15; NMR (CDC1 3 300 MHz): 7.1 1H, J 6.9 (d, 18, J 6.8 (dd, 1H, J 6.7 (br.d, 1H, J 4.7-4.6 18), 3.85 Cs, 38), 3.70-3.55 (in, 48), 3.45 6H), 2.5 Cs, 3H) 2.3 Cs, 38), 2.15 Cs, 38).

bd) CI-HRMS: Calcd: 400.2349, Found: 400.2336 (M H); :NMR (CDCl 3 300 MHz) 7.1 18, J 6.85 (d, 18H, J 1) 6. 75 (dd, 18H, J 7, 1) 4 .45-4 :20 (br.s, 48), 3.75 t, 4H, J 3.4 Cs, 6H), 2.4 Cs, 38), 2.25 38), 2.15 Cs, 38).

be) CI-HRMS: Calcd: 370.2243, Found: 370.2247 (M H); Analysis: C: 65.02; H: 7.38; N: 18.96; Found: C: 65.28; 8: 7.27; N: 18.71; NMR CCDC13, 300 MHz): 7.1 18, J 8) 6. 85 Cd, 1H, J 6.8 Cdd, 18, J 6.5 Cbr. d, 18, J 4.5-4.3 Cm, 1H) 3. 85 3H) 3.65-3.5 Cm, 2H), 3.4 Cs, 28), 2.5 Cs, 38), 2.3 Cs, 38), 2.2 Cs, 38), 1.9-1.7 (in, 28) 1 .05 Ct, 38, J 7).

bf) CI-HRMS: Calcd: 379.2246, Found: 379.2248 CM 4- 8); NMR CCDCl 3 300 MHz): 7.1 1H, J 6.85 Cd, 18, J 6.8 Cdd, 1H, J 4.3-4.0 Cm, 48), 3.85 Cs, 3H), 3.0 Ct, 2H, 1 2.45 Cs, 38), 2.3 Cs, 3H), 2.2 Cs, 3H), 1.9-1.8 C m, 28), 1.0 Ct, 38, 1 7).

bg) CI-HRMS: Calcd: 340.2137, Found: 340.2122 CM H); NMR (CDC13, 300 MHz): 7.1 1H, J 6.85 (d, 1H, J 6.75 (dd, 1H, J 4.2-4.0 (br.m, 4H), 3.85 3H, 2.4 3H), 2.3 s, 3H), 2.2 3H), 1.35 6H, J 7).

bh) CI-HRMS: Calcd: 313.1665, Found: 313.6664 (M H).

bi) CI-HRMS: Calcd: 400.2349, Found: 400.2346 (M H); NMR (CDC13, 300 MHz): 7.1 1H, J 6.9-6.75 3H), 4.7-4.55 1H) 3.8 3H), 3,7-3.5 (m, 4H), 3.45 3H), 3.35 3H), 2.5 3H), 2.3 3H), 2.2 3H), 2.1-1.95 2H) bj) CI-HRMS: Calcd: 377.2090, Found: 377.2092 (M H); Analysis: C: 67.00; H: 6.44; N: 22.32; Found: C: 67.35; H: 6.44; N: 22 .23; NMR (CDC13, 300 MHz): 7.1 1H, J 6.9 (d, 15 1H, J 6.8 (dd, 1H, J 4.55-4.4 (m, 2H), 3.85 3H), 3. 4-3.3 1H), 2.85 2H, J 2.5 3H), 2.3 3H) 2.2 3H), 1.1- 1.0 2H), 0.85-0.75 2H).

bk) CI-HRMS: Calcd: 413.2427, Found: 413.2416 (M H); 20 NMR (CDC13, 300Hz) 7 .1 1H, J 6.85 (d, 1H, J 6.75 (dd, 1H, J 4.6 1H), 3.85 3H), 3.75-3.6(m, 4H), 3.6 4H, J 7), 3H), 2.3 s, 3H), 2.2 3H), 1.25 6H, J 7).

25 bl) CI-HRMS: Calcd: 420.1802, Found: 420.1825(M H); bm) CI-HRMS: Calcd: 390.1697, Found: 390.1707(M H); bn) CI-HRMS: Calcd: 397.1465, Found: 397.1462(M H); bo) CI-HRMS: Calcd: 360.1513, Found: 360.1514(M H); bp) CI-HRMS: Calcd: 374.1748, Found: 374.1737(M H); bq) CI-HRMS: Calcd: 479.1155, Found: 479.1154 (M H); br) CI-HRMS: Calcd: 463.1219, Found: 463.1211(M H); Analysis Calcd: C: 51.96, H: 5.23, N, 15.15, Br: 17.28; Found: C: 52.29, H: 5.62, N: 14.79, Br: 17.47 bs) CI-HRMS: Calcd: 433.1113, Found: 433.1114(M, 9 Br); bt) NH 3 -CI MS: Calcd: 406, Found: 406 (M NMR (CDCI3, 300 MHz) 5 7 .28 J=lOHz, 1H) 7. 03 J=8Hz, 1H) 6 .96 1H) 6.7 J=9, 1-H) 4 .63 (in, 1H) 3.79 38) 3 .6 (mn, 4H) 3 .42 (s, 6H), 2.47 3H), 2.32 Cs, 3H).

EXAMPLE 431 Preparation of 2, 4 7 -trimethyl-8-(4-methoxy-2.

methylphenyl) 5-a]-pyrazolo-1,3,5-triazine (Formula 1, where R 3 is CH- 3 RI is CR 3 Z is C-CR 3 Ar is 2-methyl 4-inethoxy--phenyl) 5-Acetainidino-4- 4-methoxy-2-methylphenyl) -3- :15 methylpyrazole, acetic acid salt 602 mg, 2 mrnol) was mixed with a saturated NaH-C03 solution (10 mL) .The aqueous mixture was extracted with EtOAc three times.

*.:The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was .:20 taken up in toluene (10 mL) and trimethyl orthoacetate 0.36 g, 3 inrol) 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 :25 mixture was concentrated in vacuo to give an oily solid.

Column chromatography (CHCI3 :MeOH: 1) afforded, after removal of solvent in vacuo, a yellow viscous oil (Rf 0.6, 210 ing, 37% yield) NMR (CDCl3, 300 MHz) :7.15 (d, 1H, J 8) 6. 9 18, J 6.85 (dd, l1H, J 8, 1), 3. 85 3H),f 2. 95 3H), 2. 65 3R) f 2. 4 Cs, 3H), 2.15 3H); CI-RRMS: Calcd: 283. 1559, Found: 283.1554 (M H).

EXAMPLE 432 7 -hydroxy-5-methyl-3-(2-chloro- 4-methylphenyl) pyrazolo 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 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 (M+H) EXAMPLE 433 7-chloro-5-methyl-3-(2-chloro- (Formula 1 where A is CH, R1 is Me, R3 is Cl, Z is C-Me, Ar is 2-chloro-4-methylphenyl) A mixture of 7-hydroxy-5-methyl-3-(2-chloro-4- (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 methyl-3-(2-chloro-4-methylphenyl)-pyrazolo[1,5a]pyrimidine (900 mg, 84% yield) as a yellow oil: NMR

(CDCI

3 300Hz): 7. 35 1H) 7. 28-7 .26 (in, 1H) 71 .6 d, 1H, J 7) 6. 80 1H) 2 .55 3H) 2 .45 3H), 2 .40 3H) CI- MS: 306 (M+H) EXAMP LE 43 4 7- (pent yl- 3-amino) -5-methyl-3- (2-chioro- 4 -methylphenyl)pyrazolo(1, S-a)Pyrimidine (Formula 1 where A is CH, R1 is Me, R3 is pentyl1-3amino, 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-4pey~przlo15-lyimdn (200 mg, 0.65 mxnol) in dimethylsulfoxide (DMSO, 10 mL) was stirred at 150 0 C 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 dichioromethane, washing the combined organic layers :20 with brine, drying over MgSO4, filtration and removal of solvent in vacuo produced a yellow solid. Flash chromatography (EtOAc:hexanes: afforded a white solid (140 mg, 60% yield) mp 139-l41OC; NMR (CDCI 3 300Hz) :7.32 1H), 7.27 1H-, J 7.12 1H, J 6.02 1H, J 5.78 1H), 3.50-3.39 (mn, 1H) 2. 45 3H) 2. 36 6H) 82-1.60 (in, 4 H) 1.0 1 6H, J 8) Analysis Calcd for C20H25ClN 4 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 2 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, Ex is Example, EtOAc is ethyl acetate.

TABLE 2 a.

Lz..

4 3 5 b 4 3 8 e 4 3 9 f 4 4 0 9 441h 442i 443J 4 4 4 k 4451 4 4 6 m 4 4 7 n 4480 449P 450 q 4 5 1 r 4523 4 5 3 t 4 5 4 u 4 5 5 v z 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(CH2CH 2 OMe) 2 N (Bu) Et NHCH (Et) CH2OMe I 4(Pr) CH2CH 2

CN

NH-3-pentyi NHCH (CH2OMe) 2 NHCH(Et) 2 NHCH (CH 2 OMe) 2 N (CH2CH 2 OMe) 2 N (C-Pr) CH2CH 2

CN

N (CH2CH2OMe) 2 NHC- (CH2OMe) 2 NHCH (Et) 2 NEt 2 N (Pr) CH2CH2CN N (Bu) CH2CH 2

CN

NHCH (Et) CH 2 OMe NHCH (Et) 2 NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 -NHCH (CH2CH2OMe) (CH2OMe) -NHCH (CH2CH2OMe) (CH2OMe) &z 2, 4 -C1 2-Ph 2, 4-C12-Ph 2, 4 -C12 -Ph 2, 4-C12 -Ph 4-C12-Ph 2, 4 -C12-Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4-Me2-Ph 2, 4-Me 2 -Ph 2-Cl, 4-MePh 2-Cl, 4-MePh 2-Cl, 4-MePh 2, 4 -Me2 -Ph 2, 4 -Me2 -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 m21D~a 71-73 86-87 110-111 83-85 175-176 107 oil 103-105 87-89 13 3 (dec) 77-78 131-133 139-14 1 92-94 14 3-144 115-117 oil 104 -106 115-116 oil oil oil 456w' C -Me

C

4 5 7

X

458Y 4 6 0 aa 46 1 ab 4 6 2 ac 4 6 3 ad 465af 4 6 6 ag 4 6 8 ai 15 4 6 9 aj 4 7 0 ak 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 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 C -Me C-Me N (CH2CH2OMe) 2 NHEt NHCH (Et) 2 NHCH (CH2QMe) 2 N (Ac) Et -NHCH (CH2CH2OMe) (CH2OMe) N (Pr) CH2CH2CN NEt 2 -NHCH (CH2CH2oMe) (CH2OMe) NEt 2 N (c-Pr) CH2CH2CN N (c-Pr) CH2CH2CN NHCH (Et )CH2OMe NH-CH (Et)CH2OMe NHCH (CH2OMe) 2 N (CH2CH2OMe)2 NH-CH (Et) CH2OMe N (c-Pr) CH2CH2CN NEt2 NH-3-pentyl NHCH (Et) CH2CH2OMe NHCH (Me) CH2CH2OMe NHCH (Et) CH2CH2OMe NHCH (Me) CH2CH2OMe NHCH (Et) CH2CH2OMe NHCH (Me) CH2CH2OMe NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NH-CH (Et) CH 2 OMe N (c -P r) CH2CH2CN NEt2 NH-3-pentyl NHCH (Et) CH2CH2OMe 2-Me, 4-CIPh 2,4-Me2-Ph 2-Me, 4-Ciph 2-Me, 4-CIPh 2, 4 -Me2 -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-CI-4 -MeOPh 2-CI-4 -MeOPh 2-Cl -4 -MeOPh 2-Cl -4 -MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-CI-4-MeOPh 2-CI-4-MeOPh 2-Br-4 -MeOPh 2-B r-4-MeOPh 2-Me-4-MeOPh 2 -Me-4 -MeOPh 2-CI-4, 5- (MeO) 2Ph 2-CI-4, 5- (.MeO) 2Ph 2-CI-4, 5- (MeO) 2Ph 2-CI-4, 5- (MeO) 2Ph 2-CI-4, 5- (MeO) 2Ph 2-CI-4, 5-(MeO) 2Ph 2-CI-4, 5- (MeO) 2Ph oil oil 94-96 113-114 oil oil 118-119 97-99 101-103 129-130 177-178 162-163 oil 111-113 99-10 1 169-170 00 00 00 *0 0 00 0 000a00 490 491 492 493 494 495 496 497 493 499 500 501 502 503 15 504 50-5 506 507 508 509 510 511 512 513 25 514 515 516 517 518 519 520 521 522 523 524 525 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 C-Me C -Me C-Me C -Me C -Me NHCH (Me) CH 2 CH2OMe NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (Et )CH 2 OMe N C-Pr) CH2CH2CN NEt 2 NH-3-pentyl NHCH (Et) CH2CH2OMe NHCH (Me) CH2CH2OMe NHCH (CH2OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (Et CH20Me N (c-Pr) CH2CH 2

CN

NEt 2 NH-3-pentyl NHCH (Et) CH2CH 2 OMe NHCH (Me) CH2CH2OMe NHCH (CH2OMe) 2 N (CH 2

CH

2 OMe) 2 NHiCH (Et) CH2OMe N (c-Pr) CI2CH 2

CN

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

NHCH(CH

2 OMe) 2 N (CH2CH 2 OMe) 2 NHCH (Et) CH-2OMe N (C-Pr)CH 2

CH

2

CN

2-C1-4, 5- (MeO) 2Ph 2-Br-4, 5- (MeO) 2Ph 2-Br-4, 5- (Meo) 2Ph 2-Br-4, 5- (Meo) 2Ph 2-Br-4, 5- (Meo) 2Ph 2-Br-4, 5- (MeO) 2Ph 2-Br-4, 5- (Meo) 2Ph 2-Br-4. 5- (Meo) 2 Ph 2-Br-4, 5- (Meor 2 Ph 2-CI-4, 6- (Meo) 2Ph 2-C1-4, 6- (Meo) 2Ph 2-CI-4, 6- (Meo) 2Ph 2-CI-4, 6- (Meo) 2Ph 2-CI-4, 6- (Meo) 2Ph 2-CI-4, 6- (Meo) 2Ph 2-CI-4, 6- (MeO) 2Ph 2-Cl-4, 6- (MeO) 2Ph 2-Me-4, 6- (Meo) 2Ph 2-Me-4, 6- (MeO) 2Ph 2-Me-4, 6- (MeO) 2Ph 2-Me-4, 6- (Meo) 2Ph 2-me-4, 6- (MeO) 2Ph 2-Me-4, 6- (MeO) 2Ph 2-Me-4, 6- (MeO) 2Ph 2-Me-4, 6- (MeO) 2Ph 2-Br-4, 6- (MeO) 2Ph 2-Br-4, 6- (MeQ) 2Ph 2-Br-4, 6- (Meo) 2Ph 2-Br-4, 6- (MeO) 2 Ph 2-Br-4, 6- (Meo) 2Ph 2-Me-4 -MeOph 2-Me-4 -MeOPh 2-MeO-4-MePh 2-MeO-4-Meph 2-MeO-4 -MePh 2-Me 0-4 -MeP h 90-93 110 526 527 528 529 530 5.31 532 533 53 4 535 536 537 538 539 540 541 542 543 544 545 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 2 NH-3-pentyl NHCH (Et) CH 2 CH2OMe NHCH (Me) CH 2

CH

2 OMe NHCH (CH2OMe) 2 N (CH2CH42OMe) 2 NHCH (Et) CH2OMe N (c-Pr) CH 2 CH2CN 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) CH 2 OMe N (c-Pr) CH 2 CH2CN NEt 2 NH- 3-penty.

NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH2CH 2 OMe 2-Me 0-4-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-Me 0-4-MePh 2-MeO-4 -MePh 2-Me 0-4-MePh 2-MeO-4 -ClPh 2-MeO-4-ClPh 2-MeO-4-ClPh 2 -MeO-4 -CIPh 2-MeO-4-ClPh 2-MeO-4-ClPh 2-MeO-4-ClPh 2-MeO-4-ClPh at a NOTES FOR TABLE 2: a. a tat...

b) CI-HRMS: 25 c) Analysis: Found: C, d) Analysis: Found: C, e) Analysis: Found: C, if) Analysis: Found: C, h) CI-HRMS: i) Analysis: Found: C, CalCd: 423.1355; Found: 423.1337 (M H).

CalCd: C, 61.38, H, 6.18, N, 14.32: 61.54, H, 6.12, N, 14.37.

CalCd: C: 58.02, H, 5.65, N, 14.24; 58.11, H, 5.52, N, 14.26.

Calcd: C, 59.71, H, 5.26, N, 14.85; 59.94, H, 5. 09, N, 17. 23 Calcd: C, 60.48, H, 5.89, N, 14.85, 60.62, H, 5. 88, N, 14.82 CalCd: 337.2388; Found: 337.2392 CM H).

CalCd: C, 68.45, H, 7.669, N, 15.21, 68.35, H, 7.49 N, 14.91.

j) Analysis: Calcd: C, 69.08, H, 7.915, N, 14.65, Found: C, 68.85, H, 7.83, N, 14.54.

k) Analysis: Calcd: C, 73.51, H, 7.01, N, 19.48, Found: C, 71.57, H, 7.15, N, 19.12.

1) CI-HRMS: Calcd: 403.1899; Found: 403.1901 (M H).

m) Analysis: Calcd: C, 61.77, H, 6.49, N, 14.41, Cl.

9.13; Found: C, 61.90, H, 6.66, N, 13.62, Cl, 9.25.

n) Analysis: Calcd: 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.

a o) Analysis: Calcd: C, 74.50, H, 8.14, N, 17.38, Found: C, 74.43, H, 7.59, N, 17.16.

p) Analysis: Calcd: C, 73.10, H, 7.54, N, 19.37, Found: C, 73.18, H, 7.59, N, 18.81.

q) Analysis: Calcd: C, 73.57, H, 7.78, N, 18..65, Found: C, 73.55, H, 7.79, N, 18.64.

r) CI-HRMS: Calcd: 353.2333; Found: 353.2341 (M H).

s) Analysis: Calcd: C, 71.56, H, 8.02, N, 15.90, Found: C, 71.45, H,-7.99, N, 15.88.

t) Analysis: Calcd: C, 65.60, H, 7.34, N, 14.57, Found: C, 65.42, H, 7.24, N, 14.37.

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

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

w) CI-HRMS: Calcd: 383.2450; Found: 383.2447 (M H).

x) CI-HRMS: Calcd: 403.1887; Found: 403.1901 (M H).

y) CI-HRMS: Calcd: 295.1919; Found: 295.1923 (M H).

z) Analysis: Calcd: C, 67.31, H, 7.06, N, 15.70, Found: C, 67.12, H, 6.86, N, 15.53.

aa) Analysis: Calcd: C, 61.77, H, 6.49, N, 14.41, Cl, 9.13; Found: C, 62.06, H, 6.37, N, 14.25, Cl, 9.12.

ab) CI-HRMS: Calcd: 337.2017; Found: 337.2028 (M H).

ac) CI-HRMS: Calcd: 403.1893; Found: 403.1901 (M H).

ad) Analysis: Calcd: C, 70.00, H, 7.22, N, 18.55, Found: C, 70.05, H, 7.22, N, 18.36.

ae) Analysis: Calcd: C, 70.98, H, 7.74, N, 16.55, Found: C, 71.15, H,7.46, N, 16.56.

ag) Analysis: Found: C, ah) Analysis: Found: C, ai) Analysis: 9. 33; Found: C, aj) CI-HRMS: akl Analysis: Found: C, Calcd: C, 66:59, 6 6. 69, H, 6. 82, N, Calcd: C, 70.38, 70 .35, H, 6. 82, N, Calcd: C, 66.39, H, 6.76, N, 16.34, 16.20.

H, 6.71, N, 18.65, 18.83.

H, 5.85, N, 18.44, Cl, 66.29, H, 5.51, N, 18.36, Cl, 9.31.

Calcd: 369.2278; Found: '369.2291 (M H) Calcd: C, 64.42, H, 6.77, N, 15.02, 64.59, H,6.51, N, 14.81.

a. as a a a. a a. a The examples delineated in TABLE 3 may be prepared by the methods outlined in Examples 1, 2, 3 or 6. Commonly 15 used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example.

TABLE 3

WN

N N z A r 4 6 a 5 4 7 b

C-M

C-Me R.1 NHCH (Et) 2 S-NHCH (CH2CH2OMe) -CH 2OMe S-NHCH (CH2CH20Oe N (C-Pr) CH2CH 2

CN

2-Me-4 -Me2N-Ph 2, 4-Me2-Ph 2-Me-4-CI-Ph 2-Me-4-Cl-Ph H1pL~c.

164-166 oil oil 115-116 4 8C C-Me 4 9 d C-Me a. a 5 0e 5 1f 5 29 553h 558 559 560 5611 562 56 3 m 15 564 565 566 567 568 20 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 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 C-Me C -Me C-Me C-Me NHCH (Et) CH2CN N (Et) 2 N (CH2CH2OMe) CH2CH2OH N (CH2CH2OMe) 2 NHCH (Et) 2 N (CH2 -c-Pr) Pr N (c-P r) CH2CH 2

CN

N (c-Pr) Et N (c-Pr) Me N(c-Pr) Pr N (c-Pr) Bu N(Et) 2 N(c-Pr) 2 NHCH (CH2OH) 2 N(c-Pr) Et N (c-Pr) Me NH-c-Pr NHCH (EE) CH20H NMe 2 NHCH (Et) 2 N(c-Pr) Et NH-2 -pentyl NHCH (Et)CH2CN NHCH (Pr)CH2OMe NHCH (CH2-iPr) CI2OMe NH-2-butyl NH-2-pentyl NH-2-hexyl NHCH (i -P r) Me NHCH (Me) CH2-iP r NHCH (Me) -c-C6Hl 1 NH-2-indanyl NH-1-indanyl NHCH (Me) Ph NHCH (Me)CH2- (4-CIPh) 2-Me-4-Cl-Ph 2, 3-me2-4-OMe-Ph 2, 4-C12-Ph 2, 3-Me2-4-OMe-Ph 2, 3-Me2-4-OMePh 2-Me-4-CI-Ph 2, 3-Me2-4-OMePh 2-CI-4-OMePh 2-Cl-4-OMePh 2-C1-4-OMePh 2-C 1-4-OMePh 2-Cl-4-CN-Ph 2-C 1-4-OMe 2, 4-Cl2-Ph 2-Br-4, 5- (MeO) 2Ph 2-Br-1, 5- (MeO) 2Ph 2-Me-4-MeOPh 2-Me-4-MeOPh 2-Br-4, 5- (MeO) 2Ph 2 -Me-4 -MeOPh 2-Me-4 -MeOPh 2, 4-C12-Ph 2, 4-C12-Ph 2, 4-Cl2-Ph 2, 4-Cl2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 4-Me2-Ph 131-132 oil oil oil 123 -12 4 oil 158 -160 115-117 127-129 128-129 126-128 60-62 103-105 17 3-174 118 -120 141-1 4 2 87-88 amorphous oil oil oil oil oil oil oil oil oil oil vow.

6 06 000*0: 0 585 586 587 588 589 590 591n 5920 59':P 594 595q 596r 597S 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 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-c-Pr 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-OH

c _OH NHCH(Me)CH2COCH3 NHCH(Ph)CH2Ph NHCH(Me)(CH2)3NEt2 NH- (2-Ph-c-C3HO NHCH(Et)CH2CN NH-3-hexyl NEt2 NHCH(Et)2 NHCH(Et)CH20Me NMe2 NHCH(Et)2 NEt2 NHCH(CH20Me)2 N(c-Pr)Et N(c-Pr)Et N(c-Pr)Et N(c-Pr)Et N(c-Rr)Et NHCH(c-Pr)2 NHCH(c-Pr)2 NHCH(c-Pr)2 NHCH(c-Pr)2 NHCH(c-Pr)2 NHCH(.c-Pr)2 NHCH(CH20Me)2 NEt2 N (c-Pr) CH2CH2CN NHCH(Et)2 N (CH2CH2OMe) 2 NEt2 N(c-Pr)CH2CH2CN NHCH(Et)2 N(CH2CH2OMe)2 NHCH(CH20Me)2 NEt2 N (c -P r) CH2CH2CN 2, 4-Me2-Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4-Me2-Ph 2, 4 -Me2 -Ph 2-MeO-4-ClPh 2-MeO-4-CIPh 2-MeO-4-ClPh 2-MeO-4-CIPh 2-OMe-4-MePh 2-OMe-4-MePh 2,4-CI2-Ph 2,4-Me2-Ph 2,4-C12-Ph 2,4,6-Me3-Ph 2-Me-4-Cl-Ph 2-Cl-4-Me-Ph 2,4-CI2-Ph ,,4-Me2-Ph 2-Me-4-Cl-Ph 2-Cl-4-Me-Ph 2-Me-4-OMe-Ph 2-Cl-4-OMe-Ph 2,6-me2-pyrid-3-yl 2,6-Me2-pyrid-3-yl 2,6-Me2-pyrid-3-yl 2,6-Me2-pyrid-3-yi 2,4-Me2-Ph 2,4-Me2-Ph 2,4-Me2-Ph oil oil oil oil 119-120 oil oil oil oil oil oil oil oil 140 621 C-OH NHCH (Et) 2 2, 4-Me2 -Ph 623 C-OH N (CH2CH 2 oMe) 2 2,4-Me2-Ph 624 C-NEt 2

NHCH(CH

2 0Me) 2 2,4-Me2-Ph 625 C-NEt2 NEt 2 2,4-Me2-Ph 626 C-NEt2 N (c -P r)CH2CH2CN 2,4-Me2-Ph 627 C-NEt2 NHCH(Et) 2 2,4-Me2-Ph 628 C-NEt2 N(CH 2

CH

2 OMe) 2 2,4-Me 2 -Ph 629 C-Me NHCH(Et) 2 2-Me-4-CN-Ph 63i C-Me N(CH 2

CH

2 OMe) 2 2-Me-4-CN-Ph Notes for Table 3: CI-HRMS: Calcd:367.2610, Found: 367.2607 CM H); b) CI-HRMS: Calcd:384.2400, Found: 384.2393 (M H); :15 c) CI-fIRMS: Calcd:404.1853, Found: 404.1844 (M H); d) CI-HRMS: Calcd:381.1594, Found: 381.1596 (M H); Analysis: Calcd: C: 63.07, H, 5.57, N, 22.07, Cl, 9 3 :Found: C: 63.40, H, 5.55, N, 21.96? Cl: 9.15 e) CI-HRMS: Calcd:369.1594, Found: 369.1576 CM H); f) CI-fIRMS: Calcd:354.2216, Found: 354.2211 (M H); g) CI-HRMS: Calcd:410.1072, Found: 410.1075 CM H); h) CI-fIRMS: Calcd:414.2427, Found: 414.2427(M H); CI-fIRMS: Calcd:368.2372, Found: 368.2372(M H) j) CI-HRMS: Calcd:384.1955, Found: 384 .1947 (M H) k) Cl-fIRMS: Calcd:391.2168, Found: 391.2160(M H); 1) CI-fIRMS: Calcd:335.1984, Found: 335.1961CM H); m) CI-fIRMS: Calcd:382.0759, Found: 382.0765(M H); n) NH 3 -CI MS: Calcd: 360, Found: 360 (M +H) o) NH 3 -CI MS: Calcd: 374, Found: 374 (M NMR (CDCI 3 300 MHz) :8 7.29 Cd, J=8.4Hz, 1HI), 7.04 (dd, J=1.8,8Hz, 1H), 6.96 J=1.8Hz, 1H), 6.15 J=10, 1HI), 4.19 Cm, iI), 3.81 3H), 2.47 (s, 3H), 2.32 Cs, 3HI), 1.65 4H), 0.99 Ct, J=7.32Hz, 6H) p) NH 3 -CI MS: Calcd: 390, Found: 390 (M NIMR (CDCI3, 300 MHz) 5 7 .28 J=8Hz, lH) 7. 03 Cd, J=8Hz, 1H) 6. 96 1H) 6.52 J=.9Hz, .1H) 4 .36 Cm, 1H) 3. 8 3H) 3. 55 (in, 2H) 3 .39 (s, 3H) 1 2. 47 3H) 2. 32 3H) 1.76 (in, 2H), 1.01 J=7.32Hz, 3H).

q) CI-HRMS: Calcd: 354.2294, Found: 354.2279 (M +H) r) CI-HRMS: Calcd: 340.2137, Found: 340.2138 (M +H) S) CI-HRMS: Calcd: 436.1307, Found: 436. 1296 (M +H) The examples delineated in TABLE 4 may be prepared by the methods outlined in Examples 1A, IB, 432, 433, 434.

Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is 0 015 Example, EtOAc is ethyl acetate.

R0 3 0 0@ 0 Ra 63 *0eNC E)2 -r4 -(eO P 6 -6 632 TAL 4-eNC E)22B--e 1-1 633 0-eNC2HOe22B--e 47 63 C-M 0H H(H0 e -B -e 2 -3 00* 0 *o 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 20 654 655 656 6 57 658 659 660 661 662 663 664 665 666 667 668 669 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-OH

C -OH C -OH

C-OH

C -OH C -NEt 2 C-NEt 2 C-NEt 2 C-NEt 2 C-NEt 2 C-Me C-Me N (Et) 2 N (C-Pr) Et N (c-Pr) Et "N(c-Pr) Et N (c-Pr) Et N (c-Pr) Et N (c-Pr) Et N (c-Pr)-Et NHCH (c-Pr) 2 NHCH (c-Pr) 2 NHCH (c-Pr) 2 NHCH (c-Pr) 2 NHCH (c-Pr) 2 NHCH (c-Pr) 2 NHCH (CH 2 OMe) 2 NEt2 N (c-P r) CH2CH 2

CN

NHCH 2 N (CH2CH 2 OMe) 2 NEt 2 N (c-P r) CH2CH 2

CN

NHCH (Et) 2 N (CH2CH2OMe) 2 NHCH (CH2OMe) 2 NEt 2 N (c-P r) CH2CH 2

CN

NHCH(Et) 2 N (CH 2 CH2OMe) 2 NHCH (CH2OMe) 2 NEt~2 N (c-Pr) CH2CH2CN NHCH (Et) 2 N (CH2CH2OMe)2 NHCH (Et) 2 N (CH2CH2OMe) 2 2-Me-4 -CIPh 2, 4-CI 2 Pt 2, 4-Me2Ph 2,4, 6-Me 3 Ph 2-Me-4 -MeOPh 2-CI-4 -MeOPh 2-Cl-4-MePh 2-Me-4 -CIPh 2, 4-C12-Ph 2, 4-Me2-Ph 2-Me-4-Cl-Rh 2-Cl-4-Me-Ph 2 -Me-4 -OMe-Ph 2-CI-4-OMe-Ph 2-C 2, 6-Me2-pyrid-3-yl 2, 6-Me2-pyrid-3-yI 2, 6-Me2-pyrid-3-yI 2, 6-Me2-pyrid-3-yl 2, 4-Me 2 -Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2-Me-4 -CM-Ph 2-Me-4-CN-Ph 113-114 The examples in Tables 5 or 6 may be prepared by the methods illustrated in Examples 1A, 1B, 2, 3, 6, 431, 432, 433, 434 or by appropriate combinations thereof. Commonly used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is Example.

Table

N

0

N

Ar 670 671 672 673 674 675 676 677 678 679 680 681 682 683 MeA Me Me Me Me Me Me Me Me Me Me Me Me Me NHCH (CH2OMe) 2 NHCHPr 2 NEtBu NPr (CH2-c-C 3 H5) N (CH2CH2OMe)2 NII-3-rieptyl NHCH (E t)CH 2 OMe NEt 2 NHCH (CH2OEt )2 NH--3-pentyl NMe Ph NP r2 NH-3-hexyl morpholino 2,&Z12P 2, 4-C12 -Ph 2, 4-C12-Ph 2, 4-C12 -Ph 2, 4-C12 -Ph 2, 4-C12-Ph 2, 4-C12-Ph 2, 4-C12-Ph 2, 4-C12-Ph 2, 4 -C12 -Ph 2, 4 -C1 2 -Ph 2, 4-C1 2 -Ph 2, 4-C12-Ph 2, 4 -C1 2 -Ph .00.

684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 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 Me Me Me Me N (CH2 Ph) CH2CH2OMe NHCH (CH 2 Ph) CH 2 OMe NH-4 -tetrahydropyranyl NH-cyclopentyl OEt OCX (Et) CH2OMe

OCX

2 Ph 0-3 -pent yl SEt S (0)Et S02Et Ph 2-CF 3 -Ph 2-Ph-Ph 3-pentyl cyclobutyl 3-pyridyl CH (Et) CR 2 CONMe 2 CM (Et)CH2CH2NMe 2 NHCH (CH20Me) 2 MCM P r2 NEtBu NPr (CH2-c-C3HS) N (CH2CH 2 OMe) 2 NH-3-heptyl NHCH (Et) CH 2 0Me NEt 2 NHCH (CH20Et) 2 NH-3-pentyl NMePh NP r2 MM -3 -hexy 1 mo rphoIi no N (CH 2 Ph) CH2CH 2 OMe MMCX (CH 2 Ph) CH2OMe NH-4 -tetrahydropyranyl 2, 4-C12-Ph 2, 4-C12-Ph 2, 4-C12-Ph 2, 4-C12-Ph 2, 4-C12-Ph 2, 4 -C 2 -Ph 2, 4-C12-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-C12-Ph 2, 4-C12 -Ph 2, 4-C1 2 -Ph 2, 4-C12-Ph 2, 4 -C12 -Ph 2, 4 -C1 2 -Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2, 4, 6 -Me 3-Ph 2, 4, 6-Me3-Ph 2,4, 6-me3-Ph 2, 4, 6-Me 3 -Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2, 4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2,4, 6-me 3 -Ph 2, 4, 6-Me 3 -Ph a a a 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 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 Me Me Me Me NH-cyclopentyl oE t OCH (Et) CH2OMe

OCH

2 1Ph 0-3-pentyl SEt S Et

SO

2 Et CH (CO 2 Et) 2 C (Et) (CO2Et) 2 CH (Et)CH 2

OH

CH (Et) CH2OMe CONMe2

COCH

3 CH (OH) CH 3 C (OH) Ph-3-pyridyl Ph 2-Ph-Ph 3-pentyl cyclobutyl 3-pyridyl CH (Et) CH 2 CONMe 2 CH (Et) CH 2

CH

2 NMe 2 NHCH (CH2OMe) 2 N (CH 2

CH

2 oMe) 2 NHCH (Et)CH2OMe NH-3-penty.

NEt 2 N (CH2CN) 2 NHCH- (Me) CH2OMe OCH (Et)CH2OMe NP r-c-C 385 NHCH (Me)CH 2 NMe 2 N (c-C3H5)CH 2

CH

2

CN

N (P r) CH2CH2CN N (Bu) CH2CH2CN 2, 4, 6-Me3-lPh 2,4, 6-.me3-Ph 2,4, 6-me 3 -Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me3-Ph 2, 4, 6-Me 3 -Ph 2, 4, 6-Me 3 -Ph 2, 4, 6-Me 3 -Ph 2,4, 6-Me 3 -p h 2, 4, 6-Me3-Ph 2, 4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2, 4,6-Me3-Ph 2,4, 6-Me3-Ph 2, 4, 6-Me-Ph 2, 4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2,4, 6-me 3 -Ph 2,4, 6-Me3-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-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-Me2-Ph 2, 4-Me 2 -Ph 2, 4-Me2-Ph 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 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 Me Me Me Me NHCHPr 2 NEtBu NPr (CH2-c-C 3 H5) NH-3-heptyl NEt 2 NHCH (CH2OEt) 2 NH-3-pertyl NMePh NPr2 NH-3-hexyl mo rpholino N (CH 2 Ph) CH2CH2OMe NHCH (CH2Ph)C-H 2 OMe NH-4 -tet rahydropyranyl NH c c Iopen ty I

NHCH(CH

2 OMe) 2 N (CH2CH2OMe) 2 NHCH (Et) CH2OMe N (P r) CH-2CH2CN OCH (Et) CH2OMe

NHCH(CH

2 OMe) 2 N (CH2CH 2 OMe) 2 NHCH (Et) CH2OMe N (Pr) CH2CH 2

CN

OCH (Et) CH2OMe

NHCH(CH

2 OMe) 2 N(CH2CH2OMe) 2 NHCH (Et) CH2OMe N (Pr) CH2CH2CN OCH (Et) CH2OMe NHCH (CH 2 OMe) 2 N (CH2CH 2 OMe) 2 NHCH (Et) CH2OMe N (P r) CH 2 CH2CN OCH (Et) CH2OMe NHCH (CH 2 OMe) 2 2, 4 -Me2 -Ph 2 ,4-Me2-Ph 2, 4 -Me2-Ph 2, 4 -Me2-Ph 2, 4 -Me2-Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4-Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2-Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me 2 -Ph 2, 4 -Me2 -Ph 2-Me -4-MeO-Ph 2-Me-4 -MeO-Ph 2 -Me-4 -MeO-Ph 2 -Me-4 -MeO-Ph 2 -Me-4~-MeO-Ph 2-B r-4 -MeO-Ph 2-B r-4-MeO-Ph 2-B r-4-MeO-Ph 2-B r-4-MeO-Ph 2-B r-4-MeO-Ph 2-Me-4-NMe 2 -Ph 2-Me-4 -NMe 2 -Ph 2-Me-4 -NMe 2 -Ph 2-Me-4-NMe 2 -Ph 2-Me-4-NMe 2 -Ph 2-Br NMe 2-Ph 2-B r-4-NMe 2 -Ph 2-Br-4 -NMe 2 -Ph 2-Br-4 -NMe 2 -Ph 2-Br-4 -NMe2 -Ph 2-Br-4 -i-Pr-Ph a 792 793 794 795 796 797 798 799 801l 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 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 Me Me Me Me N (CH2GH2OMe) 2 NHCH (Et) CH2OMe N (Pr) CH2GEI2CN OGH (Et CH2OMe NEIGH (CH2OMe) 2 N (CH2CH2OMe) 2 NEICH (Et CH2OMe N (Pr) CH- 2

CH

2

GN

OCH (Et) CH2OMe NEIGH (CH-2Me) 2 N (CH 2

CH

2 OMe) 2 NHCH (Et CH2OMe N (Pr) GH2CH2GN OGH (Et) CH2OMe NEIGH (CH2OMe) 2 N (CH2cH 2 OMe) 2 NEIGH (CH2OMe) 2 N (CH2GH 2 OMe) 2 NEICH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NEIGH (CH2OMe) 2 N (GH2CH- 2 oMe) 2 NEIGH (CH 2 OMe) 2 N (GH2CH 2 OMe) 2 NEIGH (CH 2 OMe) 2 N (CH2GM 2 OMe) 2 NEIGH (CH 2 OMe) 2 N (CH2CH 2 OMe) 2 NEIGH (CH2OMe) 2 N (CH2CH 2 OMe) 2 NEIGH (CH-2OMe) 2 N (CH2CH 2 OMe) 2 NEIGH (CH 2 OMe) 2 N (CH2CH 2 OMe) 2 NEIGH (CH 2 OMe) 2 N (CH2CH 2 OMe) 2 2-Br-4-i-Pr-Ph 2-Br- 4 -i -P r -Ph_ 2-Br-4-i-Pr-Ph 2-Br-4-i-Pr-Ph 2-B r-4-Me-Ph 2-B r-4 -Me-Ph 2-Br-4 -Me-Ph 2-B r-4-Me-Ph 2-Br-4 -Me-Ph 2-Me-4 -Br-Ph 2-Me-4 -Br-Ph 2-Me-4 -Br-Ph 2-Me-4 -Br-Ph 2-Me-4 -Br-Ph 2-GI-4, 6-Me2-Ph 2-CI-4, 6-Me 2 -Ph 4-Br-2, 6- (Me) 2-Ph 4-Br-2, 6- (Me) 2-Ph 4-i -P r-2-S Me -Ph 4-i-P r-2-SMe-Ph 2-Br-4 -GF 3 -Ph 2-Br-4 -GF 3 -Ph 2-Br-4, 6- (MeO) 2-Ph 2-Br-4, 6-(MeO) 2 -Ph 2-CI-4, 6-(MeO)2-Ph 2-Cl-4, 6- (MeO) 2 -Ph 2,6- (Me) 2-4-SMe-Ph 2,6- (Me) 2-4-SMe-Ph 4- (COMe) -2-Br-Ph 4- (GOMe) -2-Br-Ph 2,4, 6-Me3-pyrid-3-yI 2,4, 6-Me3-pyrid-3-yI 2, 4- (Br) 2 -Ph 2, 4- (Br) 2 -Ph 4-i-Pr-2-SMe-Ph 4-i-Pr-2-SMe-Ph 148 b 828 829 830 831 832 833 834 835 833' 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 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 Me Me Me Me NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (CH2OMe)2 N (CH2CH2OMe) 2 NHCH (CH2OMe) 2 N (CH2CH2QMe) 2 NHCH (CH2OMe) 2 N (CH2CH2oMe) 2 NHCH (CH2oMe) 2 N (CH2CH2OMe) 2 NEt 2 NH -3-pen tyi NHCH (CH2OMe) 2 N (c-C3H 5 CH2CH2CN NHCH (CH2CH- 2 OMe) CH2OMe NHCH (CH2OMe) 2 N (CH2CH 2 OMe) 2 NH -3-pent yl .NEt2 NHCH (CH 2 OMe) 2 NCH (Et CH2OMe N (CH2CH2OMe) 2 -NHCH (CH2CH2OMe) CH 2 OMe N (c -C3H 5) CH 2

CH

2

CN

NEt 2 QEt CS) -NHCH (CH 2 CH2OMe)CH 2 OMe N (c-C3H 5 CH2CH 2

CN

NHCH (CH2CH2OEt) 2 N (c-C3H 5 CH2CH 2

CN

NEt 2 NH-3 -pentyl N (CH2CH 2 OMe) 2 NHCH(CH2OMe) 2 NEt 2 NEt 2 4-i-P r-2-SO2Me-Ph 4 -i-P r- 2 -SO2Me-Ph 2,6- (Me) 2-4-SMe-Ph 2,6- (Me) 2-4-SMe-Ph 2, 6 -cr.e)2-4-SO2Me-Ph 2,6- (Me) 2 -4-SO2Me-Ph 2 -I-4-i-Pr-Ph 2 -I-4-i-Pr-Ph 2-Br-4-N(Me) 2-6-MeO-Ph 2-Br-4-N (Me) 2-6-MeO-Ph 2-Br-4 -MeO-Ph 2-Br-4 -MeO-Ph 2-CN-4 -Me-Ph 2, 4, 6-Me3-Ph 2-Me-4-Br-Ph 2, 5-Me2-4-MeO-Ph 2, 5-Me2-4-MeO-Ph 2, 5-Me2-4-MeO-Ph 2, 5-Me2-4-MeO-Ph 2-Ci-4-MePh 2-CI-4-MePh 2 -C1-4-MePh 2-C 1-4-MePh 2, 5-Me2-4-MeOPh 2-Me-4-MeOPh 2-Me-4 -MeOPh 2-Me-4-MeQPh 2-Me-4-MeOPh 2-Me-4 -MeOPh 2, 4-C12-Ph 2 -Me-4 -CiPh 2-Me-4-C1Ph 2-Me-4-CIPh 2-Me-4-CIPh 2-Me-4 -CIPh 2-Cl-4-MePh 864 865 866 867 868 869 870 871 87 2 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 NH-3-pentyl NHCH (CH2OMe) 2 N (CH-2CH2QMe) 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 2CH 2 OMe NHCH (Et) CH 2CH 2 OMe NHCH (Me)CH2CH 2 OMe NHCH (Et)CH 2

CH

2 OMe ,NHCH (Me)CH2CH2OMe NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (Et) CH2OMe N (c-P r) CH 2 CH2CN NEt 2 N1H-3-pentyl NHCH (Et) CH- 2 CH2OMe NHCH (Me) CH 2

CH

2 OMe NHCH (CH 2 OMe) 2 N (C H2CH 2OMe) 2 NHCH (Et) CH2OMe N (c-Pr) CH2CH2CN NEt 2 NH-3-pentyl NHCH (CH 2 OMe) 2 N (CH2Cl{ 2 OMe) 2 NEt2 NH- 3-pentyl NHCH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (Et) CH2OMe NEt 2 NH -3-pentyl 2-Cl-4 -MePh 2-Cl -4 -MeOPh 2-CI-4-MeOPh 2-CI-4 -MeOPh 2-CI-4 -MeOPh 2-CI-4 -MeOPh 2-CI-4 -MeOPh 2-C 1-4-MeOPh 2-CI-4-MeOPh 2-B r-4-MeOPh 2-Br-4 -MeOPh 2 -Me-4 -MeOPh 2-Me-4 -MeOPh 2-Cl-4, 5- (MeO) 2 Ph 2-Cl-4, 5- (MeO) 2 Ph 2-Cl-4, 5- (MeO) 2Ph 2-CI-4, 5- (MeO) 2 Ph 2-CI.-4, 5- (MeO) 2Ph 2-Cl-4, 5- (MeO) 2 2h 2-CI-4, 5- (MeO) 2 Ph 2-CI-4, 5- (MeO) 2 Ph 2-Br-4, 5- (MeO) 2 Ph 2-Br-4, 5- (MeO) 2Ph 2-Br-4, 5- (MeO) 2 Ph 2-Br-4,5- (MeO) 2Ph 2-Br-4, 5- (MeO) 2Ph 2-Br-4, 5- (MeO) 2 Ph 2-Cl-4, 6-(MeO) 2Ph 2-CI-4, 6- (MeO) 2 Ph 2-CI-4, 6- (MeO) 2Ph 2-Cl-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) 2 Ph 900 901 902 903 904 905 906 907 909 910 911 912 913 15 914 915 916 917 918 919 920 NHCH (Et) CH2CH 2 OMe NHCH (Me) CH2CI- 2 OMe

NHCH(CH

2 0Me) 2 N (CH2CI-2OMe) 2 NHCH (Et) CH2OMe N (c-Pr) CH2CH 2

CN

NEt 2 NH-3-pentyl NHCGH (Et) CH 2 CH2OMe NHCH (Me) CH 2

CH

2 OMe NHCH (CH20Me) 2 N (CH 2 CH2OMe) 2 NEIGH (Et) CH2OMe N (c-Pr) CH 2

CH

2

CN

NEt2 NH- 3-pentyl NEIGH (CH 2 OMe) 2 N (CH2CH2OMe) 2 NEIGH (Et) CH2OMe NEt 2 NH-3-pentyl 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-Me 0-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-Me 0-4-MePh 2-Me 0-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-MeO-4 -CIPh 2-MeO-4-CIPh 2-MeO-4-ClPh 2-MeO-4-ClPh 2 -MeO-4 -ClPh Table 6

SN~

N

Ar a.

a a a 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943

BIA

Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me Me NH-CH (CH2OMe) 2 NHCHPr2 NEtBu NPr (CH2-c-C3H5) N (CH2CH2OMe) 2 NH-3 -heptyl NEIHH(Et)CH2OMe NEt2 NHCH (CH2OEt) 2 NH-3-pentyl NMe Ph NPr2 NH-3-hexyl mo rph olin 0 N (CH2Ph) CH2CH2OMe NHCH (CH2 Ph) CH2OMe NH-4 -tet rahydropyranyl NH-cyclopentyl QEt OCH (Et CH 2 OMe OCH2Ph O-3-penty.

SEt 2,&L12P 2, 4-C12-Ph 2, 4 -C12 -Ph 2, 4 -C12-Ph 2, 4-C12-Ph 2, 4-C12 -Ph 2, 4-C12-Ph 2, 4 -C1 2-Ph 2, 4-C12-Ph 2, 4-C12 -Ph 2, 4-C12 -Ph 2, 4 -C12 -Ph 2, 4-C12-Ph 2, 4-C12-Ph 2, 4 -C1 2-Ph 2, 4-C12-Ph 2, 4 -C12-Ph 2, 4 -C12-Ph 2, 4-C12-Ph 2, 4-C12-Ph 2, 4-C12-Ph 2, 4-C12-Ph 2, 4 -C1 2-Ph a.

-a *aaa*.

944 945 946 947 948 949 950 951 952 953 954 955 956 957 15 958 959 960 961 962 20 963 964 965 966 967 968 969 970 971 972 973 974 975 976 977 978 979 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 Me Me Me Me S Et S02Et Ph 2-CF 3-Ph 2-Ph-Ph 3-pentyl cyclobutyl 3 -pyridyl CH (Et) CH2C0NMe 2 CH (Et) CH2CH2N~e 2 NHCH (CH20Me) 2 NHCHP r2 NEtBu NPr (CH2-c-C3H5) N (CH2CH2OMe) 2 NH- 3-heptyl NHCH (Et) CH20Me N~t 2 NHCH (CH2OEt) 2 NH-3 -pen tyl NMePh NPr2 NH-3-hexyl morpholino N (CH 2 Ph) CH2CH 2 OMe NHCH (CH 2 Ph) CH 2 0Me NH-4 -tetrahydropyranyl NH-cyclopentyl QEt OCH (Et)CH 2 OMe OC H2 Ph 0-3-pent yl SEt S(0) Et S02Et

CH(CO

2 Et) 2 2, 4-C12-Ph 2, 4 -C12-Ph 2, 4-C12-Ph 2, 4 -C1 2 -Ph 2, 4 -C1 2 -Ph 2, 4 -C12 -Ph 2, 4-C12-Ph 2, 4 -C 2 -Ph 2, 4-C12-Ph 2, 4-C12-Ph 2,4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2, 4, 6-Me 3 -Ph 2, 4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2, 4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2, 4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2, 4, 6-Me 3 -Ph 2, 4, 6-Me 3 -Ph 2,4, 6-Me 3 -Ph 2, 4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me3-Ph 2, 4, 6-Me3-Ph 2, 4, 6-Me3-Ph a.

a a. a a 980 981 982 983 984 985 986 987 968 989 990 991 992 993 15 994 995 996 997 998 20 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 C (Et) (CO 2 Et) 2 CH (Et)CH 2

OH

CH (Et)CH2OMe CONMe2

COCH

3 CH (OH) CH3 C (OH) Ph-3-pyridyl Ph 2-Ph-ph 3-pentyl cyclobutyl 3-pyridyl CH (Et)CH2CONMe 2 CH (Et) CH2CH2NMe 2 NHCH (CH 2 OMe) 2 N (CH2CH 2 OMe) 2 NHCH (Et) CH2OMe NH-3-pentyl NEt 2 N (CH 2 CN) 2 NHCH (Me)CH2OMe OCH (Et)CH 2 OMe NPr-c-C 3

H

5 NHCH (Me) CH 2 NMe 2 N (c-C 3

H

5

)CH

2

CH

2

CN

N (P11 CH 2

CH

2

CN

N (Bu) CH 2

CH

2

CN

NHCHPr 2 NEtBu NPr (CH 2 -c-C 3

HS)

NH-3-heptyl NEt 2 NHCH (CH2OEt) 2 NH-3-pentyl NMePh NP t2 2,4, 6-Me3-Ph 2 4, 6-Me3-Ph 2,4, 6-Me3-Ph 2, 4, 6-Me3-Ph 2,4, 6-Me3-Ph 2, 4, 6-Me3-Ph 2,4, 6-Me3-Ph 2,4, 6-Me 3 -Ph 2, 4, 6-Me3-Ph 2, 4, 6-Me3-Ph 2,4, 6-Me3-Ph 2, 4, 6-Me3-Ph 2, 4, 6-Me3-Ph 2,4, 6-Me3-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-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me 2 -Ph 2, 4-Me 2 -Ph 2, 4-Me 2 -Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph 2, 4-Me2-Ph *w S.

S

*5 S S

S.

S

1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 15 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 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 Me Me Me Me NH-3-hexyl mo rpholino N (CH 2 Ph) CH2CH20Me NHCH (CH 2 Ph) CH20Me NH-4 -tet rahydropyranyl NH-cyclopentyl NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (Et) CH2OMe N (Pr) CH2CH2CN 0CH (Et) CH2OMe NHCH (CH2OMe) 2 N (CH2CH 2 0Me) 2 NHCH (Et) CH2OMe N (Pr) CH 2

CH

2

CN

0CM (Et) CM2OMe NHCH (CH2OMe) 2 N (CH2CH2oMe) 2 NHCH (Et) CH20Me N (Pr) CH2CH 2

CN

0CM (Et)CH2OMe NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (Et)CH20Me N (Pr)CH2CH 2

CN

0CM (Et)CI-2OMe NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (Et)CH20Me N (Pr) CH 2 CH2CN 0CM (Et)CH2OMe NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (Et)CH2oMe N (Pr) CH2CM2CN OCH (Et) CH20Me 2, 4-Me2-Ph, 2,4-Me2-Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4 -Me2 -Ph 2, 4-Me 2 -Ph 2-Me-4 -Me0-Ph 2 -Me-4 -MeO-Ph 2 -Me-4 -MeO-Ph 2-Me-4-MeO--Ph 2-Me-4-MeO-Ph 2 -Br-4-MeO-Ph 2 -Br-4 -MeO-Ph 2 -Br-4 -Me0-Ph 2 2-Br-4-Me0-Ph 2-Me-4-NMe 2 -Ph 2-Me-4-NMe 2 -Ph 2-Me-4-NMe 2 -Ph 2-Me-4-NMe 2 -Ph 2-Me-4-NMe 2 -Ph 2-B r-4-NMe 2 -Ph 2-B r-4-NMe2-Ph 2-B r-4 -NMe2-Ph 2-B r-4-NMe2-Ph 2-Br-4-NMe2-Ph 2-Br-4 -i -Pr-Ph 2-Br-4-i-Pr-Ph 2-Br-4-i-Pr-Ph 2-Br-4-i-Pr-Ph 2-Br-4-i-Pr-Ph 2-Br -4-Me-Ph 2-Br-4-Me-Ph 2 -Br-4 -Me-Ph 2-Br-4 -Me-Ph 2-Br-4 -Me-Ph S. a

*S

S

0* 5* 0* C. C Ce CC C C a.

C

1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 15 1066 1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1083 1084 1085 1086 1087 NI{CH (CH 2 OMe) 2 N (CH 2 CH2OMe) 2 NHCGH (Et )CHI2Me N (Pr) CH2CH2CN OCH (Et) CH2OMe NEIGH (CH2OMe) 2 N (CH 2 CH2OMe) 2 NEIGH (CH2QMe) 2 N (CH 2 CH-2OMe) 2 NEIGH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NEIGH (CH 2 OMe) 2 N (CH 2 CH2OMe) 2 NEICH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (CEI2OMe) 2 N (CH2GH2OMe) 2 NEIH(CH2oMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (CH 2OMe) 2 N (CH2CH2OMe) 2 NHCH (CH2OMe) 2 N (GH 2 CH2OMe) 2 NEICH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (CH-i 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NHICH (CH2OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (CH 2 OMe) 2 N (CH 2

CH

2 OMe) 2 NEIGH (CH 2 OMe) 2 N (CH 2 CH2OMe) 2 NIHH(CH2OMe) 2 2-Me-4-Br-Ph 2-Me -4-Br -Ph 2-Me-4 -Br-Ph 2-Me-4-Br-Ph 2-Me-4 -Br-Ph 2-CI-4, 6-Me2-Ph 2-CI-4, 6-Me2-Ph 4-Br-2, 6-(Me) 2-Ph 4-Br-2, 6- (Me) 2 -Ph 4-i-Pr-2-SMe-Ph 4 -i-Pr-2-SMe-Ph 2-Br-4 -CE'3-Ph 2-8r-4 -CF 3 -Ph 2-Br-4, 6-(MeO) 2 -Ph 2-Br-4, 6- (MeO) 2 -Ph 2-Cl-4, 6- (MeO) 2-Ph 2-CI-4, 6- (Meo) 2-Ph 2, 6- (Me) 2-4-SMe-Ph 2,6- (Me) 2-4-SMe-Ph 4- (COMe) -2-Br-Ph 4- (COMe) -2-Br-Ph 2,4, 6-Me3-pyrid-3-yl 2,4, 6-Me3-pyrid-3-yl 2,4- (Br) 2-Ph 2,4- (Br) 2 -Ph 4-i-Pr-2-SMe-Ph 4-i-Pr-2-SMe-Ph 4-i-Pr-2-SO2Me-Ph 4-i -Pr -2-so 2 Me-Ph 2,6- (Me) 2 -4-SMe-Ph 2,6- (Me) 2 -4-SMe-Ph 2,6- (Me) 2-4-SO 2 Me-Ph 2,6- (Me) 2-4-SO 2 Me-Ph 2-1-4-i-Pr-Ph 2-1-4-i-Pr-Ph 2 -Br-4 -N (Me)2-6-MeO-Ph CC C

*C

C.

C

156 .9 .9 *99* *9 99 9* *9 *9 99

S

9* 9 9* *9 999 9 9 S.

S

90 900990 9 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 15 1102 1103 1104 1105 1106 20 1107 1108 1109 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1123 1124 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 Me Me Me Me N (CH2CH2OMe) 2 NEt2 NH-3-pentyl NI-CH (CH2OMe) 2 N (C-C3H 5 CH2CH 2

CN

NHCH (CH2CH 2 OMe) CH2OMe NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NH-3-pentyl NEt 2 NHCH (CH2OMe) 2 NCH (Et) CH 2 OMe N (CH2CH2OMe) 2 -NHCH (CH2CH2OMe) CH 2 OMe N (c-C 3

H

5 CH2CH2CN NEt 2 QEt -NHCH (CH2CH2OMe) CH- 2 OMe N (c-C3H5) CH2CH 2

CN

NHCH (CH2CH 2 OEt) 2 N (c-C3H5)CH2CH 2

CN

NEt 2 NH-3-pentyl N (CH-2CH2OMe) 2 NHCH (CH2OMe) 2 NEt 2 NEt 2 NH-3-pentyl NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (Et)CH2OMe N (C-Pr) CH2CH2CN NEt 2 NH-3-pentyl NHCH (Et)CH 2

CH

2 OMe NHCH (Me)CH 2

CH

2 OMe 2-Br-4-N (Me) 2-6-MeO-Ph 2 -Br-4 -MeO-Ph- 2-Br-4 -Meo-Ph 2 -CN-4 -Me-Ph 2,4, 6-Me 3 -Ph 2 -Me-4 -Br-ph 5-Me2-4-MeO-Ph 2, 5-Me2-4-MeO-Ph 2, 5-Me2-4-MeO-Ph 2, 5-Me2-4-MeO-Ph 2-CI-4 -tiePh 2-CI-4 -MePh 2-Cl -4 -MePh 2 -CI-4 -MePh 2, 5-Me2-4-MeOPh 2 -Me-4 -MeOPh 2 -Me-4 -MeOPh 2 -Me-4 -MeOPh 2 -Me-4 -MeOPh 2 -Me-4 -MeOPh 2, 4-C1 2 -Ph 2-Me-4 -CIPh 2 -Me-4-ClPh 2 -Me-4 -CiPh 2 -Me-4 -CIPh 2 -Me-4 -CiPh 2 -CI-4 -MePh 2 -CI-4 -MePh 2-Cl-4 -MeOPh 2-Cl -4 -MeOPh 2-CI-4-MeOPh 2-C 1-4-MeOPh 2-Cl-4-MeOPh 2-Cl -4 -MeOPh 2-CI-4 -MeOPh 2-Cl -4 -MeOPh 00.

.00. S *a0 0 S 0 *5 a 0 0 1125 1126 1127 1128 1129 1130 1131 1132 1133 1134 1135 1136 1137 1138 15 1139 1140 1141 1142 1143 20 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 1154 1155 1156 1157 1158 1159 1160 NHCH (Et) CH2CH 2 OMe NHCH (Me) CH2CH2OMe NHCH (Et) CH2CH2OMe NHCH (Me) CH 2 CH2OMe NHCH (CH2OMe) 2 N (CH 2 CH2OMe) 2 NHCH (Et) CH 2 OMe N (c-Pr) CH 2 CH2CN NEt2 NH- 3-penty.

NHCH (Et) CH2CH2OMe NHCH (Me) CH 2 CH2OMe NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (Et) CH2OMe N (c-P r) CH 2

CH

2

CN

NEt2 NH-3-pentyl NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NEt 2 NH-3-pentyl NHCH (CH2OMe) 2 N (CH 2

CH

2 OMe) 2 NHCH (Et) CH2OMe NEt2 NH- 3-pentyl NHCH (Et) CH 2

CH

2 OMe NHCH (Me) CH2CH2OMe NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCH (Et) CH 2 OMe N (c -P r) CH2CH2CN NEt2 NH-3-pentyl NHCH (Et) CH2CH2OMe 2-B r-4-MeOPh 2-B r-4-MeOPh 2-Me-4-MeOPh 2 -Me-4 -MeOPh 2-CI-4, 5-(MeO) 2 Ph 2-Cl-4, 5- (MeO) 2Ph 2-C1-4, 5-(MeO) 2 Ph 2-CI-4, 5- (MeO) 2 Ph 2-C1-4, 5-(MeO)- 2 Ph 2-C1-4, 5- (MeO) 2 Ph 2-C1-4, 5- (MeO) 2 Ph 2-CI-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) 2Ph 2-Br-4, 5- (MeO) 2 Ph 2-Br-4, 5- (MeO) 2Ph 2-CI-4, 6- (MeO) 2Ph 2-CI-4, 6-(MeO) 2 Ph 2-CI-4, 6- (MeO) 2 Ph 2-C1-4, 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)2Ph 2-Me-4, 6- (MeO) 2Ph 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-Me 0-4-MePh 1161 1162 1163 1164 116s 1166 1167 1168 1169 1170 1171 1172 NHCH (Me) CH2CH20Me NHCH (CH2OMe) 2 N (CH2CH2OMe) 2 NHCHI(Et)CH2OMe N Cc-Pr) CH2CH2CN NEt 2 NH-3-perityl NHCH (CH2OMe) 2 N (CH2CH20Me) 2 NHCH (Et) CH2OMe NEt 2 NH- 3-pentyl 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-CIPh 2-MeO-4-ClPh 2-MeO-4-ClPh 2-MeO-4-ClPh 2-MeO-4-ClPh GRE-Ri Receptor Binding Assay for the Evaluation of Biological Activity The follow ing is a description of the isolation of cell membranes containing cloned human CRF- Ri receptors for use in the standard binding assay as well as a description of the assay itself.

Messenger RNA was isolated from human hippocampus.

The mRNA was reverse transcribed using oligo Cdt) 12-18 and the *coding region was amplified by 2CR from start to stop codons The resulting 2CR 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 MgCl2, 2 mM EGTA, 1 gg/l aprotinin, 1 gg/ml leupeptin 15 and 1 pg/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 gg/ml to 20 be used in the assay.

Binding assays are performed in 96 well plates; each well having a 300 Il capacity. To each well is added 50 Cl of test drug dilutions (final concentration of drugs range from 10- 1 0 10-5 100 p. of 125I- 25 ovine-CRF 1 2 5 I-o-CRF) (final concentration 150 pM) and 150 1 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 1 2 5 I-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 Adenvlate 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-HC1 (pH 7.4 at 370 15 10 mM MgCl2, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10 9 to 10 6m) and 0.8 20 mg original wet weight tissue (approximately 40-60 mg protein). Reactions are initiated by the addition of 1 mM ATP/ 3 2 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 p1 of 3 H]cAMP (approximately 40,000 dpm) is added to each tube prior to separation. The separation of 32 p]cAMP from 32 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 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 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 15 can also be administered parenterally in sterile liquid dose formulations.

Gelatin capsules can be used to contain the active ingredient and a s'uitable carrier such as but .not limited to lactose, starch, magnesium stearate, 20 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 25 can be sugar-coated or film-coated 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, methylor propyl-paraben, and chlorobutanol.

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

15 Useful pharmaceutical dosage-forms for Sadministration of the compounds of this invention can S. 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.

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 15 thereof.

This is a divisional application of AU 38942/97 the disclosure of which is incorporated herein by way of reference.

o**o o 9 9.~ 08/03/02,swl 261 4spe,1

Claims

1. A compound of Formulae or A N RN RI_ N Ax Am (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms 5 thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein: A Ais Nor CR; .Z :is Nor CR 2 Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, fliranyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzoftiranyl, 2,3-dihydro benzothienyl, *:10 indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally *.*.*substituted 'with I to 5 R 4 groups and each Ar is attached to an unsaturated carbon atom; R is independently selected at each occurrence from H, CI-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, halo, CN, C ,-C 4 haloalkyl; R' is independently selected at each occurrence from H, CI-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halo, CN, CI-C 4 haloalkyl, CI-C 12 hydroxyalkyl, C 2 .C 12 alkoxyalkyl, C 2 -C, 0 cyanoalkyl, C 3 .C 6 cycloalkyl, C 4 -CIO cycloalkylalkyl, WR1R 6 CI-C 4 alkyl-NRR 0 NRCOR1 6 OR", SH or (nR2 W 2 is selected from H, CI-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C4-CIO cycloalkylalkyl, C,-C 4 hydroxyalkyl, halo, CN, -NRR 7 NRCOR' 0 -NRS(O) k 7 S(O), 1 NR 6 7 CI-C 4 haloalkyl, OR 7 SH or -S (O)nR' 2 Ris selected from: OR', SH, S(O)nR' 3 COR 7 C0 2 R 7 OC(O)R' 3 NR'COR 7 N(COR 7 2 NR'CONR 6 R 7 NR 8 COR NR 6 R 7 NR 6 ak7a N(0R 7 )R 6 CONR 6 R 7 aryl, heteroaryl and heterocyclyl, or -CI-Clo alkyl, C 2 -Clo alkenyl, C 2 -Clo alkynyl, C 3 -C 8 cycloalkyl, C 5 -C 8 cycloalkenyl, C 4 -CI 2 cycloalkylalkyl or C 6 -CIO cycloalkenylalkyl, each optionally O8/03/02,swl 261 4spe.I 66 substituted with I to 3 substituents independently selected at each occurrence from C,-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, OR" 5 SHi, COR' 5 CO 2 R' 5 OC(O)R 1 3 NR 8 COR' 5 N(COR' 5 2 NR 8 CONR' 6 NR'CO 2 R 1 3 qR' 6 R 1 5 CONRI 6 R1 5 aryl, heteroaryl and heterocyclyl; R4~ is independently selected at each occurrence from: C,-Clo alkyl, C 2 -CIo alkenyl, C 2 -Clo alkynyl, C 3 -C 6 cycloalkyl, C 4 -CI 2 cycloalkylalkyl, NO 2 halo, CN, CI-C 4 haloalkyl, NR 6 R 7 NR'COR 7 NR 8 C0 2 R 7 COR 7 OR 7 COIeR 7 CO(NOR 9 )R 7 C0 2 R 7 or SO.7 where each such CI-Clo alkyl, C 2 -Cl 0 alkenyl, C 2 -C, 0 alkynyl, C 3 -C 6 cycloalkyl and C 4 -CI 2 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from CI-C 4 alkyl, NO 2 halo, CN, NRR 7 NR 8 COR 7 NR 8 CO 2 R 7 COR 7 OR 7 CONRR 7 C0 2 R 7 CO(NOR?)R 7 or R and R 7 RWa and R 7 a are independently selected at each occurrence from: -H, :-C,-Clo alkyl, C 3 -Clo alkenyl, C 3 -Clo alkynyl, CI-C 1 0 haloalkyl with 1-10 halogens, 15 C 2 -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -CI 2 cycloalkylalkyl, Cs-Clo cycloalkenyl, or C 6 C 14 cycloalkenylalkyl, each optionally substituted with I to 3 substituents independently selected at each occurrence from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halo, Cl-C 4 haloalkyl, cyano, OR 15, SH, S(O)nR'3, COR' 5 C0 2 R 15, OC(O)R 13, NR 8 COR1 5 N(COR") 2 ooosoo NR 8 CONR' 6 R' 5 NR 8 CO 2 R 1 3 RI 6 R 1 5 CO R' 6 R1 5 aryl, heteroaryl or heterocyclyl, 00. 20 -aryl, aryl(CL-C4 alkyl), heteroaryl, heteroaryl(CI-C 4 alkyl), heterocyclyl or heterocyclyl(CI-C8 alkyl), alternatively, NR 6 R 7 and NR aR' aeidpndently piperidine, *o pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each 9:000:optionally substituted with 1-3 CI-C 4 alkyl groups; R 8 is independently selected at each occurrence from H or CI-C 8 alkyl;- and R1 0 are independently selected at each occurrence from H, CI-C 4 alkyl, or C 3 -C 6 cycloalkyl; R 1 is selected from H, CI-C 4 alkyl, CI-C 4 haloalkyl, or C 3 -C 6 cycloalkyl; R2 is CI-C 4 alkyl or CI-C 4 haloalkyl; R 1 3 is selected from CI-C 4 alkyl, CI-C 4 haloalkyl, C 2 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C, 2 cycloalkylalkyl, aryl, aryl(CI-C8 alkyl)-, heteroaryl or heteroaryl(CI-C4 alkyl)-; R 1 4 is selected from C,-Clo alkyl, C 3 -C, 0 alkenyl, C 3 -C, 0 alkynyl, C 3 -C 8 cycloalkyl, or C 4 -C, 2 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from cI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 O8/03/02,swl 261 4spe1 67 haloalkyl, cyano, SI-, COR' 5 CO 2 R' 5 OC(O)R' 5 NR'COR' 5 N(COR 5 2 NR'CONR 6 NR'CO 2 R' 5 NR1 6 R' 5 CONR 16R", and CI-C 6 alkylthio, CI-C 6 alkylsulfinyl and CI-C 6 alkylsulfonyl; and R'1 6 are independently selected at each occurrence from H, CI-C 6 alkyl, C 3 CIO cycloalkyl, C 4 -C 16 cycloalkylalkyl, except that for 5 R' 5 cannot be H; aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR" 5 SH, S(O)nR' 5 COR' 5 C0 2 R' 5 OC(O)R", NR'COR N(COR 16 5 1 1516 1 NR'CONR' 6 NR'CO 2 R" 5 NR' 6 and CONR R; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3 -dihydrobenzothienyl or 2,3 dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR' 5 SH, S(O)nR' 5 CORI 5 C0 2 R' 5 OC(O)R' 5 NR'COR' 5 N(COR 5 2 NR'CONR1 6 R' 5 NR'CO 2 R' 5 NR 16R 1, and OR1 heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from C I-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, OR' 5 SH, COR' 5 C0 2 R' 5 OC(O)R' NR'COR' 5 N(COR 5 2 NR'CONR1 6 R 1 5 NR 8 C0 2 R'1 5 NR 5 R 1 6 and CONR1 6 R'1 5 n is independently at each occurrence 0, 1 or 2, with the provisos that: when A is N, Z is C2, R 2 is H, R 3 is -OR 7 or -OCOR'1 3 and R' is H, then *R1 is not H, OHor SH; 25 when Ais N, Zis CR,R is CIA 3 or C 2 H 5 R 2 is H, and R 3 is OH, H, CIA 3 C 2 H 5 C 6 H 5 n-C 3 H 7 i-C 3 H 7 SH, SCH 3 NHC 4 H 9 or N(C 2 Hs) 2 then Ar is not phenyl or m- CH 3 -phenyl; 0(3) when A is N, Z is CR2, R2 is H, and Ar is pyridyl, pyrimidinyl or pyrazinyl, 0 0and R3 is NR 6 aR then Ra and R.a are not H or alkyl; 7* 3 30 when A is N, Z is CR 2 and R 2 is S0 2 NR 6 R then R? is not OH or H when A is N, Z is CR 2 and R2 is -NR 6 SO 2 R 7 or -SO 2 NR R then R3 is not OH or SIA; I 7/02/04,at I2614.specipgs,2 168 2 p1 when A is N, Z is CR2, R' is H, SCH 3 methyl or ethyl, R 2 is H, and R 3 is H, OH, CH 3 C 2 H 5 CsH 5 n-C 3 H 7 iso-C 3 H 7 SH, SCH 3 NH(n-C 4 H 9 or N(C 2 Hs) 2 then Ar is not unsubstituted phenyl or m-methylphenyl; when A is N, Z is CR2, R1 is methyl or ethyl, R 2 is H, and R 3 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 then Ar is not unsubstituted phenyl or m-methylphenyl; when A is CR and Z is CR 2 then R 2 is not -NR 6 SO 2 R 7 or -SO 2 NR 6 R 7 when A is CR, Z is CR 2 R 2 is H, phenyl or alkyl, R 3 is NR 8 COR 7 and Ar is phenyl or phenyl substituted with phenylthio, then R 7 is not aryl, aryl(CI-C 4 alkyl), heteroaryl, heteroaryl(CI-C 4 alkyl), heterocyclyl or heterocycly(Ci-C 4 alkyl); when A is CR, Z is CR2, R 2 is H or alkyl, Ar is phenyl, and R 3 is SR 3 or NR 6 aR 7 a, then R' 3 is not aryl or heteroaryl and R 6 a and R 7 a are not H or aryl; or (11) when A is CR, R is H, and Z is CR2, Ar is not phenyl or substituted phenyl; (12) when A is CH, Z is CR 2 R' is OR", R is H, R 3 is OR 7 and R 7 and R 1 are both H, then Ar is not pyridyl or naphthyl.

2. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof with the additional provisos that when A is N, R' is H, CI-C 4 alkyl, halo, CN, C 1 -C 2 hydroxyalkyl, CI-C 4 alkoxyalkyl or S0 2 (CI-C 4 alkyl), R 3 is NR 6 aR 7 a and R 6 a is unsubstituted CI-C 4 alkyl, then R 7 a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C 3 -C 6 cycloalkyl; and A is N, R' is H, CI-C 4 alkyl, halo, CN, CI-C 12 hydroxyalkyl, CI-C 4 alkoxyalkyl or S0 2 (C1-C 4 alkyl), R 3 is NR 6 aR 7 a and R 7 a is unsubstituted CI-C 4 alkyl, then R a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, 25 benzofuranyl, benzothiazolyl, indolyl or C 3 -C 6 cycloalkyl.

3. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R 4 substituents. 30 4. A compound of claim 3 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- 17/02/04,at2614.specipgs,2 169 drug forms thereof wherein A is N, Z is CR 2 Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R' and R 2 are CH 3 and R 3 is NR 6 aR 7 a. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 3.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 4.

8. Use of compound of Formulae or R 3 R 3 R 4 A N A N\ Z0 N Ar Ar (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, in manufacturing a pharmaceutical composition for treatment of affective disorder, anxiety, depression, 15 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, wherein: A is N or CR; Z is N or CR2; Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 170 08/03/02,swl 2614spe, indanyl, 1 ,2-benzopyranyl, 3 ,4-dihydro- 1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R 4 groups and each Ar is attached to an unsaturated carbon atom; R is independently selected at each occurrence ftrm H, C,-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, halo, CN, C I-C 4 haloalkyl; R1 is independently selected at each occurrence from H, CI-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halo, CN, CI-C 4 haloalkyl, CI-CI 2 hydroxyalkyl, C 2 -CI 2 alkoxyalkyl, C 2 -CIO cyanoalkyl, C 3 -C 6 cycloalkyl, C 4 -CIO cycloalkylalkyl, NR 9 R' 0 C,-C 4 alkyl-NRR' 9 NR 9 COR1 9 OR", SH or S(O)nR 1 2 R2 is selected from H, CI-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 4 -CIO cycloalkylalkyl, C,-C 4 hydroxyalkyl, halo, CN, "NR 6 R 7 NRCOR' 0 -NR 6 S(O)nR 7 S(O)nNR 6 R 7 C,-C 4 haloalkyl, -OR 7 SH or SOR2 R 3 is selected from: H, OR 7 SH, S(O)nR' 3 COR 7 C0 2 R 7 OC(O)R 1 3 NR'COR 7 N(COR 7 2 **:NB.CONR6R 7 NR'CO 2 R 1 3 NR7, R a ,N(OR')R,CONR7R, aryl, heteroaryl and 15 heterocyclyl or -Cl-Clo alkyl, C 2 -Cjo alkenyl, C 2 -Clo alkynyl, C 3 -C8 cycloalkyl, C 5 -C 8 cycloalkenyl, C 4 -C, 2 cycloalkylalkyl or C 6 -CIO cycloalkenylalkyl, each optionally 2.:substituted with I to 3 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR" 5 SH, S(O), 1 R' 3 COR' C0 2 R'1 5 OC(O)R'1 3 NRCOR1 5 N(COR' 5 2 NRCONR6 NR 8 C0 2 R 3, NR16 CONRE6 R 15, aryl, heteroaryl and heterocyclyl; R4 is independently selected at each occurrence from: C,-Clo alkyl, C 2 -Cl 0 alkenyl, C 2 -Cjo alkynyl, C 3 -C 6 cycloalkyl, C 4 -CI 2 cycloalkylalkyl, NO 2 halo, CN, C,-C 4 haloalkyl, NR 6 R 7 NR8COR 7 NR'CO 2 R 7 COR 7 OR 7 CONR 6 R 7 CO(NOR 9 )R 7 C0 2 R 7 or SOn7 where each such C,-Clo alkyl, C 2 -Cjo alkenyl, C 2 -Cjo alkynyl, C 3 -C 6 cycloalkyl and C4-CI 2 cycloalkylalkyl are optionally substituted with I to 3 substituents independently selected at each occurrence from CQ-C 4 alkyl, NO 2 halo, CN, NR 6 R 7 NR 8 COR 7 NR 8 C0 2 R 7 COR 7 OR 7 CONR 6 R 7 C0 2 R 7 CO(NOR 9 )R 7 or R6 and RR 6 a anR 7 a aeindependently selected ateach ocurnefrom: -H, -CI-Clo alkyl, C 3 -Clo alkenyl, C 3 -CIO alkynyl, C 1 -Clo haloalkyl with 1-10 halogens, C 2 -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C4-CI 2 cycloalkylalkyl, C5-CI 0 cycloalkenyl, or C 6 C1 4 cycloalkenylalkyl, each optionally substituted with I to 3 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR' 5 SH, S(O)nR' 3 COR' 5 CO 2 R' 5 OC(O)R' 3 NR 8 COR 5 N(COR 5 2 08/03/02,swi 261 4spc,1 71 NR CONR 16 R' NR C0 2 R' 3 NR' 6 CONR' 6 R aryl heteroaryl or heterocyclyl, -aryl, aryl(C,-C 4 alkyl), heteroaryl, heteroaryl(CI-C4 alkyl), heterocyclyl or heterocyclyl(CI-C 4 alkyl); alternatively, NRR 7 and NP. R ar in eety piperidie, pyrroldne, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C,-C 4 alkyl groups; R 8 is independently selected at each occurrence from H or CI-C 4 alkyl-, R and R1 0 are independently selected at each occurrence from H, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl; R"1 is selected from H, C 1 -C 4 alkyl, CI-C 4 haloalkyl, or C 3 -C 6 cycloalkyl; *R1 2 is C,-C 4 alkyl or CI-C 4 haloalkyl; *R1 3 is selected from CI-C 4 alkyl, CI-C 4 haloalkyl, C 2 -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 1 2 cycloalkylalkyl, aryl, aryl(C 1-C4 alkyl)-, heteroaryl or heteroaryl(C 1-C4 :alkyl)-; 15 R 1 4 is selected from C,-Clo alkyl, C 3 -Clo alkenyl, C 3 -Clo alkynyl, C 3 -C 8 cycloalkyl, *:or C 4 -CI 2 cycloalkylalkyl, each optionally substituted with I to 3 substituents independently selected at each occurrence from C,-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 8. haloalkyl, cyano, OR" 5 SH, S(O), 1 C0R 15 CO 2 R' 5 OC(O)R 1 5 NR COR 5 N(COR 5 )2, *NR 8 ICONR' 6 NR 8 C0 2 R 15 NIR1 6 R1 5 CONRI 6 R1 5 and C 1 -C 6 alkylthio, CI-C 6 20 alkylsulfinyl and CI-C 6 alkylsulfonyl; R1 5 and R 1 6 are independently selected at each occurrence from H, CI-C 6 alkyl, C 3 :Cl 0 cycloalkyl, C 4 -CI 6 cycloalkylalkyl, except that for S(O)nR 15 R 1 5 cannot be H; 0 0: aryl is phenyl or naphthyl, each optionally substituted with I to 5 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR 5, SH, 5 COR' 5 C0 2 R' 5 OC(O)R", NR'COR", ,N(C0R 5 2 81615 15 16 15' 1OR6 NP. CON N 8 CO 2 R" ,NR R andCOI heteroaryl is pyridyl, pyrymidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3 -dihydrobenzathienyl or 2,3 dihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR' 5 SH, -COR' 5 C0 2 R' 5 OC(O)R' 5 NR 8 COR' N(COR' 5 2 NR 8 CONI6 R 5, N8 2R, NI( R15adCN 6R1; O8/03/02,swl 261 4spe1 72 heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, Ci-C 4 haloalkyl, cyano, OR 1 5 SH, S(O)nR 1 5 COR 1 5 CO 2 R' 5 OC(O)R' 5 NR 8 COR 1 5 N(CORs) 2 NR 8 CONR' 6 R 1 5 NRCO 2 R 5 NR5R 1 6 and CONR6R 5 n is independently at each occurrence 0, 1 or 2; with the proviso that: when A is CR, R is H, and Z is CR 2 Ar is not phenyl or substituted phenyl.

9. Use of claim 8 wherein, in the compound of Formulae or Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R 4 substituents. Use of claim 8 wherein, in the compound of Formulae or A is N, Z is CR 2 Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2, 4, 6-trimethylphenyl, R' and R 2 are CH 3 and R 3 is NR 6 aR 7 a.

11. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein A is N.

12. A compound of Formula of claim 11 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof.

13. A compound of claim 12 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R 4 substituents.

14. A compound of claim 12 and isomers thereof, stereoisomeric forms thereof, 25 or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 3 is NR 6 aR 7 a or OR 7 A compound of claim 12 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R 4 substituents, and R 3 is NR 6 aR 7 a or OR 7

16. A compound of Formula of claim 11 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Z is CR 2

17. A compound of claim 16 and isomers thereof, stereoisomeric forms thereof, 17/02/04,at12614.specipgs,2 or mixtures of stereoisomeric forms thereof, and pharmnaceutically acceptable salt or pro- I 7/02/04,atl 2614.specipgs,2 1 73a drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R4 Substituents.

18. A compound of claim 16 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R is NR1aR7a or OR7.

19. A compound of claim 18 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 6 a is independently selected from: -H, -C,-Cio alkyl, C 3 -Clo alkenyl, C 3 -C10 alkynyl, CI-Clo haloalkyl with 1-10 halogens, C 2 -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C1 2 cycloalkylalkyl, Cs-Clo cycloalkenyl, or C 6 C1 4 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, ORI 5 SH, S(O)nR, 3 COR 15 CO 2 R' 5 NR 8 COR 5 N(COR1 5 2 N CNR615, 8 13, R61,C~ 16 9. 15 NR 8 CONR' 6 R, NR CO 2 R, NR' 6 R' 5 CONR R aryl, heteroaryl or heterocyclyl, -aryl, aryl(CI-C 4 alkyl)-, heteroaryl, heteroaryl(CI-C4 alkyl)-, heterocyclyl or heterocyclyl(CI-C4 alkyl)-; and :i R7' is independently selected at each occurrence from: -H, 20 -C 5 -Clo alkyl, C 3 -Clo alkenyl, C 3 -C 1 o alkynyl, CI-Clo haloalkyl with 1-10 halogens, C 2 -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C1 2 cycloalkylalkyl, Cs-Clo cycloalkenyl, or C 6 C1 4 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently .:060* selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR1 5 SH, S(O)nR' 3 COR", CO 2 R5, OC(O)R' 3 IR 8 COR 5 N(COR1 5 2 NR8CONR'R 1, NRCO 2 R 3, NR' 6 R' 5 CONR16 R 15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(CI-C4 alkyl), heteroaryl, heteroaryl(CI-C4 alkyl), heterocyclyl or heterocyclyl(C,-C 4 alkyl); alternatively, NR 6 R 7 and NRaR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 CI-C 4 alkyl groups. A compound of claim 18 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 6 a and R 7 a are identical and are selected from: 08/03/02,swl 2614spe,l 74 -CI-C 4 alkyl Or C 3 -C 6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C,-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, OR' 5 SH, S(O)"R' 3 -COR' 5 CO 2 R' 5 OC(O)R 1 3 NR'COR' 5 N(COR' 5 2 NR 8 CONR1 6 R, NIR 8 CO 2 R 1 3 qR' 6 R'1 5 CONR 6 R 15, aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl.

21. A compound of claim 18 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 6 a is selected from: -H, -CI-Clo alkyl, C 3 -Cjo alkenyl, C 3 -CIO alkynyl, C,-Clo haloalkyl with 1-10 halogens, C 2 -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C, 2 cycloalkylalkyl, C5-CIO cycloalkenyl, or C 6 C1 4 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C,-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C,-C 4 haloalkyl, 15 cyano, OR'1 5 SH, S(O),IR1 3 COR' 5 C0 2 R 15 OC(O)R'1 3 NR 8 COR' 5 ,N(COR 5 )2, *NR 0 CONWR"' 1, NRC0 2 R'1 3 NR1 6 R.' 5 CONK1 R15, aryl, hteroaryl or heterocyclyl, -aryl, aryl(C ,-C 4 alkyl), heteroaryl, heteroaryl(Ci-C4 alkyl), heterocyclyl or heterocyclyl(CI-C4 alkyl); Ra is selected from: 20 -Cl-C 4 alkyl and each such C,-C 4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from C1-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 SS~R3 1,1,1 0 so haloalkyl, cyano, OR' 5 SH, S)R',C0R 15 C0 2 R' 5 OC(O)R' 3 NR 8 COR' 5 N(COR' 5 2 NR 8 CONRI 6 R1 5 NRC0 2 R 1, NR6R, 6 R1 5 aryl, heteroaryl or heterocyclyl.

22. A compound of claim 18 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein one of R&a and R 7 a is selected from: -C 3 -C 6 cycloalkyl, each such C 3 -C 6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C,-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR'1 5 SH, S(O)"R' 3 C0R 15 C0 2 R 1 5 OC(O)R 1 3 NR 8 COR' 5 N(COR1 5 2 Nk 8 CONR1 6 R 5 NR 8 CO2R 3 NK' 6 R' 5 CONRI 6 aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, and the other of R 6 and R 7 is unsubstituted CI-C 4 alkyl. 08/03/02 ,swl 261 4spe.1

23. A compound of claim 18 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 6 and R 7 a are independently H or CI-Clo alkyl, each such Cj- CIO alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR1 5 SH, S(O)nR', C0R 15 CO 2 R' 5 OC(O)R 1 3 NR'COR", N(COR' 5 2 R 8 CONR 6 R' 5 NR 8 C0 2 R1 3 NR 6 R 1 5 CONRI 6 aryl, heteroaryl or heterocyclyl.

24. A compound of claim 16 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R. 4 substituents, and R. 3 is NR 6 aR 7 or OR 7 A compound of claim 24 and isomers thereof, stereoisomeric forms thereof, .o mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R a is independently selected from: -H, -CI-CI 0 alkyl, C 3 -CIO alkenyl, C 3 -CI 0 alkynyl, C,-Clo haloalkyl with 1-10 halogens, :C 2 -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C, 2 cycloalkylalkyl, C5-C, 0 cycloalkenyl, or C 6 C 14 cycloalkenylalkyl, each optionally substituted with I to 3 substituents independently, selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C,-C 4 haloalkyl, 20 cyano, OR5 SH, SOR 1 CO 2 R' 5 OC(O)R' 3 NR'COR' 5 N(COR 5 2 NP. CONR6 R,NR8CO 2 R 1, NR 6 R'1 5 CONqR6 R 15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(CI-C4 alkyl)-, heteroaryl, heteroaryl(C,-C4 alkyl), heterocyclyl or heterocyclyl(C,-C4 alkyl); R' is independently selected at each occurrence from: -H, -Cs-C 10 alkyl, C 3 -CjO alkenyl, C 3 -C 1 o alkynyl, CI-Clo haloalkyl with 1-10 halogens, C 2 -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C, 2 cycloalkylalkyl, Cs-Clo cycloalkenyl, or C 6 C1 4 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR5 SH, S(O)nR1' COR 1 5 CO 2 R' 5 OC(O)R 1 3 NR 8 COR' 5 N(COP.1 5 2 NRCONR6R", N1R 8 CO2R 1, NR' 6 R' 5 CON.RI R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(CI-C4 alkyl), heteroaryl, heteroaryl(C,-C4 alkyl), heterocyclyl or heterocyclyl(CI -C 4 alkyl), 176 176 08A73/02,swl 261 4spe.l 76 alternatively, NR 6 R 7 and NR 6 aR 7 a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 cl-c 4 alkyl groups.

26. -A compound of claim 24 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 6 a and R 7 a are identical and are selected from: -C,-C 4 alkyl or C 3 -C 6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR' 5 SH, S(O)"R' 3 -COR' 5 CO 2 R' 5 OC(O)R 1 3 NR'COR' 5 N(COR")2, NR 8 CONR6 NIR C0 2 R'1 3 NIR1 R 15 CONRI R15, aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl. or 27. A compound of claim 24 and isomers thereof, stereoisomeric forms thereof, ormixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- 15 drug forms thereof wherein R a and R 7 a are identical and are -CI-C 4 alkyl, each such C,-C 4 alkyl optionally substituted with 1. to 3 substituents independently selected at each occurrence from C,-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR" 5 SH, S(O).R 1 3 -COR 15 CO 2 R' 5 OC(O)R' 3 NR 8 COR' 5 N(COR' 5 2 NR 8 CONR1 R'5, NR 8C0 2 R 13, NR1 R CO RI 6 R' 5 aryl, heteroaryl or 20 heterocyclyl.

28. A compound of claim 24 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- *drug forms thereof wherein RWa is selected from: -H, -C,-Clo alkyl, C 3 -Clo alkenyl, C 3 -Clo alkynyl, C 1 -Clo haloalkyl with 1-10 halogens, C 2 -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -CI 2 cycloalkylalkyl, Cs-Clo cycloalkenyl, or C 6 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C,-C 6 alkyl, C 3 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR 1 5 SH, S(O)nR' 3 C0R 15 CO 2 R' 5 OC(O)R 1 3 NRCOR' 5 N(COR1 5 2 NR 8 CONR' 6 NR"CO 2 R 1 3 NR1 6 CONR1 6 R1 5 aryl, heteroaryl or heterocyclyl, -aryl, aryl(C,-C 4 alkyl), heteroaryl, heteroaryl(C,-C4 alkyl), heterocyclyl or heterocyclyl(CI -C 4 alkyl); R 7 is: 08/03/02,swl 261 4spejl 77 -CI-C 4 alkyl and each such CI-C 4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, OR", SH, S(O)nR' 3 COR" 5 CO 2 OC(O)R, NR'COR", N(COR' 5 2 NR 8 CONR' 6 NR 8 CO 2 R' 3 NR 6 R15, CONR 6 R15, aryl, heteroaryl or heterocyclyl.

29. A compound of claim 24 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein one of R 6 a and R 7 a is selected from: -C 3 -C 6 cycloalkyl, each such C 3 -C 6 cycloalkyl optionally substituted with 1-3 substituents' independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR' 5 SH, S(O)nR' 3 COR", CO 2 OC(O)R' 3 NR 8 N(COR'") 2 NR 8 CONR' 6 R' 5 NRsC0 2 R 13 NR 6 R' 5 CONR16R, aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or 15 -heterocyclyl, and the other of R 6 a and R7 is unsubstituted C,-C 4 alkyl. So 30. A compound of claim 24 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- 6a p7a drug forms thereof wherein Ra and R7 are independently H or CI-Clo alkyl, each such CI- 20 Clo alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR' 5 SH, *:S(O)nR' 3 COR' 5 CO 2 R' 5 OC(O)R' 3 NRCOR", N(COR") 2 R 8 NR 8 CO 2 R 3, NR' 6 R' 5 CONRi 6 R" 5 aryl, heteroaryl or heterocyclyl.

31. A compound of claim 16 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein -Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R 4 substituents, -R is NR6aR7a or OR7 and and R 2 are independently selected from H, Cl-C 4 alkyl, C 3 -C 6 cycloalkyl, C 4 Clo cycloalkylalkyl.

32. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 6 a is independently selected from: 08/03/02,sw 2614spe,l 78 -H, -C,-Clo alkyl, C 3 -Cj 0 alkenyl, C 3 -Clo alkynyl, C 1 -Clo haloalkyl with 1-10 halogens, C 2 -C8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -CI 2 cycloalkylalkyl, C5-Clo cycloalkenyl, or C 6 C1 4 cycloalkenylalkyl, each optionally substituted with I to 3 substituents independently selected at each occurrence from C,-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, OR", SH, S(O)nR' 3 COR", CO 2 OC(O)R' 3 NR 8 COR", N(COR") 2 NR 8 CONR 6 R"5, NR'CO 2 R'1 3 NR 6 R"5, CONRI 6 aryl, heteroaryl or heterocyclyl, -aryl, aryl(Cl-C4 alkyl)-, heteroaryl, heteroaryl(C,-C 4 alkyl), heterocyclyl or heterocyclyl(CI-C4 alkyl); R 7 a is independently selected at each occurrence from: -H, alkyl, C 3 -Cjo alkenyl, C 3 -Cjo alkynyl, CI-Clo haloalkyl with 1-10 halogens, C 2 -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -CI 2 cycloalkylalkyl, Cs-Clo cycloalkenyl, or C 6 SC14 cycloalkenylalkyl, each optionally substituted with I to 3 substituents independently 15 selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR" Sf1 COR", CO 2 OC(O)R' 3 N COR", N(COR") 2 NW OR6 RS 85 1302" 1R6R15 O 6 R15 arlhtroaryl or heterocyclyl, -aryl, aryl(C,-C4 alkyl), heteroaryl, heteroaryl(CI-C 4 alkyl), heterocyclyl or heterocyclyl(CI-C 4 alkyl), 20 alternatively, NR7R and NaR 7 are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C 1 -C 4 alkyl groups. *33. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 6 a and R la are identical and are selected from: -CI-C 4 alkyl or C 3 -C 6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR"5, SH-, S(O),,R 1 -COR' 5 CO 2 CC(O)R 13 NR8 COR N(COR") 2 NRCONRI R 5, NR 8 C0 2 R'1 3 NR' 6 R"1, CONR' 6 aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl.

34. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 6 a and R 7 a are identical and are 08/03/02,swi 261 4spe1 79 -CI-C 4 alkyl, each such C,-C 4 alkyl optionally substituted with I to 3 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, SH, -COR 5 COAR', OC(O)R' 3 NR'COR' 5 N(COR 5 2 NR 8 CONR' 6 NR 8 C0 2 R' 3 NR' 6 R" CONR' 6 aryl, heteroaryl or heterocyclyl. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 6 a is selected from: -H, -CI-Clo alkyl, C 3 -Cl 0 alkenyl, C 3 -Clo alkynyl, C I-C jo haloalkyl with 1 -10 halogens, C 2 -C 8 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -Cl 2 cycloalkylalkyl, C5-ClO cycloalkenyl, or C 6 C1 4 cycloalkenylalkyl, each optionally substituted with I to 3 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 haloalkyl, ~cyano, OR' 5 SH, S(O)nR', COR' 5 C0 2 R' 5 OC(O)R' 3 NR 8 COR' 5 N(COR' 5 2 NR8CON16 15, 8 3NI 5 CN NRCN R ,NR C0 2 R' 3 NRR 5 CO RR aryl, heteroaryl or heterocyclyl, -aryl, aryl(C,-C 4 alkyl), heteroaryl, heteroaryl(CI-C 4 alkyl), heterocyclyl or :heterocyclyl(C I-C 4 alkyl); iR~a is: -C,-C 4 alkyl and each such CI-C 4 alkyl is substituted with 1-3 substituents 20 independently selected at each occurrence from C,-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 15 13 15 1513 8 51 haloalkyl, cyano, OR' 5 SH, S(O)nR' 3 COR' 5 CO 2 R' 5 OC(O)R NR8C0R 15 N(C0R 5 2 NR8*CN16 15, 8 3N1 5,O 61 NR 8 CCN8CNR R I NR C R',N'RCORR', aryl, heteroaryl or heterocyclyl. *36. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein one of R 6 and R"a is selected from: -C 3 -C 6 cycloalkyl, each such C 3 -C 6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C,-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, OR SH, COR' 5 C0 2 R' 5 OC(O)R' 3 NR'COR' N(COR1 5 2 NR 8 CONRI 6 R1 5 N 8 C0 2 R 1 3 NR' 6 R 5 CONR' 6 aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, and the other of R a and R 7 a is unsubstituted C,-C 4 alkyl. 08/03/02,swl 261 4speI

37. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 6 and R 7 are independently H or Ci-Clo alkyl, each such Ci- Clo alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-C 6 alkyl, C3-C6 cycloalkyl, halo, CI-C 4 haloalkyl, cyano, OR 1 5 SH, S(O)nR", COR 1 CO 2 R' 1 OC(O)R 3 NR 8 COR 1 N(COR" 5 2 R 8 CONR 6 R 15 NR 8 CO 2 R 13 NR 6 R 15 CONR1 6 R" 5 aryl, heteroaryl or heterocyclyl.

38. A compound of claim 31 of Formula R 3 N ;0N-N N.^ ft *r ft R 4 b R 4 c 10 Formula and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, selected from the group consisting of: a compound of Formula (50) wherein R 3 is -NHCH(n-Pr) 2 R 4 a is Cl, R 4 b is H, R 4c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -N(CH 2 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 is H; a compound of Formula (50) wherein R 3 is -NHCH(Et)(n-Bu), 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 (50) wherein R 3 is -NHCH(Et)(CH 2 OMe), R 4 a is Cl, R 4 b i H, R 4 c is Cl, R 4 d is H and R 4 is H; a compound of Formula (50) wherein R 3 is -N(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 (50) wherein R 3 is -NHCH(CH 2 0Et) 2 R 4 a is Cl, R 4b is H, R 4 C is Cl, R 4d is H and R 4 e is H; S 08/03/02,swl 2614spe,181 a compound of Formula (50) wherein R3 is -NI{CH(Et),, RWa is Cl, R 4 b is H, Rc is Cl, R dis H and W~e is H; a compound of Formula (50) wherein R 3 is R 4 a is Cl RWb is H, plc is. Cl, Wdis H and W~e is H; a compound of Formula (50) wherein R3 is -NHCH(Et)(n-Pr), RWa is Cl, RWb is H, R 4 c is Cl, RWd is HandR We is H; a compound of Formula (50) wherein W 3 is -NHCH(CH 2 OMe) 2 R 4ais Me Rb is H, W'C is Me, R 4 d is HandRWe is Me; a compound of Formula (50) wherein R 3 is -NHICH(CH 2 OMe) 2 RWa is Me, R 4 b is H, Ric is Me, R 4 dis HandWe is H; a compound of Formula (50) wherein R3 is -N(CH 2 CH 2 OMe) 2 Ra is Me, R 4bis H, W'R~ is Me, R 4 d is Hand R 4 'is H; a compound of Formula (50) wherein W 3 is -NHCH(Et)(CH 2 OMe), RWa is Me, RWb is H,Wc is Me,RWd is H andWe is H; 15i a compound of Formula (50) wherein R 3 is -NHCH(Et) 2 Rais MeR~ is H, W' is is H and We is H; a compound of Formula (50) wherein R is -OEt, Ra is Cl,RW is H, Rc is Cl,RW is H and Reis H; a compound of Formula (50) wherein RW is -N(Et) 2 RWa is Me, RWb is H, R 4 c is Me, fed is HandWe is H; a compound of Formula (50) wherein R 3 is -N(CH 2 CN) 2 W'a is Me, Rb is H, Rc is Me, Rd is H andRWe is H; a compound of Formula (50) wherein R3 is -NI{CH(Me)(CH 2 OMe), Ra is Me,RW is H, R 4 c is Me, fed is H and R 4 e is H; a compound of Formula (50) wherein R 3 is OCH(Et)(CH 2 OMe), RWa is Me, Rb is H, W'C is Me, R 4d is H and W~e is H; a compound of Formula (50) wherein R3 is -N(n-Pr)(CH 2 cPr), RWa is Me, Rb is H, Wc is Me, R 4 d is HandWe is H; a compound of Formula (50) wherein R 3 is -NHCH(Me)(CH 2 N(Me) 2 W'a is Me, Rbis H,Ris Me,RW is HandR 4eis H; a compound of Formula (50) wherein R 3 is -N(cPr)(CH 2 CH 2 CN), RWa is Me, Rib is H, R 4 c is Me, Rak is Hand R 4 e isH; a compound of Formula (50) wherein R 3 is -N(n-Pr)(CH 2 CH 2 CN), RWa is Me R 4 b is H, R 4 c is Me, R 4d is H andRi4e is H; O8/03/02,swI 261 4spe,l 82 a compound of Formula (50) wherein R3 is -N(n-Bu)(CH 2 CN), Ra is Me, R" is H, R 4 is Me, R 4 d is H and R 4 is H; a compound of Formula (50) where in R 3 is -NH-CH(Et)(CH 2 OMe), R 4 a is Me, ROb is H, R 4 C is Me, R 4 d is H and R 4 is Me; a compound of Formula (50) wherein R3~ is -NI-ICH(Et) 2 R 4 a is Me, R 4 b is H, R 4 c is Me, R 4 d is Hand R 4 'is Me; a compound of Formula (50) wherein R 3 is -N(CH 2 CH 2 OMe) 2 R 4 a is Me, ROb is H, R 4 c is Me, R 4 d is H and R 4 is Me; a compound of Formula (50) wherein R3 is -NHCH(CH 2 OMe) 2 R 4ais Br, Rb is H, R 4 c is OMe, R 4 d is Hand R 4 'is H; a compound of Formula (50) wherein R3 is -NHCH(Et)(CH 2 OMe), R 4 a' is Br, ROb is :i H, R 4 c is OMe, R 4 d is Hand R 4 e isH; Ri NE),RsMR i ,Ri e a compound of Formula (50) wherein R s-(t2 ai e bi ,Rci e Rd is Hand Re is Me; 15 a compound of Formula (50) wherein R 3 is -N T ICH(CH 2 OEt) 2 R is Me, Rb is H, R 4 is Me,R is Hand R 4 is Me; :a compound of Formula (50) wherein R3 is -NHCH(CH 2 CH 2 OMe)(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 Me;, a compound of Formula (50) wherein R 3 is mopoieW is Me, R 4 b is H, Rc is 20 Me,RWd is Hand R 4 'is H; a compound of Formula (50) R3~ is -N(CH 2 CH 2 OMe) 2 RWa is Br, Rb is H, R 4 c is OMe,R 4dis HandWe is H; *a compound of Formula (50) wherein R 3 is -NHCH(Et) 2 R0' is Br, ROb is H, Rc is OMe, R 4d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is R 4 a is Me, ROb is H, R 4 c is Me, R 4 d is Hand R 4 'is H; a compound of Formula (50) wherein R 3 is -NHCH(CH 2 OMe) 2 R 4 a is CN, ROb is HWc is OMeR 4 d is H andRWeisH; a compound of Formula (50) wherein R 3 is -N(c-Pr)(CH 2 CH 2 CN), R 4 a is Me, ROb is H, Rc is Me, Rd is H and R 4 e is Me; a compound of Formula (50) wherein R 3 is -NCH(CH 2 OMe) 2 R 4 a is Me, R 4 is H, R 4 c is Br, R 4 d is Hand R 4 e is H; a compound of Formula (50) wherein R 3 is -NI{CH(CH 2 OMe)(CH 2 CH 2 OMe), R 4 a is Me,R 4bisH, R 4cisBr,R 4dis Hand R 4 'is H; 08/03/02,swl 261 4speI 83 a compound of Formula (50) wherein R 3 is -NHCH(CH20OMe) 2 R 4 a is Me, R 4 b is H, R 4 is OMe, R 4d is Me and R 4 e is H; a compound of Formula (50) wherein R 3 is -NHCH(Et) 2 R 4a is Me, R 4b is H, R 4c is OMe, R 4 d is Me and R 4 e is H; a compound of Formula (50) wherein R 3 is -NHCH(CH 2 0Me) 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 (50) wherein R 3 is -NHCH(Et)(CH20Me), R 4 a is Cl, R 4b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -N(CH 2 CH 2 0Me) 2 R 4 a is Cl, R 4 b is H, R 4 c is Me, R 4d is H and R 4e is H; a compound of Formula (50) wherein R 3 is -NHCH(CH 2 0Me)(CH 2 CH 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 4e is H; a compound of Formula (50) wherein R 3 is -N(c-Pr)(CH 2 CH 2 CN), 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; 15 a compound of Formula (50) wherein R 3 is -N(c-Pr)(CH 2 CH 2 CN), 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 (50) wherein R 3 is (S)-NHCH(CH 2 0Me)(CH 2 CH 2 OMe), W. °°R 4a is Cl, R 4b is H, R 4 c is CI, R 4 d is H and R 4e is H; a compound of Formula (50) wherein R 3 is -NHCH(CH 2 0Me)(CH 2 CH20OMe), R 4 a 20 is Cl, R 4 b is H, R 4 c is CI, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -NHCH(Et) 2 R 4 a is Me, R 4b is H, R 4 is Br, R 4 is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -NH(CH 2 0Me)(CH 2 -iPr), R 4a is Me, R 4b is H, R 4 c is Me, R 4 d is H and R 4e is H; a compound of Formula (50) wherein R 3 is -N(CH 2 CH 2 0Me) 2 R 4 a is Me, R 4 b is H, R 4e is H, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -N(CH 2 CH 2 OMe) 2 R 4 a is Me, R 4 b is H, R 4c is NMe 2 R 4 d is H and R 4e is H; a compound of Formula (50) wherein R 3 is -NHCH (CH 2 0Me)(n-Pr), R 4a is Me, R 4b is H, R 4 c is Me, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -NHCH(CH20Et)(Et), R 4a 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 (50) wherein R 3 is -NHCH(CH 2 0Me)(CH 2 CH 2 OMe), R 4 a is Me, R 4b is H, R 4 c is NMe 2 R 4d is H and R 4 e is H; 08/03/02,swl 261 4 spc,l 84 a compound of Formula (50) wherein R3 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 (50) wherein R is -NHCH(Et) 2 R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R is -N(CH 2 CH 2 OMe) 2 R 4 a is Me, R 4 b is H, R 4 c is Cl, R4d is H and R 4 e is H; a compound of Formula (50) wherein R3 is -NHCH(CH 2 0Me) 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 (50) wherein R3 is -N(Et) 2 R 4 a is Me, R 4 b is H, R 4 c is Br, R 4 d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(Et) 2 R 4 a is Cl, R4b is H, R 4 C is Me, R4d is H and R4"e is H; .a compound of Formula (50) wherein R3 is -NHCH(Et) 2 R 4 a iS Cl, R 4 b is H, R 4 c iS Me, R4d iS H and R4e iS H; 15 a compound of Formula (50) wherein R is -NHCH(Et) 2 R 4 a is Me, R 4 b is H, H; R 4 C is NMe 2 R4d is H and R 4 e is H; a compound of Formula (50) wherein R is (S)-NHCH(CH20Me)(CH 2 CH 2 Me), R4a is Me, R 4 b is H, R 4 C is Me, R4d is H and R 4 e is H; a compound of Formula (50) wherein R3 is -NHCH(CH 2 OMe)(CH 2 CH 2 OMe), R4a S 20 is Me, R 4 b is H, R4c iS Me, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R is (S)-NHCH(CH20Me)(CH 2 CH 2 OMe), R4a is Me, R4b is H, R 4 C is Cl, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -NHCH(CH 2 OMe)(CH 2 CH 2 OMe), R 4 a is Me, R4b is H, R 4 C is Cl, R4d is H and R 4 e is H; a compound of Formula (50) wherein R is -N(c-Pr)(CH 2 CH 2 cN), R4a is Me, R 4 b is H, R 4 c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NH(Et)(CH 2 CN), R 4 a is Me, R4b is H, R 4 c is Cl, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R is -N(Et) 2 R4a is Me, R4b is Me, R4c is OMe, R 4 d is H and R4e is H; a compound of Formula (50) wherein R 3 is -N(CH 2 CH20Me)(CH 2 CH 2 OH), R4a is Cl, R 4 b is H, R4c iS Cl, R 4 d is Hand R 4 e is H; a compound of Formula (50) wherein R is -N(CH 2 CH 2 0Me) 2 R4a is Me, R4b is Me, R4' is OMe, R4d is H and R4e is H; 08/03/02,swl 2614spel a compound of Formula (50) wherein R 3 is -NHCH(Et) 2 R 4 a is Me, R 4b is Me, R 4 is OMe, R 4 d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -N(CH 2 c-Pr)(n-Pr), R 4 a is Me, R 4b is H, R 4 c is Cl, R 4d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -N(c-Pr)(CH 2 CH 2 CN), R 4 a is Me, R 4 b is Me, R 4 c is OMe, R 4d is H and R 4e is H; a compound of Formula (50) wherein R 3 is -NHCH(Et) 2 R 4 a is Cl, R 4 b is H, R 4 c is OMe, R 4d is H and R 4 is H; a compound of Formula (50) wherein R 3 is -NHCH(Et)(CH20Me), R 4a is Cl, R 4 b is H, R 4 is OMe, R 4 d is H and R 4 isH; a compound of Formula (50) wherein R 3 is -N(Et) 2 R 4 a is Cl, R 4 b is H, R 4 c is CN, R 4d is H and R 4 e is H; a compound of Formula (50) wherein R 3 is -N(c-Pr)(CH 2 CH 2 CN), R 4 a is Cl, R 4 b is H, R 4 c is OMe, R 4 d is H and R 4 e is H; 15 a compound of Formula (50) wherein R 3 is -NHCH(CH20H) 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; and a compound of Formula (51) wherein R 3 is -N(CH 2 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; and a compound of Formula (51) wherein R 3 is -NHCH(CH 2 0Me) 2 R 4 a is Cl, R 4 b is H, 20 R 4 c is Cl, R 4d is H and R 4e is H.

39. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, *I or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof, wherein said compound is 4-(bis-(2-methoxyethyl)amino)-2,7- dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine.

40. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof, wherein said compound is 4-(bis-(2-methoxyethyl)amino)-2, 7 dimethyl-8-(2,5-dimethyl-4-methoxyphenyl)-[1,5-a]-pyrazolo-1,3,5-triazine.

41. A compound of claim 1 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein A is CR.

42. A compound of Formula of claim 41 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof. 08/03/02,swl 2614spe,1 86

43. A compound of claim 42 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R 4 substituents.

44. A compound of claim 42 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 3 is NR 6 aR 7 a or OR 7 A compound of claim 42 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R 4 substituents, and R 3 is NR 6 aR 7 a or OR 7

46. A compound of Formula of claim 41 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Z is CR 2 15 47. A compound of claim 46 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R 4 substituents.

48. A compound of claim 46 and isomers thereof, stereoisomeric forms thereof, 20 or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 3 is NR 6 aR 7 a or OR 7 S. 49. A compound of claim 46 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R 4 substituents, and R 3 is NR 6 aR 7 a or OR 7 A compound of claim 49 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 6a and R 7a are independently H or C 1 -Clo alkyl, and each such Ci-Co alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 haloalkyl, cyano, OR 1 5 SH, S(O)nR 1 3 COR 1 5 CO 2 R" 5 C(O)R 1 3 NRCOR 15 N(COR 5 2 R'CONR 6 R 1 5 NR CO 2 R 13 NR16R 1 5 CONRI 6 R1 5 aryl, heteroaryl or heterocyclyl. 08/03/02,swi 2614spe,187

51. A compound of claim 46 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein -Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R 4 substituents, -R is NRaR7a or OR 7 and -R 1 and R 2 are independently selected from H, Ci-C 4 alkyl, C 3 -C 6 cycloalkyl, C 4 Clo cycloalkylalkyl.

52. A compound of claim 51 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof wherein R 6 a and R 7 a are independently H or Ci-Clo alkyl, and each such CI-Clo alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, Ci-C 4 haloalkyl, cyano, OR 1 5 SH, S(O)nR", COR' 5 CO 2 R' 1 OC(O)R 3 NR 8 COR15, N(COR5)2, R 8 CONR1 6 R1, 15 NRCO 2 R 13 NR 6 R 15 CONR 6 R 15 aryl, heteroaryl or heterocyclyl.

53. A compound of claim 51 of Formula (51) R 3 ^N-N N 4 R R 4 a 4 dR' y R 4 b R 4 Formula (51) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof selected from the group consisting of: a compound of Formula (51) wherein R 3 is -NHCH(n-Pr) 2 R 4a 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 (51) wherein R 3 is -NHCH(CH 2 0Me) 2 R 4 a is Me, R 4b is H, R 4 c is Me, R 4d is H and R 4e is H; a compound of Formula (51) wherein R 3 is -N(CH 2 CH 2 0Me) 2 R 4a is Me, R 4 b is H, R 4 c is Me, R 4 d is H and R 4 e is H; 08/03/02,swl 2614spe, 88 a compound of Formula (5 1) wherein R 3is -N(c-Pr)(CH 2 CH 2 CN), Ra is Me, R" is H, e~ is Me, R 4 d is H and Wei H; a compound of Formula (5 1) wherein R3 is -N(CH 2 CH 2 OMe) 2 Rja is Cl, RWb is H, R~is Me, R"kis Hand R4'isH; a compound of Formula (5 1) wherein R3 is -NHCH(CH 2 OMe) 2 R 4 a is Cl, Rb is H, R 4 c is Me, R 4 dis Hand R 4 e is H; a compound of Formula (5 1) wherein R 3 is NHCH(Et) 2 R 4 a is Cl, ROb is H, R 4 c is Me,RW is H and R 4 'is H; a compound of Formula (5 1) wherein W 3 is -N(Et) 2 R 4 a is Me, ROb is H, R 4 c is Me, R 4 dis HandRWeis H; a compound of Formula (5 1) wherein R 3 is -N(n-Pr)(CH 2 CH 2 CN), RWa is Me, ROb is H, Ric is Me, R 4 d is H and R 4 is H; a compound of Formula (5 1) wherein R 3 is -N(n-Bu)(CH 2 CH 2 CN),RaisM Rb ~isH, R' is Me, R~is H andR~ s;4 15 a compound of Formula (5 1) wherein R3 is -NHCH(n-Pr)(CH 2 OMe), R 4 a is Me, Rb is.:HsR 4 c is Me, R 4 d is H and R 4 e is H; :a compound of Formula (5 1) wherein R 3 is -NI{CH(Et) 2 W'a is Me, ROb is H, R 4 c is 4e OMe,RW is H and Re is H; a compound of Formula (5 1) wherein R 3 is -NHiCH(CH 2 OMe) 2 RWa is Me, Rb is H, 20 R 4 c is OMe,R~ is HandRW"is H; compound of Formula (5 1) wherein R 3 is (S)-NH(CH 2 CH 2 OMe)CH 2 OMe R 4 a is Me, Rb is H, R 4 c is Me, Rdis H and R 4 eis H; a compound of Formula (5 1) wherein R3 is -NFI(CH 2 CH 2 OMe)CH 2 OMe, RWa is Me, R 4b is H, R 4 is Me, R 4 d is H and R 4 is H; a compound of Formula (5 1) wherein R 3 is -N(CH 2 CH 2 OMe) 2 R 4 a is Me, RWb is H, R 4 c is Cl, R 4 d is Hand R 4 e is H; a compound of Formula (5 1) wherein R 3is -NH(Et), R 4ais Me, R 4bis H, WR is Me, R 4d is H and R'is H; a compound of Formula (5 1) wherein R3 is -NHCH(n-Pr) 2 R 4ais Me, R 4bis H, R 4 is Cl, R4d is Hand R 4 'isH;, a compound of Formula (5 1) wherein R 3 is -NHCH(CH 2 OMe) 2 RWa is Me, Rib is H, R 4 c is Cl, R 4 d is Hand R 4 e is H; a compound of Formula (5 1) wherein R 3 is (S)-NH(CH 2 CH 2 OMe)CH 2 OMe, Ri4a is Me, R 4 b is H, R 4 c is C l, R~k is Hand We is H; O8/O3/O2,sw1 261 4spel 9 a compound of Formula (5 1) wherein R3 is -NE(CH 2 CH 2 OMe)CH 2 OMe, R 4 a is Me, RO~ is H, Rcis Cl, RWd is HandWe is H; a compound of Formula (5 1) wherein R3 is -N(n-Pr)(CH 2 CH 2 CN), Ra is Me, R 4'is H, R:4is OMe,RWd is H and We isH;, a compound of Formula (5 1) wherein R 3 is -N(Et) 2 R 4 a is Me, RWb is H, R 4 c is OMe, R 4 d is H and e is H; a compound of Formula (5 1) wherein R3 is (S)-NH(CH 2 CH 2 OMe)CH2OMe, W'a is Cl, ROb is H, R 4 c is Me, Wd is HandRWe is H; a compound of Formula (5 1) wherein R3 is -NH(CH 2 CH 2 OMe)CH 2 OMe, R 4 is Cl, ROb is H, R 4 c is Me, Wd is Hand R 4eisH; a compound of Formula (5 1) wherein W 3 is -N(Et) 2 R 4 a is Cl ROb is H, Ric is Me, R R 4 d is HandRWe isH; a compound of Formula (5 1) wherein R 3 is -N(c-Pr)(CH 2 CH 2 CN), R 4 a is Cl, R 4 b is H, H isiOMe,R 4dis HandRW sH a. #0 15 a compound of Formula (5 1) wherein W 3 is -N(c-Pr)(CH 2 CH 2 CN), RWa is Me, Rb is R 4 cisIMe, R 4 d is H and W~e is H; 00* a compound of Formula (5 1) wherein R3 is -NHCH (n-Pr)(CH 2 OMe), RWa is Me, 4 b is H, R 4 c is OMe, RWd is H and W~e is H; 9** a compound of Formula (5 1) wherein R3 is -NIICH (n-Pr)(C .H 2 OMe), R 4 a is Cl, RWb a. *0, 0 20 is H, R 4 c is Me,e 4 is H andRWe is H; a compound of Formula (5 1) wherein W? is -NHCH(Et) 2 R 4 a is Br, R 4 b is H, R 4 c is OMe, R 4dis OMe and Rile is H; a compound of Formula (5 1) wherein R3 is -NHCH(Et) 2 R 4ais Br, Rb is H, Rc is OMe, R 4 d is H and R 4 'esH a compound of Formula (5 1) wherein R3 is -N(CH 2 CH 2 OMe) 2 RWa is Br, RWb is H, R 4 c is OMe, R 4 d is H and R 4 is H; a compound of Formula (5 1) wherein W? is -NEICH(CH 2 OMe) 2 R 4 a is Br, pb is H, R~c is OMe, R 4d is H and R 4 is H; a compound of Formula (5 1) wherein W? is -N(Et) 2 W'a is Me, ROb is H, R 4 c is Cl, R 4 d is Hand R 4 e is H; a compound of Formula (5 1) wherein R 3 is -N(Et) 2 R 4 a is Cl, R 4 b is H, R 4 c is 0OMe, RWd is OMe and R 4 e is H; a compound of Formula (5 1) wherein R3 is -NHCH(Et) 2 RWa is Cl, ROb is H, R 4 c is OMe, R 4 d is OMe and R 4 C is H; 08/03/02,swi 261 4spe,l a compound of Formula (5 1) wherein R3 is -N(CH 2 CH 2 OMe) 2 RWa is Cl, RWb is H, "R 4 cis Cl, R 4 d is Hand R is H; a compound of Formula (5 1) wherein R3 is -NHCH(CH 2 OMe) 2 RWa is Cl, Rb is H, "R 4 c is Cl, RWd is H and W~e is H; a compound of Formula (5 1) wherein R3 is -N(Pr)(CH 2 CH 2 CN), RWa is Cl, RWb is H,_ Rc is ClR 4dis Hand R 4 isH; a compound of Formula (5 1) wherein R3 is W'a is Cl, Rb is H, Rc is CR4d isHand W~e is H a compound of Formula (5 1) wherein R 3 is -NHCH(Et)CH 2 OMe, R 4 a is Cl R 4 b is H,RWc is Cl,RWd is H and R 4 e is H; a compound of Formula (5 1) wherein R 3 is -NHCH(Et) 2 W a is H, pjb is Cl, Rc is Cl, R 4 d is Hand W~e is H, a opudo oml 51 hri 3 is4HHE),ai e b isH 4c i a compound of Formula (5 1) wherein R is -NHCH(Et) 2 RWa is M, Rb is H, Re is 4d 4e Me, Rd is H and Re is H; compound of Formula (5 1) wherein R 3 is -NHCH(Et) 2 RWa is Cl, Rb is H, Rc is d 4 M, is H and R is H;n :4da compound of Formula (5 1) wherein W? is -NHP)CHt 2 CN, R 4 a is Mei, R 4 C is H, 9 cl isHOe anR 4 is H;adW sH a4 compound of om lai 51 wherein ers -Ntee, seR is Horms theeo, 20 dug andR iseeof ahrnd si opudi -3pnylmn)25dmty--

54. A compound of claim 51 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- forms thereof, wherein said compound is 7-(3etylamino)-2,5-dimethyl-3-(2-mehl me0l4-methoxyphenyl-]-1, A compound of claim 51 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro- drug forms thereof, wherein said compound is 7-(N-(3-cyanopropyl)-N-propylamino)-2,5- dimethyl-3-(2,4-dimethylphenyl)-[1,5-a] pyrazolopyrimidine. O8/03/02,swl 261 4speI 91

57. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 24.

58. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 38.

59. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 39. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim

61. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 53.

62. A pharmaceutical composition comprising a pharmaceutically acceptable Soo*carrier and a therapeutically effective amount of a compound of claim 54. :.0'S

63. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim is 64. A pharmaceutical composition comprising a pharmaceutically acceptable 0.o carrier and a therapeutically effective amount of a compound of claim 56.

65. Use of compound of claim 1 in manufacturing of a pharmaceutical composition for treatment of affective disorder, anxiety, depression, headache, irritable 00 bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, %"se 20 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 °o0 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.

66. Use of compound of claim 24 in manufacturing of a pharmaceutical composition for treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other 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 08/03/02,swi 261 4spc.,1 92 which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals.

67. Use of compound of claim 38 in manufacturing of a pharmaceutical composition for treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other 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. oO.o Use of compound of claim 39 in manufacturing of a pharmaceutical composition for treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, S. 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, 20 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 S"disorders induced or facilitated by CRF, in mammals.

69. Use of compound of claim 40 in manufacturing of a pharmaceutical composition for treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other 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. Use of compound of claim 53 in manufacturing of a pharmaceutical composition for treatment of affective disorder, anxiety, depression, headache, irritable 08/03/02,swl 2614spe,l 93 which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals. 67. Use of compound of claim 38 in manufacturing of a pharmaceutical composition for treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other 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. Use of compound of claim 39 in manufacturing of a pharmaceutical composition for treatment of affective disorder, anxiety, depression, headache, irritable S: 15 bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, S. 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, 20 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 o disorders induced or facilitated by CRF, in mammals. 69. Use of compound of claim 40 in manufacturing of a pharmaceutical composition for treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other 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. Use of compound of claim 53 in manufacturing of a pharmaceutical composition for treatment of affective disorder, anxiety, depression, headache, irritable 08/03/02,swl 2614spe.1 93 bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervous 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.

71. Use of compound of claim 54 in manufacturing of a pharmaceutical composition for treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervous or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus 15 infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of S. -which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals.

72. Use of compound of claim 55 in manufacturing of a pharmaceutical 20 composition for treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other 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.

73. Use of compound of claim 56 in manufacturing of a pharmaceutical composition for treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus 08/03/02,swl 2614spe 94 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 facilitated by antagonizing CRF, including but limited to disorders induced or facilitated by CRF, in mammals.

74. A compound of any one of claims 1 to 4, or claims 11 to 56, substantially as herein described with reference to any one of the Examples. A pharmaceutical composition of any one of claims 5 to 7 or claims 57 to 64, substantially as herein described with reference to any one of the Examples.

76. Use of any one of claims 8 to 10 or claims 65 to 73, substantially as herein described with reference to any one of the Examples.

77. A method for treatment of an 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, S 15 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 a patient/mammal 20 requiring said treatment which method comprises administrating to said patient/mammal an effective amount of compound of Formulae or R R 3 14 A N N N \0 Ar Ar (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein: A is N or CR; Z is N or CR2; 08/03/02.swl 2614spe.l Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuiranyl, 2,3 -dihydrobenzofuranyl, 2,3 -dihy 'dro benzothienyl, indanyl, l,2-benzopyranyl, 3,4-dihydro-l,2-benzopyranyl, tetralinyl, each Ar optionally substituted with I to 5 R 4 groups and each Ar is attached to an unsaturated carbon atom, R is independently selected at each occurrence from H, C,-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, halo, CN, CI-C 4 haloalkyl; R'I is independently selected at each occurrence from H, C,-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, halo, CN, CI-C 4 haloalkyl, CI-C 1 2 hydroxyalkyl, C 2 -CI 2 alkoxyalkyl, C 2 -CIO cyanoalkyl, C 3 -C 6 cycloalkyl, C 4 -CIO cycloalkylalkyl, NR 9 R 10 C 1 -C 4 alkyl-NR 9 R' 9 NR9COR9 SR or S(O),,R R 2 is selected from H, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, .C 4 -C, 0 cycloalkylalkyl, C 1 -C 4 hydroxyalkyl, halo, CN, -NR 6 NR 9 COR' 0 -N-R 6 7 (ONRR 7 CI-C 4 haloalkyl, OR SH R3 is selected from: H, OR SH, 3 COR C0 2 R OC(O)R. NR'COR 7 N(COR 2 NR 8 CONR6 R 7, NR'CO 2 R 1 3 NP. R 7, NRa aR 7 a, N(0R 7 )R 6 CONR6 R 7, aryl, heteroaryl and heterocyclyl or -C 1 -C 10 alkyl, C 2 -Cio alkenyl, C 2 -Cio alkynyl, C 3 -C8 cycloalkyl, C 5 -C 8 cycloalkenyl, C 4 -C, 2 cycloalkylalkyl or C 6 -CIO cycloalkenylalkyl, each optionally 20 substituted with I to 3 substituents independently selected at each occurrence from C 1 -C 6 :alkyl, C 3 -C 6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, OR" SH, 3 C0R 15 C0J2R, UC(U)R"' NR"COR' 5 N(C0R') 2 N CO NR'CO 2 R' 3 NR 16 R' CONR6 R 15, aryl, heteroaryl and heterocyclyl; R 4 is independently selected at each occurrence from: CI-C 10 alkyl, C 2 -Clo alkenyl, C 2 -Clo alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 1 2 cycloalkylalkyl, NO 2 halo, CN, C 1 -C 4 haloalkyl, NR 6R', NP. COR', NR 8 C0 2 R 7 COR 7 OR 7 CONR 6 R 7 CO(NOR 9 )R 7 C0 2 R 7 or SOn' where each such CI-C 10 alkyl, C 2 -Clo alkenyl, C 2 -Clo alkynyl, C 3 -C 6 cycloalkyl and C 4 -C] 2 cycloalkylalkyl are optionally substituted with I to 3 substituents independently selected at each occurrence from CI-C 4 alkyl, NO 2 halo, CN, N 6 NR'COR 7 NR'CO 2 COR 7 7, CN6 7, ,7 7- OR O R RC0 2 R 7 CO(NOR 9 )R 7 or S(O),R;I R 6and R 7, R la and R 7 a are independently selected at each occurrence from: -H, -CI-Cl 0 alkyl, C 3 -Ci 0 alkenyl, C 3 -Clo alkynyl, CI-Clo haloalkyl with 1 -10 halogens, C 2 -Cg alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -CI 2 cycloalkylalkyl, C 5 -CI 0 cycloalkenyl, or C 6 C 14 cycloalkenylalkyl, each optionally substituted with I to 3 substituents independently 08103/02,m)v 261 4 spe.1 96 selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, OR' 5 SH, COR 5 C0 2 R 5 OC(O)R' 3 NR'COR 15 N(CO.R) 2 NR 8 CONR 6 NR'CO 2 R' 3 PqR1 6 R 5 CONR 6 R 1 5 aryl heteroaryl or heterocyclyl, -aryl, aryl(CI -C 4 alkyl), heteroaryl, heteroaryl(C 1 -C 4 alkyl), heterocyclyl or heterocyclyl(C 1 -C 4 alkyl); alternatively, NR 6R 7and NR 6 a R 7 a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3C C-C 4 alkyl groups; R8 is independently selected at each occurrence from H orC C-C 4 alkyl;- R9 and RIO are independently selected at each occurrence from H, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl; R" is selected from H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 3 -C 6 cycloalkyl; R 2 is CI-C 4 alkyl or C 1 -C 4 haloalkyl; R 13is selected fromC C-C 4 alkyl, C 1 -C 4 haloalkyl, C 2 -C 8 alkoxyalkyl, C 3 -C 6 15i cycloalkyl, C 4 -C 1 2 cycloalkylalkyl, aryl, aryl(C,-C 4 alkyl)-, heteroaryl or heteroaryl(CI-C 4 alkyl)-; R. 1 4 is selected from CI-C 1 0 alkyl, C 3 -Cl 0 alkenyl, C 3 -C~o alkynyl, C 3 -C 8 cycloalkyl, or C 4 -C1 2 cycloalkylalkyl, each optionally substituted with I to 3 substituents independently selected at each occurrence from CI-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, CI-C 4 20 haloalkyl, cyano, OR" 5 SR. S(O)nR' 5 COR", CO 2 R' 5 OC(O)R", NR'COR 15, N(COR' 2 *:NR 8 CONR 1 6 NR'CO 2 R' 5 PNR1 6 R1 5 COTqR1 R 15, and Cl-C 6 alkylthio, C,-C 6 alkylsulfinyl andC C-C 6 alkylsulfonyl; R 15and R 16are independently selected at each occurrence from H, C,-C 6 alkyl, C 3 CIO cycloalkyl, C 4 -C 1 6 cycloalkylalkyl, except that for S(O)nR, 5 R 1 5 cannot be H, aryl is phenyl or naphthyl, each optionally substituted with I to 5 substituents independently selected at each occurrence fromC C-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C,-C 4 haloalkyl, cyano, OR' 5 SH, 5 COR 5 CO 2 R' 5 OC(O)R' 5 NR'COR N(COR 5 2 N CNR6 15 816 15~ 16 NRCORR ",NR'CO 2 R',R R" ,and CO R' heteroaryl is pyridyl, pyrymidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3 -dihydrobenzathienyl or 2,3 dihydrobenzofuranyl, each being optionally substituted with I to 5 substituents independently selected at each occurrence fromC C-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, C 1 -C 4 08/03/012.swi 261 4spe. 197 haloalkyl, cyano, OR 1 5 SH, S(O)nR 15 -COR" 1 CO 2 RI 1 OC(O)R" S NR'COR 5 N(COR")2, NR'CONR6R 1 5 NRCO 2 R",NR 6R 15 and CONR6R 1 heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, halo, Ci-C 4 haloalkyl, cyano, OR 1 5 SH, S(O)nR 15 COR' 5 CO 2 R 5 OC(O)R 5 NR 8 COR 1 5 N(COR 5 2 NR 8 CONRI 6 R 1 5 NR'CO 2 R 5 NR 5 R 6 and CONR 6R 5 n is independently at each occurrence 0, 1 or 2.

78. A method for the treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other 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 patient/mammal which method comprises administrating to said patient an effective amount of a compound of any one of claims 1, 24, 38 to 40, or claims 53 to 56.

79. A method of claim 77 or claim 78 which method is substantially as herein described with reference to any one of the Examples.

80. A compound of claim 31, and geometric isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein: R' and R 2 are methyl; R 3 is NHCH(Et) 2 and Ar is 25 methoxyphenyl.

81. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim

82. Use of a compound according to claim 80 in the manufacture of a medicament for 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, 17/02/04,atl 2614.specipgs,2 0* *~o oo* 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. Dated this 17 th day of February, 2004 DU PONT PHARMACEUTICALS COMPANY By their Patent Attorneys: CALLINAN LAWRIE 17/02/04.atl 2614. specipgs,2 199