NZ333777A

NZ333777A - (1,5-a) pyrazolo and triazole triazines and pyrimidines

Info

Publication number: NZ333777A
Application number: NZ333777A
Authority: NZ
Inventors: Argyrios Georgious Arvanitis; Robert John Chorvat
Original assignee: Du Pont Pharm Co
Priority date: 1996-07-24
Filing date: 1997-07-23
Publication date: 2000-07-28
Also published as: EE9900019A; CN1225637A; CA2259583A1; CN1250223C; SI9720045A; EA199900158A1; IL164513A; IL150163A; NO990264D0; EA004403B1; IL164513A0; NO315610B1; NO315610B3; JP2002513382A; IL127871A0; CN1327793A; AR049583A2; NO990264L; SK286461B6; CN1388126A

Abstract

A method for treating anxiety, depression, and other psychiatric, neurological disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress with compounds of formulae (1) or (2) where Z is N or CR2 ; Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R4 groups and each Ar is attached to an unsaturated carbon atom; R is independently selected at each occurrence from H, C1 -C4 alkyl, C2 -C4 alkenyl, C2 -C4 alkynyl, C3 -C6 cycloalkyl, C4 -C7 cycloalkylalkyl, halo, CN, C1 -C4 haloalkyl; R1 is independently selected at each occurrence from H, C1 -C4 alkyl, C2 -C4 alkenyl, C 2 -C4 alkynyl, halo, CN, C1 -C4 haloalkyl, C1 -C12 hydroxyalkyl, C2 -C12 alkoxyalkyl, C2 -C10 cyanoalkyl, C3 -C6 cycloalkyl, C4 -C10 cycloalkylalkyl, NR9 R10, C1 -C4 alkyl-NR9 R, NR9 COR10, OR11, SH or S(O)R12 ; R3 is selected from: OR7, SH, S(O)R13, COR7, CO2 R7, OC(O)R13, NR8 COR7, N(COR7)2, NR8 CONR6 R7, NR8 CO2 R13, NR6 R7, NR6a R7a, N(OR7)R6, CONR6 R7, aryl, heteroaryl and heterocyclyl, or --C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C3 -C8 cycloalkyl, C5 -C8 cycloalkenyl, C4 -C12 cycloalkylalkyl or C6 -C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1 -C6 alkyl, C3 -C6 cycloalkyl, halo, C1 -C4 haloalkyl, cyano, OR15, SH, S(O)R13, COR15, CO2 R15, OC(O)R, NRCOR, N(COR)2, NR8 CONR16 R15, NR8 CO2 R13, NR16 R15, CONR16 R15, aryl, heteroaryl and heterocyclyl; R14 is selected from C1 -C10 alkyl, C3 -C10 alkenyl, C3 -C10 alkynyl, C3 -C8 cycloalkyl, or C4 -C.sub.12 cycloalkylalkyl, 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, OR15, SH, S(O)R15, COR15, CO2 R15, OC(O)R15, NR8 COR15, N(COR15)2, NR8 CONR16 R15, NR8 CO2 R15, NR16 R15, CONR16 R15, and C1 -C6 alkylthio, C1 -C6 alkylsulfinyl and C1 -6 alkylsulfonyl;

Description

New Zealand Paient Spedficaiion for Paient Number 333777 Intellectual Property Office of New Zealand IP Summary Report Page: 1 of 2 Date: 14 July 2000 Time: 10:14:09 (iprip02 2.00.28) (51) Classification: A61K31/505, A61K31/53, C07D231/00, C07D249/00, C07D251/72, C07D253/08 IPC Edition: Status: 70 Accepted 333777 Client Ref: OP657/9001/JAR/lp Version number: 7 IP type: Patent PCT Inward (86) International Application number: US97/13072 (87) WO Publication number: 98/03510 Elected: Y (22) NZ Filing date: 23 July 1997 Date entered National phase: 18 January 1999 (30) Priority Data: (31) 96 23290 (32) 24 July 1996 (33) US (30) Priority Data: (31)96 686047 (32) 24 July 1996 (33) US (30) Priority Data: (32) 23 July 1997 (33) US (71) Applicant: DU PONT PHARMACEUTICALS COMPANY, Chestnut Run Plaza, 974 Centre Road, Wilmington, Delaware, 19805, United States of America (72) Inventors: Arvanitis, Angyrios Georgious Chorvat, Robert John Contact: CALLINAN LAWRiE, PO Box 43, Matamata, New Zealand Primary Examiner: ERIKA ANDERSON Journal: 1453 Owner change: Yes Date actions completed: Application Accepted Change Ip Owner Next renewal date: 14 July 2000 28 October 1999 23 July 2001 Office title: (1,5-a) pyrazolo and triazofe triazines and pyrimidines (54) Applicant title: Azolo triazines and pyrimidines Intellectual Property Office of New Zealand IP Summary Report Page: 2 of 2 Date: 14 July 2000 Time: 10:14:09 (iprip02 2.00.28) (11) NZ Patent number: 333777 (57) Abstract: Patent 333777 A method for treating anxiety, depression, and other psychiatric, neurological disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress with compounds of formulae (1) or (2) where Z is N or CR2 ; Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triaziriyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R4 groups and each Ar is attached to an unsaturated carbon atom; R is independently selected at each occurrence from H, C1-C4 alkyl, C2 -C4 alkenyl, C2 -C4 alkynyl, C3 -C6 cycloalkyl, C4 -C7 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl; R1 is independently selected at each occurrence from H, G1-C4 alkyl, C2 -C4 alkenyl, C 2 -C4 alkynyl, halo, CN, C1-C4 haloalkyl, C1 -C12 hydroxyalkyl, C2-C12 alkoxyalkyl, C2-C10cyanoalkyl, C3 -C6 cycloalkyl, C4-C10 cycloalkylalkyl, N R9 R10, C1-C4 afkyI- MRS R, NR9 COR 10, OR 11, SH or S(0)R12 ; R3 is selected from: OR7, SH, S(0)R13, COR7, C02 R7, 0C(0)R13, NR8 COR7, N(COR7)2, NR8 CONR6 R7, NR8 C02 R13, NR6 R7, NR6a R7a, N(OR7)R6, CONR6 R7, aryl, heteroary! and heterocyclyl, or -C1 -C10 alkyl, C2 -C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C12 cycloalkylalkyl or C6-C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3 -C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S{0)R13, COR15, C02 R15, OC(G)R, NRCOR, N(COR)2, NR8 CONR16 R15, NR8 C02 R13, NR16 R15, CONR16 R15, aryl, heteroaryl and heterocyclyl; R14 is selected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, orC4 -C.sub.12 cycloalkylalkyl, 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, OR15, SH, S(0)R15, COR15, C02 R15, 0C(0)R15, NR8 COR15, N(C0R15)2, NR8 CONR16 R15, NR8 C02 R15, NR16 R15, CONR16 R15, and C1 -C6 alkylthio, C1 -C6 alkylsulfinyl and C1 -6 alkylsulfonyl; Drawing: ** End of report " TITLE AZOLO TRIAZINES AND PYRIMIDINES 5 FTFT.D OF THF TNVFNTTDN This invention relates a treatment; of psychiatric disorders and neurological diseases including major depression, anxiety-related 10 disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and 15 stress, by administration of certain [1,5-a]- pyrazolo-1,3,5-triazines, [1,2, 3-triazolo-1,3,5-triazines, (1,5-a]-pyrazolo-pyrimidines and [l,5-a]-l,2,3-triazolo-pyrimidines.

BACKGROUND OF THE INVENTION Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC) -derived peptide secretion from the anterior 25 pituitary gland [J. Rivier et al.( Prcc. Nat. Acad. Scl. (USA) 90:4851 (1983>; W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone 30 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 [W, Vale et al,, Rec. 35 Prog. Harm. Res. 39:245 (1983); G.F. Koob, Persp. Behav. Med. 2:39 (1985); E.B. De Souza et al., J.

Printed frorri Mirr.c3a 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 10 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 asnyotrcphic lateral sclerosis 15 as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E.B. De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder, or major depression, the concentration of CRF is significantly increased in 20 the cerebral spinal fluid (CSF) of drug-free individuals [C.B. Neraeroff et al,, Science 226:1342 (1984); C.M. Banki et al., Ani. J. Psychiatry 144:873 (1987); R.D. France et al., Biol. Psychiatry 29:06 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)] . Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C.B. Nemeroff et al., Arch, Sen. Psychiatry 45:577 (1988)]. In addition, there is a blunted 30 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 35 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the Printed from WO 98/03510 PCT/US97/13072 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 5 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 10 the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine / non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety 15 models [D.R. Britton et al., Life Sci, 31:363 {1982); C.W. Berridge and A.J. Dunn Regul. Peptides 16:83 (1986) ] . Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigins demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines [C.W, Berridge and A.J. Dunn Harm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test [K.T. Britton et 30 al., Psychopharmacology 86:170 (1985); K.T, Britton et al. , Psychopharmacology 94:306 (1988)1 and in the acoustic startle test [N.R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Rol5-1788), which 35 was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose- Printed from Mimosa dependent manner while the benzodiazepine inverse agonise (FG7142) enhanced the actions of CRF [K.T. Britton et al., Psychopharmacology 94:306 (1988)J .

The mechanisms and sites of action through which 5 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 10 interest is that preliminary studies examining the effects of a CRF receptor antagonist (a-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to 15 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 Sou2a and C.B. Nemeroff eds . , CRC Press p221 (1990)], Several publications describe corticotropin 20 releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT application US94/11050 , Pfizer WO 95/33750, Pfizer WO 95/34563, Pfizer WO 95/33727 and 25 Pfizer EP 0778 277 Al.

Insofar as is known, [1,5-aJ-pyrazolo-1,3,5-triazines, [l,5-a]-l,2,3-triazolo-l,3,5-triazines, [1,5-a)-pyrazolo-pyrimidines and [1,5-aJ-1, 2,3-triazolo-pyrimidines, have not been previously 30 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 Ri where R1 is OH or alkanoyl, R2 is H, 0Hr or SH, and R3 is 5 an unsaturated heterocyclic group, naphthyl or substituted phenyl, and states that the compounds have xanthine oxidase inhibitory activity and are useful for treatment of gout.

EP 0 S94 149 (Ostuka, 1994) discloses pyrazolotriazine and pyrazolopyrimidine compounds of the formula OH where A is CH or N, R° and are H or alkyl, and R1 and r2 are H, alkyl, alkoxyl, alkylthio, nitro, etc., and states that the compounds inhibit androgen and are useful in treatment of benign prostatic hypertrophy and 20 prostatic carcinoma.

US 3,910,907 (ICI, 1975) discloses pyrazolotriazines of the formula: Printed frorr. Miir.csa z n n Y N x wh<±re R1 is CH3, C2H5 or C6H5, X is H, CgHs, H1-CH3C6H4, CN, COOEt, CI, I or Br, Y is H, C6H5, 0-CH3CSH4, or p-5 CH3C6H4, and Z is OH, H, CK3, C2H5, CgHs, n~C3H7, i-C3H7, SHr SCH3, NHC4H9, or N(C2H5) 2> and states that the compounds are c-AMP phosphodiesterase inhibitors useful as bronchodilators.

'JS 3,995,039 discloses pyrazolotriazines of the formula: where R1 is H or alkyl, R2 is H or alkyl, R3 is H, alkyl, alkanoyl, carbamoyl, or lower alkylcarbamoyl, and R is pyridyl, pyrimidinyl, or pyrazinyl, and states that the compounds are useful as bronchodilators. nr2R3 r US 5, 137,887 discloses pyrazolotriazin.es of the formula Printed from Mimosa wlKsre R is lower alkoxy, and teaches that the compounds are xanthine oxidase inhibitors and are useful for 5 treatment of gout.

US 4,892,576 discloses pyrazolotriazines of the formula where X is O or S, Ar is a phenyl, naphthyl, pyridyl or thienyl group, Rg-Re are H, alkyl, etc., and R9 is H, alkyl, phenyl, etc. The patent states that the 15 compounds are useful as herbicides and plant growth regulants.

US 5,484,760 and WO 92/10098 discloses herbicidal compositions containing, among other things, 20 a herbicidal compound of the formula x S N Ar Printed from Minos PCIYUS97/13072 where A can be N, B can be CR3, R3 can be phenyl or substituted phenyl, etc., R is -N{R4>S02R5 or -S02N(R6)R7 5 and Rj and R2 can be taken together to form where X, Y and Z are H, alkyl, acyl, etc. and D is 0 or s.

US 3,910,907 and Senga et al., J. Med. Chem., 1982, 25, 243-249, disclose triazolotriazines CAMP phosphodiesterase inhibitors of the formula where Z is H, OH, CH3, C2H5, CgHs, n-C3H?, iso-CsH?, SH, SCH3, NH(n-C4H9), or N{C2H5)2< R is H or CHj, and Ri is 20 CH3 or C2Hs- The reference lists eight therapeutic areas where inhibitors of cAMP phosphodiesterase could have utility: asthma, diabetes mellitus, female fertility control, male infertility, psoriasis, thrombosis, anxiety, and hypertension.

P r in ~ed f rcm Mimo s a FCT/US97/13072 W095/35298 (Otsuka, 1995) discloses pyrazolopyrimidines and states that they are useful as analgesics. The compounds are represented by the formula where Q is carbonyl or sulfor.yl, a is 0 or 1, A is a single bond, alkylene or alkenylene, R1 is H, alkyl, 10 etc., R2 is naphthyl, cycloalkyl, heteroaryl, substituted phenyl or phenoxy, R3 is H, alkyl or phenyl, R* is H, alkyl, alkoxycarbonyl, phenylalkyl, optionally phenylthio-substituted phenyl, or halogen, R5 and R6 are H or alkyl.

EP 0 591 528 (Otsuka, 1991) discloses antiinflammatory use of pyrazolopyrimidines represented by the formula where Ri, Rz, R3 and R4 are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl, or phenyl, R5 Printed from Mimosa is SRs or NRiRg, R6 is pyridyl or optionally substituted phenyl, and R7 and Rg are H or optionally substituted phenyl, Springer et al, J. Med. Chem., 1976, vol. 19, no, 2, 291-296 and Springer U.S. patents 4021,556 and 3,920,652 disclose pyrazolopyrimidines of the formula oh where R can be phenyl, substituted phenyl or pyridyl, and their use to treat gout, based on their ability to inhibit xanthine oxidase.

Joshi et al., J. Prakt. Chemie, 321, 2, 1979, 341-344, discloses compounds of the formula R2 where R1 is CF3, C2F5, or CgH^F, and R2 is CH3, C2H5, CF3, or C6H4F.

Printed from Mimoss Maquestiau et al., Bull. Soc. Belg., vol.101, no. 2, 1992, pages 131-136 discloses a pyrazolof1,5-ajpyrimidine of the formula C6H6 Ibrahim et al., Arch. Pharm. (weinheim) 320, 487-491 (1987) discloses pyrazolo11,5-a]pyrimidines of the formula OH} Ch3 where R is NH2 or OH and Ar is 4-phenyl-3-cyano-2-aminopyrid-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).

Printed from Mimosa SUMMARY OF THR INVENTTON In accordance with one aspect, the present invention provides novel compounds, pharmaceutical 5 compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, 10 anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonising CRF, including but not limited to 15 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 30 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 35 disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress,- WO 98/03510 PCT/US97/13072 stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g.. 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 10 induced immune dysfunctions <e . q., 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-ar.imal 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 fe.a.. dependencies on alcohol, cocaine, heroin, 20 benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in a mammal.

The present invention provides novel compounds 25 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 30 disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and 35 stress in a mammal.

Printed froir. Mirr.csa According to another aspect, the present invention provides novel compounds of Formulae (1) and (2) (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 10 of Formulae (1) and (2), 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) are also useful as standards and reagents in determining the ability o.f a potential pharmaceutical to Joind to the CRF receptor, DFTATT.ED HESCRIPTION OF INVENTION [1] The present invention comprises a method of treating affective disorder, anxiety, depression, 25 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, 30 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 35 lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by Printed frorc. Mimosa antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in nairmals comprising administering to the mammal a therapeutically effective amount of a compound of 5 Formulae (1) or (2): (1) (2) and isomers thereof, stereoisomeric forms thereof, or 10 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^; Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, 20 benzothienyl, benzofuranyl, 2,3- dihydrobenzofuranyl, 2, 3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-l,2-benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R^ groups and each Ar is 25 attached to an unsaturated carbon atom; Pt'intad fron Mimosa R is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl; R1 is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, CN, C1-C4 haloalkyl, C]_-Cx2 hydroxyalkyl, C2-C12 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6 10 cycloalkyl, C4-C10 cycloalkylalkyl, Ci~ C4 alkyl-NR9R10, NR9COR10, OR11, SH or S(0)nR12; R^ is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 15 cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN, -NR^R7, NR^COR10, -NR6S(0)nR7, S(0)nNR6R7, Ci~ C4 haloalkyl, -OR7, SH or -S(0)nR12; R^ is selected from: -H, OR7, SH, S(0)nR13' COR7, CO2R7, 0C(0)R13, NR8COR7, N(COR7)2/ NRaCONR6R7, NR8C02R13/ NR6R7, NR6aR7a, N(OR7)R6, CONR6R7, aryl, heteroaryl and heterocyclylf or —C1—C10 alkyl, C2-C1Q alkenyl, C2-C1Q alkynyl, C3-Cg cycloalkyl, C5-C9 cycloalkenyl, C4-C^2 cycloalkylalkyl or Cg-Cio cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents 30 independently selected at each occurrence from Ci-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR1^, SH, S(0)nR13, COR15, CO2R15, 0C(0)R13, NR®COR15, N<COR15>2, NRaCONR16R15, 35 NR8C02R13, NR16R15, CONR16R15, aryl, heteroaryl and heterocyclyl; Printed from Min.csa WO 98/03510 FCT/US97/13072 is independently selected at each occurrence from: Ci-CiO alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, NO2, 5 halo, CN, C1-C4 haloalkyl, NReR7, NRaCOR7, NR8C02S7, COR7, OR7, CONR6R7, CO(NOR9)R7, CO2R7, or S(0)nR7, where each such C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylai-kyl are cptionally 10 substituted with 1 to 3 substituents independently selected at each occurrence.from C1-C4 alkyl, NO2, halo, CN, NR5R7, NReC0R7, NR8C02R7, COR7 OR7, CONR6R7, CO2R7, CO(NOR9)R7, or S(O)nR7; R6 and R7, R^a and R7a are independently selected at each occurrence from; -H, .

-Ci-Cj.0 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, 20 C1-C10 haloalkyl with 1-10 halogens, C2-Cg alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or Cs~Ci4 cycloalkenylalkyl, each optionally substituted with 1 to 3 25 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-Cg cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, CO2R15, 0C(0)R13, NReC0R15, N(CORls)2, NRsC0NR16R15, 30 NR8C02R13, NR16R15, C0NRi6R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(Ci-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl); Printed from Minesa WO 98/03510 PCT/US97/13072 alternatively, NR^R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups; R8 is independently selected at each occurrence from H or C1-C4 alkyl; R- and R1® are independently selected at each 10 occurrence from H, C1-C4 alkyl, or C3-C5 cycloalkyl; R11 is selected from H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl; R1^ iS C1-C4 alkyl or C1-C4 haloalkyl; is selected from Ci-C-fj alkyl, C2.-C4 haloalkyl, C2-Cg alkoxyalkyl, C3-C6 cycloalkyl, C4-20 C12 cycloalkylalkyl, aryl, aryl(Ci~C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl)-; R14 is selected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, or C4-25 Ci2 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-Cg cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S<0)nR15/ COR15, CO2R15, 0C(0)R15, 30 NR8C0R15, N(COR1s)2, NRaCONR16R15, NR8C02R15, nr16r1S, cONR16R15, and Ci-Cfi alkylthio, Ci-Cfi alkylsulfinyl and Cx^Cg alkylsulfonyl; and R1® are independently selected at each 35 occurrence from H, Ci-Cg alkyl, C3-C10 Printed from Minosa WO 98/03510 PCT/US97/13072 cycloalkyl, C4-C16 cycloalkylalkyl, except that for S(0)nR15, R1"' cannot be H; aryl is phenyl or naphthyl, each optionally 5 substituted with 1 to 5 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-Cg cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(C)nR15, COR15, C02ft1S, 0C(O)R15, 10 NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R15, NR16R15; and co[jb16r15; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, 15 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 20 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S{0)nR15- -COR15, C02R15, 0C{0)R15, NRBC0R15, N(COR15>2/ NR8CONR16R15, NRaC02R15, NR16R15, and 25 CONR16R15; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each 30 occurrence from C^-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR15/ COR15, C02R15, 0C{0)R15, NR8COR15, N(COR15) 2, NR9CONRl6R15, NR8C02R15, NR15R16, and CONR16Rls; intcd from Mimosa n is independently at each occurrence 0, 1 or 2, 12] Preferred methods of the present invention are methods in wherein in the compound of Formulae <1) or 5 (2), Ar is phenyl, pyridyl or 2,3- dihydrobenzofuranyl, each optionally substituted with 1 to A r4 substituents. [3 7 Further preferred methods of the above invention 10 are methods wherein, in the compound of Formulae (1) or (2), A is N, Z is CR^, Ar is 2,4-dichlorophenyl, 2, <l-dimethylphenyl or 2, 4, 6-trimethylphenyl, R1 and Rz are CH3, and R3 is . £41 The present invention comprises compounds of Formulae (1) or (2): and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutical^ acceptable salt or pro-drug forms 25 thereof wherein: A is N or CR; Ac Ar (1) (2) Printed from Mimosa 2 is N or CR^; Ar is selected from phenyl, naphthyl, pyridyl, 5 pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-l,2-benzopyranyl, tetralinyl, each Ar optionally 10 substituted with 1 to 5 R4 groups and each Ar is attached to an unsaturated carbon atom; R is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2_C4 alkynyl, 15 C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl; R1 is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, 20 halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl, C2~Ci2 alkoxyalkyl, C2_Cio cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR^R^®, Ci~ C4 alkyl-NR^R10, NR9COR10, OR11, SH or S(0)nRl2; R^ is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C1Q cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN, -KR6R7, NR9COR10, -NR6S(0)nR7, S(O)nNR6R7, Ci~ C4 haloalkyl, -OR7, SH or -StOJnR1^; R3 is selected from: -H, OR7, SH, S<0)nR13/ COR7, CO2R7, 0C(0)R13, NR9COR7, N{COR7)2, NR8CONR6R7, NR8C02R13, NR6R7, NR6aR7a, N(OR7)R6, 35 CONR^R7, aryl, heteroaryl and heterocycly1, or Printed frcn Miir.csa WO 98/03510 PCT/US97/13072 -C1-C10 alkyl, C2-C10 alkenyl, C2-Cj,o alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4-C12 cycloalkylalkyl or Cg-Cio cycloalkenylalkyl, each optionally 5 substituted with 1 to 3 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, CO2R15, 0C<0)R13, 10 NR8COR15, N(COR15)2r NR8C0NR16R15, NR8C02R13, HRi6R15, CONR16R15, aryl,. heteroaryl and heterocyclyl; is independently selected at each occurrence from: 15 C1-C10 alkyl, C2-C10 alkenyl, C2-C1Q alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, N02/ halo, CN, C1-C4 haloalkyl, NR6R7, NR3COR7, NR&C02H7/ COR7, OR7,. CONR6R7, CO(NOR9)R7, CO2R7, or S(0)nR7' where each such C1-C10 alkyl, C2-20 C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NO2, halo, CN, NR6R7, NR0COR7, 25 NR®C02R7> COR7 OR7, CONR&R7, CO2R7, CG(N0R9)R7, or S(0)nR7; and R7, R®a and R7a are independently selected at each occurrence from: -H, -C1-C10 alkyl, C3-C10 alkenyl, C3~C].0 alkynyl, Ci-C10 haloalkyl with 1-10 halogens, C2~Cg alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, 35 or Cg-Ci4 cycloalkenylalkyl, each optionally substituted with 1 to 3 Printed f ron Mimo s a WO 98/03510 PCT/US97/13072 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, CO2R15, 0C<0)Rl3, NRflcOR1^, N(COR15)2, NR^CONR1 ^R1 , NR3C02RL3, NR1SR15, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl<Ci-C4 alkyl), heteroaryl, heteroaryl(C3.-C4 alkyl), heterocyclyl or 10 heterocyclyl{C1-C4 alkyl), alternatively, NR^R7 and NR®aR7a are independently piperidine, pyrrolidine, piperazine; N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups; R® is independently selected at each occurrence from H or C1-C4 alkyl; r9 and R1® are independently selected at each 20 occurrence from H, C1-C4 alkyl, or C3-C6 cycloalkyl; R11 is selected from H, C1-C4 alkyl, Ct._C4 haloalkyl, or C3-C6 cycloalkyl; R1^ is C1-C4 alkyl or C1-C4 haloalkyl; R13 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2~Cg alkoxyalkyl, C3-C6 cycloalkyl, C4-30 C12 cycloalkylalkyl, aryl, aryl(Ci~C4 alkyl)-, heteroaryl or heteroaryl{C1-C4 alkyl)-; R14 is selected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3~Cg cycloalkyl, or C4-35 C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected Prin~ ed from at each occurrence from Ci-Cg alkyl, C3-Ce cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR15, COR15, C02R15, 0C(0)R15, NR9C0R15, N(COR15)2, NR8CONR16R15, NR8CO2R15, 5 NrISr15, CONR1^r15/ arid ci-Cg alkylthio, Ci-Cg alkylsulfinyl and Ci-Cg alkylsulfonyl; R15 and R^-^ are independently selected at each occurrence from Hr Ci-Cg alkyl, C3-C10 10 cycloalkyl, C4-C16 cycloalkylalkyl, except that for S(0)nR^, cannot be H; aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents 15 independently selected at each occurrence from Ci-Cg alkyl, C3-Cg cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S (0) nR15, .COR15, C02R15, OCfORiS, NR8COR-5, N|COR1S)2, NRbCONR16R15, NR8C02R15, 20 NRlfiR15, and CONRl6R15; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinoliny1, thienyl, imidazolyl, thiazolyl, indolyl, 25 pyrrolyl, oxajolyl, 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 30 occurrence from Ci-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR15, "COR15, C02R15, 0C{O)Rls, NR8COR15, N(COR15)2, NR8CONRl5R15, NR8C02R15, NR1^R151 and CONR16R15; Printed from Mirc.nsa WO 98/0351© PCT/US97/13072 heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to S substituents independently selected at each occurrence from Ci-Cg alkyl, C3-C6 cycloalkyl, 5 halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR15, COR15, CO2R15, 0C(0)R15, NR^COR15, N(COR1^)2 r NRScONRiSRlS, NR0CO2R15, NRl5R16r and CONR16R15; n is independently at each occurrence 0, 1 or 2, with the provisos that: (1) when A is N, Z is CR2, R2 is H, R3 is -OR7 or -0C0R13, and R7 is H, then R1 is not H, OH or SH; (2) when A is N, Z is CR2, R1 is CH3 or CjHs, R2 is H, and R3 is OH, H, CH3, C2H5, CgH5, n—C3H7, i—C3H7, SH, SCH3, NHC4H9, or N(C2H5)2, then Ar is not phenyl or m-CH3-phenyl; (3) when A is N, Z is CR2, R2 is H, and Ar is pyridyl, pyrimidinyl or pyrazinyl, and R3 is NRSaR7a, then R6a and R7a are not H or alkyl; (4) when A is N, Z is CR2, and R2 is S02NR6R7, then R3 is not OH or SH; (5) when A is CR and Z is CR2, then R2 is not-NR^S02R7 or -S02NR6R7; (6) when A is N, Z is CR2 and R2 is -NR6SO2R7 or -SO2NR6R7, then R3 is not OH or SH; (7) when A is N, Z is CR2, R1 is methyl or ethyl, R2 is H, and R3 is H, OH, CH3, C2H5, CgHs, n-C3Hv, Printed from Mimosa WO 98/03510 PCTYUS97/13072 iso-C3H7, SH, SCH3, NH(n-C4H9)f or N(C2H$)2f then Ar is not unsubstituted phenyl or m-methylphenyl; (s) when a is CR, Z is CR2, R2 is h, phenyl or alkyl, 5 R3 is NR&COR7 and Ar is phenyl or phenyl substituted with phenylthio, then R7 is not aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocycly(C1-C4 alkyl); (9) when A is CR, 2 is CR2, R2 is H or alkyl, Ar is phenyl, and R3 is SR13 or NR6aR7a, then R13 is nor aryl or heteroaryl and R6a and R7a are not H or aryl; or (10) when A is CH, 2 is CR2, R1 is OR11, R2 is H, R3 is OR7, and R7 and R11 are both H, then Ar is not phenyl, p-Br-phenyl, p-Cl-phenyl, p-NHCOCH^-phenyl, p-CH3~phenyl, pyridyl or naphthyl; (11) when A is CH, Z is CR2, R2 is H, Ar is unsubstituted phenyl, and R3 is CH3, C2H5, CF3 or CgHflF, then Ri is not CF3 or C2F5; (12) when A is CR, R is H, Z is CR2, R2 is OH, and R1 and R3 are H, then Ar is not phenyl; {13) when A is CR, R is H, Z is CR2, R2 is OH or NH21 R1 and R3 are CH3, then Ar is not 4-phenyl-3-cyano-2-aminopyrid-2-yl. [5] Preferred compounds of the above invention are compounds of Formulae (1) and (2) 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: (1) when A is N, R1 is H, C1-C4 alkyl, halo, CN, C1-C12 hydroxyalkyl, C1-C4 -2 6- Printed from. Miir.csa alkoxyalky1 or S02{Cj.-C4 alkyl), r3 is NRSaR7a arKj R®a is unsubstituted C1-C4 alkyl, then R^a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, 5 benzothiazolyl, indolyl or C3-C6 cycloalkyl; and (2> A is N, R1 is H, C1-C4 alkyl, halo, CN, C1-C22 hydroxyalkyl, C1-C4 alkoxyalkyl or S02(Ci-C4 alkyl), R3 is NR^aR^a and R7a is unsubstituted C1-C4 alkyl, then R^a is not phenyl, naphthyl, thienyl, 10 benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C3-C6 cycloalkyl. [6] Preferred compounds of the above invention also 15 include compounds of Formulae (1) and (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutical^ acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydroben2ofuranyl, each 20 optionally substituted with 1 to 4 R^ substituents. [7] . Preferred compounds of the above invention also include compounds of Formulae (1) and (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceut!cally acceptable salt or pro-drug forms thereof wherein A is N, Z is CR2, Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R1 and R2 are CH3, and R3 is NR6aR7a. [11J 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 35 thereof wherein A is N.

Printed from Mimosa WO 98/03510 PCT/US97/13072

[12] More preferred compounds of the above inven-ion also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically 5 acceptable salt or pro-drug forms thereof. [13J 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 R4 substituents.

[14] 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 R3 is NR6aR7a or OR7 .

[15] 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 R4 substituents, and r3 is nr6aR7a or OR7 .

[16] 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 CR2.

Prir.-ed from Mimosa

[17] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of 5 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 R4 substituents.

[18] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or nixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein r3 is 15 NR6*R7a or OR7.

[19] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of 20 stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R®a is independently selected from: -H, -Ci-Cio alkyl, C3-C10 alkenyl, C3-C10 alkynyl, 25 C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or Cg-Ci4 cycloalkenylalkyl, each optionally substituted with 1 to 3 30 substituents independently selected at each occurrence from Ci-Cfi alkyl, C3-Cs cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0>nR13, COR15, CO2R15, 0C<O)R13, NR8COR15, N(COR15) 2, NR0CONRieR15, 35 NR8C02R13, NRl6Rl5f CONR^R15, aryl, heteroaryl or heterocyclyl.

Printsd from Mirr.osa WO 98/03510 PCT/US97/I3072 -aryl, aryl(Ci~C4 alkyl)-, heteroaryl, heteroaryl(Ci-C4 alkyl)-, heterocyclyl or heterocyclyl(C1-C4 alkyl)-; and R7a is independently selected at each occurrence from; -H, -C5-C1Q alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2~Ce alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, 10 or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from Cj-Cg alkyl, C3-C& cycloalkyl, halo, C1-C4 haloalkyl, 15 cyano, OR15, SH, S(0)nR13, COR15, CO2R15, 0C(0)R13, NR^COR15, N(COR15) 2 < NReCONR1SR15, NRaC02R13, NR16R15, CONRi5R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl (C1-C4 alkyl), heteroaryl, 20 heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl); alternatively, NR^R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-25 methylpiperazine, morpholine or thiomorphoiine, each optionally substituted with 1-3 C1-C4 alkyl groups.

[20] More preferred compounds of the above invention also include compounds and isomers thereof, 30 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are identical and are selected from: -C1.-C4 alkyl or C3-C6 cycloalkyl, each optionally 35 substituted with 1 to 3 substituents independently selected at each occurrence from Printed fro r:. Miir.o 3 a PCT/US97/I3072 Ci~Cg alkyl, C3-C5 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, -COR15, C02R15, OC(O)R13, NRBCOR15, N(CORl5)2, NRBCONR16r15, NReC02R13, NRICRIS, CONR16r15, 5 aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl.

[21] More preferred compounds of the above invention also include compounds and isomers thereof, 10 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R*>a is selected from: -H, -C1-C10 alkyl, C3-C1Q alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2~Cg alkoxyalkyl, C3-C6 cycloalkyl, C4-C±2 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each 20 optionally substituted with 1 to 3 substituents independently selected at each occurrence from C\—Cg alkyl, C3-C6 cycloalkyl, halo, Ci—C4 haloalkyl, cyano, OR15, SH, S<0)nR13, COR15, CO2R15, 25 0C(0)R13, NR8COR15, N(COR15)2, NR8conr16R:l5, NR8C02R13, NR1SR15, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(Ci~C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or 30 heterocyclyl(C1-C4 alkyl); R7a is selected from: -C1-C4 alkyl and each such C1-C4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from 35 Ci-Ce alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, ORIS, SH, S(0)nRi3, CORiS, Printed fron Mimosa WO 98/03510 PCT/US97/13072 C02R15r 0C(O)Rl3, NR^COR15, N(COR15)2/ NR0CONR16R15, NF8C02R13, NR1BR15, CONR16R15, aryl, heteroaryl or heterocyclyl.

[22] 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 10 one of and R13 is selected from: -C3-C6 cycloalkyl, each such C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from C^-Cg alkyl, Ct-Cs cycloalkyl, halo, C1-C4 15 haloalkyl, cyano, OR15, SH, S(0)nRl3, COR15, CQ2R15, OC CO) R1^, NR8COR1-5, N(C0R1S)2. NRBCONR1, NR8CO2R13, NRiGRlS, CONRifiRlS, aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, and the other of R6a and R7a is unsubstituted Cx-C^ alkyl.

[23] 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 30 R®a and R7a are independently H or C1-C10 alkyl, each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR1^, SH, S(0)nR^f 35 COR15, C02R15, 0C(O)R13, NReC0R15, N(COR15)2, Prir.'.ed from Mimosa R8CONR16R15, MR8C02R13, NR16R15, CONRlsR15, aryl, heteroaryl or heterocyclyl.

[24] More preferred compounds of the above invention 5 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 10 is optionally substituted with 1 to 4 R4 substituents, and is NR6aR7a or OR"7. [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 R^a j_3 independently sele'cted from: -H, —CC10 alkyl, C3-C1O alkenyl, C3-C10 alkynyl, Cl-Cio haloalkyl with 1-10 halogens, C2_Cg alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or Cg-Cj.4 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, OR15, SH, S(0)nR13, COR15, CO2R15, OC{0)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR0CO2R13, NRi6R15, C0NR15R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(Ci-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl{C1-C4 alkyl); Printed trom Minosa rCT/US97/lM?2 R7a is independently selected ac each occurrence from; -H, -C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C5 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 Ci-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, 5(0) nR13, COR15, CO2R15, 0C(0)R13, NR8COR15, N{C0R15)2, NR8CONR16R15, NR8C02R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl (C1-C4 alkyl), heteroaryl, heteroaryl (C1-C4 alkyl), heterocyclyl or heterocyclyl(CJ-C4 alkyl), alternatively, NR^R7 and NR^aR_?a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morphoiine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups. [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 R6a 30 and R7« are identical and are selected from: -C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-Ce alkyl, C3-C6 cycloalkyl, halo, C1.-C4 haloalkyl, cyano, OR15, SH, S{0)nR13f -COR15, Printed from Mime3a CO2R15, 0C(O)Rl3, NR8C0R1S, N(CORlS>2, NR8CONRlfiR15, NR8C02R13, NRI^RIS, CONR1-6R15, aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl.

[27] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically JO acceptable salt or pro-drug forms thereof wherein and R7a are identical and are —C1-C4 alkyl, each such C1-C4 alkyl

[28] 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: optionally substituted with 1 to 3 substituents independently selected at each occurrence from Cj-Cg alkyl, C3-C5 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nRl3, -CORlS, CO2R15, OC(0)R13, NRScORlS, N(COR15)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.

-H, -C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, Ci~Ciq haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or Cg-Ci4 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-Cs alkyl, C3-Cg cycloalkyl, halo, C1-C4 haloalkyl, Pri.nted from Minos a cyano, OR15, SH, S(0)nR13r COR15, CO2R15, 0C(0)R13, NR8COR15, N(COR15)2/ NR8CONR16R15, NR8C02R13, NR16R15, C0NR16R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl{Ci-Cdj alkyl), heteroaryl, heteroaryl (C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl); R7a is : -C1-C4 alkyl and each such C1-C4 alkyl is 10 substituted with 1-3 substituents independently selected at each occurrence from Ci-Cg alkyl, Ci-Cg cycloalkyl, halo, C1-C4 haloalkyl, cyano, ORIS, SH, S(0)nRl3, COR15, CO^R15, 0C(0)R13, NRbCOR15, N{COR15)2/ 15 NR8CONRl6Rl5, NR8CO2R13, NR16R1&, CONR16R15, aryl, heteroaryl or heterocyclyl.

[29] More preferred compounds of the above invention also include compounds and isomers thereof, 20 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R6a and R7a is selected from: -C3-Cg cycloalkyl, each such C3-C6 cycloalkyl 25 optionally substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, ORIS, SH, S(0)nRl3, COR15, CO2R15, OC(O)Rl3, NR0CQR15, N(COR*5) 2, 30 NRflCONRlfiRlS, NR0CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, and the other of R6a and R7a is unsubstituted C1-C4 alkyl, Printed from Mimosa

[30] 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®a and R^a are independently H or C^-Cxo alkyl, each such Ci-C^O alkyl optionally substituted with 1 to 3 substituents independently selected at each 10 occurrence from C^-Cg alkyl, C3-C5 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nRl3r COR15, CO2R15, 0C(0)R13, NR8COR15, N(COR13)2, R8CONRl6R15, NR8C02R13, NR16RiS, CONR16R15, aryl, heteroaryl or heterocyclyl.

[31] 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 R4 substituents, -R3 is NR6aR7a or OR7 and 25 -R1 and R^ are independently selected from H, C^-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.

[32] More preferred compounds of the above invention 30 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 r6b independently selected from: -H, Printed from Mmos WO 98/03510 PCT/US97/13072 ~Ci-Cio alkyl, C3~Cio alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2~Cg alkoxyalkyl, C3~Cg cycloalkyl, C4-Cl2 cycloalkylalkyl, C5-C10 cycloalkenyl, 5 or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, 10 cyano, OR15, SH, S(0)nR13, COR15, CO2R15, OCfO)R13, NR8COR15, N(COR15)j, NR8CONR!^R15# NR8C02R13» NRx^R15, CONR^rIS, aryl, heteroaryl or heterocyclyl, -aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl (C1 — 15 C4 alkyll, heterocyclyl or heterocyclyl(C1-C4 alkyl); R7a is independently selected at each occurrence from: -H, -C5-C1Q alkyl, C3-C10 alkenyl, C3-C1Q alkynyl, 20 C1-C10 haloalkyl with 1-10 halogens, C2-C3 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 25 substituents independently selected at each occurrence from C1-C6 alkyl, C3-Cg cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR^"~^ COR15, CO2R15, 0C(0)R13, NR8COF15, N(COR15)2, NR8CONR16R15, 30 NR8C02R13r NRlfeR15, CONR16R1s, aryl, heteroaryl or heterocyclyl, -aryl, &ryl(Ci-C4 aUyLl , hete.raa.cyl, heteroaryl(Cj-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl), Printsd from Minosa alternatively, NR^R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups.

[33] 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 farms'thereof wherein R^a and R7a are identical and are selected from: -C1-C4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from 15 Ci-Cg alkyl, C3-C6 cycloalkyl, halo, Cx~C^ haloalkyl, cyano, OR15, SH, S(0)nRl3, -CORlS, CO2R15, 0C(0)Rl3, NR8COR1S, N(COR-S)2, NR8CONR16R15, Nft8C02R13, NR16R*-5, CONRl6Rls, aryl, heteroaryl or heterocyclyl, and 20 -aryl or heteroaryl.

[34] 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 R7a are identical and are -C1-C4 alkyl, each such C1-C4 alkyl optionally substituted with 1 to 3 30 substituents independently selected at each occurrence from Ci-Cg alkyl, Cs-Cg cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, -CORlS, CO2R15, 0C(O)Rl3, NR8COR1S, N(COR15)2, NR8CONR16R15, NR8C02R13, NRl&R15, 35 CONRi6R15, aryl, heteroaryl or heterocyclyl.

Frintsd z rcici Miir.osa

[35] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of 5 stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is selected from: -H, -Ci-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, 10 Cx-C]_0 haloalkyl with 1-10 halogens, C2~Cg alkoxyalkyl, C3-C6 cycloalkyl, C4-Ci2 cycloalkylalkyl, C5-C1Q cycloalkenyl, or Cg-Ci4 cycloalkenylalkyl, each optionally substituted with 1 to 3 15 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-Cs cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, CC>2R1S, 0C<O)R13, NR0COR15, N (COR1^, NR3CONR16R15/ 20 NRSCO2R13, NR15f COHR16r15> acyl, heteroaryl or heterocyclyl, -aryl, aryl(Ci-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl); R7a : -C1-C4 alkyl and each such C1-C4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from Cj-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 30 haloalkyl, cyano, OR15, SH, S(Q)nRl3, COR1S, CO2R15, 0C(0)Rl3, NR9COR15, N(CORlS)2, NR8CONR1SR15, NR8CO2R13, NRl6Rl5r CONR16R*S, aryl, heteroaryl or heterocyclyl. [3 6] More preferred compounds of the above invention also include compounds and isomers thereof, Printed from Minosa stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one.of RSa and R^a is selected from: "C3-C6 cycloalkyl, each such C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from Cj-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR1^, SH, S(Q)nRi3r COR15, 10 CO2R15, 0C|0>R13, NR8COR1S, N<CORlS)2, NR0CONR16R1S( NR0CO2R13, NR16R1S, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or 15 -heterocyclyl, and the other of R6a and R7a is unsubstituted C^-C^ alkyl.

[37] More preferred compounds of the above invention 20 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 Rea and R?a are independently H or C1-C10 alkyl, each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR1^j SH, S(0)nR^f COR15, CO2R15, 0C(0)R13, NR8COR15, N(C0R15>2, 30 R0CONR16R15, NR8C02R13, NR16R15, CONRi6R15, aryl, heteroaryl or heterocyclyl.

[38] Specifically preferred compounds of the above invention are compounds of Formula (50) Printsd fron Mimos a FORMULA (50) 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 H; R4a is CI, R4b is H, R4c is CI, R4d is H and R4e is a compound of Formula (50) wherein R3 is -N(Et)(n-Bu)t R4a is ci, R4b is H, R4c is CI, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -(n- Pr) (CH2cPr), R4a is qi, R4b i3 h, R4c is CI, R4d is 20 h and R4e is H; a compound of Formula (50) wherein R-^ is -N (CH2CH20Me) 2, R4a is CI, R4b is H, R4c is CI, R4d is H and R4e is h; a compound of Formula (50) wherein is -NHCH(Et)(n- Bu) , R4a is CI, R4b is H, R4c is CI, R4d is H and _4e is h; a compound of Formula (50) wherein R3 is -NHCH (Et) (CH2QMe) , Ri)a is CI, R4b is K, R4c is CI, R4d is H and R4e is Hi Frin-.ed from Mirr.nsa WO 98/03510 PCT/US97/13072 a compound of Formula (50) wherein R-3 is -NHCH (CH20Me) 2, R4a is CI, R4b is H, R4c is CI, R4d is H and R4e is H; a compound of Formula (50) wherein R-3 is -N(Et)2, R4a is CI, R4b is H, R4c is CI, R4d is H and R4e is H; a compound of Formula (50) wherein R^ is -NHCH(CH20Et)2, R4a is CI, R4b is H, R4c is CI, R4d is H and R4e is 10 H; a compound of Formula (50) wherein R^ is -NBCH(£t)2, R4a is CI, R4b is H, R4c is CI, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(Me)(Ph), R4a is CI, R4b is H, R4c is CI, R4d is H and R4e is H; a compound of Formula (50) wherein R^ is -N(n-Pr)2, R4a is CI, R4b is H, R4c is CI, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(Et)(n-Pr> , R4a is CI, R4b -is H, R4c is CI, R4d is H and R4e is H; a compound of Formula (50) wherein is -NHCH(CH20Me)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me; a compound of Formula (50) wherein is -NHCH(CH20Me)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(CH2CH20Me)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is 35 H; a compound of Formula (50) wherein R-^ is -NHCH(Et)(CH20Me), R4a is Me, R4b is H, R4c is Me, 40 R4d is H and R4e is H; 45 a compound of Formula (50) wherein R3 is -NHCH(Et)2r R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R^ is -OEtf R4a is CI, R4b is H, R4c is CI, R4d is H and R4e is H; Printed from Mimosa a compound of Formula (50) wherein R3 is -N<Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(CH2CN)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(Me)(CH2OMe)f R4a -s ^ R4b -s Hf R4c is R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -OCH(Et)(CH2OMe>, R4a is Me^ R4b is Hf R4c is R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(n- Pr)(CH2cPr), R4a is R4b ig H< R4c i{J Me R4d ±s H and R4e is H; a compound of Formula (SO) wherein R3 is 20 -NHCH(Me)(CH2N(Me)2), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(cPr)(CH2CH2CN), R4a is Me, R^b ig H< R4c is Me R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(n- Pr> <CH2CH2CN), R4a is MS/ R4b is H/ R4c is R4d 45 is H and R4e is H; a compound of Formula (50) wherein R3 is -N(n- Bu) (CH2CN) ( R4a is R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(Et)(CH20Me), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me; a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a 40 is Me, R4b is H, R4c is Me, R4d is H and R4e is Me; a compound of Formula (50) wherein R3 is -N(Cf^CHjOMe)2, R4a Me; R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Printed from. Mirriosa PCT/US97/1307I a compound of Formula (50) wherein R^ is -NHCHfCH20Me)2 R4a is Br, R4b is H, R4g is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein is -NHCH(Et)(CH20Me), R«a is Br? R4b ig Hf R4c is QMe R4d is H and R4e is H; a compound of Formula (50} wherein is -N(Et)2 R4a i 10 Me, R4b is H, R4c is Me, R4d is H and R4e is Me; a compound of Formula (50) wherein R^ i3 -NHCH(CH20Et)2 R4a is Me, R4b is H, R4c is Me, R4d is H and R4e i Me; a compound of Formula (5C) wherein is -NHCH(CH2CH20Me)(CH20Me)2, R4a is Me, R4b is H, R4 is Me, R4d is H and R4e is Me; a compound of Formula (50) wherein r3 is morpholino, r4' is Me, r4t> is H, r4c is Me, r4d is H and r4e is H; a compound of Formula (50) wherein is -N(CH2CH20Me)2, R4a i: is H; R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e a compound of Formula (50) wherein R^ is -NHCH(Et)2, R4' is Br, R4b is H, R4c is OMe, R4d is H and R4e is H, a compound of Formula (50) wherein is -N(Et)2, R4a is Br, is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein R^ is -NH(c-Pr)r is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein is -NHCH(CH20Me)2, R4a is CN, R4b is H, R4c is OMe, R4d is H and R4e is H; 40 a compound of Formula (50) wherein R^ is -N(c- Pr)(CH2CK2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me/ a compound of Formula (50) wherein R^ is -NCH(CH20Me>2, 45 R4a iS Me, R4b is H, R4c is Br, R4d is H and R4e is H; Printea from Mimosa a compound of Formula (50) wherein R-^ is -NHCH(CH2OMe> (CH2CH20Me) , r^ is Me> R4b is R4c is Br, R4d is H and R4e is H; a compound of Formula (50) wherein is -NHCH(CH2OMe)2 R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H; a compound of Formula (50) wherein R^ is -N(CH2CH20Me)2 R4a i: is H; R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e a compound of Formula (50) wherein is -NHCH(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and P4e is H; a compound of Formula (50) wherein a compound of Formula (50) wherein is -N(Et)2, R4a is Me, R4b is H, 20 r4c is OMe, R4d is Me and R4e is H; a compound of Formula (50) wherein is -NHCH(CH2OMe)2, R4a is CI, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein is -NHCH(Et) !CH20Me), R4a is CI, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R^ is -N(CH2CH20Me)2, R4a is CI, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein is 35 -NHCH(CH2OMe)(CH2CH20Me), R4a is el, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R^ is -N(c- Pr) (CH2CH2CN), r4* is R4b ia ^ R4c ig 0Mg^ R4d 40 is Me and R4e is H; a compound of Formula (50) wherein R^ is -N(c- Pr)(CH2CH2CN), R4a is CI, R4b is H, R4c is Cl, R4d is H and R4e is H; 45 -4 6- Print.ed from a compound of Formula (50) wherein R3 is (S>- NHCH(CH2OMe) <CH2CH20Me), R4a is Cl, R4b is H, R4c is CI, R4d is H and R4e is H; a compound of Formula (50) wherein R^ is -NHCH(CH20Me)(CH2CH2OMe), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a 10 is Me, R4b is H, R4c is Br, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NH(CH20Me)(CH2-iPr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is H, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(CH2CH20Me)2, 25 R4a is Me, R4b is H, R^c is NMe2, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH{CH2OMe)(n-Pr), R4a i3 Me, R4b is H, R4c is 30 Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(CH2OEt)(Et), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(CH2OMe) (CH2CH20Me) , R4a is Me, R4b is H, R4c d A is NMe2, R is H and R is H; 40 a compound of Formula (50) wherein R^ is -N(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 -NHCH(Et)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; 45 Printed frorr. Mimosa 45 a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2 R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 i5 -NHCH(CH20Me)2 r4 H; R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is a corapound of Formula <50) wherein R3 is -N(Et!2, R4a ij 1° Me, R4b is H, R4c is Br, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(Et>2, R4a Cl, R4b is H, R4c is Me, R4d is H and R4e ia H; as a compound of Formula (50) wherein R3 is -NHCH{Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (SO) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is H, R4c is NKe2, R4d is H and R4e is 20 H; a compound of Formula (50) wherein R3 is (5)- NHCH(CH20Me) <CH2CH20(4e), R4a ls Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH{CH2OMe) (CH2CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is (S)- NHCH(CH20Me)(CH2CH2CMe>, R4a i3 Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula <50} wherein R3 is 35 -NHCH<CH2OMe> (CH2CH2OMe), KAa is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N{c- Pr> <CH2CEi2CN) , R4a is Me, R4b is H, R4c is Cl, R4d 40 is H and R4e is H; a comDOund of Formula (50) wherein R3 is -NH(Et)(CH2CN)t R4 H; R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is Printed from. Mimosa a compound of Formula (50) wherein r3 is -N{Et)2(. R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein R^ is -N<CH2CH2OMe) (CH2CH2OH), R<a is cl> R4b ig R4c is Ci, R4d is H and R4e is H; a compound of Formula (50) wherein is -M(CH2CH2OMe)2 R4a i is H; R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e a compound of Formula (50) wherein is -NHCH(Et)2f R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is K; a compound of Formula (50) wherein is -N(CH2c-Pr) (n- PD, 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(c-Pr) (CH2CH2CN)f R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H; a compound of Formula [50} wherein R^ is -NHCH (Et)2, R4a i3 cl, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein R^ is -N(Et)2/ R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein R^ is -N<CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein R^ is -NHCH(Et) <CH2OMe), R4a is Cl, R4b is H, R4c is OMe, R4d, is H and R4e is H; a compound of Formula (50) wherein r3 is -N<Et)2, R4a is 40 Cl, R4b is H, R4c is CN, R4d is H and R4e is H,- a compound of Formula (50) wherein R^ is -N<c- Pr)(CH2CH2CN), R4a is clf R4b is R4c is 0Me^ R4d 45 is H and R4e is H; -4 9- Printed trorr. Mimosa PCT /US97/13072 a compound of Formula (50) wherein R3 iS -NHCH(CH2OH)2 R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; and a compound of Formula (50) wherein r3 i3 N(CH2CH20Me)2, R^a is Me, R4b is K, R4c is OMe, R4d is K and R4e is H.

[39] More specifically preferred is 4-(bis-(2-methoxyethyl)amino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-[1,5-a1-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.

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

[41] 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.

[42] 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.

Printed from Mimosa

[43] More preferred compounds of Che 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 R4 substituents.

[44] More preferred compounds of the above invention 10 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 R3 is NR5aK7a or OK7.

[45] 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 R4 substituents, and R3 is NRSaRla or OR7. (46] 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 30 CR2.

[47] More preferred compounds of the above invention also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of 35 stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is •51- Frir.'sd from. Mimosa phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R4 substituents.

[48] More preferred compounds of the above invention 5 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 R3 is NR6aR7a or OR7.

[49] 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 prc-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, and R3 is NRSaR7^ or OR7.

[50] 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 25 R6a and R7a are independently H or Ci~Cio alkyl, and each such C1.-C10 alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-Cg cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR^, 30 SH, S(0)nR13, COR15, CO2R15, 0C(0)R13, NR8COR15, N(COR15>2, R8CONRi6R15, NR8C02R13, NR16R15, CONrI6pl5f aryl, heteroaryl or heterocyclyl.

[51] More preferred compounds of the above invention 35 also include compounds and isomers thereof, stereoisomeric forms thereof, or mixtures of printed frorr Mimosa 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 5 to 4 R4 substituents, -r3 is NR^aRTa or OR7 and -Rl and R2 are independently selected from Hr C1-C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl. (52] 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®a and R7a are independently H or C],-Ciq alkyl, and each such C1-C10 alkyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-Cs alkyl, C3-20 Cg cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, C02R15, 0C{0)R13, NRaC0R15, N(COR15)2, R8CONR16R15, NR8C02R13, NRi6Rls, CONRl^Rl5f aryl, heteroaryl or heterocyclyl. [53) Specifically preferred compounds of the above invention are compounds of Formula (51) Printed from Miic.osa WO 98/03510 PCT/US97/13072 R3 FORMULA (SI) 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 R3 is -NHCH(n-Pr)2, R4 K; R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is a compound of Formula (51) wherein R-? is -NHCH (CH20Me) 2 r4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -N (CH2CH20Me) 2f R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -N(c- Pr) (CH2CH2CN), r4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -N (CH2CH20Me)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NHCH(CH20Me)2, R4 H; R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is Printed from Mimosa WO 98/035JO PCI7TJS97/13072 a compound of Formula (51) wherein is -NHCH(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein is -N{Et}2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R^ is -N(n- Pr) (CH2CH2CN), R4a is Me^ R4b is H< R4c ig ^ R4d is H and R4e is H; a compound of Formula (51) wherein is -N(n- Bu)(CH2CH2CN), R4a is Mg/ R4b is Hi r4c ig ^ R4d is H and R4e is K; a compound of Formula (51) wherein R^ is -NHCH(n- Pr) <CH2OMe), R4a is Me, R4t> is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R^ i3 -NHCH(Et}2, R4a 20 is Me, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula {51} wherein R^ is -NHCH(CH2OMe>2, R4c1 is Me, R4b is K,' R4c is OMe, R4d is H and R4e is H; a compound of Formula (51) wherein is (£) -NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R^ is -NH(CH2CH2OMe)CH2OMe, r4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H,- a compound of Formula (51) wherein is -N(CH2CH2QMe)2/ R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein is -NH(Et)r R4a is 40 Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NHCH(n-Pr)2f R4 H; R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is Printed from Mirr.osa FCT/US97/13072 a compound of Formula (51) wherein R-5 is -NHCH (CH2OMe) 2 R4 H; R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is a compound of Formula (51) wherein is (S) -NH(CH2CH20Me}CH20Me, R4a is Me, R4b is H, R4c is Cl, R4d is H ana R4e is H; a compound of Formula (51) wherein R^ is 10 -NH(CH2CH2OMe)CH2OMe, R4a is MS/ R4b is R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -N(n- Pr)<CH2CH2CN), R4a is Me, R4b is ^ R4c -3 0Me> R4d is H and R4e is H; a compound of Formula (51) wherein is -N<Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (51) wherein r3 j.3 (s) -NH<CH2CH2OMe)CH2OMe, r4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R^ is 25 -NH(CH2CH2OMe)CH2OMe, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R^ is -N(Et)2, R4a j_s Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R^ is -N(c- Pr) (CH2CH2CN) , R4a is Me, R4b is H, R4c is OMe, R4d is H and S4e is H; a. compound of Formula (51) wherein R^ is -N(c- Pr) (CH2CH2CN), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein is -NHCH (n-40 Pr)(CH2OMe), R4a ig Me, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (51) wherein R^ is -NHCH (n- Pr)(CH20Me), r4a is cl, R4b is H, R4c is Me, R4d is 45 h and R4e is H; Printed "rem Minosa WO 98/03510 PCT/US97/13072 a compound of Formula (51) wherein R^ is -NHCH(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H; a compound of Formula (51) wherein is -NHCH(£t)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (51) wherein R^ is -N(CH2CH20Me)2, 1° R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (51) wherein is -NHCH(CH20Me)2 R4a j is H; R4a is Br, R4b is H, R4c is OMe, R4d is H.and R4e a compound of Formula (511 wherein is -N(Et)2, R4a Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -N(Et)2, R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H; a compound of Formula <5\) wherein is -NHCH(Et)2, R4a is H; is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is a compound of Formula (51) wherein R^ is -N (CH2CH20Me)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NHCH(CF^OMe)2, R4a is Cl, R4b is Hf R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R^ is -N(Pr) (CH2CH2CN), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (31) wherein R-^ is -N(Bu) (Et) t R4a 40 is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R^ is -NHCH<Et)CH2OMe, R4a is Cl, R4b is H, R4c is Cl, 45 R4d is H and R4e is H; Printed trcm Mimosa a compound of Formula {51) wherein R3 i3 -NHCH(Et)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein is -NHCH(Et)2, R4a 5 is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein r3 is -NHCH (Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein is -NHCH(Et)2, R4a is Me, R4b is H, R4g is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R^ is -NEt2 R43 is Me, R4b is H, R4c is OMe, R4d is H and R4e is H; 15 and a compound of Formula (51) wherein is -N(Pr> (CH2CH2CN), is mr R4b is r4c is QMe^ R4d is H and R4e is H.

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

[55] More specifically preferred is 1-(Diethylamino)-30 2, 5-dimethyl-3- <2-methyl-4-meth.oxyphenyl- [ 1, 5-a] - pyrazoiopyrimidine and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof. [561 More specifically preferred is 7 — <N— 13— cyanopropyl)-N-propylamino)-2,5-dimethyl-3-(2,4-dimethylphenyl) - [ 1, 5-a] -pyrazoiopyrimidine and isomers thereof, stereoisomeric forms thereof, or 40 mixtures of stereoisomeric forms thereof, and Printsd from Mimosa pharmaceutically acceptable salt or pro-drug forms thereof.

The present invention also provides 5 pharmaceutical compositions comprising compounds of Formulae (1) and (2) and a pharmaceutically acceptable carrier.

Many compounds of this invention have one or more 10 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 active or racemic forms. It is well known in the art 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.

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 "n" means a straight 30 chain alkyl. The prefix "c" means a cycloalkyl. The prefix "(S)" means the S enantiomer and the prefix "(R)" means the R enantiomer. Alkenyl" includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-35 carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the Printed from Mirr.o^n 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, 5 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 10 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, cyclchexyl, and so forth. "Halo" or "halogen" includes fluoro, chioro, 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 stable compound. When a substitent is keto (i.e., =0), 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 carboxyiic acid groups. Such amine protecting groups include those listed in Greene and Wuts, "Protective Groups 35 in Organic Synthesis" John Wiley & Sons, New York (1991) and "The Peptides: Analysis, Synthesis, Printed :rcm Mimosa 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 5 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 benzyloxycarbor.yIs, 1- (p-biphenyl)-1-10 methylethoxycarbonyl, and 9-fluorenylmethyloxycarbony1 (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types 15 such as cyclopentyloxycarbonyl and adamantyloxyearbonyl; 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 (1) and (2). 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 carboxyiic 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 30 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 35 suitable salts are found in Remington's Pharmaceutical Scienr.es. 17th ed., Mack Publishing Printed from Mimcsa WO 98/03510 PCT/US97/13072 Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

"Prodrugs" are considered to be any covalentiy bonded carriers which release the active parent drug 5 of formula (I) or (II) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, 10 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 cf prodrugs include, but are not limited to, acetate, formate and ben2oate derivatives of alcohol and amine functional groups in the compounds "of formulas (I) and (II); and the like.

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

Syntheses Some compounds of Formula (1) may be prepared from 30 intermediate compounds of Formula (7), using the procedures outlined in Scheme 1: Printed fror. Mimics a SCHEME 1 Y halogenating agent or aulfonylating agent + / - bate, + / - »oJ X z z Ar Ar (7) Y = 0 (8) B3H, + / - base + / - aolvent Z Ax (1) A = N Compounds of Formula (7) (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 5 of an inert solvent at reaction temperatures ranging from -80°C to 250°C to give products of Formula (6) (where X is halogen, alkanesulfonyloxy, arylsulfonyloxy or haloalkane-sulfonyloxy). Halogenating agents include, but are not limited to, SOCI2, POCI3, PCI3, 10 PCI5, POBr3, PBrj or PBrj. 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 15 anhydride) or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, alkali metal Printed frorr. Mirr.c WO 98/03510 PCT/US97/13072 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-5 isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), crialkyl amines {preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Ir.ort solvents may include, but are not limited to, 10 lower alkanenir.riles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane}, N,N-dialkylformamides (preferably dimethyIformamide), N,N-dialkylacetamides (preferably 15 dimethylacetamide), cyclic amides (preferably N- methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). 20 Preferred reaction temperatures range from -20°C to 100°C.

Compounds of Formula (8) may be reacted with compounds of Formula R^H (where is defined as above except R3 is not SH, COR7, CO2R7, aryl or heteroaryl) in 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°C to generate compounds of Formula (1). Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), 30 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 35 bis{trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably Printed from Mimosa N,N-di-isapropyl-N-ethvI 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 5 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-diaikylacetarnides (preferably dimethylacetamide), cyclic amides 10 {preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 Halogens (preferably dichloromethane). Preferred reaction temperatures range 15 from 0°C to 140°C.

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

Printed fron Miir.csa SCHEME 2 HN' N' ,N V Rl3X, + / - base, + / - solvent.

N Ar (7) Y = S (12) oxidizing agent, solvent r3h, + / - base, + / - solvent y R3H, + / - baa + / - solvent Ar Ar (13) (1) A = N Compounds of Formula (7) (where Y is S) may be treated with an alkylating agent R13X (where R13 is defined as above, except R13 is not aryl or heteroaryl) in the presence or absence of a base in the presence or absence □f an inert solvent at reaction temperatures ranging from -80°C to 250°C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis(trialkylsilylJ amides (preferably sodium Printed from Minosa WO 98/03510 PCT/US97/13072 bis(trimethylsilyl)amide), trialkyi amines (prefereabiy N,N-di-isopropyi-N-ethyl amine or triethyl amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 5 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 10 dimethy1formamide) , N,N—dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethyIsulfoxide), 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 -fl0°C to 100°C.

Compounds of Formula (12) '(Formula (1) where R3 is SR13) may then be reacted with compounds of Formula R3H 20 to give compounds of Formula (1), using the same conditions and reagents as were used for the conversion of compounds of Formula (8) to compounds of Formula (1) as outlined for Scheme 1 above. Alternatively, compounds of Formula (12) (Formula (1) where R3 is SR^-3) 25 may be oxidized to compounds of Formula (13) (Formula (1} where R3 is S(0)nR13' n is 1,2) by treatment with an oxidizing agent in the presence of an inert solvent at temperatures ranging from -S0°C to 2 50°C. Oxidizing agents include, but are not limited to, hydrogen 30 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), 35 aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens Printed from Mimosa (preferably dichloromethane) or combinations thereof. The choices of oxidant and solvent are known to those skilled in. the art (cf. Oemura, S., Oxidation of Sulfur, Selenium and Tellurium, in Comprehensive nraanir Synthesis. Trost, B.M. ed., (Elmsford, NY: Pergamon Press, 1991), 7, 762-769) . Preferred reaction temperatures range from -20°C to 100°C. Compounds of formula (13) (Formula (1) where R3 is S(0)nR13- n is 1,21 may then be reacted with compounds of Formula R3H to give compounds of Formula (1), using the same conditions and reagents as were used for the conversion of compounds of Formula (8) to compounds of Formula (1) as outlined for Scheme fl) above.

Compounds of Formula (1), where R3 may be -NR®C0R7, -N(COR7)a, -NR0CONR6R7, -NR8C02R13, -NR6R7, -NR8S02R7, may be prepared from compounds of Formula (7), where Y is NH, by the procedures depicted in Scheme 3.

SCHEME 3 alkylating, sulfonylating or acylating agenta + / - basa,solvent A R* (7) Y NH (1) A * H; R3 « NRtR7,URaCOR1, H (COR7) 2, NReCONR'R7, HRBC02R13 Reaction of compounds of Formula (7), where Y is NH, with alkylating agents, sulfonylating agents or acylating agents or sequential reactions with Printed from Mimosa WO 98/03510 PCT/US97/13072 combinations thereof, in the presence or absence of a base in an inert solvent at reaction temperatures ranging from -80°C to 250°C may afford compounds of Formula (1), where R3 may be -NR^COR7, -N(COR7)2, 5 -NRaCONR6R7, -NRbC02R13, -NR6R7' -NR8S02R7. Alkylating agents may include, but are not limited to, Ci-Cio alkyl -halides, -tosylates, -mesylates or -triflates; C^-Cio haloalkyl(1 - 10 halogens)-halides, -tosylates, -mesylates or -triflates,- C2-C8 alkoxyalkyl-halides, 10 -tosylates, -mesylates or -triflates; C3-C5 cycloalkyl-halides, -tosylates, -mesylates or -triflates; C4-C12 cycloalkylalky1-halides, -tosylates, -mesylates or -triflates; aryl(C1-C4 alkyl)-halides, -tosylates, -mesylates or -triflates; heteroaryl(C^-C^ alkyl)-15 halides, -tosylates, -mesylates or -triflates; or heterocyclyl(C1-C4 alkyl)-halides, -tosylates, -mesylates or -triflates. Acylating agents may include, but are not limited to, Ci-Ciq alkanoyl halides or anhydrides, C1-C2.0 haloalkanoyl halides or anhydrides 20 with 1-10 halogens, C2_Cg alkoxyalkanoyl halides or anhydrides, C3-C6 cycloalkanoyl halides or anhydrides, C4 —C12 cycloalkylalkanoyl halides or anhydrides, aroyl halides or anhydrides, aryl(Ci~C4) alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, 25 heteroaryl(C1-C4) alkanoyl halides or anhydrides, heterocyclylcarboxylic acid halides or anhydrides or heterocyclyl(C1-C4) alkanoyl halides or anhydrides. Sulfonylating agents include, but are not limited to, C1-C10 alkylsulfonyl halides or anhydrides, C1-C10 30 haloalkylsulfonyl halides or anhydrides with 1-10 halogens, C2-C8 alkoxyalkylsulfony1 halides or anhydrides, C3-C5 cycloalkylsulfonyl halides or anhydrides, C4-C12 cycloalkylalkylsulfony1 halides or anhydrides, arylsulfonyl halides or anhydrides, aryl{Ci~ 35 C4 alkyl)-, heteroarylsulfony1 halides or anhydrides, heteroaryl{C1-C4 alkyl1sulfonyl halides or anhydrides, Prin~ed from Mimosa WO 98/03510 PCT/US97/13072 heterocyclylsulfonyl halides or anhydrides or heterocyclyl(C1-C4 alkyl)suifonyl halides or anhydrides. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride) , alkali metal 5 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 bisttrialkylsilyl)amides (preferably sodium 10 bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethy1 amine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1 to B 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 dimethylformanu.de), ' N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides 20 (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0°C to 100°C.

Scheme 4 delineates procedures, which may be 25 employed to prepare intermediate compounds of Formula (7), where Y is 0, S and 2 is CR-2.

Print.ed ^rcr. Mimosa WO 98/03510 PCT/US97/13072 SCHEME 4 R2CORb, b»S«, _ solvent ArCHjCN MH2HHz - H2O, solvent HjN NH A.

Rl- (5)~OR° + / - acid, solvent (6) Ar Y=C(Ra)i, base, solvent HH X^ Az (7) Y = O, S; Z = CR2 Compounds of the formula ArCH2CN are reacted with compounds of the formula R2C0Rb, where R2 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°C to 200°C to afford compounds of Formula (3). 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 Printed from Minos?-;.

WO 98/03510 PCT/US97/13072 diaikylamides (preferably lithium di-isopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis{trialkyIsily1|amides (preferably sodium bis(trimethylsily1)amide), trialkyi amines (preferably 5 N,N-di — i sopropyl-N-e thyl 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 10 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), 15 dialkylsulfoxides (preferably dimethylsuifoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0°C to 100°C.

Compounds of Formula (3) may be treated with hydrazine-hydrate in the presence of an inert solvent at 20 temperatures ranging from 0°C to 200°C, preferably 70°C to 15Q°C, to produce compounds of Formula (4), Inert solvents may include, but are not limited to, water, alkyl alcohols (1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, 25 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 30 (preferably dimethylsuifoxide) or aromatic hydrocarbons (preferably benzene or toluene). Compounds of Formula (4) may be reacted with compounds of Formula (5) (where Rc is alkyl {1-6 carbons)) in the presence or absence of an acid in the presence of an inert solvent at 35 temperatures ranging from 0°C to 200°C to produce compounds of Formula (6). Acids may include, but are Printed from Minosa WO 98/035] 0 not limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), haloalkanoic acids (2 - 10 carbons, 1-10 halogens, such as trifluoroacetic acid), arylsulfonic acids (preferably p-toluenesulfonic acid or 5 benzenesulfonic acid), alkanesulfonic acids of 1 to 10 carbons (preferably rr.ethanesulfonic 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, 10 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°C.

Compounds of Formula (5) may be converted to intermediate compounds of Formula {7) by treatment with 20 compounds C=¥(Rd)2 (where Y is O or S and Rd is halogen (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) in the presence or absence of a base in an inert solvent at reaction temperatures from -50°C to 200°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-di-30 isopropyl-N-ethy1 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 35 acetonitrile), cyclic ethers (preferably tetrahydrofuran or 1f4-dioxane), N,N-dialkylformamides (preferably PrintGci from Minosa dimethylformamide >, N,N~diaikylaeetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably 5 benzene or toluene) . Preferred temperatures are 0DC to 150°c.

Intermediate compounds of Formula (7), where Z is N, may be synthesized according the methods outlined in Scheme 5. frf nted from Miir.csa WO 98/03510 PCT/US07/13O72 SCHEME 5 R%a2N3, baaa, solvent ArCH2CN reducing agont, solvent (10) NH (5) 0RC + / - acid, solvent -N NH HN ^ (11) Ar Tf=C(Rd)2, ba»«, aolvant^ N' Ar (7) X = O, S; Z =K Compounds of ArCH^CN are reacted with compounds of Formula R3CH2N3 (where is a phenyl group optionally substituted by H, alkyl (1 to 6 carbons) or alkoxy {1 to 6 carbons) in the presence or absence of a base in an inert solvent at temperatures ranging from 0°C to 200°C to generate compounds of Formula (9). Bases may include, but are not limited to, alkali metal hydrides Printed from Mimosa (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 dial Icy lamides (preferably lithium 5 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). 10 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 dimethylfcrmamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrc?lidin-2-one) , dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons 20 (preferably benzene or toluene). Preferred reaction temperatures range from ambient temperature to 100°C.

Compounds of Formula (9) may be treated with a reducing agent in an inert solvent at -100°C to 100°C to afford products of Formula <1G). Reducing agents 25 include, but are not limited to, (a) hydrogen gas in combination with noble metal catalysts such as Pd-on-carbon, Pt02/ Pt-on-carbon, Rh-on-alumina or Raney nickel, (b) alkali metals (preferably sodium) in combination with liquid ammonia or (c) eerie ammonium 30 nitrate. Inert solvents may include, but are not limited to, alkyl alcohols (1 to 8 carbons, preferably methanol or , lo'rfer alkanenitriles ^1 to 5 carbons, preferably acetonitrile), water, dialkyl ethers (preferably diethyl ether) , cyclic ethers (preferably 35 tetrahydrofuran or 1, 4-dioxane) , N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides Printed freni Mirr.c.sa (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). The preferred reaction 5 temperatures are -50°C to 60°C. Compounds of Formula (9) are then converted to compounds of Formula (7) (where Z is N) via intermediates of Formula (11) using the reagents and reaction conditions outlined in Scheme 4 for the conversion of compounds of Formula (4) to 10 compounds of Formula (7) (where 2 is CR^).

Compounds of Formula (1) may also be prepared from compounds of Formula (7) (where Y is O, S and Z is defined above) as outlined in Scheme 6: SCHEME S Compounds of Formula (7) may be reacted with compounds of Formula R^H in the presence of a dehydrating agent in an inert solvent at reaction temperatures ranging from 0°C to 2S0°C. Dehydrating agents include, but are not 20 limited to, P2°5f 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 25 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid, Inert solvents may include, but are not limited to, Frintsd frcm Miir.csa alkyl alcohols {1 to 8 carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably glyrae or diglyme), cyclic ethers (preferably 5 tetrahydrofuran or 1,4-dioxane)r N,N-dialkylformamides (preferably dimethylformaniide) , N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxide (preferably dimethylsulfoxide), aromatic hydrocarbons 10 (preferably benzene or toluene) or halocarbons of 1 to 10 carbons and 1 to 10 halogens (preferably chloroform) Preferred reaction temperatures range from ambient temperature to 150°C. also be prepared by the methods shown in Scheme : Intermediate compounds of Formula (14), where Z is defined above, may be reacted with compounds of Formula 20 R3C(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°C to 250°C. Acids may include, but are net limited to alkanoic acids of 2 to 10 carbons (preferably acetic acid), arylsulfonic acids 25 (preferably p-toluenesulfonic acid or benzenesulfonic acid)r aikanesulfonic acids of 1 to 10 carbons (preferably methanesulfonic acid), hydrochloric acid, sulfuric acid or phosphoric acid. Stoichiometric or Some compounds of Formula (1) (where A is N) may SCHEME 7 (14) Ax (1) A = N Prtr.zecl fr^m Mimosa 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 5 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 10 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°C to 150°C . .

Intermediate compounds of Formula (7) may also be synthesized by the reactions displayed in Scheme 8.

SCHEME a Y X = Br, Cl, I, B(OR"")2 Compounds of Formula (15), (where Y is OH, SH, NR®R7; Z is defined above, X is Br, Cl, 1, O3SCF3 or B(OR"")2 and R"" is H or alkyl (1 to 6 carbons)) may be reacted with a compound of Formula ArM (where M is halogen, alkali metal, SnCl, ZnBr, Znl, MgBr, MgCl, Mgl, CeCl2, CeBr2 or 25 copper halides) in the presence or absence of an Printed frorc. Kimosa organometallic catalyst in the presence or absence of a base in an inert solvents at temperatures ranging from -100°C to 2Q0°C. Those skilled in the art will recognize that the reagents ArM may be generated in 5 situ. Organometallic catalysts include, but are not limited to, palladium phosphine complexes (such as Pd(PPh3>4>, palladium halides or alkanoates (such as PdCl2(PPh3>2 or PdtOAc)?) or nickel complexes (such as NiCl2(PPh3)2> . Bases may include, but are not limited 10 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 cr 1,4-15 dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably 20 benzene or toluene) or water. Preferred reaction temperatures range from -80°C to 100°C.

The choices of M and X are known to those skilled in the art (cf. Imamoto, T., Organocerium Reagents in Comprehensive Organic Synthesis, Trost, B.M. ed., 25 (Elmsford, NY: Pergamon Press, 1991), 1, 231-250; Knochel, P., Organozinc, Organocadmium and Organomercury Reagents in Comprehensive Organic Synthesis. Trost, B.M. ed., (Elmsford, NY: Pergamon Press, 1991), 1, 211-230; Knight, D.W,, Coupling Reactions between sp2 Carbon 30 Centers, in Comprehensive Organic Synthesis. Trost, B.M. ed., (Elmsford, NY: Pergamon Press, 1991), 3, 401-520), Compounds of Formula (1) may also be prepared using the methods shown in Scheme 9.

Printec from Mimosa SCHEME 9 Z ArM, + / - catalyst, solvent (16) X = Br, Cl, I, B(0R"")2, 03SCF3 Compounds of Formula (16), where A, Z, R1 and R3 are defined above and X is Br, Cl, I, O3SCF3 or B(OR"")2 and 5 R"" is H or alkyl (1 to 6 carbons)) may be reacted with a compound of Formula ArM (where M is halogen, alkali metal, ZnCl, ZnBr, Znl, MgBr, MgCl, Mgl, CeCl2, CeBr2 or copper halides) in the presence or absence of an organometallic catalyst in the presence or absence of a 10 base in an inert solvents at temperatures ranging from -100°C to 200°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(PPh3)fl), palladium halides or alkanoates (such as PdCl2(PPh3)2 or Pd(0Ac)2> or nickel complexes (such as NiCl2{PPh3>2) . Bases may include, but are not limited to, alkali metal carbonates or trialkyl amines 20 (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) . Inert solvents may include, but are not limited to, dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably 25 dimethylformamide), N,N-dialkylacetamides (preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsuifoxide), aromatic hydrocarbons (preferably Prir.Ted from Mimosa W0 9W035I© PCT/US97U3072 benzene or toluene) or water. Preferred reaction temperatures range from -0O°C to 100°C.

Intermediate compounds of Formula (7)(where Y is 0, Sf NH, Z is CR2 and R1, R2 and Ar are defined as above} may be prepared as illustrated in Scheme 10.

SCHEME 10 Ar (3) NH2NH2 (C=Y) NHj + / - bas« or acid, aolvtnt H2N (17) Ar ^CJOR-Ja, + / - acid, solvent.

Ar (7) If = O, S, NH; 2 =* CR2, Compounds of Formula (3) may be reacted with compounds 10 of Formula H2NNH(C=Y)NH2, 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°C to 25Q°C to produce compounds of Formula (17). Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons 15 (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 Printed from Mimosa 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 5 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 10 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 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 20 (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane).

Preferred reaction temperatures range from 0°C to 1S0°C. Compounds of Formula (17) may then be reacted 25 with compounds of Formula R^C(0Re)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°C to 250°C. Acids may include, but are not limited to alkanoic acids of 2 to 10 carbons {preferably acetic 30 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 35 used. Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably Printed from Kimosa acetonitrile), dialkyl ethers (preferably diethyl ether) , cyclic ethers (preferably tetrahydrofurar. or 1, 4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetatnides (preferably 5 dimethylacetamide), cyclic amides (preferably n- methylpyrrolidin-2-one) , dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane), 10 Preferred reaction temperatures range from 50°C to In Scheme 11, the procedures which may be used to convert compounds of Formula (1), where R-* is COR7, CO2R7, NR®COR7 and CONR^R7, to other compounds of Formula 15 (1), where R3 is CH{OH}R7, ch2oh, NR8CH2R7 and CH2NR6R7 by treatment with a reducing agent in an inert solvent at temperatures ranging from -80°C to 250°C.

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 25 metal (trialkoxy)aluminum hydrides, or dialkyl aluminum 150°c.

SCHEME 11 Ar (1) R3 = COR7, C02R7 CONR6R7 (1) R3 = C (OH) R7, CH2OH, CHsNR6R7 -b4- Printed from. Miir.csa PCT/US97/I3072 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 5 tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene), Preferred reaction temperatures range from -80°C to 1C0°C.

In Scheme 12, the procedures are shown which may be used to convert compounds of Formula (1), where R3 is 10 COR7 or CO2R7, to other compounds of Formula (l>, where R? is C(0H) (R7)2 by treatment with a reagent of Formula R^M in an inert solvent at temperatures ranging from -80°C to 250°C .

SCHEME 12 (1) R3 = COR7, C02R7, (1) r3 C(OH)(R7)2 M is halogen, alkali metal, ZnCl, ZnBr, Znl, MgBr, MgCl, Mgl, CeCl2, CeBr2 or copper halides. Inert solvents may include, but are not limited to, dialkyl ethers 20 (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from -80°C to 100°C.

Compounds of Formula (1), where R3 may be -NR^COR7, 25 -NtCOR7)2, -NR8CONR6B.7, -NR0CO2R13, ~NR%7f -NR8S02R7, may be synthesized as depicted in scheme 13.

Prin.ed frorr. Mimosa NC. (18) R h2N Ar (4) Z = CR2 (10) Z = N SCHEME 13 + / - bui, aolvant Ar (19) alkylating, sulfonylating ox acylating aganta + / - basa,aolvant ► (1) A = CR R3 =NR6R7, NRbCOR7, N(COR7)2, NReCONRfiR7, NR3CO2R13 Reaction of compounds of Formula (18), where R and R1 5 are defined above, with compounds of Formula (4) or (10) in the presence or absence of base in an inert solvent may produce compounds of Formula (19) at temperatures Printed from Miir.csa ranging from -50°C to 250°C, Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides fl to 6 carbons)(preferably sodium methoxide or sodium .5 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 10 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°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 -80°C to 250°C may afford compounds of Formula (1), where R3 may be -NR8COR7, ~N(COR7)2, -NK8CONR6R7, 30 -NR®C02R^, -NR^r"7' -NR®S02R7: Alkylating agents may include, but are not limited to, Cj-Cio alkyl -halides, -tosylates, -mesylates or -triflates; Ci-Ciq haloalkyld - 10 halogens)-halides, -tosylates, -mesylates or -triflates; C2-Cg alkoxyalkyl-halides, -tosylates, 35 -mesylates or -triflates; C3-C6 cycloalkyl-halides, -tosylates, -mesylates or -triflates; C4- Printed from Mimosa WO 98/03510 PCT/US97/13072 c12 eyeloalkylalkyl-halides, -tosylates, -mesylates or -triflates; aryl(C1-C4 alkyl)-halides, -tosylates, -mesylates or -triflates; heteroaryl{C1-C4 alkyl)-halides, -tosylates, -mesylates or -triflates; or 5 heterocyclyl(C1-C4 alkyl)-halides, -tosylates, -mesylates or -triflates. Acylating agents may include, but are not limited to, C1-C10 alkanoyl halides or anhydrides, Cj-Cio haloalkanoyl halides or anhydrides with 1-10 halogens, C2-C8 alkoxyalkanoyl halides or 10 anhydrides, C3-C6 cycloalkanoyl halides or anhydrides, C4-C12 cycloalkyialkancy1 halides or anhydrides, aroyl halides or anhydrides, aryl(Ci~C<3) alkanoyl halides or anhydrides, heteroaroyl halides or anhydrides, heteroaryl(C1-C4} alkanoyl halides or anhydrides, 15 heterocyclyIcarboxylic acid halides or anhydrides or heterocyclyl (Ci,-C4) alkanoyl halides or anhydrides. Sulfonylating agents include, but are not limited to, C1-C10 alkylsulfonyl hali-des or anhydrides, C1-C10 haloalkylsulfonyl halides or anhydrides with 1-10 20 halogens, C2_Cg alkoxyalkylsulfonyl halides or anhydrides, C3-C6 cycloalkylsulfonyl halides or anhydrides, C4-C12 cycloalkylalkylsulfonyl halides or anhydrides, arylsulfonyl halides or anhydrides, aryl(Ci-C4 alkyl)-, heteroarylsulfonyl halides or anhydrides, 25 heteroaryl(C1-C4 alkyl)suifonyl halides or anhydrides, heterocyclylsulfonyl halides or anhydrides or heterocyclyl(C1-C4 alkyl)suifonyl halides or anhydrides. Bases may include, but are not limited to, alkali metal hydrides . (preferably sodium hydride), alkali metal 30 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 35 bis(trimethylsilyl)amide), trialkyl amines (prefereably di-isopropylethyl amine) or aromatic amines (preferably Printsd from Mimosa pyridine), Inert solvents may include, but are not limited to, alkyl alcohols (1 to S carbons, preferably methanol or ethanol), lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers 5 (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 10 (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from 0°c to 100°c.

Compounds of Formula [1), where A is CR and R is defined above, may be synthesized by the methods 15 depicted in Scheme 14. -8 9- ? r in to d t rorr. Mimo a SCHEME 14 h3N (4) Z ® C&2 (10) Z = N Ar RO + / - base, solvent OH R3H, + / - base, + / - solvent f X halogenating agent or sulfonylating agent / - base, / - solvent , W. H Ar (22) (23) Compounds of Formula (4) or (.10) may be treated with compounds of Formula (20), where and are defined above in the presence or absence of base in an inert solvent at temperatures ranging from 0°C to 250°C to give compounds of Formula (1), where A is CR and R is defined above. Bases may include, but are not limited Printed frorr. Mimosa WO 98/03510 PCT/US97/13072 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 5 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 10 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 dimethylsuifoxide) or aromatic hydrocarbons {preferably benzene or toluene). Preferred reaction 20 temperatures range from 0°C to 100°C. Alternatively, compounds of Formula (1) where A is CR and R is defined above, may be synthesized through intermediates (22) and (23) , Compounds of Formula {1) or (10) may be treated 25 with compounds of Formula (21), where R1 is defined above and Ra is alkyl (1-6 carbons), in the presence or absence of base in an inert solvent at temperatures ranging from 0°C to 250°C to give compounds of Formula (1), where A is CR and R is defined above. Bases may 30 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), 35 alkali metal carbonates, alkali metal bis(trialkylsilyl)amides {preferably sodium Printed from Ki.iiosa WO 98/03510 PCT/US97/13072 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 5 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 10 {preferably dimethylacetamide), cyclic amides (preferably N-methylpyrrolidin-2-one) , dialkylsulfoxides (preferably dimethylsulfoxide) or aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from C°C to 100°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 -90°C to 250°C to give products of Formula (23) (where X is halogen, 20 alkanesulfonyloxy, arylsulfonyloxy or haloalkane- sulfonyloxy). Halogenating agents include, but are not limited to, SOCI2, POClj, PCI3, PCI5, PQBr3, PBr3 or PBr5. Sulfonylating agents include, but are not limited to, alkanesulfony1 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, 30 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), 35 alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl amines (preferably Printed from Mimosa 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 5 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-10 methylpyrrolidir.-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°C to 15 100°C.

Compounds of Formula (23) may be reacted with compounds of Formula R3H (where R3 is defined as above except R^ is not SH, COR7, CO2R7, 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°C to 250°C to generate compounds of Formula (1). Bases may include, but are not limited to, 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 30 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 35 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably Printed frorc. Mimcsa tetrahydrofuran or 1,4-dioxane}, N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetanides (preferably dimethylacetamide) , cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides 5 (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from 0°C to 140°C.

Some compounds of Formula (1) may also be prepared using the methods shown in Scheme 15, Printed from Mimosa SCHEME 15 A compound of Formula (24> (Rc is a lower alkyl group and Ar is defined as above) may be reacted with 5 hydrazine in the presence or absence of an inert solvent to afford an intermediate of Formula (25), where Ar is defined as above. The conditions employed are similar to those used for the preparation of intermediate of Formula (4) from compound of Formula (3) in Scheme 4.

Compounds of Formula (25), where A is N, may be reacted with reagents of the formula R1C(=NH)ORe, where Rl is Printed from Mirr.osa PCT/US97U3072 defined above and R® is a lower alkyl group) in Che presence or absence of an acid in an inert solvent, followed by reaction with a coir,pound of formula ¥isC(Rd)2 (where Y is O or S and Rd is halogen 5 (preferably chlorine), alkoxy (1 to 4 carbons) or alkylthio (1 to 4 carbons)) in the presence or absence of a base in an inert solvent to give compounds of Formula (27) (where A is N and Y is 0, S). 7he conditions for these transformations are the same as 10 those employed for the conversions of compound of Formula (4) no compound of Formula (7) in Scheme 4.

Alternatively, compounds of Formula (25), where A is CR, may be reacted with compounds of the formula R1(C=0)CHR(C=Y)0RC (where R1 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 haiogenating agents or sulfonylating agents in the presence or absence of a base in an inert solvent, followed by reaction with R3H or R^h in the presence or absence of a base in an inert solvent to give compounds of Formula (X) (where Z is CR2). 25 It will be recognized by those skilled in the art that various combinations of haiogenating agents, sulfonylating agents, R3H or R2H may be used in different orders of reaction sequences in Scheme 15 to afford compounds of Formula (1). For example, in some 30 cases, it may be desirable to react compounds with stoichiometric amounts of haiogenating agents or sulfonylating agents, react with R^K (or R^H) , then repeat the reaction with haiogenating agents or sulfonylating agents and react with R3H (or R2H) to give 35 compounds of Formula (1). The reaction conditions and reagents used for these conversions are similar to the Printed from Mirr.osa PCIYUS97/13072 ones employed for the conversion of intermediate compounds of Formulae (22) to (23) to (1) in Scheme 1<1 (for A is CR) or the conversion of intermediate compounds of Formulae (7) to (8) to (1) in Scheme 1 5 (where A is N).

Alternatively, compounds of Formula (27) (where Y is S) may be converted to compounds of Formula (1) in Scheme 15. Intermediate compounds of Formula (27) may be alkylated with a compound RfX (where Rf is lower 10 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 R3H in the presence or absence of a base in an inert solvent to give a compound 15 of Formula (1}. The conditions and reagents employed are similar to those used in the conversion of intermediate compounds of Formulae (7) to (12) (or to (13)) to compounds of Formula (1) in Scheme 2.

Compounds of Formula (1) may be prepared from 20 compounds of Formula (24), using an alternate route as depicted in Scheme 15. Compounds of Formula (24) may be converted to compounds of Formula (27) via reaction with compounds of formula NK2NH(C=NH)NH2 in the presence or absence of an acid in an inert solvent, followed by 25 reaction with compounds R1C(0Rc)3 (where Rc is lower alkyl and R1 is defined as above), using the conditions employed for the conversion of compounds of Formulae (3) to (17) to (7) in Scheme 10.

Some compounds of Formula (2) may be prepared by 30 the methods illustrated in Scheme 16.

Printed from Mimosa WO 98/03510 PCT/US97/13072 SCHEME 16 R14X, +/- but solvent 3«a taxt Ac (X) Z = COB Ar (2) Compounds of Formula (27b) may be treated with various alkylating agents R-^X (where R14 is defined above and X 5 is halogen, aiJcanesulfonyloxy or haloalkanesulfonyloxy) in the presence or absence of a base in an inert solvent to afford structures of Formula (28). Compounds of Formula (28) (Y is O) may then be converted to compounds of Formula (2) by treatment with haiogenating agents or 10 sulfonylating agents in the presence or absence of a base in an inert solvent, followed by reaction with R^H in the presence or absence of a base in an inert solvent to give compounds of Formula (2). The reaction conditions used for these conversions are similar to the Printed from Minosa WO 98/03510 PCT/US97/13072 ones employed for the conversion of intermediate compounds (22) to (23} to (1) in Scheme 14 (for A is CR) or the conversion of intermediate compounds of Formulae (7} to (8) to (1) in Scheme 1 (where A is N).

Alternatively, compounds of Formula (28) (Y is S) may be alkylated with a compound R^X (where Rf is lower alkyl and X is halogen, alkanesulfonyloxy or haloalkanesulfonyloxy) in an inert solvent, (then optionally oxidized with an oxidizing agent in an inert 10 solvent) and then reacted with R-^H in the presence or absence of a base in an inert solvent to give a compound cf Formula (1). The conditions and reagents employed are similar to those used in the conversion of intermediate compounds of Formulae (7) to (12) (or to 15 (13)) to compounds of Formula (1) in Scheme 2.

Compounds of Formula (1), where Z is COH, may be converted to compounds of Formula (2) as illustrated in Scheme 16. Treatment with various alkylating agents R14X (where R14 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 (2). It will be recognized by one skilled in ths art that the methods used in Scheme 16 may also be used to prepare compounds of Formula (1) 25 where z is COR7.

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 30 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 35 N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents Printed from Mirr.csa 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 5 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 10 benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20°C to 100°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 (6) 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 NH3 as the carrier gas or gas chromatography (GC) as specified below) or a Hewlett Packard 5 9S8A model spectrometer. Melting points were recorded on a Buchi Model 510 30 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 35 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 Printed from Miir.csa 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 10 illustrate and not to limit the invention.

EXAMPLE 1 Preparation of 2,7-dimethyl-8-(2,4-dimethylpheny1) [1,5-a] -pyrazolo-[l,3,5]-triazin-4(3H)-one [Formula 7, where Y is O, Ri is CH3, 2 is C-CH3, Ar is 2,4-dimethyiphenyl) A. 1-Cyano-l-(2,4-dimethylphenyl)propan-2-one Sodium pellets (9.8g, 0.43 mol) were added portionwi.se to a solution of 2,4- dimethylphenylacetonitrile (48 g, 0.33 moll in ethyl acetate (150 mL) at ambient temperature. The reaction 25 mixture was heated to reflux temperature and stirred for 16 hours. The resulting suspension was cooled to room temperature and filtered. The collected precipitate was washed with copious amounts of ether and then air-dried. The solid was dissolved in water and a IN HC1 solution 30 was added until the pH = 5-6. The mixture was extracted with ethyl acetate (3 X 2C0 mL) ; the combined organic layers were dried over MgSO^ and filtered. Solvent was removed in vacuo to afford a white solid (45.7g, 74% yield): NMR (CDC13,30Q MHz):; CI-MS: 188 {M + H) , B. 5-Amino-4-(2,4-dimethylphenyl)-3-methylpyrazole Printed from. Mimosa WO 98/03510 PCTrtJS97/13Q72 A mixture of 1-cyano-l-(2,4-dimethylphenyl)propan-2-one (43.8g, 0.23 raoL) , 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 5 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 10 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 Mg5C>4 and filtered. Solvent was removed in vacuo to give a pale brown viscous oil (34.6g, 75% 15 yield): NMR (CDC13, 300 MHz): 7.10 [s, 1H) , 7.05 (d, 2H, J=l), 2.37 (s, 3H), 2.10 (s, 3H) ; CI-MS: 202 (M + H).

C, 5-Acetamidino-4-(2, 4-dimethylphenyl)-3-methylpyrazole, acetic acid salt 20 Ethyl acetamidate hydrochloride (60g, 0.49 mol) was added quickly to a rapidly stirred mixture of potassium carbonate (69.5g, 0.50 mol), dichlorcmethane (120 mL) and water (350 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2 X 25 120 mL). The combined organic layers were dried over MgSC>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 30 a stirred mixture of 5-amino-4-(2,4-dimethylphenyl)-3-methylpyrazole ( 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 35 vacuo to about one-third of its original volume. The resulting suspension was filtered and the collected Printed from Kinross solid was washed with copious amounts of ether. The white solid was dried in vacuo (31.4gr €11 yield): NMR (DMSO-ds,300 MHz): 7.00 (s, 1H), 6.90 (dd, 2H, J=7, 1), 2.28 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.90 <s, 3H) , 5 1.91 (s, 3H); CI-MS: 243 (M + H).

D. 2,7-dimethyl-8-(2,4-dimetbylphenyl)[1,5-a]-pyrazolo-(1,3,5)-tria2in-4(3H)-one Sodium pellets (23g, 1 mol) were added portionwise 10 co ethanol (500 mL) with vigorous stirring. After all the sodium reacted, 5-acetamidino-4-(2, 4-dimethylphenyl)-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 HC1 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 MgS04 ana filtered. Solvent was removed in vacuo to give a pale tan solid (26g, 98% yield): NMR (CDCl3,3QG MHz): 7.15(s, 1H), 7.09 (s, 2H), 2.45 (s, 3H), 2.39 (s, 3H), 2.30 (s, 3H); CI-MS: 269 (M + H).

EXAMPLE 2 Preparation of 5-methyl-3-(2,4,6-trimethylphenyl)[ 1, 5-a]-(l,2,3)-triazolo-[l,3,5]-triazin-7(6H)-one 30 (Formula 7, where y is 0, Ri is CH3, Z is N, Ar is 2,4,6-trimethylphenyl) A. l-Phenylmethyl-4-(2,4,6-trimethylphenyl)-5-aminotriazole A mixture of 2,4,6-trimethylbenzyl cyanide (l.Og, 6.3 mmol), benzyl azide (0.92g, 6.9 mmol) and potassium Printed frcir. Mimes a t-butoxide (0.78g, 6.9 mmol) in tetrahydrofuran (lOmL) 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 5 organic layers were dried over MgS04 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 (CDCl3, 300 MHz) :7 . 60-7.30 (n>, 5H) , 7.30-7.20 (m, 2H) , 5.50 (s, 2H) , 3.13 (br sp 10 2H), 2.30 (s, 3H), 2.10 (s, 6H); CI-MS: 293 (M + H).

B . 4-(2, 4,6-Trimethylpheny1)-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, 4,6-1rimethylphenyl)-5-aminotr iazole (l.lg, 3.8 mmol) , The reaction mixture was stirred until a dark green color persisted. An ammonium chloride solution ( mL) was added and the mixture was stirred while warming to ambient temperature over 16 hours. The residue was 20 treated with a 1M HC1 solution and filtered. The aqueous layer was basified with a concentrated ammonium hydroxide solution (pH = 9) and then extracted with ethyl acetate three times. The combined organic layers were dried over MgSO^ and filtered. Solvent was removed 25 in vacuo to give a yellow solid (520 mg), which was homogeneous by thin layer chromatography (ethyl acetate) : NMR (CDC13,300 MHz): 6.97 (s, 2H) , 3.68-3.50 (br.s, 2H), 2.32 <s, 3H), 2.10 (s, 6H>; CI-MS: 203 (M + H).

C . 4-(2, 4,6-Trimethylpheny1)-5-acetamidinotriazole, acetic acid salt A mixture of 4-(2,4,6-trimethylphenyl)-5— aminotriazole (400 mg, 1.98 mmol), ethyl acetamidate ( 35 261 mg, 3 mmol) and glacial acetic acid (0.1 mL, 1.98 mmol) in acetonitrile (6 mL) was stirred at ambient Printed from Mimosa 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-dfi, 300 MHz):7.90-5 7.70 (br s, 0.5H), 7.50-7.20 (br. s, 0.5H), 6.90 < s, 2H) , 6.90 <s, 2H) ,■ 3.50-3.10 (br s, 3H) , 2,30-2.20 {br s, 3H) , 2.05 (d, 1H, J = 7), 1.96 (sr 6H) , 1.87 <s, 6H) ; CI-MS: 244 (M +■ H) .

D. 5-methy1-3-{2,4,6-trimethylphenyl)(1,5-a ] -[1,2,3]-tr iazolo-[1,3,5]-triazin-7(4H)-one Sodium (368 mg, 16.2 mmol) was added with stirring to ethanol (10 mL) at room temperature. After the sodium had reacted, 4-{2,4,6-trimethylphenyl)-5-15 acetamidino-triazole, acetic acid salt (490 mg, 1.6 mmol) and diethyl carbonate (1.6 mL, 13 mmol) were added. The reaction mixture was stirred at reflux temperature for 5 hours, then cooled to room temperature. The reaction mixture was diluted with 20 water; a IN HC1 solution was added until pH = 5-6 and three extractions with ethyl acetate.were performed. The combined organic layers were dried over MgSO^ 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 (CDC13,300 MHz): 6.98 (s, 2H) , 2.55 (s, 3H), 2.35 (s, 3H) , 2.10 (s, 6H); CI-MS: 270 (M + H) .

EXAMPLE 3 Preparation of 4-(di(carbomethoxy)methyl)- 2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a]-pyrazolo- 1,3,5-triazine (Formula 1, where R3 is CH(CHCO2CH3} 2, is CH3, Z is C-CH3, Ar is 2,4-dimethylphenyl) Printed frcrn Mimosa A. 4-chloro-2,7-dimethyl-8-<2,4-dichlorophenyI)(1,5-a]- pyrazolotriazine A mixture of 2,7-dimethyl-8-(2,4-dimethylphenyl)[1,5-a] -pyrazolo-1,3,5 — triazin-4-one (Example 1, 1.38g, 4.5 mmol), N,N-dimethylaniline (1 mL, 9 mmol) and phosphorus oxychloride (10 mL) was stirred at reflux temperature for 4 8 hours. The excess phosphorus oxychloride was removed in vacuo. The residue was poured onto ice-10 water, stirred briefly and extracted quickly with ethyl acetate three times, The combined organic layers were washed with ice water, then dried over MgSC>4 and filtered. Solvent was removed in vacuo ca give a brown oil. Flash column chromatography (ethyl 15 acetate:hexanes::1:4) gave one fraction (Rf = 0.5) Solvent was removed in vacuo to afford a yellow oil (l.Og, 68% yield): NMR (CDCL3,300 MHz): 7.55 <d, 1H, J = 1), 7.38 <dd, 1H, J = 7,1), 7.30 (d, 1H, J = 7), 2.68 (S, 3H), 2,45 (5, 3H); CI-MS: 327 (M + H), B. 4-(di(carbomethoxy)methyl)-2,7-dimethy1-9-(2,4-dimethylphenyl) [l,5-a]-pyrazolo-l,3, 5-triazine Sodium hydride (60% in oil, 80 mg, 2 mmol) was washed with hexanes twice, decanted after each washing 25 and taken up in anhydrous tetrahydrofuran (THF, 1 mL).

A solution, of diethyl malonate (Q.32g, 2 ramol) in THF (2 mL) was added dropwise over 5 min, during which time vigorous gas evolution ensued. A solution of 4-chloro-2,7-dimethy1-8-(2,4-dichlorophenyl)[1,5-a]-30 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 35 were washed once with brine, dried over MgSO^ and filtered. Solvent was removed in vacuo to give a brown Printed from Mimosa WO 98/03510 PCT/US97/13072 oil. Column chromatography (ethyl acetate:hexanes ::1:9) afforded, after removal of solvent in vacuo, a pale yellow solid (Rf = 0.2, 2S0 mg, 35% yield); mp 50-52°C; NMR (CDCI3, 300 MHz): 12.35 (br.s, 1H, 7.15-7.00 (m, 5 3H), 4.40 (q, 2H, J = 7), 4.30 (q, 2H, J = 7), 2.4, 2.35, 2.3, 2.2, 2.1 (5 s, 12H), 1.4 (t, 3H, J = 7), 1.35-1.25 (m, 3H); CI-HRMS: Calcd: 411.2032, Found: 4 11.2023 .

EXAMPLE 6 Preparation of 4-(1,3-dimethoxy-2-propylamino)-2,7-dimechyl-8-(2,4-dichlorophenyl)[1,5-a]-pyrazolo- 1,3,5-triazine (Formula 1, where R3 is NHCH{CH2OCH3)2, Ri is CH3, Z is C-CH3, Ar 15 2,4-dichlorophenyl) A. 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl)[1,5-a]- pyrazolotriazine 20 A mixture of 2,7-dimethyl-8-(2,4 dimethylpheny1)(1,5-a)-pyrazolo-1, 3,5-triazin-4-one (Example 1, 1.38g, 4.5 mmol), N,N-dimethylaniline (1 mL, 8 mmol) and phosphorus oxychloride (10 mL) was stirred at reflux temperature for 48 hours. The excess 25 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 MgSC>4 and filtered. Solvent was removed in 30 vacuo to give a brown oil. Flash column chromatography (ethyl acetate:hexanes::1:4) gave one fraction (Rf = 0.5) Solvent was removed in vacuo to afford a yellow oil (l.Og, 68% yield): NMR (CDC13,300 MHz): 7.55 (d, 1H, J => 1), 7.38 (ddf 1H, J = 7,1 ), 7.30 (d, 1H, J = 7), 35 2.68 <s, 3H>, 2.45 Is, 3H); CI-MS: 327 (M + H).

Printsd ircm Mimesa WO 98/03510 PCT/US97/13072 S . 1 - (1, 3-dimethoxy-2-propylamine)) - 2, 7-dimethy1-8-(2,4- dichlorophenyl)(1,5-a]-pyra2olo-l,3,5-triazine A mixture of 4-chloro-2,7-dimethyl-8-(2,4-dichlorophenyl) [1,5-a]-pyrazolo-1,3, 5-triazine (Part A, 5 570 mg, 1,74 mmol), 1,3-dimethoxypropyl-2-aminopropane (25mg, 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 10 dried over MgSO^ and filtered. Solvent was removed in vacuo. Column chromatography (CH2CI2:CH3OH: :50 ; 1) afforded or.e fraction. Removal of solvent in vacuo gave a solid (250 mg, 35i yield); mp 11B-120°C; NMR {CDCI3,300 MHz): 7.50 (s, 1H), 7.28 <ddf 2H, J - 0,1), 15 6.75 (d, 1H, J = 0), 4.70-4,53 <m, 1H), 3.70-3.55 (m, 4H), 3.43 (S, 6H), 2.50 is, 3H), 2.35 (s, 3H); CI-HRMS: Calcd: 409.1072, Found: 409.1085; Analysis Caicd. for C18H21CI2N5O2 : C, 52.69, H, 5.17,. N, 17,07, Cl, 17.28; Found: C, 52.82, H, 5.06, N, 16.77, Cl, 17.50.

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

The examples delineated i.n 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 30 Example.

Printed from Kimoca 6* 7b B<= 9d 10e 11* 129 13h 141 155 16k 171 16m 19 21 22 23 24 TABLE 1 R3 N N ^ N N Ar £ &2. ^ inp <&C) C-Me NHCH(CH20Me)2 2,4-Cl2-Ph 118-12C C-Me NHCHPC2 2,4-Cl2-Ph 114-116 C-Me NEtBu 2,4-Cl2-Ph oil C-Me NPr(CH2-C-C3H5) 2,4-Cl2-Ph oil C-Me N{CH2CH20Me)2 2,4-Clj-Ph oil C-Me NH-3-tieptyl 2,4-Cl2~Ph 90-92 C-Me NHCH (Et)-CH20Me 2,4-Cl2-Ph 179-181 C-Me NEt2 2,4-Cl2"Ph 133-134 C-Me NHCH(CHjOEt } 2 2,4-Cl2~Ph oil C-Me NH-3-pentyl 2,4-Cl2~Ph 139-140 C-Me NMePh 2,4-Cl2~Ph 60-62 C-Me NPr 2 2,4-Cl2~Ph oil C-Me NH-3-hexyl 2,4-Cl2~£h 130-132 C-Me morpholino 2,4-Cl2-Ph C-Me N(CH2Ph)CH2CH2OMe 2,4-Cl2-Ph C-Me NHCH(CHjPh)CH20Me 2,4-Cl2~Ph C-Me NH-4-tetrahydropyrar.yl 2,4-Cl2~Ph C-Me NH-cyclopentyl 2,4-Cl2~Ph C-Me 1,2,3,4-tetrahydro- 2,4-Cl2~Ph i 3 oqui no1iny1 C-Me CH2-(1,2,3,4-tetrahydro- 2,4-Cl2~Ph isoquinolinyl) C-Me OEt 2,4-Cl2~Ph 141-143 C-Me OCH (Et)CHjOMe 2,4-Cl2~Ph Printad frem Miit.osa 28 29 31 32 33 34 36 ■ 37 3a 39 40 41 42 43 44 45 46 47 48 49° 50 51 52 3a" 54 55a' 56a: 57a 5fla' 59 60 61 62 63 PCTAJS97/13072 C-Me OCH^Ph 2,4-Cl2-Ph C-Me O-3-pentyl 2,4-Cl2~Ph C-Me SEt 2,4-Cl^-Ph C-Me S(0) Et 2 , 4-Cl^-Ph C-Me S02Et 2,4-Cl2"Ph C-Me CH<C02Et)2 2,4-Cl2~Ph C-Me C(Et) <C02Et>2 2,4-Clz-Ph C-Me CH(EtICH2OH 2, 4-CI2-Ph C-Me CH(Et)CH20Me 2,4-Cl2-Ph C-Me CONM«2 2,4-Cl2-Ph C-Me COCH3 2,4-Cl^-Ph C-Me CH(OH|CH3 2,4-Cl2"Ph C-Me C(OH)Ph-3-pyridyl 2,4-Cl2-Ph C-Ke Ph 2,4-Cl2~Ph C-Me 2-CF3-PI1 2,4-Cl2-Ph C-Me 2-Ph-Ph 2,4-Cl2"Ph C-Me 3-pentyl 2,4-Cl^-Ph C-Me cyclobutyl 2,4-Cl2-Ph C-Me 3-pyridyl 2,4-Cl2~Ph C-Me CH(Et)CH2C0NMe2 2,4-Clj-Ph C-Me CH(Et)CH2CH2NMe2 2,4-Cl2-Ph C-Me NHCH(CH20Me>2 2,4,6-Me3-Ph 12S-127 C-Me NHCHPC2 2,4,6-Me3-Ph C-He NEtBu 2,4,6-Me3-Ph C-Me NPr(CH2-C-C3H5) 2,4,6-Mea-Ph C-Me M(CH2CK2QMel2 2,4,6-Me3"Ph 123-124 C-Me NH-3-heptyl 2,4,6-Me3~Ph C-Me MHCH(Et)CH20Me 2,4,6-Me3~Ph 145-146 C-Me NEt2 2,4,6-Me3-Ph 88-90 C-Me NHCH(CHjOEt)2 2, 4, 6-M<»3-Ph 132-134 C-Me NH-3-pen.tyl 2,4,6-Me3-Ph 134-135 C-Me NMePh 2,4,6-Me3-Ph C-Me NPr2 2,4,6-Me3~Ph C-Me NH-3-hexyl 2,4,6-Me3-Ph C-Me nrarpholino 2,4,6-Me3~Ph C-Me N (CH2Ph)CH2CH20Me 2,4,6-Me3"Ph -no- Printed from Micaoss 6 4 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 96 97 B8 09 90 91 92P 9 33 94 r 9SS get 97u C-Me NHCH(CH2PhtCH20Me 2,4,6-Me3-Ph C-Me nh-4-te^rahydropyranyl 2,4, 6-Me3-Ph C-Me NH-cyclopentyl 2,4,6-Me3-Ph C-Me 1,2,3f4~tetrahydro- 2,4,6-Me3-Ph isoquinolinyl C-Me CH^-(1/2, 3,4-tetrahydro- 2,4,6-Me3-Ph isoquinolinyl) C-Me OEt 2,4,6-Me3-Ph C-Me OCH(£t)CH^OMe 2,4,6-Me3~Ph C-Me OCH2Ph 2,4,6-Me3-Ph C-Me O-3-pentyi 2,4,6-Me3~Ph C-Me SEt 2,4, 6-Me3~Ph C-Me 5(0)EC 2,4,6-Me3~Ph C-Me S02Et 2,4,6-Me3-Ph C-Me CH(C02EtJ2 2,4,6-Mea-Ph C-Me C(Et) (C02Et)2 2, 4,6-M«3-Ph C-Me CHIEtJCHjOH 2, 4 , 6-Me3-£>h C-Me CH(Et!CH20Me 2,4,6-Me3~Ph C-Me C0NMe2 2,4,6-Me3-Ph C-Me C0CH3 2,4,6-Me3~Ph C-Me CH(OH)CH3 2, 4, 6-Me3-Ph C-Me C(OH)Ph-3-pyridyl 2,4,o-Me3-Ph C-Me Ph 2, 4,6-Me3-Ph C-Me 2-CF3-Ph 2,4,S-Me3-Ph C-Me 2-Ph-Ph 2,4,6-Me3~Ph C-Me 3-pentyl 2,4,6-Me3"Ph C-Me cyclobutyl 2,4,6-Me3-Ph C-Me 3-pyridyl 2,4,S-Me3~Ph C-Me CH(Et)CH2CONMe2 2,4,6-Me3"Ph C-Me CH(Et)CH2CH2NMe2 2,4,6-Me3~Ph C-Me NHCK(CH20Me)2 2,4~Me2"Ph C-Me N(CH2CH20Me)2 2,4-Me2"Ph C-Me NHCH(£t)CHjOMe 2,4-Me2"Ph C-Me NH-3-pentyl 2,4-Me2-Ph C-Me NEt2 2,4-Me2-Ph C-Me N(C«2CN>2 2,4-Me2"Ph 44-45 oil 102-104 102-104 oil 148-150 Printed f rom Miir.o $ a PCT/US97/I3072 KO CD < c-Me NHCH(Me)CH20Me 2,4-Me2~Ph 102-104 99w C-Me OCH (Et!CHjOMe 2,4-Me2~Ph oil 100x C-Me NP r-c-C3H5 2, 4-Me2~Ph oil 101* C-Me NHCH(Me)CH2WMe2 2,4-Me2~Ph 47-48 1Q2Z C-Me N(C-C3Hg)CH2CH2CN 2, 4-M«2-Ph 117-118 103aa C-Me N (Pr)CH2CH2CN 2, 4-Me2"Ph oil 104ab C-Me N (Bu>CH2CH£Cff 2, 4-Me2~Ph oil 105 C-Me MKCHP r2 2,4-Me2-Ph 1 0G- c-Me NEtBu 2,4-Me2-Ph 107 C-Me NPr (CH2-C-C3H5) 2,4-Me2-Ph 108 C-Me NH-3-fteptyl 2, 4-Me2"Ph 109 C-Me NEt2 2, 4-Me2~ph 110 C-Me NHCH(CH20Et)2 2,4-Me2-Ph 111 C-Me NH-3-pen^vl 2,4-Me2"Ph 112 C-Me NMePh 2,4-Me2~Ph 113 C-Me NPr2 2,4-Me2~Ph 114 C-Me NH-3-hexyl 2,4-M«2-ph 115 C-Me morpha-lino 2,4-Me2"Ph 116 C-Me N <CH2Ptl! CH2CH20Me 2,4-Me2-Ph 117 C-Me NHCH(CH2Ph)CH^OMe 2,4-Me2_Ph ne C-Me NH-4-tet rahydropyranyl 2,4-Me2_Ph 119 C-Me NH-cyclopentyl 2,4-Me2"Ph 120 C-Me 1,2,3,4-tetrahydro-i soquinolinyl 2,4-Me2~Ph 121 c-Me CH2~(1>2,3,4-tetrahydro- isoquinolinyl) 2,4-Me2"Ph 122 C-Me OEt 2,4-Me2"Ph 123 C-Me OCH(Et)CH20Me 2,4-Me2~Ph 124 C-Me OCH2Ph 2,4-Me2~Ph 125 C-Me O-3-pentyl 2,4-Me2"Ph 12€ C-Me SEt 2,4-Ke2"Ph 127 C-Me (0> Et 2,4-Me2~Ph 128 C-Me S02Ct 2,4-Me2-Ph 3 C-Me CH(C02Et)2 2,4-Me2-Ph 50-52 129 C-Me C (Et) (C02Et>2 2,4-Me2-Ph Printed from Mimosa 130 131 132 133 134 135 136 137 13C- 139 140 141 142 143 144 145b 146b l47b' 148b 149 150a 151a 152ai 153 154 155 156 157 ise 159 ISO 161 162 163 164 165 PCTVUS97/13072 C-Me CH (Et) CHjOH 2,4-Me2_Ph C-Me CH(Et)CH20Me 2,4-Me2-Ph C-Me CH(Et)CH20Et 2,4-Me2-Ph C-Me CONMe2 2,4-Me2-Ph C-Me COCH3 2,4-Me2~Ph C-Me CH(OH)CH3 2 , 4-Me2~Ph C-Me C(OH)Ph-3-pyridyl 2,4-Mez-Ph C-Me Ph 2,4-Me2-Ph C-Me 2-CF3-Ph 2,4-Me2-Ph C-Me 2-Ph-Ph 2,4-Me2-Ph c-Me 3-pentyl 2,4-Me2~Ph C-Me cyclobuty1 2,4-Me2~Ph C-Me 3-pyridyl 2,4-Me2~Ph C-Me CH(Et)CH2CONM62 2,4-Me2-Ph C-Me CH(Et)CH2CH2NM€2 2,4-Me2-Ph C-Me NHCH(0H2OMe)2 2-Me-4-MeO-Ph 45-46 C-Me N(CH2CH20Me)2 2-Me-4-MeO-Ph oil C-Me NHCH(EtJCH^OMe 2-Me-4-MeO-Ph 96-88 C-Me N(Pr> CH2CH2CN 2-Me-4-MeO-Ph oil C-Me CCH(Et)CH20Me 2-Me-4-MeO-Ph C-Me NHCH!CH20Me> 2 2-Br-4-MeO-Ph 83-90 C-Me N(CH2CH20Met 2 2-Br-4-MeCt-Ph oil C-Me NHCHJEt)CH20Me 2-Br-4-MeO-Ph 95-97 C-Me N (Pr)CH2CH2CN 2-Br-4 —MeO-Ph C-Me OCH(Et)CH20Me 2-Br-4-MeO-Ph C-Me KHCH(CH20Me)2 2-Me-4-NMe2"Ph C-Me N(CH2CH20Me)2 2-Me-4-NMe2~Ph oil C-Me NHCH(Et)CH20Me 2-Me-4-NMe2-Ph C-Me N(PC)CH2CH2CN 2-Me-4-NMe2~Ph C-Me OCH{E t)CH20Me 2-Me-4-MMe2-Ph C-Me NHCH(CH20Me> 2 2-Btr-4-NMe2-Ph C-Me K(CH2CH2<3Me)2 2-Br-4-NMe2-Ph C-Me NHCH(Et)CH20Me 2-Br-4-KMe2~Ph C-Me N {Pr)CH2CH2CM 2-Br-4-NMe2-Ph C-Me OCH(Et)CH20Me 2-Br-4-NMe2-Ph C-Me NHCH(CH20Me)2 2-Br-4-i-Pr-Ph Printed zrem Mimosa 166 c-Me N (CHjCHjOMe)2 2—9r-4-i-Pr-Pb 167 c-ne NHCH (Et)CH20Me 2-Br-4-i-Pr-Ph 158 C-Me N {P r)CH2CH2CN 2-Bc-4-i-Pr-Ph 169 C-Me OCH(Et)CH20Me 2-Br-4-i-Pr-Ph 170 C-Me NHCH (CH20Me)2 2-Br-4-Me-Ph 171 C-Me N ICH2CK20Me) 2 2-Br-4-Me-Ph 172 C-Me NHCH(Et>CH20Me 2-Br-4-Me-Ph 173 C-Me N(PrICH2CH2CN 2-BC-4-Me-Ph m C-Me OCH(Et)CHjOMe 2-Br-4-Me-Ph 175ar c-Me NHCH <CH20Me!2 2-Me-4-Br-Ph 176 C-Me N(CH2CH20Me)% 2-Me-4-Br-Ph 177 C-Me NHCH(Et)CH20Me 2 -.Me-4 -B r-Ph 178 C-Me N(Pr)CH2CH2CN 2-Me-4-Br-Ph 179 C-Me OCH(Et)CH20Me 2-Me-4-Br-Ph 130 C-Me NHCH(CH20Me|2 2-C1-4,6-Me2-Ph 181 C-Me N[CH2CH20Met2 2-C1-4,6-Me2-Ph 182 c-Me NHCH (CHjOMe)2 4-Br-2,6-(Met 2~Ph 103 C-Me N (CH2CH-20Me) 2 4-Br-2,6-(Me)2-Ph 18 4 C-Me NHCH(CH20Me)2 4-i-Pr-2-3Me—Ph 185 c-Me N(CH2CH20Me)2 4-i-Pr-2-SMe-Ph 186 C-Me NHCH(CH20Me)2 2-Br-4-CF3-Ph 187 C-Me N (CH2CH20Me)2 2-Br-4-CF3-Ph 138 c-Me NKCH(CH20Mei 2 2-Br-4,6-(MeO)2"Ph 139 C-Me M(CH2CH20Mel2 2-BE-4,6-(MeO)2"Ph 190 C-Me NHCH(CH20Me>2 2-C1-4,6-(MeO)2"Ph 191 C-Me N(CH2CH20Met2 2-C1-4,6-(MeO)2~Ph 192 C-Me NHCH ICH20Me)2 2,6-(Me)2-4-SMe-Pb 193 C-Me N<CH2CH20Me)2 2,6-(Me)2-4-SMe-Ph 194 C-Me NHCH(CHjOMe)2 4-(COMe)-2-Bt-Ph 195 C-Me N(CH2CH.20Me)2 4-(COMe)-2-Br-Ph 196 C-Me NHCH <CH20Me)2 2,4,6-Me3-pyrid-3-yl 197 C-Me N(CH2CH20Me)2 2,4,6-Me3-pyrid-3-yl 198 C-Me NHCH(CH20Me)2 2,4-(Br)2"Ph 199 C-Me N (CH2CH20Me)2 2,4- (Br)2-Ph 200 C-Me NHCH(CH2OMe)2 4-i-Pr-2-SMe-Ph 201 C-Me N (CK2CH20Me)2 4-i-Pr-2-SMe-Ph Printed frorv- Miir.osa 202 C-Me MHCH <CH20Met 2 4-i-Pr-2-S02Me-Ph 203 C-Me N (CF.2CH20Me) 2 4-i-Pr-2-S02Me-Ph 204 C-Me NHCH (CH2OMe)2 2,6-(Met 2-1-SMe-?h 205 C-Me N(CH2CH2OMe> 2 2, 6-(Me)2 ~4-SMe-Ph 206 C-Me NHCH(CH20Me)2 2,6-(Me)2-4-S02«e-Ph 207 C— Me N(CH2CH20Me)2 2,6-(Me)2-4-S02Me-Ph 203 C-Me NHCH(C»20Me)2 2-t-4-i-Pr-Pb 209 C-Me N(CH2CH20Met 2 2-l-4-j.-Pr-Ph 21 C C-Me NHCH(CH^OMet 2 2-Be-4-N(Me)2-6-MeO-Ph 211 C-Me N(CH2CH20Me)2 2-Bc-4-N(Me)2"6-MeO-Ph 212 C-Me NHCH (CK2<>Me) 2 2,4-[SMe]2-Ph 213 C-Me N(CH2CH2OMe)2 2,4-[SMe]2-Ph 214 C-Me NHCH(C»20Me)2 2, 4-[S02Me]2-Ph 215 C-Me K(CH2CH20Mel 2 2,4-[S02Me}2-Ph 216 C-Me NHCH(CH20Me) 2 i-i-Pc-2-SMe-Ph 217 C-Me N (CH2CH20Me)2 4-i-Pr-2-SMf?-Pb 218 C-Me NHCH(CH20Me)2 4-i-Pr-2-S02Me-Ph 219 C-Me N(CH2CH20Me)2 4-i-Pr-2-S02Me-Ph 220 C-Me NHCH(CHjOMe)2 2-N{Me)2-4-Me-Ph 221 C-Me N)CH2CH20Me)2 2-N(Me)2-4-Me-Ph 222 C-Me NHCH(CH2QMe)2 2-MeS-4,6-(Me)2-Ph 223 C-Me N(CH2CH20Me)2 2-MeS-4,6-(Me> 2"fh 224 C-Me NHCH(CH20Me)2 2- (CH3CO) -4, 6- (Me) 2""Ph 225 C-Me N(CH2CH2OMe)2 2- (CH3CO)-4,6-(Me)2-Ph 226 H NHCH [CH2°Me>2 2, 4 —Me2-Ph 227 H NHCH[CH20Me)2 2, 4-Me2~Ph 228 CF3 N(CH2CH2OMe)2 2,4-Me2-Ph 229 CF3 N[CH2CH2OMe>2 2,4-Me2-Ph 230 N NHCH(CH2OMel2 .2,4,6-Me3-Ph 231 N NHCHPr2 2,4,6-Me3~Ph 232 N NEtBu 2,4,6-Me3~Ph 233 N NPr(CH2-C-C3H5) 2,4,6-Me3~Ph 234 N N(CH2CK2°Me)2 2,4,6-Me3~Ph 235 N NH-3-heptyl 2,4,6-Mfi3~Ph 236 N NHCH(Et|CH20Me 2,4,6-Me3~Ph 237 N NEt2 2,4,6-M«3-Ph Printed froir: Mimosa 240 241 242 243 244 245 240 247 2 4 & 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 265 267 268 269 270 271 N MHCH(CH^CEt)2 N NH-3-pentyl N NMePh N NPr2 N NH-3-hexyi N morpholinc N N{CH2?h)CH2CH20Me N NHCH(CH2Fh)CH20Me N NH-4-tetrahydcopyranyl N NH-cyclopentyl N 1,2,3,4-tetrahydro- isoquinoliny1 N CH2" (1,2,3,4-tetrahydro- iaoquinolinyl) M QEt N OCH(EC)Cf^OMe N OCH2ph N O-3-pentyl N SEt N S10)Et N SO;jEt N CH(C02Et}2 N C(Et)(CQ2Et)2 N CH(Et > CH2OH K CH(Et)CHjOMe N CONMe2 N COCH3 N CH(OH)CH3 N C (OK) Pfi-3-pycidyl N Ph N 2-CF3-Ph N 2-Ph-Ph N 3-pentyl N cyclobutyl N 3-pyridyl N CH(Et)CH2CONMe2 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-Me3~Ph 2,4,6-Me3-Ph 2,4,6-Me3~Ph 2,4,6-He3-Ph 2,4,6-Me3-Ph 2.4.5-He3-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-Ke3~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-He3~Ph 2,4,6-Me3-Ph 2,4,6-Me3~Ph 2,4,6-Me3~Ph 2,4,6-He3-Ph 2,4,6-H«3-Ph 2,4,6-Me3~Ph 2,4,6-He3~Ph Printed from Mimosa 273 274 275 276 277 278 279 28 j 231 282 283 284 285 2 0 S 287 288 289 290 291 292 293 294 295 296 297 299 299 300 301 302 303 N CH j Et JCH2CH2KMe2 2,4,6-Me3~Ph N NHCH(CH20Me)2 2,4-Me2-Ph N NHCHPC2 2,4-He2-Ph N NEtBU 2,4-Me2~Ph N NPr(CH2-C-C3H5) 2,4-Me2"Ph N N(CH2CH20Me> 2 2,4-Me2"Ph N NH-3-heptyl 2,4-Me2"ph N NHCH(Et)CH2OMe 2,4-Me2~Ph N NEC 2 2,4-Me2"Ph N NHCH(CH20Et)2 2,4-Mej-Ph N NH-3-pentyl 2,4-Me2~Ph N NMePh 2,4-Me2~Ph N NPr 2 2,4-He2_Ph N NH-3-hexyl 2,4-Me2-Ph N morpholino 2,4-Me2-ph N N(CH2Ph)CH2CH20Me 2, 4 -Me2_pl1 N NHCH(CH2Ph)CH20Me 2,4-Me2"Ph N NH-4 - tet rahyeiropyranyl 2,4-Me2~Ph N NH-cyclopentyl 2,4-Me2~Ph fJ 1,2,3,4-tetrahydro- 2,4-Me2-Ph isoquinolinyl N CHj-(1,2,3,4-tetrahydro- 2,4-Me2-Ph isoquinolinyl) N OEt 2,4-Me2"Ph N OCH(Et)CH20Me 2,4-Me2-Ph N OCHjPh 2, 4-Me2-Ph N o-3-pentyl 2,4-Mej-Ph N SEt 2,4-Me2"Ph N 3 (Ol EC 2,4-M«2"Ph N S02Et 2,4-Me2-Ph N CH(C02Et)2 2,4-MG2-Ph N C(Et)(C02Et)2 2,4-Me2~Ph H CH(Et)CH2OH 2,4-Me2"Ph N CH(Et)CH20Me 2,4-Me2-Ph N CONM«2 2,4-Me2-Ph N COCH3 2,4-He2-Ph Printed from Mimosa PCT/US97/I3072 306 N CH(OH)CH3 2,4-Me2-P^ 307 N C(OH)Ph-3-pyridyl 2,4-M62-Ph 308 M Ph 2,4-Me2~Ph 309 N 2-CF3-Ph 2,4-Me2-Ph 310 N 2-Ph-Ph 2,4-Me2"Ph 311 N 3-pentyl 2,4-Me2-Ph 312 N cyclobutyl 2,4-Me2-Ph 313 N 3-pyndyl 2,4-Me2~Ph 31 i N CH(Et)CH2CONMe2 2,1-Me2~ph 315 N CH(Et)CH2CH2NMe2 2,4-Me 2"Ph 316an C-He NEt2 2-Br-4-MeO-Ph oil 317alTl C-Me NH-3-pentyl 2-Bc-4-MeO-Ph oil 3l8a3 C-Me NHCH (CH2CH20Me)CH2OMe 2,4,G-Me3~Ph 101-103 319ao C-Me NH ( C -C 3H 2,4-Me^-Ph oil 320ak C-Me morpholino 2,4,6-Me3-Ph 139-141 321aP C-Me NHCH(CH20Me)2 2-CN-4-Me-Ph 152-L53 322 atI C-Me n{c-C3H5)ch2ch2cn 2,4,6-Me3-Ph 149-151 324as C-Me NHCH(CH2CH20Me)CH20Me 2-Me-4-Br-Ph 115-117 325at C-Me NHCH <CH20Me)2 2,5-Me2_4-MeO-Ph 55-57 326au C-Me N(C H 2 C H 2 OMe)2 2,5-Me2~4-Meo-Ph 72 327av C-Me NH-3-penty1 2,5-Me2_4-MeO-Ph 45-47 328aw C-Me NEt2 2,5-Me2~4-MeO-Ph oil 329ax C-Me NHCH(CH2OMe)2 2-Ci-4-MeFh 80-81 330ay C-Me NCH(Et > CH20Me 2-Cl-4-MePh 77-79 331az C-Me N(CH2CH20Me)2 2-Cl-4-MePh oil 332ba C-Me (S)-NHCH(CH2CH20Me)CH20Me 2-Cl-4-MePh 139-140 333bb C-Me N(c-C3H5)CH2CH2CN 2,5-Me 2-4-MeOPh 120-122 334b5 C-Me NEC2 2-Me-4-MeOPh oil 33Sbh C-yMe OEt 2-Me-4-MeOPh oil 336bi C-Me (S)-NHCH(CH2CH20Me)CH20Me 2-Me-4-MeOPh oil 337b3 C-Me N(C-C3H5]CH2CH2CN 2-Me-4-MeOPh 129 33Bbk C-Me NHCH(CH2CH2OEt)2 2-Me-4-MeOPh arco rph. 339 C-Me N{C-C3H5)CH2CH2CN 2.4-Cl2-Ph 109-110 340 C-Me (S)-NHCH(CH2CH20Me)CHjOMe 2,4-Cl2"Ph 93-94 341 C-Me NH-3-perttyl 2-Me-4-BrPh 119-119 342 C-Me N (CH2CH20Me)2 2-Me-4-BrPh oil -US- Printed from Mimosa 343 344 345 346 347 34 8 349 350 351 352 353 354 SSS^1 356b" 357bn 3 58150 359bP 360 361 362 363 364 365 366 367 36B 369 370 371 372 373 374^ 37 5 376bt c-Me NHCH(CH2-iPr)CH20Me 2,4-Me2~ph oil C-Me NHCH(Pr)CH2CMe 2, 4-Me2"-Ph 94-95 OMe NHCH [Et)CH2QEt 2,4-Me£-Ph 76-77 C-Me NHCH <CH20Me)CHjCHjOMe 2-Me-4-Me2NPh oil C-Me NEt2 2-Me-4-CIPh oil C-Me NH-3-pencyl 2-Me-4-CIPh 122-124 C-Me N(CH2CH20Me) 2 2-Me-4-Cl?h oil C-Me NHCH(CH20Me)2 2-Me-4-CIPh 122-123 C-Me NEt 2 2-Me-4-ClPh oil C-Me MEt2 2-Cl-4-MePh oil C-Me N'H-3'pency 1 2-Cl-4-MePh 120-121 C-Me NHCH(CH20Me)2 2-Cl-4-MeOPh C-Me N(CH2CH20Me)2 2-Cl—4-MeOPh oil C-Me NHCH(Et)CH20Me 2-Cl-4-MeOFh 108-110 C-Me M(c-Pr)CH2CH2CN 2-Cl-4-MeOPh 127-129 C-Me NEt2 2-Cl-4-MeOPh oil C-Me NH-3-penty1 2-Cl-4-MeOPh 77-79 C-Me NHCH (Et)Ctf2CH20Me 2-Cl-4-MeOPh C-Me NHCH[Me)CH2CH20MB 2-Cl-4-MeOPh C-Me NHCH{Et)CH2CH20M6 2-Br-4-MeOPh c-Me NHCH{Me)CH2CH20Me 2-Bc-4-MeOPh C-Me NHCH{Et)CH2CH20Me 2-Me-4-MeOPh C-Me NHCH(Me>CH2CH20We 2-Me-4-MeOPh C-Me NHCH(CH20Me)2 2 -Cl-4,5-(MeO)2ph C-Me N(CH2CH20Me)2 2 -Cl-4,5-(MeO)2Ph C-Me NHCH(EtlCH20Me 2 -Cl-4,5-(MeO)2Ph C-Me N < c - P r)CH2CH2CN 2 -Cl-4,S-(MeO)2Ph C-Me NEC 2 2 -Cl-4,5-(MeO J 2Ph 0 1 i? NH-3-pentyl 2 -Cl-4, 5-meO)2Ph C-Me MHCH(Et|CH2CH20Me 2 -Cl-4,5-(MeO)2Ph C-Me NHCH[Me ICH2CH20Me 2 -Cl-4,5-(MeO)2Ph C-Me NHCH <CH20Me)2 2 -Br-4,5-(MeO)2?h 137-138 C-Me N(CH2CH20Me)2 2- -Br-4,5-(MeO)2Ph C-Me NHCH(Et)CH20Me I- -Br-4,5 -(MeO)2Ph 147-148 C-Me N (C-Pr»CH2CH2CN 2- -Br-4,5-(MeO)2Ph C-Me NEt 2 2- -Br-4,5-(MeO)2Ph 52-58 Printeci from Mimosa P CT/US97/I3072 379 C-Me 330 C-Me 381 C-Me 382 C-Me 383 C-Me 384 C-Me 385 C-Me 386 C-Me 38V C-Me It) 368 C-Me 389 C-Me 390 C-Me 391 C-Me 392 C-Me 393 C-Me 395 C-Me 396 C-Me 397 C-Me 398 C-Me 399 C-Me 400 C-Me 401 C-Me 402 C-Me 403 c-Me 404 C-Me 405 C-Me 406 C-Me 407 C-Me 403 C-Me 409 C-Me 410 C-Me 411 c-Me 412 c-Me 413 C-Me 414 C-Me 415 C-Me NK-3-pentyl NHCH(Et)CHjCH20Me NHCH(Me)CH2CH20Me NHCH(CH20Mel2 N(CH2CH2OM6)2 NHCH(EtICH2OMe N (c-PrICH2CH2CN NEt2 NH-3-perityi NHCH(Et)CHjCt^OMe NHCH(Me)CH2CH20Me NHCH(CH20Me)2 NtCHjCH^OMe)2 NHCH(Et)CH20Me N[c-Pr)CH2CH2CN NEt2 NH-3-pentyl MHCH (Et)CH2CH20M<* NHCH(Me>CH2CH20Me N (C-Pr) CH2CH2CN NEt2 NH-3-pentyl NHCH(Et)CH2CH20Me NHCH(Me)CH2CH2OMe NHCH(Et)CH2CH2OMe NHCH(Me)CH2CH20Me NHCH(CH2OMe)2 N(CH2CH20Me)2 NHCH(Et>CH20Me N(c-Pr)CH2CH2CN NEt 2 NH-3-pentyl NHCH(Et)CH2CH20Me NHCH(Me)CH2CH20MS NHCH(CH20Me)2 N(CH2CH20Me)2 2-Br-4,5-(MeO)2Ph 2-Br-4,5-(MeO)2Ph 2-Br-4r5-(MeO)2Ph 2-C1-4,6-(MeO)2Ph 2-Cl-4,6-<MeO>2Ph 2-Cl-4,6-(MeO)2Ph 2-C1-4,6-(MeO)2Ph 2-Cl-4r 6-(MeO)2Ph 2-Cl-4,b-(MeO)2^h 2-Cl-4,6-(MeOt 2^h 2-Cl-4,6-(MeO)2ph 2-Me-4,6-(MeO)2Ph 2-Me-4,6-(MeO)2?h 2-Me-4,6-(MeO)2?h 2-Me-4,6-(MeO)2Ph 2-Me-4,6-(MeO)2?h 2-Me-4,6-(MeO)2Ph 2-Me-4,6-(MeO)2Ph 2-Me-4,6-(MeO)2?h 2-Br-4,6-(MeO)2Ph 2-Br-4, 6- (MeO) 2Ph 2-Br-4,6-(MeO)2Ph 2-Br-4 , 6 - (MeO) 2P'1 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-Me0-4-MePh 2-MeO-4-MePh 2-Me0-4-MePh 2-MeO-4-MePh 2-Me0-4-MePh 2-MeO-4-M«Ph 2-MeO-4-MePh : J frorri \ ' ■[ ■ ■ r: PCIYUS97/13072 416 C-Me NHCH(St)CH2CMe 2-MeO-4-MePh 417 C-Me N (c-Pr)CH2CH2CN 2-MeO-4-MePh 410 C-Me NEC 2 2-MeO-4-MePh 419 C-Me NH-3-pentyl 2-Me0-4-Mef>h 4 20 C-Me NHCH(Et)CH2CH20Me 2-MeO-4-MePh 421 C-Me NHCH(Me)CH2CH20Me 2-MeO-4-MePh 423tt C-Me MHCH(CH20Me)2 2-MeO-4-ClPh 424 C-Me N{CH2CH20Me> 2 2-MeO-4-ClPh 42s C-Me NHCH(Et>CH20Me 2-MeO-4-CIPh 426 C-Me N(c-Pr)CH2CH2CN 2-MeO-4-CIPh 427 C-Me NEt2 2-MeO-4-CiPh 420 C-Me NH-3-penty1 2-MeO-4-CIPh 429 C-Me NHCH fEt1CH2CH20Me 2-MeO-4-CIPh 430 C-Me NHCH(Me)CH2CH2QMe 2-Me0-4-ClPh NOTES FOR TABLE 1: a) Analysis Calcd: C, 52.69, H, 5.17, N, 17.07, Cl, 17.28,* Found: C, 52.132, H, 5.06, N, 16.77, Cl, 17.50. b> CI-HRMS: Calcd: 406.1565, Found: 405.1573 <M + H); Analysis Calcd: C: 59.11; H: 6.20; N: 17,23; Cl: 17.45? Found: C: 59.93; H: 6.34; N; 16.50; Cl: 16,95; NMR (CDCI3, 300 MHz); 0.95 (t, J - 8, 4H) , 1.30-25 1,40 (m, 4H), 1.50-1.75 <m, 4H), 2.35 (s, 3H), 2.49 (s, 3H) , 4,30-4.45 (m, 1H), 6.15 (d, J=B, 1H), 7.30 (s, 2H), 7.50 (5, 1H) c) Cl-HRMS: Calcd: 392.1409, Found: 392.1368 (M + H); NMR (CDCI3, 300 MHz): 1.00 (t, J =8, 3H), 1,35 <tr J = 8, 3H), 1.41 (q, J = 3, 2H>, 1.65-1.85 (m, 2H), 2.30 (S, 3H), 2.40 (s, 3H> , 3.85-4.20 (m, 4H>, 7.30 (5, 2H) , 7.50 (s, 1H) . d) CI-HRMS: Calcd: 404.1409, Found: 404.1408 (M + H); NMR{CDCI3, 300MHz): 0.35-0.45 (m, 2H), 0.52-0.62 (m, 2H), 0.98 {t, J - 8, 3H) , 1.70-1 . 90 (m, 2H), Printed from Mimosa WO 98/03510 PCT7US97/13072 2.30 (s, 3H), 2.40 (s, 3H}, 3.85-4.02 (m, 2H), 4.02-4.20 (ro, 2H), 7.30 <s, 2H), 7.50 (s, 1H), e) CI-HRMS : Calcd: 424.1307, round: 424.1307 (M +■ H): NMR (CDCI3, 300 MHz): 2.20 (s, 3H), 2.40 (s, 3H), 3.40 (s, 6H), 3.75 (t, J = 8, 4H), 4.20-4.45 <m, 4H), 7.30 (s, 2H), 7.50 (s, 1H). f) CI-HRMS: Calcd: 406.1565, Found; 405.1573 {M + H) ; NMR (COCI3, 300 MHz}: 0.90 (t, J= 8, 3H), 1.00 (t, J = 8, 3HI, 1.28-1.45 (m, 4H), 1.50-1.80 <m, 4H), 2.35 (3, 3H), 2.50 <s, 3H), 4.20-4.35 (m, 1H), 6.10-G.23 <m, 1H>, 7,30 (5, 2H) , 7,50 {s, 1H) . g) CI-HRMS: Calcd: 394.1201, Found: 394.1209 <M + H); NMR (CDCI3, 300 MHz): 1.02 (t, J = 8, 3H), 1.65-1.90 (m, 2H)2.35 (S, 3H) , 2.48 (s, 3H>, 3.40 (s, 3H) , 3.50-3.60 (m, 2H} , 4.35-4.45 (brs, 1H), 6.50- 6.60 (m, 1H), 7.30 [s, 2H> , 7.50 <5, 1H). h) CI-HRMS: Calcd: 364.1096, Found: 364.1093 {M + H) ; Analysis: Calcd: Cr 56.05; H: 5.27; N: 19.23; Cl: 19.4 6; Found: C: 5 5.96; H: 5.24; N: 10.93; Cl: 19,25; NMR (CDCI3, 300 MHz): 1.35 (t, J= 8, 6H), 2.30 {3, 3H), 2.40 <s, 3H), 3.95-4.15 <m, 4H), 7.30 <s, 2H)r 7,50 (d, J = 1, 1H) . i) CI-HRMS: Calcd: 438.1464, Found: 438.1454 (M + H) ; 25 NMR (CDCI3, 30C MHz): 1.22 (t, J = 8, 6H), 2,35 (s, 3H) , 2.47 (s, 3H), 3.39 (q, J = 8, 4H), 3.65 (dd, J = 8, 1, 2H), 3.73 (dd, J = 8, 1, 2H), 4.55-4.65 <m, 1H) , 6,75 <d, J - 8, 1H}, 7.30 {d, J = 1, 2H>, 7.50 (s, 1H> . j) CI-HRMS: 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 (t, J = 8, 6HJ, 1.55-35 1.70 (m, 2H), 1.70-1.85 (m, 2H) , 2.35 (s, 3H) , 2.50 Printed from Mimosa WO 98/03510 PCT/US97/13072 (s, 3H>, 4.15-4.25 <m, 1H) , 6.10 <d, J = 8, 1H) , 7,30 (s, 2H) , 7.50 (S, XH) . k) CI-HRMS: Calcd: 398.0939, Found: 398.0922 (M + H>; Analysis: Calcd: C: 60.31; H: 4.30; N: 17.58; Cl: 5 17.80; Found: C: 60.29; H: 4.59; N: 17.09; Cl: 17.57; NMR (CDCI3, 300 MHz): 2.05 (s, 3H) , 2.50 (s, 3H) , 3.78 {s, 3H), 7.20-7.45 (m, 7H), 7.50 (d, J= 1, 1H) . 1) CI-HRMS: Calcd: 392.1409, Found: 392.1391 (M + H); NMR {CDCI3, 300 MHz): 0.98 (t, J = 8, 6H)-, 1.70-1.85 (m, 4H>, 2.30 (s, 3H), 2.40 (s, 3H), 3.80-4.10 <m, 4H) , 7.30 (s, 2H), 7.50 <d, J - 1, 1H) . m) CI-HRMS: Calcd: 392.1409, Found: 392.1415 (M + H) ; 15 Analysis: Calcd: C: 58.17; H: 5.92; N: 17.85; Cl: 18.07; Found: C: 58.41; ti: 5.85: N: 18.10; Cl: 17.75; NMR {CDCI3, 300 MHz)-: 0.90-1.05 (m, 6H) , 1.35-1.55 (m, 2H), 1.55-1.85 (m, 4H) , 2.35 <s, 3H) , 2.48 (5, 20 3H), 4.20-4.35 (m, 1H), 6.15 (d, J = 8, 1H) , 7.30 (s, 2H} , 7 . 5C (d, 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 (t, J = 8, 3H) , 2.40 (s, 3H), 2.55 (S, 3H), 4.80 (q, J = 9, 2H), 7.30 {d, J = 8, 1H), 7.35 (dd, J = 8, 1, 1H) , 7.55 <d, J = 1, 1H) . o) CI-HRMS: Calcd: 383.2321, Found: 383.2309 (M + H) ; NMR (CDCI3, 300 MH2): 2.00 (s, 6H), 2.20 (s, 3H), 2.30 (s, 3H), 2.45 (s, 3H>, 3.4S (s, 6H>, 3.61 (dd, J = 8, 8, 2H), 3.70 (dd, J = 8, 8, 2H), 4.60-4.70 (m, 1H), 6.70 (d, J = 8, 1H), 6.94 (s, 2H). 35 p) CI-HRMS: Calcd: 370.2243, Found: 370.2246 (M + H); Printed froir. Mi.rr.osa q) r) 20 s) t) u) Analysis: Calcd: C: 65.02; H: 7.38; N: 13.96; Found: C: 65.22; H: 7.39; N: 18.71; NMR (CDCI3, 300 MHz): 2.18 <s, 3H) , 2.30 {5, 3H) , 2.45 (5, 3H), 3.45 <s, 6H) , 3.60 (dd, J = 8, 0, 2H), 3.69 (dd, J « 8, 0, 2H} , 4.60-4.70 (m, 1H) , 6.70 (d, J = 8, 1H), 7,05 <d, J = 3, 1H), 7.07 <d, J = 8, 1H), 7.10 [s, 1H) .

CI-HRMS: Calcd: 384.2400, Found: 384.2393 {M + H) ; NMR (CDCI3, 300 MHs) : 2.16 (s, 3H), 2.25 (s, 3H) , 2,35 (s, 3H) , 2,39 (s, 3H) , 3.40 (s, 6H), 3.77 (t, J = 8, 4H) , 4.20-4.45 <m, 4H) , 7.02 id, J = 8, 1H) 7.05 (s, 1H) r 7. 10 (d, J = 7, 1H) .

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 <t, J = 6, 3H), 1.65-1.88 (m, 2H>, 2.17 (s, 3H> , 2.30 (5, 3H), 2.35 (s, 3H), 2.45 is, 3H), 3.40 (s, 3H>, 3.50-3.62 (m, 2H) , 4.30-4.45 (m, 1H) r 6.51 (d, J = 8, 1H) , 7.04 (d, J = 8, 1H), 7.10 (d, J =8, 1H), 7.12 {3, 1H).

CI-HRMS: Calcd: 338.2345, Found: 338.2332 (M + H); Analysis: Calcd: C: 71,18; H: 8.06; N: 20.75; Found: C: 71.4 3; H: 7.80; N: 20.70; NMR {CDCI3, 300 MHz): 1.00 (t, J = 8, 6H)r 1.55-1.70 (ra, 2H), 1.70-:.85 (m, 2H), 2.19 (s, 3H), 2.30 (s, 3H), 2.35 (3, 3H>, 2.46 (3, 3H) , 4,15-4.26 (m, 1H>, 6.17 (d, J = 8, 1H), 7.06 (d, J = 8, 1H), 7,10 (d, J = 1, 1H) , 7.13 (s, 1H) .

CI-HRMS: Calcd: 324.2188, Found: 324.2138 <M +■ H) ; NMR (CDCI3, 300 MHz): 1.25 (t, J = 8, 6H), 2.16 (s, 3H), 2.28 (s, 3H), 2,35 (s, 3H), 2.40 (s, 3H), 3.95-4.20 (m, 4H), 7.05 (dd, J = 8, 1, 1H) , 7.07 (s, 1H) , 7.10 (d, J = 1, 1H) 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; Printed from Mimeoa WO 98/03510 PCT/US97/13072 NMR (CDCI3, 300 MHz): 2.15 (5, 3H} , 2.32 (s, 3H) 2.17 (s, 3H>, 2.52 (5, 3H) , 5.25-5.35 (m, 4H) , 7.08 (s, 2H) , 7 . 15 (s, 1H) . v) CI-HRMS: Calcd: 340.2137, Found: 340.2137 <M + H); 5 Analysis: Calcd: C: 67.23; H: 7.42; N: 20,63; Found:C: 67.11; H: 7,39; N: 20,26; NMR (CDCI3, 300 MHz): 1.40 (d, J = 8, 3H), 2.16 <s, 3H), 2.32 (5, 3H), 2.35 (s, 3H), 2.47 (s, 3H), 3.42 (S, 3H), 3.50-3.60 (m, 2H), 4,50-4,15 (m, 1H), 6.56 10 <d, J = 8, 1H), 7.00-7.15 <m, 3H) . w) CI-HRMS: Calcd: 355.2134, Found: 355.2134 (M + H); NMR (CDCI3, 300 MHz): 1.05 (t, J = B, 3H), 1.85-2.00 (m, 2H), 2.17 (s, 3H) , 2.36 (3, 6H), 2.50 (s, 3H) , 3.41 (5, 3H), 3.45 (dd, J « 8, 3, 1H) , 3.82 15 (dd, J = 8, 1, 1H) , 5.70-5.BO (m, 1H) , 7.00-7.20 <m, 3H). x) CI-HRMS: Calcd: 364.2501, Found: 364.2501 (M + H) ; NMR (CDCI3, 300 MH2)": 0.35-0.43 (m, 2H) , 0.50-0.60 (m, 2H) , 0.98 (n, J = 8, 3H) , 1.20-1.30 (m, 1H) , 20 1.72-1.90 (m, 2H), 2.18 (s, 3H) 2.28 (S, 3H), 2.35 <s, 3H) , 2.40 (s, 3H), 3.88-4.03 (m, 2H), 4.03-4.20 (m, 2H), 7 .00-7,15 (m, 3H) . y) CI-HRMS: Calcd: 353.2454, Found: 353.2454 (M + H); Analysis: Calcd: C: 68.15; H: 8.02; N: 23.84; 25 Found: C: 67.43; H; 7.81; N: 23.45; NMR (CDCI3, 300 MHz): 1.38 (d, J = 8, 3H), 2.18 (s, 3H), 2.30-2.40 (m, 12H), 2.47 93, 3H), 2.60-2.75 (m, 2H), 4.30-4.50 (m, 1H), 6.60-6.70 (m, 1H) , 7 . 00-7 .15 (m, 3H) . z) CI-HRMS: Calcd: 361.2X40, Found: 361.2128 (M + H); NMR (CDC13, 300 MHz): 0.75-0.83 <m, 2H), 1.00-1.10 (m, 2H), 2.17 (s, 3H), 2.30 <S, 3H) , 2.36 <S, 3H), 2.47 (s, 3H), 2.85 (t, J-8, 2H) , 3.30-3.40 (m, 1H), 4.40-4.55 <m, 2H) , 7.00-7.18 (m, 3H) . 35 aa) CI-HRMS: Calcd: 363.2297, Found: 363.2311 (M +■ H) ; Printed iron. Mimosa NMR (CDCI3, 300 MH2I : 1.01 <t, 3H, J=8), 1.75-1.90 2.15 (s,3H), 2.19 (5, 3H), 2.35 (s, 3H>, 2.40 <s, 3H), 2.40 <s, 3H) , 2.93 (t, 2H, J = 8), 3.97-4.15 (m, 2H), 4.15-4.30 (m, 2H), 7.03(3, 1H, 1H) , 7 ,08 <d, 1H, J = 8) , 7 , 10 (s, 1H) .

CI-HRMS: Calcd: 363.2297, Found: 363.2295 (M * H) ; NMR {CDCI3, 300 MHz): 1.01 (t, 3H, J = 8), 1.35-1.55 (m, 2H), 1.75-1.90 <m, 2H), 2,15 (5, 3H) , 2.30 {5, 3H), 2.36 <s, 3H), 2.46 (s, 3H) , 4.10-4.3D (m, 2H), 4.95-5.10 (br s, 2H), 7.05 (d, 1H, J - 8), 7.10 (d, 1H, J = 3) , 7.15 { s, 1H).

CI-HRMS: Calcd: 368.2450, Found: 368.2436; Analysis: Calcd: C, 66.62, H, 7.95, N, 19.06; Found: C, 68.73, H, 7.97, N, 19,09; NMR (CDCI3, 300 MHz): 1.05 (t, J = 8, 3H> , 1.70-1.90 (m, 2H), 2.01 (d, J = 3, 6H), 2.20 (s, 3H>, 2,30 (s, 3H) , 2.46, 2.465 (5, s, 3H), 3.42, 3,48 (s, S, 3H), 3.53-3.63 <m, 2H), 4.35-4.45 (m, 1H), 6.73 (d, J = 8, 1H)r 6.97 {s, 2H) . (ad) CI- HRMS: Calcd: 352.2501, Found: 352.2500 (M + H): Analysis: Calcd: 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{t, J = 8, 6H), 1.58 -1.70 <m, 2H), 1,70-1.85 (m, 2H), 2.02 {s, 6H), 25 2.19 (s, 3H), 2.45 (s, 3H), 4.12-4.28 (m, 1H), 6.18 (d, J = 8, 1H) , 6.95 (s, 2H) . <ae) CI- HRMS: Calcd: 398.2556, Found: 398.2551 (M + H) ; Analysis: Calcd: C: 66 . 47; H: 7.86,* N: 17.62, Found: C: 66.74; H: 7,79; N: 17,70; 30 NMR (CDCI3, 300 MHz) : 2.00 (s, 6H), 2.12 (s, 3H) , 2.30 <s, 3H), 2.37 (s, 3H), 3.40 (s, 6H), 3.78 <t, J = 8, 4H), 4.25-4.40 <m, 4H), 6.93 (s, 2H). (af) CI-HRMS: Calcd: 450.1141, Found: 450.1133 (M + H) ; Analysis: Calcd: C: 50.67; H: 5.37; N: 15.55; Br: 35 17.74; Found: C: 52.36; H: 5.84; N: 14.90; Br: 17 .44; ab) ac) Printed from Mirnos NMR (CDC13, 300 MHz): 2.32 Is, 3H) , 2.57 (s, 3H) , 3.42 (5, 6H), 3.60 (q, J =■ 8, 2H) , 3.69 (q, J = 3, 2H), 3.82 (s, 3H) , 4.60-4.70 (m, 1H) , 6.73 (d, J = 8, 1H), 6.93 (dd, J = 8, 1, 1H>, 7.22 (d, J = 8, 5 1H) . ag) CI-HRMS: Calcd: 434.1192, Found: 434.1169 (M +■ K); 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 (CDCI3, 300 MHz): 1.00-1.07 {m, 3K) , 1.65-1.85 (m, 2H), 2.35 (s, 3H), 2.46, 2.47 (s, 5, 3H), 3.40, 3.45 (s, s, 3H), 3.83 (3, 3H), 4.35-4.45 (m, 1H>, 6,55 (d, J = 8, 1H), 6.92 (dd, J = 8, 1, 1H} , 7.20-7 .30 (m, 2H) . ah) 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 (CDCI3, 300 MHzf: 1.35 (t, J = 8, 6H), 2.01 (s, 6H>, 2.15 (s, 3H), 2.30 (s, 3H) , 2.38 (5, 3H), 4.07 20 <q, J - 8, 4H), 6.93 {s, 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 (CDCI3, 300 MHz):1.24 (t, J = 8, 6H), 2.00 (s, 25 6H), 2.20 (s, 3H), 2.30 (s, 3H), 2.43 (s, 3H), 3.60 (q, J - 8, 4H), 3.66 (dd, J = 8, 3, 2H>, 3.75 (dd, J = 3, 3, 2K>, 4.55-4.65 <ra, 1H) , 6.75 (d, J = 8, 1H), 6.95 (s, 2H). aj) CI-HRMS: Calcd: 398.2555, Found: 398 .2545 <M + H) ; 30 Analysis: Calcd: C: 66.47; H: 7.86; N: 17.62; Found: C: 66.87; H: 7,62; N: 17.75; NMR (CDCI3, 300 MHz): 1.95-2.10 <m, 8H), 2.20 (s, 3H), 2.32 <sr 3H), 2.44 (s, 3H), 3.38 (s, 3H), 3.42 (s, 3H), 3.50-3.70 (m, 4H) , 4.59-4.70 (m, 1H), 6.87 35 (d, J = 8, 1H) , 6.95 (s, 2H) . ak) CI-HRMS: Calcd: 338.1981, Found: 338.1971 (M + H); Pr^nted from Mimesa WO 98/03510 PCT/US97/13072 Analysis: Calcd: C: 67.63; H: 6.87; N: 20.06; Found: C: 67.67; H: 6.82; N: 20.31; NMR (CDC13, 300 MHz): 2.15 (s, 3HJ , 2.29 (s, 3H) , 2.35 (s, 3H), 2.43 <s, 3H} , 3.90 (t, J = 8, 4H) , 5 4.35-4.45 <m, 4H) , 7,00-7.15 (m, 3H) . al) CI-HRMS: Calcd: 464.1297, Found: 464.1297 (M + H); NMR (CDCI3, 300 MHz): 2.29 (s, 3H) , 2.40 (s, 3H>, 3.40 (3, 6H), 3.75 (t, J = 8, 4H) , 3.83 <s, 3H) , 4.20-4.50 (m, 4H) , 6.93 (dd, J = 8, 1, 1H), 7,20 10 (S, 1H), 7.24 (d, J = 1, 1H), am) CI-HRMS: Calcd: 418,1242, Found: 418.1223 (M + H) ; NMR (CDCI3, 300 MHz): 1.00 (t, d, J = 8, 1, 6H) , 1.55-1.75 <m, 4H), 2.34 (s, 3H), 2.49 (s, 3H>, 2.84 (S, 3H), 4.15-4,27 (m, 1H), 6.19 [d, J = 8, 1H), 15 6.93 (dd, J = 8, 1, 1H), 7.21-7.30 (m, 2H). an} CI-HRMS: Calcd: 404,1086, Found: 404.1079(M + H); NMR (CDCI3, 300 MHz): 1.35 (t, J = 8, 6H) , 2.28 (s, 3H), 2.40 (s, 3H), 3,83 (s, 3H}, 3.90-4,08 (m, 2H), 4.08-4.20 (m, 2H), 6.92 (dd, J = 8, 1, 1H), 7.20-20 7.25 (m, 2H) . ao) CI-HRMS: Calcd: 308.1875, Found: 308.1872 (M + H>; NMR (CDCI3, 300 MHz): 0.75-0.80 <m, 2H) , 0.93-1.00 (m, 2H), 2.16 (s, 3H>, 2.28 (s, 3H), 2.35 (s, 3H) , 2.53 (s, 3H), 3.00-3.10 (m, 1H) , 6.50-6.55 (m, 1H), 25 7,00-7.15 (m, 3H). ap) CI-HRMS: Calcd: 397.1988, Found: 397.1984 (M + H); NMR (CDCla, 300 MHz): 2.43 (s, 3H), 2.50 (s, 3H) , 3.43 <s, 3H), 3.61 (dd, J = 8, 8, 2H), 3,69 (dd,J = 8, 8, 2H), 3.88 (s, 3H) , 4.58-4.70 [m, 1H) , 6.75 30 (d, J = 8, 1H), 7.20 (dd, J = 8, 1, 1H), 7,25 (d, J =1, 1H), 7.40 (s, 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; 35 NMR (CDCI3, 300 MHz): 0,79-0.85 (m, 2H), 1.00-1.05 (m, 1H), 2.CO (s, 6H), 2.19 (5, 3H> , 2.32 (s, 3H), Printed from Minosa WO 98/03510 PCT/US97/13072 2,44 Is, 3H), 2,84 (t, J = 8, 2H) , 3.30-3.40 <m, 1H>, 4.50 <t, J = 8, 2H), 6.95 ts, 2H). ar) CI-HRMS: Calcd: 434.1192, Four.d; 434.1189 (M + H) ; Analysis: Calcd: C: 52.54; H: 5,58; N: 16,12; Br: 5 18.40; Found: C: 52.75; H: 5.59; Mr 16.09; Br: 18.67; NMR (CDCI3, 300 MHz): 2.19 (s, 3H) , 2.30 (s, 3H) , 2.47 (s, 3H), 3.43 (s, 6H>, 3.60 (dd, J = 8, 8, 2H), 3.70 (dd, J = 8,8, 2H>, 4.58-4.70 (m, 1H), 10 6.71 <d, J = 8, 1H), 7.08 (d, J = 8, 1H) , 7.37 (dd, J = 8, 1, 1H) , 7.45 (d, J = 1, 1H) . as) CI-HRMS: Calcd: 448.1348, Found: 449.1332{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: 15 13.03; NMR (CDCI3, 300 MHz): 1.95-2.10 (m, 2H) , 2.20 (5, 3H), 2.30 (s, 3H), 2.47 (s, 3H), 3.38 (s, 3H), 3.41 (s, 3H>, 3.50-3.67 (m, 4H) ,' 4 . 55-4 . 70 (m, 1H) , 6,89 (d, J = 8, 1H), 7.05 <d, J = 8, 1H), 7.35 (dd, J = 20 8, 1, 1H) , 7.47 (d, J = 1, 1H) . at) CI-HRMS: Calcd: 400.2349, Found: 400.2348 (M + H); Analysis: Calcd: C: C: 53.14; H: 7.32; N: 17.53; Found: C:63.40; H: 7.08; N: 17.14; NMR (CDCI3, 300 MHz): 2.16 (s, 3H) , 2.20 <5, 3H) , 25 2.30 (s, 3H), 2.46 (s, 3H), 3.42 (s, 6H), 3.60 (q, J = 8, 2H), 3.70 (q, J = 8, 2H), 3.85 (S, 3H), 4.59-4.70 (m, 1H), 6.70 <d, J = 8, 1H), 6.76 <s, 1H), 6.96 (S, 1H). au) CI-HRMS: Calcd: 414.2505, Found: 414.2493 (M +■ H) ; 30 NMR (CDCI3, 300 MHz): 2.15 (s, 3H>, 2.19 (5, 3H) , 2.25 (S, 3H), 2.40 (s, 3H), 3.40 {s, 6H), 3.76 (t, J = 8, 4H) , 3.84 (s, 3H) , 4,20-4.45 <m, 4H) , 6.77 (s, 1H) , 6.93 (S, 1H) . av) CI-HRMS: Calcd: 368.2450, Found: 368.2447 (M + H) ; 35 NMR (CDCI3, 300 MHz): 1.00 (t, J - 8, 6H), 1.55- 1.85 (m, 4H), 2.19 (s, 3H), 2.20 Is, 3H), 2.30 (s.

Printed from Miir.csa WO 98/03510 PCTAJS97/I3072 3H), 2.47 (s, 3H >, 3.80 (s, 3H), 4.10-4.30 (m, 1H) , 6.15 (d, J = 8, 1H), 6.78 (s, 1H>, 6.98 (s, 1H). aw) CI-HRMS: Calcd: 353.2216, Found: 353.2197(M + H) ; NMR (CDCI3, 300 MHz): 1.35 (t, J = 0, 6H), 2,17 (s, 5 3H), 2.19 {s, 3H), 2.28 (3, 3H) , 2.40 (s, 3H) , 3.85 (S, 3H>, 3.90-4.20 (m, 4H) , 6.78 (s, 1H) , 6,95 (s, 1H) . ax) CI-HRMS: Calcd: 390 . 1697, Found: 390.1588 (M + H) ; Analysis: Calcd: C: 58.53; H: 6.20; N: 17,96; Cl: 10 9.09; Found: C: 58.95; H: 6.28; N: 17.73; Cl: 9.15; NMR CCDCI3, 300 MHz): 2.35 ts, 3H), 2.37 (3, 3H) , 2.48 Is, 3H), 3.42 {s, 6H), 3.60 (dd, J = 3, 8, 2H) 3.68 (dd, J = B, 3, 2H) , 4.59-4.72 (it., 1H) , 6.72 (d, J - 8, 1H) , 7.12 (d, J = 8, 1H), 7.23 <d, J =■ 15 8, 1H) , 7. 32 <s, 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 (CDCI3 P 300 MHz:): 1.01 (t, J = 8, 3H) , 1.62-20 1.88 (m, 4 H), 2.35 <S, 3H) , 2.37 (s, 3H), 2.48 (d, J = 1, 3H) , 3.40, 3.45 <s, s, 3H) , 3.50-3.64 (m, 2H), 4.38-4.47 <m, 1H), 6.53 (d, J = 8, 1H), 7.12 (d, J = 8, 1H), 7.07 (d, J - 8, 1H), 7.12 <S, 1H) . az) CI-HRMS: Calcd: 404.1853, Found: 404.1839 (M + H> ; 25 NMR (CDCI3, 300 MHz): 2.29 (s, 3H), 2.38 (s, 3H), 2,40 (S, 3H) , 3.40 ts, 6H> , 3.76 (t., J - 8, 4H) , 4.20-4.45 (m, 4H), 7.11 <d, J = 9, 1H), 7.22 (d, J - 8, 1H), 7.31 ts, 1H). ba.) CI-HRMS: Calcd: 404.1853, Found: 404.1859 (M + H) ; 30 Analysis: C: 59,47; H: 6.50; N: 17.34; Cl: 8.79; Found: C: 59.73; H: 6.46; N: 17,10; Cl: 8.73; NMR (CDCI3, 300 MHz): 1.95-2.08 (jr., 2H) , 2.35 <sr 3H), 2.38 <S, 3H), 2.46 ts, 3H>, 3.30 (s, 3H), 3.41 <s, 3fl), 3.50-3.65 (m, 4H) , 4.56-4.70 (m, 1H), 6.85 35 (d, J = 8, 1H) , 7,12 (dr J « 8, 1H) , 7.45 <d, J - 8, IK), 7.32 ts, 1H).

Printed from Mirr.osa WO 98/03510 PCT/US97/13072 bb) CI-HRMS: Calcd: 391.2246, Found: 391.2258 (M -t- H) ; Analysis: C: 67.67; H: 6,71; N; 21.52; Found: C: 67.93; H: 6.70; N: 21.48; NMR (CDCI3, 300 MHz) : 0.76-0 .84 (m, 2H), 0.84-0.91 5 <m, 2H), 1.00-1.08 <m, 2H) , 2.15 [s, 3H), 2.20 (s, 3H), 2.29 {5, 3H) , 2.45 (s, 3H), 2.85 (t, J = 8, 2H), 3.28-3.30 <m, 1H), 3.65 (s, 3H) , 6.78 (s, IK)r 6.95 (s, 1H). be, CI-HRMS: Calcd: 386.2192, Found: 386.2181 (M + H) ; 10 Analysis: C: 62.32; H: 7.06; N: 18.17; Found: C: 62.48; H: 6,83; N: 18.15; NMR {CDCI3, 300 MHz): 7.1 (d, 1H, J = 8), 6.9 (d, IK, J = 1), 5.8 (dd, 1H, J = 8,1), 6.7 (br.d, 1H, J = 8) , 4.7-4.6 (m, 1H) , 3.85 (s, 3H), 3,70-3.55 15 (m, 4H), 3.45 (s, 6H), 2.5 (s, 3H) , 2.3 Is, 3H), 2.15 (S, 3H). bd) CI-HRMS: Calcd: 400.2349, Found: 4 00 . 2336 <M -1- H) ; NMR (CDCI3, 300 MHz): 7,1 (d, Iff, J = 7), 6.85 (d, 1H, J = 1), 6.75 {dd, 1H, J = 7,1), 4.45-4.25 (br.s, 4H), 3.75 (t, 4H, J - 7), 3.4 (s, 6H), 2.4 (s, 3H), 2.25 (s, 3H), 2,15 (s, 3H). be) CI-HRMS: Calcd: 370.2243, Found: 370.2247 (M + K) ; Analysis: C: 65.02; H: 7.38; N: 18.96; Found: C: 65,28; H: 7.27; N-. 18.71; NMR (CDCI3, 300 MHz): 7.1 (d, 1H, J = 8), 6.85 <d, 1H, J = 1), 6.8 (dd, 1H, J » 8,1), 6.5 (br. d, 1H, J = 1), 4.5-4.3 (m, 1H), 3.85 (s, 3H), 3.65-3.5 {m, 2H), 3.4 <3, 2H), 2.5 <s, 3H> , 2.3 (s, 3H) , 2.2 (s, 3H) , 1.9-1.7 (m, 2H), 1.05 (t, 3H, J = 7) , 30 bf) CI-HRMS: Calcd: 379.2246, Found: 379.2248 <M + H); NMR (CDCI3, 300 MHz): 7.1 (d, 1H, J - 8), 6.85 (d, 1H, J = 1), 6.8 (dd, 1H, J = 8,1), 4.3-4.0 <m, 4H) , 3.85 (s, 3H), 3.0 (t, 2H, J = 7), 2.45 (s, 3H), 2.3 [S, 3H), 2.2 (3, 3H) , 1.9-1.8 ( m, 2H) , 1.0 (t, 3H, 35 J = 7) . bg) CI-HRMS: Calcd: 340.2137, Found: 340.2122 (M + H); Printed from Mimosa NMR ICDC13, 300 MHz): 7.1 (d, 1H, J ~ B), 6.05 (d, 1H, J = 1), 6.75 (dd, 1H, J = 8,1), 4.2-4.0 (br.m, 4H), 3.85 {s, 3H, 2.4 (s, 3H), 2.3 ( s, 3H), 2.2 (5, 3H>, 1.35 (t, 6H, J = 7). bh) CI-HRMS: Calcd: 313.1665, Found: 313.6664 (M +■ H> bi) CI-HRMS: Calcd: 400.2349, Found: 400.2346 (M + H) NMR (CDCI3, 300 MHZ): 7.1 <d, 1H, J = 1), 6.9-6.75 (m, 3K), 4.7-4.55 (m, 1H) , 3.8 (s, 3K) , 3,7-3.5 4H) , 3.45 (s, 3H), 3.35 <s, 3H), 2.5 (s, 3H) , 2.3 10 (s, 3H) , 2.2 (s, 3H), 2.1-1.95 (m, 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 (CDCI3, 300 MHz): 7.1 <d, 1H, J = 9), 6.9 (d, 15 1H, J = 1), 6.8 (dd, 1H, J = 8,1), 4.55-4.4 (m, 2H), 3.B5 <s, 3H) , 3.4-3.3 (m, 1H), 2.85 (t, 2H, J = 7), 2.5 (5, 3H), 2.3 (s, 3H) , 2.2 {s, 3H) , 1.1-1.0 <m, 2H), 0. 95-0.75 <nv 2H> . bk) CI-HRMS: Calcd: 413.2427, Found: 413.2416 (M + H) 20 NMR <CDCl3, 300Hz): 7.1 (d, 1H, J = 8), 6.85 (d, 1H, J = 1), 6.75 (dd, 1H, J - 8,1), 4.6 (m, 1H) , 3.85 (s, 3H), 3.7 5-3.6(m, 4H), 3.6 (q, 4H, J = 7), 2.5 (s, 3H), 2.3 s, 3H), 2.2 (s, 3H), 1.25 (t, 6H, J = 7) . 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) 30 bq) CI-HRMS: Calcd: 479.1155, Found: 479.1154(M + H) br) CI-HRMS: Calcd: 463.1219, Found: 463.1211(K + 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: 433.1U4(M, 19Br) bt) NH3-CI MS: Calcd: 406, Found: 406 (M + H)+; ?rir_"ted from Miif.csa NMR (CDCI3, 300 MHz J :5 7.28 (d, J=10Hz, 1H) , 7.03 (d, J=8Hz, 1H), 6.96 (s, 1H), 6.7 (d, J=9, 1H) , 4.63 <m, 1H), 3.79 <5, 3H), 3.6 (m, 4H) , 3.42 (s, 6K), 2.47 (3, 3H), 2,32 (s, 3H).

EXAMPLE 431 Preparation of 2, 4,7-dimethyl-8-(4-methoxy-2-10 methylphenyl)(1,5-a)-pyrazolo-1,3,5-triazine (Formula 1, where R3 is CHj, Ri is CH3, Z is C-CHa, Ar is 2, 4-dimethylphenyl) -Acetamidino-4-(4-methoxy-2-methylphenyl)-3-15 methylpyrazole, acetic acid salt { 602 mg, 2 mmol) was mixed with a saturated NaHC03 solution (10 mL). The aqueous mixture was extracted with EtOAc three times. The combined organic layers were dried over MgSO<], filtered and concentrated in vacuo. The residue was 20 taken up in toluene (10 mL) and trimethyl orthoacetate { 0.36 g, 3 mmol) was added to the suspension. The reaction mixture was heated to reflux temperature under a nitrogen atmosphere and stirred for IS hours. After being cooled to ambient temperature, the reaction 25 mixture was concer.trated in vacuo to give an oily solid. Column chromatography (CHCI3:MeOH::9:1) afforded, after removal of solvent in vacuo, a yellow viscous oil (Rf = 0.6, 210 mg, 37% yield): NMR (CDCI3, 300 MHz): 7.15 (d, 1H, J = 8), 6.9 (d, 1H, J = 1), 6.85 (dd, 1H,' J = 8,1) , 30 3.85 <s, 3H), 2.95 (s, 3H), 2.65 (s, 3H) , 2.4 (s, 3H) , 2,15 (s, 3H); CI-HRMS: Calcd: 283.1559, Found: 283.1554 (M + H).

Printed from Mimosa PCT/US97/I3072 EXAMPLE 432 7-hydroxy-5-methyl-3-(2-chloro-4-methylpheny1)pyrazolo[1,5-a)pyrimidine (Formula 1 where A is CH, R1 is Me, R3 is OH, Z is C-Me, Ar is 2-chloro-4-methylphenyl) -Amino-4-(2-chloro-4-methylphenyl>-3-methylpyrazole (1.86 g, 8.4 mmol) was dissolved in glacial acetic acid {30 mL) with stirring. Ethyl 10 acetoacetate (1.18 mL, 9.2 mmolI 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 15 filtration. Drying in vacuo afforded a white solid ( 1.0 g, 42% yield): NMR (CDC13, 300Hz): 8.70 (br.s 1H), 7.29 ( s, 1H), 7.21-7.09 < m, 2H) , 5.62 (s, 1H) , 2.35 (s, 6H), 2.29 (s, 3H); CI-MS: 280 (M+H).

A mixture of 7-hydroxy-5-methyl-3-{2-chloro-4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (1.0 g, 3.5 mmol), phosphorus oxychloride (2.7 g, 1.64 mL, 17.4 30 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::1:2) on the residue gave 7-chloro-5-35 methyl-3-(2-chloro-4-methylphenyl)-pyrazolo(1,5- ajpyrimidine (900 mg, 84% yield) as a yellow oil: NMR EXAMPLE 433 7-chloro-5-methyl-3-(2-chloro-4-methylphenyl) pyrazolo[1, 5-a ] pyricnidine (Formula 1 where A is CH, R1 is Me, R3 is Cl, Z is C-Me, Ar is 2-chloro-4-methylphenyl) Printed from Mimosa PCT/US97/J3072 (CDCI3, 300Hz): 7.35 <s, 1H) , 7.28-7.26 <m, 1H), 71.6 ( d, 1H, J = 7), 6.BO (s, 1H), 2.55 (s, 3H) , 2.45 <s, 3H) , 2.40 <s, 3H); CI-MS: 306 (M+H).

EXAMPLE 434 7-(pentyl-3-amino)-5-methyl-3-(2-chloro-4-methylphenyl)pyrazolo[1,5-a]pyrimidine {Formula 1 where A is CH, R1 is Me, R3 is pentyl-3-10 amino, Z is C-Me, Ar is 2-chloro-4-methylphenyl) A solution of 3-pentylamine (394mg, 6.5 mmol) and 7-chloro-5-methy1-3-(2-chloro-4- methylpher.yl) pyrazolo[ 1, 5-a]pyrimidine (200 mg, 0.65 IS mmol) in dimethylsulfoxide (DMSO, 10 mL) was stirred at 150°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 dichloromethane, washing the combined organic layers 20 with brine, drying over MgSQ-j, filtration and removal of solvent in vacuo produced a yellow solid. Flash chromatography (EtOAc:hexanes::1:4) afforded a white solid (140 mg, 60% yield): mp 139-141°C; NMR (CDCI3, 300Hz) :7.32 (s, 1H), 7.27 (d, 1H, J = 3), 7,12 <d, 1H, J 25 = 7), 6.02 (d, 1H, J = 9), 5.73 ( s, 1H) , 3.50-3.39 <m, 1H), 2.45 (s, 3H), 2.36 (s, 6H>, 1.82-1.60 (m, 4H), 1.01 (t, 6H, J = 8); Analysis Calcd for C2OH25CIN4: C, 67.31, H, 7.06, N, 15.70, Cl: 9.93; Found: C, 67.32, K, 6.95, N, 15.50, Cl, 9.93.

The examples delineated in TABLE 2 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 35 Example, EtOAc is ethyl acetate.

Primc-d from Mirr.csa EA«. R.j_ 43Sb C-He N(CH2CH20Me)2 436c C-Me N(BuJEt 437d C-Me NHCH(Et}CH20Me 43Se C-He N(Pr)CH2CH2CN 439^ C-Me NH-3-pentyl 4 4 09 C-Me NHCH(CH20He)2 441h C-Me NHCH(Et) 2 4421 C-Me NHCH(CH20Me>2 4433 C-Me N(CH2CH20Me)2 444k C-Me N(c-Pr)CH2CH2CN 4451 C-Me N[CH2CH20Me)2 446m C-Me NHCH(CH20Mel 2 447" C-Me NHCH (Et)2 446° C—Me NEt 2 449P C-Me N(Pr)CH2CH2CN 450*5 C-Me N (Bu)CH2CH2CN 451r C-Me NHCH(EC)CHjOMe 4 52® C-Me NHCH(Et)2 453t C-Me NHCH(CHjOMe)2 454u C-Me N (CH2CHjOMe)2 455v C-Me (S)-MHCH(CH2CH20Me)- (CH2OMe) 456" C-Me IS)-NHCH(CH2CH20Me)- (CH20Me) &£ 2,4-Cl2-Ph 2,A —CI2-Ph 2,4-Cl2-Ph 2,4-CL2-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-C1,4-MePh 2-C1,4-MePh 2-Cl,4-MePh 2,4-Me2~Ph 2,4-M&2-Ph 2,4-Me2-Ph 2,4-Me2-Ph 2-Me,4-MeOPh 2-Me,4-MeOPh 2-Me,4-MeOPh 2-Me,4-MeOPh 2, 4-Me2~Ph .■no fflQ 71-73 66-87 110-111 83-85 175-176 107 oil 103-105 87-B9 133(dee) 77-7B 131-133 139-141 92-94 143-144 115-117 oil 104-106 115-116 oil oil oil Pririted from Mimosa 4S7X C-Me 458Y C-Me 4591 C-Me 460aa C-Me 461ab C-Me 462ac C-Me 463ad C-Me 464ae C-Me JO 465af C-Me 466a9 C-Me 4 67ah C-Me 460ai C-Me 469ai C-Me 470ak C-Me 471 C-Me 472 C-Me 473 C-Me 474 C-Me 475 C-Me 476 C-Me 477 C-Me 478 C-Me 479 C-Me 480 C-Me 481 c-Me 482 c-Me 483 C-Me 484 C-Me 485 C-Me 4BG C-Me 487 c-Me 489 C-Me 489 C-Me N(CH2CH20Me)2 NHEt NHCH(Et)2 NHCH <CH20Me)2 N(Ac)Et (S)-NHCH (CH2CH20Me)-(CH20Me) N(Pr)CH2CH2CN NEt 2 (S)-NHCH (CH2CH20Me)-(CH20Me) NEt2 N|c-Pr)CH2CH2CN H(c-Pr)CHJCH2CN NHCH(EtJ CH^OMe NHCH (Et)CH20Me NHCH(CH20Me>2 N{CH2C«20He)2 NHCH(Et)CH20He N(c-Pr)CH2CH2CN NEt2 NH-3-pentyl NHCH(Et)CH2CH20Me NHCH(He)CH2CH20Me NHCH(Et)CH2CH20He NHCH(Me)CH2CH20Me NHCH(Et)CH2CH2DMe NHCH(Me)0H2CH2OMS NHCH(CH20Me)2 N(CH2CH20Me)2 NHCH fEt)CH20M® N<c-Pr)CH2CH2CN NEt 2 NH-3-pentyl NHCH(EtlCH2CH20Me 2-Me,4-CIPh oil 2,4-Me2-Ph oil 2-Me,4-CIPh 94-96 2-Me,4-CIPh 113-114 2,4-Me2"Ph oil 2-Me,4-CIPh oil 2"Me,4-MeOPh 116-119 2-Me,4-MeOPh 97-99 2-C1,4-MePh 101-103 2-C1,4-MePh 129-130 2-Me,4-MeOPh 177-178 2-C1,4-MePh 162-163 2-Me,4-MeOPh oil 2-C1,4-MePh 111-113 2-Cl-4-MeOPh 2-Cl-A-MeOPh 2-Ci-4-MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-Br-4-MeOPh 2-Br-4-MeOPh 2-Me-4-MeOPh 2-Me-4-MeOPh 2-Cl-4,5-(MeO)2?h 2-Cl-4,S-(MeO)2Ph 2-Cl-4,5-(MeO)2?h 2-Cl-4,5-(MeO)2Ph 2-C1-4,5-(MeO)2ph 99-101 2-C1-4,S-(MeO)2?h 169-170 2-Cl-4,5-(MeO)2Ph Printsd rrorr. Miir.csa 490 C-Me NHCH(Me)CH2CH20Me 491 C-Me NHCH(CH20Me)2 492 C-Me N(CH2CH20Me)2 493 C-Me NHCH(Et)CH20Me 494 C-Me N<c-Pr}CH2CH2CN 495 C-Me NEt2 496 C-Me NH-3-pentyl 4 97 C-Me NHCH (Et)CH2CH2CMe 49^ C-Me NHCH(Me > C H 2 CH 2 OMe 499 C-Me NHCH(CH2OMe>2 500 C-Me N(CH2CH20Me)2 501 C-Me NHCH(Et)CH2OMe 502 C-Me N(c-Pr)CH2CH2CN 503 C-Me NEt2 504 C-Me NH-3-pentyl 505 C-Me NHCH(EtlCH2C«20Me 506 C-Me NHCH(Me)CH2CH20Me S07 C-Me NHCH(CH2OM0)2 soa C-Me N(CH2CH20Me)2 509 C-Me NHCH[Et)C«20Me 510 C-Me N (C-Pr)CH2CH2CN 511 C-Me NEt2 512 C-Me NH-3-pentyl 513 C-Me NHCH(Et)CH2CH20Me 514 C-Me NHCH(Me)CH2CH2OMe 515 C-Me N(c-Pr)CH2CH2CN 516 C-Me NEt2 517 C-Me NH-3-pentyl 518 C-Me NHCH(E-)CH2CH2OMe 519 C-Me NHCH(Me)CH2CH20M6 520 C-Me NHCH(Et)CH2CH20Me 521 C-Me NHCH(Me)CH2CH20Me 522 C-Me NHCH(CH20M6)2 523 C-Me N(CH2CH20Me>2 524 C-Me NHCH(EC)CH20Me 525 C-Me N (C-Pr)CH2CH2CN -138 PCT/US97/I3072 2-Cl-4,5-(MeO)2Ph 2-BC-4,S-(MeO)2Ph 90-93 2-Br-4,5-(MeO)2 Ph 110 2-Br-4,5-(MeO)2Ph 2-Br-4,5-(MeO)2Ph 2-Br-4,5-(MeO)2Ph 2-Br-4,5-[MeO)2Pb 2-Br-4,5-(MeO)2Ph 2-Br-4,5-(MeO)jPh 2-C1-4,6-(MeO)2Ph 2-Cl-4,6-(MeO)2Ph 2-Cl-4,6-(MeO)2Ph 2-Cl-4,6-(MeO)2Ph 2-Cl-4,6-(MeO)2Ph 2-Cl-4,6-(MeO)2Ph 2-C1-4,6-(MeO)2Ph 2-C1-4,6-(MeO)2Ph 2-Me-4,6-(MeO)2Ph 2-Me-4,6-(MeO)2?^ 2-Me-4,6-(MeO)2Ph 2-Me-4,6-<MeO>2Ph 2-Me-4, 6-(MeO)2?^ 2-Me-4,6-(MeO)2Ph 2-Me-4,6-(MeO)2Ph 2-Me-4,6-(MeO)2Ph 2-9r-4,6-(MeO)2Ph 2-Br-4,6-(MeO)2Ph 2-Br-4,6-(MeO)2Ph 2-Br-4,S-(MeO)2Ph 2-Br-4,6-(MeO)2Ph 2-Me-4-MeOPh 2-Me-4-MeOPh 2-Me0-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh [Jrinted from Mimosa 526 c-Me NEt2 2-MeO-4-MePh 527 c-Me N H - 3 - pe n t y 1 2-MeO-4-MePh S2B C-Me NHCH(Et)CH2CH2OMe 2-MeO-4-MePh 529 C-He NHCH <Me)CH2CH20Me 2-Me0-4-MeFh 530 C-Me NHCH(CH20Me)2 2-MeO-4-MePh 531 C-Me N(CH2CH2OMe>2 2-MeO-4-MePh 532 C-Me NHCH(Et)CH20Me 2-MeO-4-MePh 533 C-Me N(C- Pr)CH2CH2CN 2-MeO-4-MePh 53-T C-Me NEt 2 2-Me0-4-MePh 535 C-Me NH -3-pentyl 2-MeO-4-MePh 536 C-Me NHCH(Et)CH2CH20Me 2-MeO-4-MePh 537 C-Me NHCH(Me)CH2CH20Me 2-MeO-4-MePh 530 C-Me NHCH(CH20Me)2 2-Me0-4-CIPh 539 C-Me N <CH2CH20Me> 2 2-MeQ-4-ciPh 540 c-Me NHCH(Et)CH20Me 2-MeO-4-ClPh 541 c-Me N (c- Pr)CH2CH2CN 2-MeO-4-CIPh 542 C-Me NEt2 2-Me0-4-CIPh *3 C-Me N H -3-pentyi. 2-MeO-4-CIPh 54 4 C-Me NHCH(Et)CH2CH20Me 2-MeO-4-CIPh 545 C-Me NHCH(Me)CH2CH20Me 2-Me0-4-ClPh NOTES FOR TABLE ! 2 : b) CI-HRMS: Calcd: 423.1355; Found : 423.1337 <M C) Analysis: Calcd: C, 61.30, H, 6 . 18 , N, 14.32: Found: C, 61.54, H, 6.12, N, 14 . 37 . d> Analysis: Calcd: C: 58.02, H, 5 . 65 ., N, 14.24; Found: C, 58.11, H, 5.52, N, 14 . 26. e) Analysis: Calcd: C, 59.71, H, 5 .26 , N, 14.85; Found: C, 59.94, H, 5.09, N, 17 . 23 . f) Analysis: Calcd: C, 60.48, H, 5 .89 , N, 14.85, Found: C, 60.62, H, 5.88, N, 14 . 82 . h) CI-HRMS: Calcd: 337.2388; Four.d : 337.2392 (M i) Analysis: Calcd: C, 68.45, H, 7 ,669, N, 15.21 Found: C, 68.35, H, 7.49 N, 14.91.

Printad from Mimosa PCTVUS97/13072 j) Analysis: Calcd: C, 69.08, H, 7-915, N, 14.65, Found: C, 68.85, H, 7.S3, N, 14.54.

JO 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, 13.52, Cl, 9.25 n> Analysis: Calcd: C, SI.31, H, 7.06, K, 15.70, Cl, 9.93; Found: C, 67.32, H, 6.95, N, 15.50, Cl, 9.93 10 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, 18.91, q) Analysis: Calcd: C, 73.57, H, 7.78, N, 18.65, 15 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, 20 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: 363.2447 <M + H) X) CI-HRMS: Calcd: 403.1887; Found: 403.1901 (M +■ H) 25 y> CI-HRMS: Calcd: 295.1919; Found: 295.1923 (M +■ H) 2) 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: Cf 62.06, H, 6.37, N, 14.25, Cl, 9.12 30 ab) CI-HRMS: Calcd: 337,2017; Found: 337.2023 (M +■ H) ac) CI-HRMS: Calcd: 403.1893; Found: 403.1901 (M +■ H> ad) Analysis: Calcd: C, 70.00, K, 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, 35 Found: C, 71.15, H,7.46, N, 16.56- Fririted from Minosa ag) Analysis: Calcd: C, 66.59, Hr 6.76, N, 16.34, Found: C, 66.69, H,6.82, N, 16.20. ah) Analysis: Calcd: C, 70.38, H, 6.71, N, 18.65, Found: C, 70,35, H,6.82, N, 18.83. ai) Analysis: Calcd: C, 66.39, H, 5,85, N, 18.44, Cl, 9. 33; Found: C, 66.29, H, 5.51, N, 18.36, Cl, 9.31. aj) CI-HRMS: Calcd: 369.2278; Found: 369.2291 (M H) . ak) Analysis: Calcd: C, 64.42, H, 6.77, N, 15,02, Found: C, 64.59, H, 6.51, N, 14.81.

The examples delineated in TABLE 3 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 3 R3 Ar 546a Z. C-Me 547b C-Me 54Bc C-Me 549a C-Me fil NHCH(Et)2 S-NHCH(CH2CH20Me) -CH20Me S—NHCH(CH2CH20Me) -CH20Me N{c-P r)CH2CH2CN Ar 2-Me-4-Me2N-Ph 2,4-Me2—Ph 2-Me-4-Cl-Ph 2—Me-4-Cl-Ph IBQlfl£LL 164-166 oil oil 115-116 Prinred :ron. Miir.osa 550e 551f 552*3 5S3h 5541 5553 556k 557 558 559 560 5611 562 56 3m 564 565 566 567 568 569 570 571 572 573 574 575 576 577 570 579 560 581 582 583 584 C-Ke NHCH (EtJ CH2CN 2-Me—4-Cl-Ph 131-132 C-Ma M(Et>2 2,3-Me 2 —4-OMe-P h oil C-Me N(CH2CH20Me)CH2CH2OH 2,4-Cl2-Ph oil C-Me N{CH2CH20Me> 2 2,3-Me2~4-OMe-Ph oil C-Me NHCH(Et)2 2,3-Me2-4-OMePh 123-124 C-Me N(CH2-c-Pr)Pr 2-Me-4-Cl-Ph oil C-Me N(c-PrlCH2CH2CM 2,3-Me2~4-OMePh 158-160 C-Me N(c-Pr)Et 2-Cl-4-OMePh C-Me N (c -P r) Me 2-Cl-4-OMePh C-Me N(c-Pr)Pr 2-Cl-4-OMePb C-Me N(c-Pr)Bu 2-C1-4-OMePh C-Me N <Et)2 2-Cl-4-CN-Ph 115-117 C-Me N(c-Prt 2 2-C1-4-OMe 127-129 C-Me NHCH(CH2OH)2 2,4-Cl2-Ph 128-129 C-Me N(C-PrlEt 2-BC-4,5-(MeO)2Ph C-Me N(c-Pr)Me 2-Br-4,5-(MeO)2Ph C-Me NH-c-Pr 2-Me-4-MeOPh 126-12B C-Me NHCH(Et|CH20H 2-Me-4-MeOPh 60-62 C-Me NMe2 2-Br-4,S-(MeO)2Ph C-Me NHCH(Et)2 2-Me-4-MeOPh 103-105 C-Me N(c-Pr)Et 2-Me-4-MeOPh 173-174 C-Me NH-2-pentyl 2,4-Cl2-Ph na-120 C-Me NHCH(Et)CH2CN 2, 4-Cl2-Ph 141-142 C-Me NHCH(Pr)CH20Me 2,4-CI2-Ph 87-88 C-Me NHCH(CH2-iP r)CH20Me 2,4-Cl2-Ph amorphous C-Me NH-2-butyl 2, 4-Me2-Ph oil C-Me NH-2-pentyl 2,4-Me2-Ph oil C-Me NH-2-hexyl 2,4-Me2_Ph oil £ i • U NHCH(i-Pr)Me 2,4-Me2-Ph oil C-Me NHCH(Me)CH2-iPr 2,4-Me2-Ph oil C-Me NHCH(Me)-c-C6H11 2,4-Me2-Ph oil C-Me NH-2-indanyl 2,4-Me2-Ph oil C-Me NH-l-indanyl 2,1-Me2-Ph oil C-Me NHCH(Me)Ph 2,4-Me2-Ph oil C-Me NHCH(Me)CH2-(4-ClFh) 2,4-Me2-Ph oil Printed frorri Mimosa PCT/US97/i3072 5B5 C-Me NHCH fMe)CH2COCH3 2,4-Me2~Ph oil 586 C-Me NHCH <Ph)CH2Ph 2,4-Me2-Ph oil 587 C-Me NHCH(Me) (C«2 33NEt2 2,4-Me2-Ph oil 588 C-Me NH- (2-Ph-c-C3H4) 2,4-Me2~ph oil 589 C-Me NHCH(Et)CH2CN 2,4-Me2-Ph 119-120 590 C-He NH-3-hexyl 2,4-Me2"Ph oil 591n C-Ms NEt2 2—MeO-4-ClPh oil 592° C-Me NHCH(Et)2 2-MeQ-4-CIPh oil 59"P C-Me NHCH(Et)CH20Me 2-MeO-4-ClPh oil 594 C-Me NMe2 2-MeO-4-CIPh oil 595=1 C-Me NHCH(Et > 2 2-OMe-4-MePh oil S96r C-Me NEt2 2-OMe-4-MePh oil 5973 C-C-Pr NHCH(CH20Me>2 2,4-Cl2-Ph oil 598 C-Me N Ic-Pc)Et 2,4-Me2~Ph 599 C-Me N (c-Pr)Et 2,4-Ci2-Ph 600 C-Me N(c-Pr)Et 2,4,6-Me3~Ph 601 C-Me N(c-Pr> Et 2-Me-4-Cl-Ph 602 C-Me N (c-fir) Et 2-ci-4-Me-Ph <303 C-Me NHCH(c-Pr)2 2,4-CI2-Ph 604 C-Me NHCH(c-Pr)2 2,4-Me2~Ph 605 C-Me NHCH(c-Pr)2 2-Me-4-Cl-Ph 606 C-Me NHCH(c-Pr)2 2-Cl-4-Me-Ph 607 c-Me NHCH(C-Prl2 2—Me-4-OMe-Ph 608 C-Me NHCH(c-Pr)2 2-Cl-4-OMe-Ph 609 C-Me NHCH(CH20Me)2 Z-Cl-5-F-QMePh 610 c-Me NEtj 2-Cl-5-F-OMePh 611 C-Me N(c-Pr)CH2CH2CN 2-Cl-5-F-OMePh 612 C-Me NHCH(Et)2 Z-Cl-5-F-OMePh 613 C-Me N(CH2CH20Me)2 2-Cl-5-F-OMePh 614 C-Me NEt2 2,6-Me2~pyrid-3-yl 615 c-Me N(c-Pr)CH2CH2CN 2,6-Me2-pyrid-3-yl 616 C-Me NHCH(Et)2 2,6-Me2~pyrid-3-yl 617 C-Me N(CH2CH20Me)2 2,6-Me2-pyrid-3-yl 613 C-OH NHCH(CH20MS)2 2,4-Me2_Ph 619 C-OH NEt2 2,4-Me2~Ph 620 C-OK Nfc-PrJCHjCHjCN 2,4-Me2~Ph Printed fror. Miir.Coa 621 C-OH NHCfi (Et) 2 2, 4-Mej-Ph 623 C-OH N(CH2CH20Me)2 2,4-Me2-Ph 624 C-NEtj NHCH(CH20MS12 2, 4-M02-Ph 625 C-NEt2 NEt 2 2,4-Me2-Ph 626 C-NEtj N(c-Pr)CH2CH2CH 2,4-Me2-Ph 627 C-NEt2 NHCH(Et)2 2, 4-Me2~Pii 626 C-NEt2 N[CH2CH20MS)2 2,4-MS2~Ph 629 C-Me NHCH(Et)2 2-Me-4-CN-Ph 630" C-Me N<CH2CH20Me>2 2-Me-4-CN-Ph Notes for Table 3: a) CI-HRMS: Calcd: 367 2610, Found: 3 67 2607 (M + H) b) CI-HRMS: Calcd: 384 2400, Found: 384 2393 (M H) c) CI-HRMS: Calcd: 404 1853, Found: 404 1844 (M + H) d) CI-HRMS: Calcd: 381 1594, Found: 381 1596 (M + H) Analysis : Calcd : C 63.07 , H, 5 57, N, 22 .07 t Cl 9.32; Found: C: 63.40, H, 5.55, N, 21.96, Cl: 9.IS 20 e) CI-HRMS: Calcd: 3 69 . 1594, Found: 369.1576 (M +■ H f) CI-HRMS: Calcd:354.2216, Found: 354.2211 {M + H g) CI-HRMS: Calcd:410.1072, Found: 410.1075 (M + H h> CI-HRMS: Calcd:414.2427, Found: 414.2427(M + H) i) CI-HRMS: Calcd:368.2372, Found: 368.2372(M + H) j) CI-HRMS: Calcd: 384 . 1955, Found: 394.1947(M -t- H) k) CI-HRMS: Calcd:391.2168, Found: 391.2160(M + H) 1) CI-HRMS: Calcd:335.1984, Found: 335.1961(M + H); m) CI-HRMS: Calcd: 382 , 0759, Found: 332.0765 {M +- H) ; n> NH3-CI MS: Calcd: 3 60, Found: 3 60 (M + H)+ 30 o) NH3-CI MS: Calcd: 374, Found: 374 (M + H)+; NMR (CDCI3, 300 MHz) :6 7.29 (d, J=8.4Hz, 1H), 7.04 (dd, J=1.8,8Hz, 1H), 6.96 (d, J=1.8H2, 1H), 6.15 <d, J=10, 1H>, 4.19 (m, 1H), 3.81 (s, 3H) , 2.47 (s, 3H), 2.32 (s, 3H), 1.65 In, 4H), 0.99 {t, J-7.32Hz, 35 6H) p) NH3-CI MS: Calcd: 390, Found: 390 (M +■ H)+; -14 4- Printed from Mimosa WO 98/03510 PCT/US97/13072 NMR (CDCI3, 300 MHs) rfi 7.2S (d, J=Shz, 1H), 7.03 (d, J=8Hz, 1H) , 5.96 (s, 1H), 6.52 (d, J-9Hz, 1H) , 4.36 (m, 1H), 3.8 <s, 3H) , 3.55 (m, 2H) , 3.39 (3, 3H>, 2.47 (s, 3H), 2.32 (5, 3H) , 1.76 <ra, 2H), 1.01 5 (t, J=7.32Hz, 3 H) . q) CI-HRMS: Calcd: 354.2294, Found: 354.2279 (M + HI+ 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 Commoriiy used abbreviations are: Ph is phenyl, Pr is propyl, Me is methyl, Et is ethyl, Bu is butyl, Ex is 15 Example, EtOAc is ethyl acetate.

TABLE 4 R3 Ei*. 631 6 32 633 634 Z C-Me C-Me C-Me C-Me NHCH <Et>2 NHCH(Et)2 N<CH2CH20Me>2 NHCH(CH20Me)2 it 2-Br-4, 5-(MeO)2?h 160-161 Z-Br-4'MeOPh 110-111 2-Br-4 —MeOPh 74-76 2-Br-4-MeOPh 120-130 Printod from Mimosa 535 C-Me N (Et) 2 2-Me-4-ClPh 636 C-Me N (C-Pr)Et 2,4-Cl2Ph 637 C-Me N (C-Pr)Et 2,4-Me2Ph 638 C-Me N (C-PrlEt 2,4,6-MejPh 639 C-Me N (c-Pr)Et 2-Me-4-MeOPh 64 0 C-Me N (c-Pr)Et 2-Cl-4-MeOPh 641 C-Me N (c-Pr)Et 2-Cl-4-MePh 642 C-Me N (c-Pr)Et 2-Me-4-CIPh 64 J C-Me N'HCH (c-Pr) 2 2, 4-Cl2-Ph 644 C-Me NHCH(c-Pr)2 2,4-Me2~Ph 645 C-Me NHCH(c-Pc)2 2-Me-4-Cl-Ph 646 c-Me NHCH(c-Pr)2 2-Cl-4-Me—Ph 647 C-Me NHCH(c-Pr)2 2-Me-4-GMe-Ph 643 C-Me NHCH(c-Pr)2 2-C1-4-OMe-Ph 649 C-Me MHCH(CH20Me)2 2-Cl-5-F-OMePh 650 C-Me NEt2 2-Cl-5-F-OMePh 651 C-Me N (C-Pr)CH2CH2CN 2-Cl-5-F-OMePh 652 C-Me MHCHtEt)2 2-C1-5-F-QMePh 653 C-Me N(CH2CH20Me)2 2-Cl-5-F-OM«Ph 654 C-Me NEt2 2, 6-Me2~pyr:id-3-yl 655 C-Me N(c-Pr)CH2CH2CN 2, 6-Me2-pyrid-3-yl 656 C-Me NHCH(Et)2 2, 6-Me2-pyrid-3-yl 657 C-Me N(CH2CH2OMe)2 2, 6-Me2-pyrid-3-yl 653 C-OH NHCH(CH2OMe> 2 2,4-Me2-Ph 659 C-OH NEt2 2,4-Me2~Ph 660 C-OH N (c-Pr)CK2CH2CN 2,4-Me2-Ph 661 C-OH NHCH (Et)2 2,4-Me2"Ph 662 C-OH NtCH2CH20Me)i 2,4-Me2-Ph 663 C-NEt2 NHCH(CH20Me)2 2,4-Me2-Ph 664 C-NEt2 NEt2 2,4-Me2-Ph 665 C-NEt2 N(c-Pr)CH2CH2CN 2,4-M«2-Ph 666 C-NEC2 NHCH(EtI2 2,4-Me2-Ph 667 C-NEC2 N(CH2CH20Me)2 2,4-Me2~Ph 668 C-Me NHCH(Et)2 2-Me-4-CN-Ph 669 C-Me N(CH2CH20Me)2 2-Me-4-CN-Ph Printed from Mimosa PCTYUS97/13072 The examples in Tables 5 or 6 may be prepared by the methods illustrated in Examples 1A, IB, 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. 670 671 672 673 674 675 676 677 678 679 680 681 632 683 fiii Me Me Me Me Me Me Me Me Me Me Me Me Me Me NHCH(CH2OMe)2 NHCHPT2 NEtflu NPr(CH2-C-C3H5) N(CH2CH20Me)2 NH-3-heptyl NHCH(Et)CH20Me NEt 2 NHCH<CH20Et)2 NH-3-pentyl NMePh NPt2 NH-3-hexyl marpholino &£. 2,4-Cl2-Ph 2,4-Cl2-Fh 2,4-Cl2-Ph 2,4-Cl2-Ph 2,1-Cl2-Ph 2,4-Cl2-Ph 2,4-CI2-Ph 2,4-Cl2-Pb 2,1-Cl2~Ph 2,4-Cl2-Ph 2,4-Cl2-Ph 2, 4-Cl2"Pfl 2,4-Cl2"Ph 2,4-Cl2-Ph Frintea trom Kimosa 690 691 69^ 693 691 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 719 719 Me N (C«2Ph)CH2CH20Me 2,4-Cl2-Ph Me NHCH1CK2Ph)CHjOMe 2,4-Cl2-Ph Me NH-4-tet rahydropyranyl 2,4-Cl2-Ph Me NH-cyclopentyl 2,4-Cl2-Ph Me OEt 2,4-Cl2-Ph Me OCH(Et)CH20Me 2,4-Cl2-Ph Me OCH2Ph 2,4-Clj-Ph Me O-3-pentyl 2,4-Cl2-Ph Me SEt 2,4-Cl2-Ph Me S (0) Et 2,4-Cl2-Ph Me SC>2£t 2,4-Cl2-Ph Me ?h 2,4-Cl2-Ph Me 2-CF3-Ph 2,4-Cl2-Ph Me 2-Ph-Ph 2,4-Cl2~Ph Me 3-pentyl 2,4-Cl2-Ph Me cyclobutyl 2,4-ci2-Ph Me 3-pyridyl 2,4-Cl2-Ph Me CH(Et)CH2CONMe2 2,4-Cl2-Ph Me CH<Et>CH2CH2NMe2 2,4-Cl2-Ph Me NKCH{CH20Me)2 2,4,6-Me3-Ph Me NHCHPrj 2,4,6-Me3~Ph Me NEtBu 2,4,6-Me3~Ph Me NPr(CH2-C-C3HS) 2,4,6-Me3~Ph Me N(CH2CH20Me)2 2,4,6-Me3~Ph Me NH-3-heptyl 2,4,6-Me3-Ph Me NHCH(Et)CH20Me 2, 4,S-Mej-Ph Me NEt 2 2,4,6-Me3-Ph Me NHCH(CH2OEt)2 2,4,6-Me3-Ph Me NH-3-pentyl 2,4,6-Me3-Ph Me NMePh 2,4,S-Mejj-Ph Me NPE2 2,4,6-Me3-Ph Me NH-3-hexyl 2,4,6-Mej-Ph Me tnorpholino 2,4,6-Me3-Ph Me N(CH2Ph)CH2CH2OMe 2,4,6-Me3~Ph Me NHCH <CH2Ph> CH20Me 2,4,6-Me3-Ph Me NH-4-tetrahydropyranyl 2,4,6-Me3-ph ^rir_~Gd from Mimosa 724 725 726 727 728 729 730 731 732 733 734 735 73G 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 7 52 Me NH-cyclopentyl 2,4,6-Me3-Ph Me OEt 2,4,6-Me3-Ph Me OCH (EOCH20Me 2,4,6-Me3-Ph Me OCH2Ph 2,4,G-Mej-Ph Me 0-3-pentyl 2,4,6-Me3-Fh Me SEt 2,4,6-Me3-Ph Me S (OI Et 2, 4,6-Me3-Ph Me SOjEt 2,4,6-Me3~Ph Me CH(C02Et)2 2,4,6-Me3-Ph Me C(Et)(C02&t}2 2,4,6-Me3-Ph Me CH(Et)CH2OH 2,4,6-Me3~Ph Me CH(Et)CH20Me 2,4,6-Me3-Ph Me CONMe2 2,4,S-Mej-Ph Me COCH3 2,4,6-Me3-Ph Me CH(0H)CH3 2,4,6-Me3-Ph Me C(OH)Ph-3-pyridyl 2,4,€-Me3-Ph Me Ph 2,4,6-Me3-Ph Me 2-Ph*-Ph 2,4,S-Me3-Ph Me 3-pentyi 2,4,6-Me3~Ph Me cyciobutyl 2,4,6-Me3-Ph Me 3-pyridyl 2,4,S-Me3-Ph Me CH (Et)CH2CONMe2 2,4,6-Me3-Ph Me CH(Et)CH2CH2NMe2 2,4,6-Me3-Ph Me NHCH(CH20Me)2 2,4-Me2-Ph Me N(CH2CH20Me)2 2,4-M«2"Ph Me NHCH<Et)CH20Me 2,4-Me2"Ph Me NH-3-pentyl 2,4-Me2~Ph Me NEt2 2,4-Me2-Ph Me H(CH2CN)2 2,4-Me2~Ph Me NHCH <Me)CH20Me 2,4-Me2~Ph Me OCH (Et)CH20Me 2,4-Me2~Ph Me NPr-c-C3H5 2,4-Me2-Ph Me NHCH(Me)CH2NMe2 2,4-Me2~Ph Me N(c-C3H5)CH2CH2CN 2,4-Me2-Ph Me N(Pr)CH2CH2CM 2,4-Me2-Ph Me H(Bu)CH2CH2CN 2,4-Me2-Ph ?rir.~ed from Kimosa 75G 757 758 759 760 761 762 763 754 765 766 767 760 769 770 771 772 773 774 775 776 777 778 779 730 781 782 783 784 785 706 787 788 789 790 791 Me NHCHPr2 2,4-Me2-Ph Me NEtBu 2/4-Me2-Ph Me NP r(CH2-C-C3H5) 2,^-Mej-Ph Me NH-3-neptyl 2, 4-Me2-Ph Me NEt 2 2,4-Me2-Ph Me NHCH(CHjOEtl2 2,4-Me2-Ph Me NH-3-pentyl 2,4-Me2-Ph Me NMePh 2,4-Me2-Ph Me NPE2 2,4-Me2~Ph He NH-3-hexyl 2/4-Me2-Ph Me morpholino 2,4-Mej-Ph Me N(CH2Ph)CH2CH2OMe 2,4-Me2~Ph Me NHCH (CH2Phl CH2OMe 2, 4-Me2-Ph Me NH-4-tet rahydcopyranyl 2,4-Me2-Ph Me NH-cyclopentyl 2,4-Me2-Ph Me NHCH (CH2OMe) 2 2-Me-4-MeO-Ph Me N(CH2CH2OMe)2 2-Me-4-MeO-Ph Me NHCK!Et>CH2QMe 2-Me-4-MeO-Ph Me NIPr)CH2CH2CN 2-Me-4-MeO-Ph Me OCH(Et JCH20Me 2-Me-4-MeO-Ph Me NKCH <CH20Me)2 2-Br-4-MeO-Ph Me N(CH2CH20M6) 2 2-Br-4-MeO-Ph Me NHCH(Et)CHjOMe 2-Br-4-MeO-Ph Me N(Ptr)CH2CH2CN 2-Br-4-MeO-Ph Me OCH(Et)CH2OMe 2-Br-4-MeO-Ph Me NHCH(CH2OMe)2 2-Me-4-NMe2"P h Me N iCH2CH20Mey2 2-Me-4-WMe2"ptl Me NHCH(Et)CH20Me 2-Me-4-NMe2"Ph Me N(Pr)CH2CH2CN 2-Me-4-NMe2_Ph Me OCH(Et)CH20Me 2-Me-4-NMe2~Ph Me NHCH <CH2OMe> 2 2-Br-4-NMe2"Ph Me N<CH2CH2OMe)2 2-Br-4-NMe2~Ph Me NHCH(Et)CH2OMe 2-Br-4-NMe2-Ph Me N(Pr)CH2CH2CN 2-Br-4-NMe2"Ph Me OCH(Et > CH2GMe 2-ar-4-NMe2~Ph Me NHCH(CH2OMe)2 2-Br-4-i-Pr-Ph Printad from Mimosa 796 797 798 799 8CJ 601 802 803 804 805 806 807 aoe 809 810 811 812 813 814 815 816 817 818 819 820 B21 822 823 824 825 326 827 Me N(CH 2 CH 2 OMe)2 2-Br-4-i-Pr-Ph He WKCH(EtJ CH20Me 2-Br-4 -i-Pr-Ph Me N(Pr)CH2CH2CN 2-Br-4-i-Pr-Ph Me OCH(Et)CH20Me 2-Br-4-i-Pr-Ph Me NHCH(CH20Mel2 2-Br~4-Me-Ph Me N(CH2CH20Me>2 2-Br-4-Me-Ph Me NHCH(Et)CH20Me 2-3r-4-Me-Ph Me N(Pr)CH2CH2CN 2-Br-4-Me-Ph Me OCH(Et)CH20Me 2-Br-4-Me-Ph Me NHCH(CH20Me)2 2-Me-4-Br-Ph Me N(CH2CH20Me)2 2-Me-4-Br-Ph Me NHCH <EL)CH20Me 2-Me-4-Br-Ph Me N i Pr)CH2CH2CN 2-Me-4-Br-Ph Me QCH(Et!CH20Me 2-Me-4-Br-Ph Me NHCH(CH20Me)2 2-Cl-4,6-Me2-Ph Me N(CH2CH20Me)2 2-Cl-4,S-Mej-Ph Me NHCH(CH20Me)2 4-Br-2,6-(Me)2-Ph Me N(CH2CH20Mel2 4-Bt-2,6-(Me)2-Ph Me NHCH(CH20Me(2 4-i-PE-2-SMe-Ph Me N(CH2CH20Me)2 4-i-Pr-2-SMe-Ph Me NHCH(CH20Me)2 2-Br-4-CF3-Ph Me N(CH2CH20Me)2 2-Br-4-CF3-Ph Me NHCH(CH20Me)2 2-Br-4,6-(MeO)2-Ph Me N(CH2CH20Me)2 2-Br-4, 6-(MeO) 2-Ph Me NHCH(CH20Me)2 2-C1-4,6-(MeO)2~Ph Me N(CH2CH20Me)2 2-Cl-4,6-(KeO)2"Ph Me NHCH(CH20Me)2 2,6-(Me)2-4-SHe-Ph Me N(CH2CH20Me)2 2,6-(Me)2-4-SMe-Ph Me NHCH(CH20Me)2 4- (COMe)-2-Br-Ph Me N(CH2CH20Me>2 4-(COMe)-2-Br-Ph Me NHCH{CH2°Me>2 2,4,6-Me3~pyrid-3-yl Me N (CH2CH20Me)2 2,4,6-Me3-pytid-3-yl Me NHCH(CH20Me)2 2,4-(Br)2"ph Me N<CH2CH20Me>2 2,4-(Br)2-PH Me NHCH(CHjOMe12 4-i-P r-2-SMe-PJi Me N(CH2CH20Me)2 4-i-Pr-2-SMe-Ph ?rin~sd from Mimosa 931 832 833 034 835 833 037 338 839 840 041 842 843 844 045 046 347 348 849 050 051 652 053 854 855 856 857 858 859 860 061 B62 063 Me NHCH(CH2OMe>2 4-i-Pr-2-502Me-Ph Me N(CH2CH20Me)2 4-i-Pr-2-S02Me-P^ Me NHCH(CH20Me»2 2,6-(Mg)2"4-SMe-?h Me N(CH2CH20Me> 2 2, 6-(Me)2~4-SMe-Ph Me NHCH{CH20Me)2 2,6-(Me> 2-4-S02Me-Ph Me N<CH2CH20Me> 2 2,6-(Me)2-4-SQ2Me-Ph Me tJHCH <CH20Me) 2 2-1-4-i-Pr-Ph Me N(CH2CH20Me)2 2-l-4-i-pt-Ph Me NHCH fCU20M«)2 2-Br-4-N(Me)2-S-MeO-Ph Me N(CH2CH20Me> 2 2-Br-4-N [Me)2~6-MeO-Ph Me NEt-2 2-Br-4-MeO-Ph Me NH-3-pentyl 2-Br-4—MeO-Ph Me NHCH(CH20Me)2 2-CN-4-Me-Ph Me N(C-C3H5)CH2CH2CN 2,4,S-Me3-Ph Me NHCH <CH2CH20Me)CH20Me 2-Me-4-Br-Ph Me NHCH ICHjOMe)2 2,5-Me2-4-MeO-Ph Me N(CH2CH20Me)2 2,5-Me2~4-MeO-Ph Me NH-3-pentyl 2,5-Me2"4-MeO-Ph Me NEt 2 2,5-Mfi2_4-MeO-Ph Me NHCH )CH20Me)2 2-Cl-4-MePh Me NCH(Et)CH20Me 2-Cl-4-MePh Me N tCH2CH2OMe)2 2-Cl-4-MePh Me (S)-NHCH(CH2CH20Me)CH20Me 2-Cl-4-MePh Me N(C-C3H 5)CH2CH2CN 2, 5-Me2"4~MeOPh Me NEt 2 2-Me-4-MeOPh Me OEt 2-Me-4-MeOPh Me (S)-NHCH[CH2CH20Me|CH20Me 2-Me-4-MeOPh Me Nfc-CjHs)CH2CH2CN 2-Me-4-MeOPh Me NHCH(CH2CH20Et)2 2-Me-4-MeOPh Me N(C-C3H5)CH2CH2CN 2,4-Cl2"Ph Me NEt 2 2-Me-4-ClPh Me NH-3-pentyl 2-Me-4-CIPh Me N<CH2CH20Me)2 2-Me-4-CIPh Me NHCH(CH20Me)2 2-Me-4-CIPh Me NEC2 2-Me-4-CIPh Me NEt2 2-Cl-4-MePh PrintGd from Minosa PCTYUS97/13072 364 Me NH-3-pentyl 865 Me NHCH(CH20Me)2 866 Me M(CH2CH20M8) 2 867 Me NHCH <Et)CH20Me 868 Me N(C-PEICH2CK2CN B69 Me NEt 2 870 Me NH-3-pentyl 871 Me NHCH[Et)CH2C«20Me B7Z Me NHCH(Me)CH2CH20Me 373 Me NHCH(Et)CH2CH20Me 874 Me NHCH(Me)CH2CH20Me 875 Me WHCH(Et}CH20H2OMe 876 Me NHCH(Me)CH2CH20Me 977 Me NHCH{CH2OMe)2 878 Me N (CH2CH20Me)2 87 9 Me NHCH(Et)CH2OMe 880 Me N(c-Pr)CH2CH2CN 881 Me NEt 2 882 Me NH-3-pentyl 683 Me NHCH(Et > CH2CH20Me 884 Me NHCH(Me)CH2CH20Me 685 Me NHCH(CH20Me)2 886 Me N(CH2CH20Me)2 887 Me NHCH(Et)CH20Me 888 Me H(c-Pr)CH2CH2CN 309 Me NEt2 890 Me NH-3-per.tyl 891 Me NHCH(CH2OMe)2 392 Me N(CH2CH2OMe)2 393 Me NEt2 894 Me NH-3-pentyl 895 Me NHCH(CH20Me>2 096 Me N(CH2CH2OMe)2 897 Me NHCH(Et)CH2OMe 898 Me NEt 2 899 Me NH-3-pentyl -153 2-Cl-4-MePh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-C1-4-MeOPh 2-Cl-4-Me0Ph 2-Cl-4-MeOPh 2-Cl~4-MeOPh 2-Cl-4-MeOPh 2-Cl-4-MeOPh 2-Br-4-Me0Ph 2-Br-4-MeOPh 2-Me-4-MeOPh 2-Me-4-MeOPh 2-Cl-4,5-(MeO)2?h 2-Cl-4,5-(MeO)2Ph 2-C1-4,5-(MeO)2Ph 2-C1-4,5-(MeO) 2Ph 2-Cl-4 , 5- (MeO) 2pti 2-Cl-4,5-(MeO)jPh 2-C1-4,5-(MeO)2Ph 2-C1-4,5-(MeO)2?h 2-Br-4,5-(MeO)2Ph 2-Br-4,S-(MeO)2Ph 2-Br-4,S-(MeO) 2-Br-4,S~(MeO)2Fh 2-Br-4,5-(MeO)2Ph 2-3r-4,5-(MeO)2Ph 2-Cl-4,6-(MeO)2Ph 2-C1—41 6-(MeO)2Ph 2-Cl-4,6-(MeO)2^h 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)2?h Printed from Miiaoca 900 901 902 903 904 905 906 907 9C<5 909 910 911 912 913 914 915 916 917 918 919 920 PCT/US97/I307Z Me NHCH [Et)CHjCHjOMe 2-Me-4-MeOPh Me NHCH(Me)CH2CH20Me 2-Ma-4-MeOPh Me NHCH(CH20Me)2 2-MeO-4-MePh He N(CHjCHjOMe)2 2-Me0-4-MePh Me NHCH(Et)CH2QMe 2-MeQ-4-MePh Me N(c-Pr)CH2CH2CN 2-Me0-4-MePh Me NEt 2 2-MeO-4-MePh Me NH-3-pentyl 2-MeO-4-MePh Me NHCH(Et)CH2CH20Me 2-MeO-4-MePh Me NHCH{Me>CH2CH20Me 2-Me 0-4-KeP h Me NHCH(CH20Me> 2 2-Me0-4-MePh Me N(CH2CH2OMe)2 2-Me0-4-MePh Me NHCH(Et)CH20Me 2-MeO-4-MePh Me N (C-PrlCH2CH2CN 2-MeO-4-MePh Me N£t2 2-MeO-4-MePh Me NH-3-pentyl 2-MeO-4-MePh Me NHCH[CH20MC)2 2-Me0-4-CIPh Me N(CH2CH20Me)2 2-MeO-4-ClPh Me N'HCH (Et) CH20Me 2-MeO-4-CIPh Me NEt2 2-MeO-4-ClPh Me NH-3-pentyl 2-Me0-4-CIPh Printed from Mimosa 922 923 924 92 5 92 6 927 928 929 930 931 932 933 934 935 936 937 938 939 910 941 942 943 PCT7US97/13072 Table 6 Ar Ell £2 Ar Me NHCH(CH20Me)2 2,4-Ci2"Ph Me NHCKP r2 2,4-Cl2-Ph Me NEtBu 2,4-Cl2~Ph Me NPr{CH2-C-C3H5) 2,4-Cl2~Ph Me N(CH2CH20M6)2 2,4-Cl2~Ph Me NH-3-heptyl 2,4-Cl2-?h Me NHCHtEt)CH20Me 2,4-Cl2~Ph Me NEt2 2,4-Cl2-Ph Me NHCH(CHjOEt)2 2,4-Cl2-Ph He NH-3-pentyl 2,4-Cl2~Ph Me NMePh 2,4-Cl2~Ph Me NPr2 2,4-Cl2-Ph Me NH-3-hexyl 2,4-Cl2~Ph Me morpholino 2,4-Cl2-Ph Me N(CH2Ph)CH2CH20Me 2,4-Cl2"Ph Me NHCH (CH2Ph) CH20Me 2,4-Ci2~Ph Me NH-4-tetrahydropyranyl 2,4-Cl2~Ph Me NH-cyclopentyl 2,4-ci2-Ph Me OEt 2,4-Cl2-Ph Me 0CH(Et>CH2OMe 2,4-Cl2~Ph Me OCH2Ph 2,4-Cl2-Ph Me O-3-pentyl 2,4-Cl2~Ph Me SEt 2,4-Cl2-Ph Prir.isd trorrt Mimosa 944 945 946 941 948 949 950 951 9 52 953 954 955 956 957 958 959 960 961 962 963 964 965 966 967 966 969 970 971 972 973 974 975 976 477 978 97 9 Me S (O) Et 2,4-ci2-Ph Me S02Et 2,4-Clj-Ph Me Ph 2,4-Cl2"Ph Me 2-CF3-Ph 2,4-Cl2-Ph Me 2-Ph-Ph 2,4-Cl2-Ph Me 3-pentyl 2,4-Cl2-Ph Me cyclobutyl 2,4-Cl2-Ph Me 3-pyridyl 2,4-Cl2-Ph Me CH(Et)CH2CONME2 2,4-CI2-Ph Me CH[Et)CH2CHjNMe2 2, 4-Cl2-Ph Me NHCH(CH20«e)2 2, 4, 6-Me 3-Ph Me NHCHPrj 2,4,6-Me3~Ph Me NEtBu 2,4,6-Me3~Ph Me NPr(CH2-C-C3H5) 2,4,6-rte3~Ph Me N <CH2CH20Me!2 2,4,6-Me3-Ph Me NH-3-heptyi 2,4,6-Me3~Ph Me HHCH<Et)CH20Me 2,4,6-Me3—Ph Me Nat 2 2,4,6-Me3~Ph Me NHCH(CH20Et)2 2,4,6-Me3~Ph Me NH-3-pentyl 2,4,6-Me3"Ph Me NMePh 2,4, 6-Me3~Ph Me NPr2 2,4,6~Me3~Ph Me NH-3-hexyl 2,4,6-Me3-Ph Me morpholino 2,4,6-Me3~Ph Me H(CH2PhlCH2CH20Me 2,4,6-Me3~Ph Me NHCH(CHjPh* CH20M® 2,4,6-Me3~Ph Me NH-4-tetrahydropyranyl 2,4,6-Me3-Ph Me NH-cyclopenty1 2,4,6—Me3~Ph Me OEt 2,4,S—Me3—Ph Me 0CH(Et)CH20Me 2,4,6-Me3~Ph Me OCHjPh 2,4,6-Me3~Ph Me O-3-pentyl 2,4,6-Me3~Ph Me SEt 2,4,6-Me3-Ph Me S (0) Et 2,4,6-Me3~Ph He S02Et 2,4,6-Me3~Ph Me CH(C02Etl2 2,4,6-Me3~Ph PrintecL from Mimosa 930 981 982 983 984 985 98 6 987 9S«j 939 990 991 9 92 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 iooe 1009 1010 1011 1012 1013 1014 1015 Me C(Et) (CO2 Et)2 2,4,6-Me3-Ph Me CH(EtlCH2OH 2,4,6-Me3-Ph Me CH(Et >CH20Me 2, 4,6-Me 3-P h Me CONMej 2,4,6-Me3~Ph Me COCH3 2,4,6-M«3-Ph Me CH (OH)CH3 2,4,6-Me3-Ph Me C (OH)Ph-3-pyridyl 2,4,6-Me3~Ph Me Ph 2,4,6-Me3~Ph Me 2-Ph-Ph 2,4,S-Meg-Ph Me 3-pentyl 2,4,6-Me3-Ph Me cyclobutyl 2,4,6-Me3-Ph Me 3-pyridyl 2,4,S-Me3~Ph Me CH(Et)CH2CONMe2 2,4,6-Me3-Ph Me CH(Et)CH2CH2NMe2 2,4,S-Mej-Ph Me NHCH(CHjOMe)2 2,4-Ma2~Ph Me N(CH2CH20Me)2 2,4-Me2-Ph Me NHCH(Et)CH20Me 2, 4-Me2"Ph Me NH-3-pentyl 2,4-Me2~Ph Me NEt2 2,4-Me2_Ph Me N(CH2CN)2 2,4-Mej-Ph Me NHCH(Met CHjOMe 2,4-Me2-Ph Me OCH (Et)CH20Me 2,4-Me2~Ph Me HPr-C-CsHs 2,4-Me2_Ph Me NHCH(MeJCH2NMe2 2,4-Me2-Ph Me N (c-C3H5)CH2CH2CN 2,4-Me2-Ph Me N(Pr)CH2CH2CK 2,4-Me2~Ph Me N(Bu)CH2CK2CN 2,4-Me2~Ph Me NHCHPT2 2,4-Me2_Ph Me NEtSu 2,4-Me2~Ph Me NPr(CH2-c-C3H5) 2,4-Me2~Ph Me NH-3-heptyl 2,4-Me2~Ph Me NEt2 2,4-Me2-Ph Me NHCH(CH20Et>2 2,4-Me2-Ph Me NH-3-peneyl 2,4-Me2~Ph Me NMePh 2,4-Me2~Ph Me NPr2 2,4-Me2-Ph Printsd from Miri.oM 1016 1017 ioia 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 Me NH-3-hexyl 2, 4-Me 2-P h Me morpholino 2,4-Me2~Ph Me N{CH2Ph)CH2CH20Me 2,4-Me2-Ph Me NHCH(CH^PhJCHjOMe 2,4-Mej-Ph Me NH-4-tecrahydropyranyl 2,4-Me2"Ph Me NH-cyclopentyl 2,4-Me2-Ph Me NHCH(CHgOMe)2 2-Me-4-MeO-Ph Me N(CH2CK20Mei2 2-Me-4-MeO-Ph Me NHCH(Et)CH20Me 2-Me-4-MeO-Ph Me N (Pr)CH2CH2CN 2-Me-4-MeO-Ph Me OCH(Et)CHjOMe 2-Me-4-MeO-Ph Me NHCH(CH2OMe)2 2-Br-4-MeO-Ph Me N(CH2CH20Ma>2 2-Br-4-MeO-Ph Me NHCH(E t)C H 2 OMe 2-Br-4-MeO-Ph Me N(PE)CH2CH2CK 2-Br-4-MeO-Ph Me 0CH(Et)CH20Ke 2-Br-4-MeO-Ph Me NHCH (CH2<>Me) 2 2-Me-4-NMe2-Ph Me N(CH2CH20Ma)2 2-Me—4-NMe2"Ph Me NHCH(Et)CH20Me 2-Me-4-NMe2-Ph Me N(Pr)CH2CH2CN 2-Me-4-NMe2-Ph Me OCH(Et>CH20Me 2-Me-4-NMe2-Ph Me NHCH[CH20Me)2 2-ar-4-NMe2-Ph Me N(CH2CH20Me)2 2-Br-4-NMe2-Ph Me NHCH{Et)CH20Me 2-Br-4-NMe2-Pn Me N(Pr)CH2CH2CN 2-Br-4-NMe2~Ph Me OCH(EtlCH20Me 2-Br-4-NMe2-Ph Me NHCH(CH20Me)2 2-Br-4-i-Pr-Ph Me N(CH2CH20Me)2 2-Br-4-i-Pr-Ph Me NHCH(Et)CH2OMe 2-Br-4-i-Pr-Ph Me N(Pr)CH2CH2CN 2-Br-4-i-Pr-Ph Me OCH(Et)CH2OMe 2-Br-4 —i-Pr—Ph Me NHCH(CHjOMe)2 2-Br-4-Me-Ph Me N(CH2CH20Me)2 2-Br-4-Me-Ph Me NHCH(Et)CH20Me 2-Br-4-Me-Ph Me N(Pt)CH2CH2CN 2-Bc-4-Me-Ph Me OCH(Et)CH20Me 2-B c-4-Me-Ph Printed from Mimosa 52 1053 1054 1055 1056 5 T 1050 1059 lOiiO 1061 1062 1063 1064 1065 1066 67 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079 1080 1081 1082 1003 1084 1085 1066 1087 Me NHCH(CHjOMe)2 2-Me-4-Bt-Ph Me N(CH2CH20Me)2 2-Me-4-Br-Ph Me NHCH(Et)CH20Me 2-Me-4-9r-Ph Me N (Pr1CH2CH2CN 2-Me-4-Br-Ph Me QCH(Et)CH20Ke 2-Me-4-Br-Ph Me NHCH(CH20Me|2 2-Cl-4,6-Me2-Ph Me N(CH2CH20Me)2 2-Cl-4,6-Me2-Ph Me NHCH fCH20Me)2 4-Sr-2,6-(Me)2-Ph Me N(CH2CH20Me)2 4-Br-2,6-(Me)2"Ph Me NHCH <CH20Me)2 4 - i-p it—2-SMe-Ph Me N (CH2CH2OMe> 2 4-i-Pr-2-SMe-Ph Me NHCH(CH20Me)2 2-Bc-4-CF3-Ph Me N(CH2CH20Me)2 2-Br-4-CF3-Ph Me NHCH <CH20Me(2 2-Br-4,6-(MeO)2"P*» Me N(CH2CH2QMe}2 2-Br-4,6-(MeO)2~?h Me NHCH !CH20Me)2 2-C1-4,6-(MeO)2-Ph Me N (C»2CH20Me)2 2—Cl—4,6-(MeO)2-Ph Me NHCH(CHgOMe)2 2, 6-(Me)2-4—SMe-Ph Me N [CH2CH2QMe> 2 2,6-(Me)2-4-SMe-Ph Me NHCH(CH20Me> 2 4-(COMe)-2-Br-Ph Me N[CH2CH20Me>2 4-(COMe)-2-Br-Ph Me NHCH(CH20Me» 2 2,4,6-Me3-pyrid-3-yl Me N(CH2CH20Me>2 2,4,£-Me3-pyrid-3-yl Me NHCH(CH20M6)2 2,4-(Br)2-Ph Me N(CH2CH20Me)2 2,4-(Br)2-Ph Me NHCH(CH2OMe)2 4-i-P r-2-SMe-Ph Me N(CH2CH20Me>2 4-i-P r-2-3Me-Ph Me NHCH(CH2OMe>2 4-i-Pr-2-S02MO-Ph Me N(CH2CH20Me>2 4-i-Pr-2-S02Me-Ph Me NHCH{CH20Me)2 2,6-(Me)2-4-SMe-Ph Me N(CH2CH20Me)2 2,6-(Me)2-4-SMe-Ph Me NHCH(CH20Me)2 2,6-(Me)2-4-SQ2Me-Ph Me N(CH2CH20Me)2 2,6-(Me)2-4-S02Me-Ph Me NHCH(CH2OMB)2 2-1-4-i-Pr-Ph Me W(CH2CH20Me> 2 2-I-4-i-Pr—Ph Me NHCH(CH20Me)2 2-ar-4-N(Me)2-6-Meo-Ph -15 9- EJrintcd from Mimosa 1088 Me N(CH2CH20Me)2 2-Br -4-N[Me)2-6-MeO 1069 Me NEt 2 2-Sc-4-MeO-Ph 1090 Me NH-3-pentyl 2-Br—4-MeO-Ph 1091 Me NHCH(CH20Me) 2 2-CN-4-Me-Ph 1092 Me N(C-C3H5)CH2CH2CN 2,4,S-Me3~Ph 1093 Me NHCH(CH2CH20Me)CHjOMe 2-Me-4-Br-Ph 1094 Me NHCH(CH20Me)2 2 , 5-Me2~4-MeO-Ph 1095 Me N(CH2CH20Me)2 2: ,5-Me2~4-MeO-Ph 1096 Me NH-3-pentyl 2, r 5-Me2-4-MeO-Ph 1091 Me NEt 2 2, ,5-Me2-4-MeO-Ph 1098 Me NHCH(CH20Me)2 2-Cl-4-MePh 1099 Me NCH(Et)CH20Me 2-Cl-4-MePh 1100 Me N(CH2CH20Me)2 2-Cl-4-MePh 1101 Me (S> -NHCH (CH2CH2<>te) CHjOMe 2-Cl-4-MePh 1102 Me N(C-C3H 5)CH2CH2CN 2 ,5-Me2~4-MeOPh 1103 Me NEt2 2-Me-4-MeOPh 1104 Me OEt 2-Me-4-MeOPh 1105 Me (S)-NHCH(CH2CH20Me) CH2OMe 2-Me-4-MeOPh 1106 Me N(c-C3H51CH2CH2CN 2-Me-4-MeOPh 1107 Me NHCH(CH2CH20Etl2 2-Me-4-MeOPh 1108 Me N(C-C3H5)CH2CH2CN 2,4-Cl2-Ph 1109 Me NEt 2 2-Me-4-CIPh ■ 1110 Me NH-3-pentyl 2-Me-4-CIPh 1111 Me N{CH2CH20Me> 2 2-Me-4-ClPh 1112 Me NHCH(CH20Me)2 2-Me-4-ClPh 1113 Me NEt2 2-Me-4-CIPh 1114 Me NEt 2 2-Cl-4-MePh 1115 Me NH-3-pentyl 2-Cl-4-MePh 1116 Me NHCH(CH2OMe)2 2-Cl-4-MeOPh nn Me N(CH2CH20Me)2 2-Cl-4-MeOPh 111B Me NHCH(Et)CH20Me 2-Cl-4-MeOPh 1119 Me N lc-Pr)CH2CH2CN 2-Cl-4-MeOPh 1120 Me NEt2 2-C1-4-MeOP h 1121 Me NH-3-pentyl 2-Cl-4-MeOPh 1123 Me NHCH{Et)CH2CH20Me 2-Cl-4-MeOPh 1124 Me NHCH(Me)CH2CH20Me 2-Cl-4-MeOPh Printed from Mimosa 1125 Me 1126 Me 1127 Me 1128 Me 1129 Me 1130 Me 1131 Me 1132 Me 11J3 Me 1134 Me 1135 Me 1136 Me 1137 Me 1138 Me 1139 Me 1140 Me 1141 Me 1142 Me 1143 Me 1144 Me 1145 Me 1146 Me 1147 Me 1148 Me 1149 Me 1150 Me 1151 Me 1152 Me 1153 Me 1154 Me 1155 Me 1156 Me 1157 Me 1158 Me 1159 Me 1160 Me NHCH(Et)CH2CH20Me NHCH(Me)CH2CH20Me NHCH(Et) CHjO^OMe NHCH(Me)CH2CH20M6 NHCH(CH20Me)2 N (CH2C«20Me)2 NHCH(£t)CH2OMe N(c-Pr)CH2CH2CN NEt2 NH-3-pentyl NHCH fEt ) CH2CH20M© NHCH(Me)CH2CH20Me NHCH(CH20Me)2 N(CH2CH2OMe)2 NHCH <Et)CH2OMe N(c-Pr)CH2CH2CN NEt 2 NH-1-pentyl NHCH(CHjOMe)2 N(CH2CH20Me)2 NEt2 NH-3-pentyl NHCH(CH20«e>2 N(CH2CH20Me> 2 NHCH(Et)CH2<3Me NEt2 NH-3-pentyl NHCH(Et)CH2CHjOMe NHCH< Me)CH jCH 2 OMe NHCH(CH20Me)2 N(CH2CH20He)2 NHCH(Et)CH20Me N(c-Pr)CH2CH2CN NEt 2 NH-3-pentyl NHCH (EtJO^CHjOMe -161" 2-Br-4-MeOPh 2-3r-4-MeOPh 2-Me-4-MeQPh 2-Me-4-MeOPh 2-Z1-4,5-(MeO)2Ph 2-Cl-4,5-(MeO)2Ph 2-Cl-4,5-(MeO)2Ph 2-Cl—4,5-(MeO)2Ph 2-Cl-4,5- (MeO)2Ph 2-Cl-4,5-(MeO)2Ph 2-Cl-4,5-(MeO)2fh 2—Cl-4,5-(MeO)2?h 2-SC-4,5-(MeO)2Ph 2-Br-4,S-(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-Cl-4,S-(MeO)2Ph 2-Cl-4,6-(MeO)2Ph 2-Cl-4,6-(MeO)2ph 2-Cl-4,6-(MeO)2Ph 2-Me-4,6-(MeO)2?h 2-Me-4,6-(MeO)2Ph 2-Me-4,6-(MeO)2Ph 2-Me-4,6-(MeO)2Ph 2-Me-4,6-(MeO)2eh 2-Me-4-MeOPh 2-Me-4-MeOPh 2-Me0-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-MeO-4-MePh 2-Me0-4-MePh 2-MeO-4-MePh 2-MeQ-4-MePh Printed from Mimosa 1161 Me NHCH(Me)CH2CH20Me 2-Me0-4-MePh 1162 Me NHCH(CH20Me)2 2-Me0-4-MePh 1163 Me N(CH2CH20Me)2 2-Me0-4-MePh 1164 Me NHCH(Et)CH20MS 2-MeO-4-MePh 1165 Me N (c-Pr)CH2CH2CN 2-Me0-4-MePh 1166 Me NEt 2 2-MeO-4-MePh 1167 Me NH-3-pentyl 2-MeO-4-MePh 1166 Me NHCH(CHjOMe)2 2-MeO-4-CIPh 1169 Me N(CH2CH20Me)2 2-MeO-4-ClPh 1170 Me NHCH[Et)C«20Me 2-MeO-4-CIPh 1171 Me NEt 2 2-MeO-4-ClPh 1172 Me NH-3-pentyl 2-MeO-4-CIPh Utility CRF—R1 Receptor Binding Assay for the Evaluation of Biological Activity The following is a description of the 25 isolation of cell membranes containing cloned human CRF-R1 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 <dt> 12-18 30 and the coding region was amplified by PGR from start to stop codons The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from whence the insert was reclaimed using Xhol +■ Xbal and cloned into che Xhol + Xbal sites of vector pm3ar ( which contains a CMV 35 promoter, the SV4Q 't' splice and early poly A signals, an Epstein-Barr viral origin of replication, and a Printed from WO 98/03510 PCT/US97/13072 hygromycin selectable marker) . The resulting expression vector, called phchCRFR was transfected in 293EBNA cells and cells retaining the episotne 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 10® of the suspended cells were then centrifuged to form a pellet and frozen. 10 For the binding assay a frozen pellet described above containing 293EBNA cells transfected with hCRFRl 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 Jig/1 aprotinin, 1 Jig/ml leupeptin 15 and 1 jig/ml pepstatin) . The homogenate is centrifuged at 40,000 x g for 12 min and the resulting pellet rehomogeni2ed in 10 ml of tissue buffer. After another centrifugation at 4C,000-x g for 12 min, the pellet is resuspended to a protein concentration of 360 jjg/ml to be used in the assay.

Binding assays are performed in 96 well plates; each well having a 300 (11 capacity. To each well is added 50 ni of test drug dilutions (final concentration of drugs range from 10—^ - 10-^ M) , 100 (11 of 125j_ ovine-CRF (12^r-o-CRF) (final concentration ISO pM) and 150 |il_ 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 30 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 binding to ceil membranes at various dilutions of test drug are analyzed by the iterative curve fitting program LIGAND Printed froTi Mimosa PCT/US97/! 3072 [P.J. Munson and D. Rodbard, Anal. Biochem. 107:220 (I960), which provides Ki values for inhibition which are then used to assess biological activity.

A compound is considered to be active if it has 5 a Ki value of less than about 10000 nM for the inhibition of CRF.

Inhibit ion Oi CRF-St insulated Adenylate Cvr-l^P 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 37a C for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 3 7° 15 CJ , 10 mM MgCl2, 0.4 mM EGTA, 0.1% BSA, 1 ctM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10~^ to 10~^m) and 0.B 20 mg original wet weight tissue (approximately 40-60 mg protein). Reactions are initiated by the addition of 1 mM ATP/32P]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 25 order to monitor the recovery of cAMP, 1 (il of []cAMP (approximately 40,000 dpm) is added to each tube prior to separation. The separation of [32P)cAMP from [32p]ATP is performed by sequential elution over Dowex and alumina columns.

In viva 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 35 the art. Illustrative of these tests include the Printsd froir. Mi_rr.cs a 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 5 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 10 treatment of unbalances 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 15 to treat these abnormalities by means that produce contact of the active ager.t with the agent's site of action in the body of a mammal. The compounds can be administered by any conve-ntional means available for use in conjunction with pharmaceuticals either as 20 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 25 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, 30 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 35 dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 Printed from Minosa WO 98/03510 PCT/US97/13072 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 5 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 0.5 to 95% by weight based on the total weight of the 10 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 suitable 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 35 sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for Printed from Mimosa WO 98/03510 PCT/US97/13072 parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances.

Antioxidising 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 benzalkoniun chloride, methyl-or propyl-paraben, and chlorobutanol.

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

L5 Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: Capsules A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

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

Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was ?r ir.t-ed irorn Minora

Claims

WO 98/03510 t $$6/7 FCT/US97/13072 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 kje applied to 5 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. 10 Although the present invention has been described and exemplified in terms of certain preferred embodiments, other embodiments will be apparent to those skilled in Che art. The invention 15 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. 20 Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification, they are to be interpreted as specifying the presence of the stated features, integers, steps or components referred to, but not to preclude the presence or addition of one or more other feature, integer, step, component or group thereof. -168- 06/03/00, gcop657.spe, 2 O o. WHAT IS CLAIMED IS: 10 15 20 1. A method of treating affective dfsorder7anxiety, depression, headache, irritable bowel syndrome, post-tpumatia stress disorder, supranuclear palsy, immune suppression/Alzheimer's disease, gastrointestinal diseases, anorexia nerv/sa or other feeding disorder, drug addiction, drug or alcohol withdrawal s/mptome, inflammatory diseases, cardiovascular or heart-related disea/es, fertility problems, human immunodeficiency virus infections, j/emorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, s/roke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder tlVtreatment of which can be effected or facilitated by antagonizing QRF, including but not limited to disorders induced or facilitated by CRF/in non/iuman mammals comprising administering to the mammal a therapeutically effective amount of a compound of Formulae (1/or (2): ■ N Ar (t) (2) 25 and isome/s thereof, stereoisomeric forms thereof, or mixtures of stereoisofneric fo/ms thereof, and ■ ii-i;u" I 1 3 2W 169 J HECPiVEi:' 07/03/00,|cop657. spe.doc, 169 H! ^ / vfI' ^ h^iPji 3Is WO 98/03510 PCTYUS97/13072 pharmaceutically acceptable salt/or pi thereof, wherein: 3-drug forms A is N or CR; 5 Z is N or CR2; Ar is selected from phenyl,/ napht/hyl, pyridyl, pyrimidinyl, triazinyA, fuyanyl, thienyl, 10 benzothienyl, benzofpranyl/, 2, 3- dihydrobenzofuranyl/ 2,3-Aihydrobenzothienyl, indanyl, 1,2-benzogyranyi, 3,4-dihydro-l,2-benzopyrany 1, tetmlinyf, each Ar optionally substituted with I to 5 E4 groups and each Ar is 15 attached to an unsatuj/ated carbon atom; 20 R is independently ^electdd at each occurrence from H, Cx~C4 alkyl/, C2~?4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, 94-C7 cycloalkylalkyl, halo, CN, C1-C4 ha/oalki R1 is independei/t ly selected at each occurrence from H, C1-C4 ^.kyl,/C2~C4 alkenyl, C2-C4 alkynyl, halo, CN,/ Ci~C 1 haloalkyl, C1-C12 hydroxyalkyl, 25 C2-C12 avkoxya/kyl, C2-C10 cyanoalkyl, C3-C5 cycloalkyl, O4-C10 cycloalkylalkyl, MR^R10, Ci~ C4 alk/l-NR9/10, NR9COR10, OR11, SH or S(0)nR12; R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, 30 C2~Ck alkenyl, C3-C5 cycloalkyl, C4-C10 cyc/oalkwlalkyl, C1-C4 hydroxyalkyl, halo, CN, -NR6R7, MR^COR10, -NR6S(0)nR7 , S(0)nNR6R7, C c/ halo/lkyl, -OR7, SH or -S(0)nR12; 35 selected from: -170- Printed from Mimosa WO 98/03510 m sua PCT/US97/13072 & 10 15 OR7, SH, S(0) nR13. COR7, C(D2R7 < oc(0)R13, nr8cor7, n(cor?)2/ nr8c/onr6r7, NR8C02R13, NR6R7, NR6aR/a, N (OR/) R6, CONR^R7, aryl, heteroaryl and heterocyclyl, or -Ci-Cio alkyl, C2"CiO alkenyl, C2VC10 alkynyl, C3-C8 cycloalkyl, C^J-Cq cycloalkenyl, C4 -C12 cycloalkylalkyl/or Cq-Uiq cycloalkenylalkyl,/each optionally substituted with t to 3 Substituents independently selected ak. each occurrence from C1-C6 alkyl, C3-C6/ cycloalkyl, halo, C1-C4 haloalkyl/, cyano/ OR1^, SH, S (0) nR13r COR lP, C02Rf5r OC (0) R13, NR8COR15, N (C/OR1 ^) 2 r /NR8CONR16R15, NR8C02R13, NR16R15, /cONR16R15, aryl, heteroaryl and heterocyclyl; 20 25 30 R^ is independently /selected at each occurrence from: C1-C10 alkyl, /C2~C10 /lkenyl, C2-C10 alkynyl, C3-C6 cycloaMcyl, C4/C12 cycloalkylalkyl, N02, halo, CN, C1/-C4 haloalkyl, NR6R7, NR8COR7, NR8C02R7, COR7, OR1/, CONR6R7, CO (NOR9) R7, C02R7, or S(0)nR7/ where/each such C1-C10 alkyl, C2~ C10 alken/l, C2-/10 alkynyl, C3-C6 cycloalkyl and C4-C/2 cycloalkylalkyl are optionally substituted witfh 1 to 3 substituents independently /selected at each occurrence from C1-C4 Alkyl, AIO2, halo, CN, NR6R7, NR8COR7, NR8CO/R7, COJR7 OR7, CONR6R7, CO2R7, CO (NOR9) R7, or s/o)nR7;y r6 and R7, R6a/and R7a are independently selected at each occurrence from 35 -/H, -171- WO 98/03510 PCT/US97/13072 10 15 -Ci-Cio alkyl, C3-C10 alkenyl, CI3-C10 alkynyl, C1-C10 haloalkyl with 1-10/halogens, C2-C8 alkoxyalkyl, C3-CS cycloalkyl, C4-C12 cycloalkylalkyl, C5-CT10 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, rf 1-C4 haloalkyl, cyano, or15, sh, s (0)/nr13, cor15, CO2R15, 0c(0)r13, nr8/cOR15, M(cor15) 2, nr8conr16r15, NR8c02r13, nlr16R15, /c0NR16R15, aryl, heteroaryl pr hetenocycly1, -aryl, aryl (C1 —(J4 alkyl/, heteroaryl, heteroaryY<Ci-C4 alkyl), heterocyclyl or heterocyc/yl (C1 — Gr^ alkyl) ; alternatively, nr^r7 and'wr6ar7a are independently piperidine, pyrrolidine, piperazine, N-20 methylpiperazine,/ morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups; 25 R® is independently selected at each occurrence from H or Ci-Ch alkylj r9 and R1^ are independently selected at each occurrence frop H, C1-C4 alkyl, or C3-C6 cycloalkyl; 30 R11 is selected fiom H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl; r!2 is C/-C4 alfyl or C1-C4 haloalkyl; 35 R13 is 4electe6 from C1-C4 alkyl, C1-C4 haloalkyl, Cd-Cq alkoxyalkyl, C3-C6 cycloalkyl, C4- -172- Printed from Mimosa WO 98/03510 PCT/US97/13072 Cl2 cycloalkylalkyl, ar; heteroaryl or heteroar fl, ary/1(C1-C4 alkyl)-, (ci-ci alkyl) r14 is selected from alkylI C3-C10 alkenyl, C3- C10 alkynyl, C3-C9 arcloallwl, or C4-Cl2 cycloalkylalkyl/ each optionally substituted with 1 to 3 substituents independently selected at each occurrence from £i-Cg alkyl, C3-C6 cycloalkyl, haflo, C1/C4 haloalkyl, cyano, 10 OR15, SH, S(0)nJ#5/ CO»15, C02R15, OC(O) R15, NR8COR15, N(C0F/5)2, NR8CONR16R15, NR8C02R15, NR16R15, CONR^R15, and Ci-Cg alkylthio, C1-C6 alkyisuifinyl/and Ci/C§ alJcylsulfonyl; 15 R15 and R1® are independently selected at each occurrence /from HJ Ci-Cg alkyl, C3-C10 cycloalkyl/ C4-CV6 cycloalkylalkyl, except that for S (0) rt/15, R^r cannot be H; 20 aryl is phenyl or nafphthyl, each optionally substituted with 1 to 5 substituents independently selected at each cccurrsnce from C^-Cg alkyl, C3-C6 c/cloaligyl, halo, C1-C4 haloalkyl, cyano, 25 or1/' SH' p(0)nR15r COR15, C02R15, 0C(0)R15, NR^COR15,/N(COR15)2, NR8COMR16R15, NR9C02R15, NB!16R15,/and CONR16R15; heteroaryl ys pyridyl, pyrimidinyl, triazinyl, 30 /furanm, pyranyl, quinolinyl, isoquinolinyl, thierwl, imidazolyl, thiazolyl, indolyl, pyrrclyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-diMydrobenzothienyl or 2,3-dihydrobenzofuranyl, 35 / each being optionally substituted with 1 to 5 -173- Printed from Mimosa substituents independently selected at/ each occurrence from Cj-Cg alkyl,/ C3-C6 cwcloalkyl, halo, C1-C4 haloalkyl, cyanj OR 15 5H, S(0)nR15, -COR15, C02R15, ^C (O) R15, /NR8COR15, N (COR15) 2, NR8CONR16r15/ NyR8C02R15,/NR16R15, and CONR16R15; .15 .15 heterocyclyl is saturated or/partialis saturated heteroaryl, optionally /subst itut/ed with 1 to 5 10 substituents independently selected at each occurrence from Ci-Cg/alkyl, c/j-cg cycloalkyl, halo, C1-C4 haloalky y, cyano, /OR15, SH, s (0) nR15, COR15, CO2P15, OC «/) R15, NR8COR15, N (COR15) 2, NR8CONR1%15, NR8jC02R15, NR15Rl6, and 15 CONR16R15; n is independently at each occurence 0,1 qr 2; provided that R1 is not H or OR11 when A is CR and Z is CR2.
2. A method of claiirJ 1 whereAn, in the compound of 20 Formulae (1) or (2),/Ar is pftenyl, pyridyl or 2,3- dihydrobenzofuranyl/ each optionally substituted with 1 to 4 substituents.
3. A method of claim 1 wfterein, in the compound of 25 Formulae (1) or U2) , A id N, Z is CR2, Ar is 2,4- dichlorophenyl, II, 4 -dimcrthylphenyl or 2,4,6- trimethylphenyl/ R1 and/ R2 are CH3, and R3 is NR6aR7a A compouryd of Formulae (1) or (2) : 30 -174- ojili'J| WO 98/03510 PCT/US97/13072 .N N ^ N -N Ar (1) (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and 5 pharmaceutically accfptablf salt or pro-drug forms thereof wherein: A is N or CR; 10 2 is N or CR2; 15 20 25 Ar is selected fjfom phenyl, naphthyl, pyridyl, pyrimidinyli, triajzinyl, furanyl, thienyl, benzothienyl, bertzofuranyl, 2,3-dihydroberfeofuranyl, 2,3-dihydrobenzothienyl, indanyl, i,2-benzopyranyl, 3,4-dihydro-l,2-be.nzopyrafny 1, getralinyl, each Ar optionally substituted wijfh 1 to 5 groups and each Ar is attacheqf to arf unsaturated carbon atom; R is independent 1y selected at each occurrence from H, Cl-€4 alkkl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6/cycloalkyl, C4-C7 cycloalkylalkyl, halo, CN, C|l-C4 haloalkyl; R1 is independently selected at each occurrence from H, fi~C4 Alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -175- Printed from Mimosa WO 98/03 Iff mmm PCTi /1 halo, CN, C1-C4 haloalkyl, C1-CI2 hydroxyalkyl, Cz~Ci2 alkoxyalkyl, C2-C10 cyanealkyl, C/-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NRJR1^, C]-C4 a Iky 1-NrSr1 0, NR9COR10, OR/1, SH or/S(0)nR12; 10 r2 is selected f rom H, C1-C4 alky/L, C2-C4/alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, Cq-i^io cycloalkylalkyl, C1-C4 hydyoxyalkyif halo, CN, -NR6R7 NR9COR10, -NR6S (0)/jR7, S(0)/nNR6R7, Cr C4 haloalkyl, -OR7, SH or/-S(0)nR|2; R- 15 20 25 30 is selected from: OR7, SH, S(O)nR131 OC(O)R13, . NR8COR' NR8C02R13, NR6R7 CONR6R7, :or7, coin , N(COR7)/, NR8CONR6R7, NR6aR7a/, N (OR7) R6, and ,7 R 35 aryl, tyetcroary/ heterocyclyl, Gi -C1-C10 alkyl, C2~cJo alkeny/L, C2-C10 alkynyl, C3-C8 cycloalwl / Cs-CyB cycloalkeny 1, C4-Cl2 cycloalkylalkyl or Cg-Ci0 cycloalkenylalkyl, eafch optionally substituted /with 1 tp 3 substituents independently selected at each occurrence from Ci-Cg/alkyl, f3~CQ cycloalkyl, halo, C1-C4 haloalkyl, rfyano, OR15, SH, S (0) nR13 //COR15, JDO2R15, OC (O) R13 , NR8COR15/ N (COR1/)2, NR8CONR16R15, NR8C02rV3, NR16H15, CONR16R15, aryl, heteroaaryl and meterocyclyl; is independera: ly selected at each occurrence from: C1-C10 alkvl, C2-C/10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl,/C4-C12 cycloalkylalkyl, NO2 , halo, CN,/ C1-C4 Haloalkyl, Nr6r7, NR8COR7, MR8C02R7/ COR7, pR7, CONR6R7, CO(NOR9)R7, CO2R7, •176- ■Mf \i WO 98/03510 PCT/US97/I3072 or S(O)nR'/ where each /such Ci-Cio alkyl, C2~ Cio alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl and C4-C12 cycloalkylilkyA are optionally substituted with 1 to 3 substituents independently selected art each occurrence from C1-C4 alkyl, N02, halo,/CN, NR6R7, NR8COR7, NR6CO2R7, COR7 0R7,/C0^6R7, C02R7, CO (NOR9) R7, or S(0)nR7; 10 r6 and R7, R6a and R7y aref independently selected at each occurrence /fron -H, -C1-C10 alkyl,/C3-rfio alkenyl, C3-C10 alkynyl, Ci-Cio haloaBcyl with 1-10 halogens, C2_Cg 15 alkoxyalkyl,/C3-C6 cycloalkyl, C4- C'12 cycfoal^ylalkyl, C5-C10 cycloalkenyl, or C5-C/14 cycloalkenylalkyl, each optionally/substituted with 1 to 3 substituents independently selected at each 20 occuj/rencje from C1-C6 alkyl, C3- Cg c^'clo^lkyl, halo, C1-C4 haloalkyl, lO, UK15, SH, S(0)nR13, COR15, C02R15, R lf, NR8COR15, N(C0R15)2, NR8C0NR16R15, Nfy°C02^13, NR16R15, CONR16R15 25 hpter^aryl or heterocyclyl, -aryl,/ aryl (C1-C4 alkyl), heteroaryl, leteyoaryl(C1-C4 alkyl), heterocyclyl or hetenrocyclyl (C1-C4 alkyl), alternativelyJ NR^R7 and NR^aR7a are independently 30 piperidipe, jwrrolidine, piperazine, N- methylptperaline, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups; aryl, 35 R8 is/independently selected at each occurrence from fH or/C1-C4 alkyl; -177- Printed from Mimosa 'I'll M-Wfflf WO 98/03510 PCT/U S97/13072 R9 and R1® are independently selected occurrence from H, C1-C4 a/kyl, 0/ cycloalkyl; R11 is selected from H, Ci-C4/alkyl,/C1-C4 haloalkyl, or C3~C$ cycloalkyl; 10 15 20 25 R 12 is C1-C4 alkyl or C1-C4/haloalKyl; R13 iS selected from C1-C4/alkyl,/C1-C4 haloalkyl, C2-C8 alkoxyalkyl, Cs-Cg cyaloalky1, C4-C12 cycloalkylalkyl,/ aryl, aryl (Ci-C4 alkyl) -heteroaryl or heteroaryl(CJ-C4 alkyl)-; R14 is selected from C]Acio alrfy1, C3-C10 alkenyl, C3-C10 alkynyl, C3-C13 cycloalkyl, or C4~ C12 cycloalkylalkyl, "eadn optionally substituted with 1 to 3 subst ituentfe independently selected at each occurrence from Cj-C6 alkyl, C3-Cf, cycloalkyl,/halo, Ch-Cq haloalkyl, cyano, OR15, SH, S (0)/nR15, C©R15, CO2R15, OC (O) R15, NReC0R15, N(CpR15) 2, NR8CONR16R15, NR8C02R15, nr16r15, cONR16R15, And cj-Ce alkylthio, cj-cg alky lsulf in\/l and C/-C5 alkylsulfonyl; 30 R15 and R1^ are/indepenflently selected at each occurrence from H/ C}-C6 alkyl, C3-C10 1 / cycloalkyA, C4-C]/6 cycloalkylalkyl, except that for S(0)AR15, R1/ cannot be H; 35 aryl is phenyl or naphthyl, each optionally substituted wijth 1 to 5 substituents independently/selected at each ,pccurrery:e from C1 -Cg alkyl, C3-C6 c^cloalky|., halo, C1-C4 haloalkyl, cyano, -178- Printed from Mimosa fit WO 98/03510 PCT/US97/13072 OR15, SH, S(0)nR 15 CORJ C02R1/, OC(0)R15, NR8COR15, N (COR15) 2, NR8(^ONR16R1f, NR8C02R15, nr16r15, ancj C0NRl6R15; 10 15 5 heteroaryl is pyridyl, pyrirfiidinyl,/ triazinyl, furanyl, pyranyl, quinolinyl,/isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, »enzofu»anyl, benzothienyl, benzothiazolyl, isoxpzolyl,/pyrazolyl, 2,3-dihydrobenzothienylj or 2, 3fdihydrobenzofuranyl, each being optionally substituted with 1 to 5 substituents independent ]/' selected at each occurrence from Cy-Cg alMyl, C3-C6 cycloalkyl, halo, C1-C4 haloa/kyl, ayano, OR15, SH, , 0C(0)R15, NR8COR15, NR8C02R15, NR16R15, and S(0)nR15, -COR15/ CO2R1' N(COR15)2, NR8C0^R16Ri: CONR16R15; heterocyclyl is saturated /or partially saturated 20 heteroaryl, ootionaMy substituted with 1 to 5 substituents independently selected at each occurrence fffom C]VCg alkyl, C3-C6 cycloalkyl, halo, C1-C4 paloalicyl, cyano, OR15, SH, S(0)nR15, C®R15, CO2R15, OC(O)R15, NR8COR15, 25 N (COR15) 2- ^R8C0^16R15, nr8C02R15, NR15R16, and CONR16R15• n is independently dt each occurrence 0, 1 or 2, / / 30 with the provisos that: 35 (1) when jh is jN, Z is CR2, R2 is H, R3 is -OR7 or -OCOp13, qnd R7 is H, then R1 is not H, OH or SH; -179- Printed from Mimosa «W S:H®. WO 98/03510 PCT/TJS97/13072 10 (2) (3) (4) when A is N, Z is CR2, R-1/is CH3 oi C2Hsr R2 is H, and R3 is OH, H, CH3, C2Hfc, C6H5, /-C3Ht, i-C3H7, SH, SCH3, NHC4H9, or N (c/h5)2, th</n Ar is not phenyl or m-CH3-phenyl; when A is N, Z is CR2,/R2 is H,/and Ar is pyridyl, pyrimidinyl ar pyrazifnyl, and R3 is NR6aR7a, then R6a and jR1& are pot H or alkyl; when A is N, Z is CI is not OH or SH; and Rf is S02NR6R7, then R3 15 20 25 (5) when A is CR and 2j is CR2,/ then R2 is not-NR6S02R7 or -S02NR6R7; (6) when A is N, Z iL CR2 arii R2 is -NR6S02R7 or -S02NR6R'?, then R3 is ndt OH or SH; (7) when A is N, Z/is CR2,/ R1 is methyl or ethyl, R2 is H, and R3 ife H, Oh/ CH3, C2H5( CgHs, n-C3H7, iso-C3H7, SH,/SCH3, NH (n-C^Hg), or N(C2H5> 2, then Ar is not unsubst ityted phenyl or m-methylphenyl; (8) when A is CR, z is/CR2, R2 is H, phenyl or alkyl, R3 is NReCOR7 and Ar is phenyl or phenyl substituted with yphenylthio, then R7 is not aryl, aryl(C\-Cj alkyl/, heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocycly(C1-C4 alkyl); 30 (9) when A Is CR, L is CR2, R2 is H or alkyl, Ar is phenyl,/ and R/ is SR-3 or NR^aR7a, then R13 is not aryl or heteroaryl and R6a and R7a are not H or aryl;/or 35 (10) when/A is p, Z is CR2, R1 is OR11, R2 is H, R3 is OR7,/ and Iy and R11 are both H, then Ar is not -180- Printed from Mimosa WO 98/03510 PCT/US97/13072 10 phenyl, p-Br-phenyl, p-phenyl, p-CH3~phenyl, fl fyri -gfhenyl, p-NHCOCH3-yl or naphthyl; (11) when A is CH, Z is CR?, Pp is H, Ar is unsubstituted phenyl/ ana R3 is CH3, C2H5, CF3 or C6H4F, then Ri is not CF13 or C2F5; (12) when A is CR, R is/H, £ is CR2, R2 is OH, and R1 and R3 are H, theiy Ar /is not phenyl; (13) when A is CR, R is rJ, Z is CR2, R2 is OH or NH2, R1 and R-^ a/re GTH3, then Ar is not 4-phenyl-3-cyano-/2-aminopyrid-2-yl. 15 5. A compound of gflairrf 4 and isomers thereof, stereoisomeric formi thereof, or mixtures of stereoisomeric forrfis taereof, and pharmaceutically acceptable salt oy pro-drug forms thereof with the additional provisos that: (1) when A is N, R^ is H, 20 C1-C4 alkyl, hale, CM, C1-C12 hydroxyalkyl, C1-C4 alkoxyalkyl or SO2(U1-C4 alkyl), R3 is NR^aR7a and R^a is unsubst#tut$a C1-C4 alkyl, then R7a is not phenyl, naphtrfyl, yfchienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, 25 benzothiazol/l, i/ndolyl or C3-C6 cycloalkyl; and (2) A is N, Rl is H,/C1-C4 alkyl, halo, CN, C1-C12 hydroxyalkyl, C/-C4 alkoxyalkyl or SO2(C1-C4 alkyl), R3 is NR^^R7a and R7a is unsubstituted C1-C4 alkyl, then R^a As not phenyl, naphthyl, thienyl, 30 benzothienyl,/pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl/ benzothiazolyl, indolyl or C3-C6 cycloalkyl 6. jh compound of claim 4 and isomers thereof, 35 stereoisomeric forms thereof, or mixtures of ste/eois^meric forms thereof, and pharmaceutically Printed from Mimosa WO 98/03510 PCT/US97/13072 acceptable salt or pro-drug forrfs theredf wherein Ar is phenyl, pyridyl or 2,3-dihydtobenzofaranyl, each optionally substituted with 1 t/o 4 R4 substituents. 10 7. A compound of claim 6 and isomer^ 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 CR2, Ar is 2, 4-dychlorcphenyl, 2,4 — dimethylphenyl or 2,4,6-trimethylphenyl, R1 and R2 are CH3, and R3 is NR6aR7a. 15 8. A pharmaceutical composition comprising a pharmaceutically acceptabie carrier and a therapeutically effective amount of a/compound of claim 4. 20 25 30 9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of /a compound of claim 6. 10. A pharmaceutical /composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount <jf a compound of claim 7. 11. A compound of <£laim 4 ind isomers thereof, stereoisomeric forme thereof, or mixtures of stereoisomeric forrfis thereof, and pharmaceutically acceptable salt or/ pro-drug forms thereof wherein A is N . 12. A compound hf Formula (2) of claim 11 and isomers thereof, stereoi/someric /forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salty or pro-/drug forms thereof. 35 -182- Ptfinted from Mimosa WO 98/03510 PCT/US97/13072 13. A compound of claim f\2 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, ana pharmaceutically acceptable salt or prodrug forms thereof wherein Ar is phenyl, pyridyl or 2,3fdihydrobenzofuranyl and each Ar is optionally substituted with/l to 4 R4 substituents. 14 . A compound of qfraim 12 afnd isomers thereof, stereoisomeric form/ thereof/, or mixtures of 10 stereoisomeric forrjls thereof, and pharmaceutically acceptable salt oxf pro-drujf forms thereof wherein r3 is NR6aR7a or OR7. 15. A compound /of claim? 12 and isomers thereof, 15 stereoisomeric forms thereof, or mixtures of stereoisomeric/forms taereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,fl-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, 20 and R3 is NH6aR7a or/OR7 . 16. A compound off Formula (1) of claim 11 and isomers thereof, Etereoisomeric forms thereof, or mixtures of stereoisomeric farms thereof, and pharmaceutically 25 acceptal^le salt /or pro-drug forms thereof wherein Z is CR2 17. i. compound of claim 16 and isomers thereof, sterepisomer/c forms thereof, or mixtures of 30 stereoisomeiic forms thereof, and pharmaceutically acceptable /salt or pro-drug forms thereof wherein Ar is phenyl, pyfcidyl or 2,3-dihydrobenzofuranyl and each Ar is/ optionally substituted with 1 to 4 R4 substituents. 35 }f8. A Compound of claim 16 and isomers thereof, /stereoi/someric forms thereof, or mixtures of -183- Printed from Mimosa WO 98/03510 PCT7US97/13072 stereoisomeric forms therecf, and oharmaceutically acceptable salt or pro-dru|y forms /.hereof wherein R3 is NR6aR7a or qr7 , 5 19. A compound of claim lid and Isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, arid pharmaceutically acceptable salt or pro-drug forps thereof wherein R®a is independently se/lected tfrom: 10 -H, -Ci-Cio alkyl, C3/-C10 alWenyl, C3-C1Q alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2~Cq alkoxyalkyl/, C3-C6/cycloalkyl, C4-C12 cycloalkylalkyl, C5-C1Q cycloalkenyl, 15 or C6_Ci4 cycloalkenylalkyl, each optionally/ substituted with 1 to 3 substituents independently selected at each occurrence from sP\-Cs alkyl, C3-Cg cycloalkyl, hfalo, C1-C4 haloalkyl, 20 cyano, OR15, SH/ S(0)nR13, COR15, CO2R15, OC (O) R13/, NR8COR15, N (COR15) 2, NR8CONR1 6R15 , NR8C02Rf3, NRifR15, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl/C1-C4 alkyl)-, heteroaryl, 25 heterojaryl (C1/-C4 alkyl)-, heterocyclyl or heterdfcyclyl JC1-C4 alkyl)-; and R7a is independently selected at each occurrence from: -H, -C5-C10 alkyl, Cfi-Cio alkenyl, C3-C10 alkynyl, 30 Ci-Ofio haloalkyl with 1-10 halogens, C2-Ce alkixyalkyi, C3-C6 cycloalkyl, C4-C12I cycloalkylalkyl, C5-C10 cycloalkenyl, or /c6_Ci<j/ cycloalkenylalkyl, each optionally substituted with 1 to 3 35 siibstitufents independently selected at each :currei/ce from C1-C5 alkyl, C3- -184- Printed from Mimosa * ma WO 98/03510 j / PCT/US97/13072 Cg cycloalkyl, halo, / Ci-C4/haloalkyl, cyano, OR15, SH, S (j) nR13,/ COP.15, CO2R15, OC(O)R13, NR8C0R15,/ N(COR?5)2, NR0CONR15R15, NR8C02R13, NR16R1y, CONrPr15, aryl, 5 heteroaryl or heterocyc/yl, -aryl, aryl (C1-C4 alkyl), he/eroaryl, heteroaryl(Ci-Cf alkyl/, heterocyclyl or heterocyclyl (CU-C4 alyyl) ; 10 alternatively, NR^R7 ana NR^aR?a are independently piperidine, pyrrolidine/, pipeoazine, N-methylpiperazine, morpholine pr thiomorpholine, each optionally substitute^ with /-3 C1-C4 alkyl groups, 15 20. A compound of tfLaim 1El and isomers thereof, stereoisomeric formp thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt oxj prc-dnug forms thereof wherein R6a and R7a are identical anA are selected from: 20 -C1-C4 alky* or C-}1C$ cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C\—Cf alkyl/ C3-C5 cycloalkyl, halo, C1-C4 haloalkyl,/cyano, OR15, SH, S(0)nRl3' -COR15, 25 CO/R15, 00<0)R13, NRflCORlS, N(CORl5)2, N5^C0NR16R15, NR8CO2R13, NR15R15, C0NR16R15, :yl, heteroaryl or heterocyclyl, and -aryl/or heteroaryl. 30 21. A cqfnpound Ibf claim 18 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoi/omeric/forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a is/selected from: 35 /-H, -185- Printed from Mimosa 'ill'- WO 98/03510 PCT/US97/13072 -Ci-Cio alkyl, C.3-C10 al/enyl, C/-C10 alkynyl, C1-C10 haloalkyl wyth 1-10/halogens, C2-C8 alkoxyalkyl, C3-C6/ cycloaj/cyl, C<j-C12 cycloalkylalkyl, C5-CA0 cycloalkenyl, or C6-C14 cycloaj/cenylalltyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from/ Ci-Cg alkyl, C3-C6 cycloalkyl,/halo, (J1-C4 haloalkyl, 10 cyano, OR15, 3H, S{0)/R13, COR15, CO2R15, OC(0)R13, NR8COR15, U(COR15) 2, NRSCONR16R15, NR9C02R13, NSI^rIS ,/c0NR16R15, aryl, heteroaryl ar heterocyclyl, -aryl, aryl(Cl-Cl alkyl/, heteroaryl, 15 heteroaryl/C1-C4 alkyl), heterocyclyl or heterocyc i/yl (C1 —</4 alkyl) ; R7a is selected fror -C1-C4 alkyl a/id eachf such C1-C4 alkyl is substituted wit/h 1-3 substituents 20 independently selected at each occurrence from C^-Cg alkyl, a3-C6 cycloalkyl, halo, C1-C4 haloalfcyl, c/ano, OR*5, SH, S(0)nRl3, CORlS, C02R1f/ OC(o/R13, NR8COR15, N(COR15)2, NR8CONRI6RI5/ NR8CO2R13, NR!6R15, C0NR16R15, 25 aryl/ heteroaryl or heterocyclyl. 22. A compound of jfclaim 18 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomerac fonrns thereof, and pharmaceutically 30 acceptable salt or pro-drug forms thereof wherein one of R6a and R7A is selected from: -C3-Cfc cycloalkyl, each such c3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected at each occurrence from 35 / Ci~«s alkyl, C3-C6 cycloalkyl, halo, C1-C4 ha/oalkyl, cyano, or15, SH, S (0) nR13, COR15, -186- Printed from Mimosa 81;! WO 98/03510 PCT/US97/13072 CO2H15, OC(0)Rl3, NR9COR15 , / N (COR15) 2, NRSCOHRiSRlS, NR8C02R13, NRMr15, CONR16R15, aryl, heteroaryl of heterpcyclyl, -aryl, -heteroaryl or -heterocyclyl, and the other of R6a and R?a is ^substituted C1-C4 alkyl. 10 23. A compound of claim/18 and? isomers thereof, stereoisomeric forms tharreof, <pr mixtures of stereoisomeric forms thereof, /and pharmaceutically acceptable salt or pro/drug forms thereof wherein R^a and R7a are independently H or C1-C10 alkyl, 15 each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-Cfe alkyy, C3-C6 cycloalkyl, halo, c1-C4 haloalkyl, cyaho, or15, sh, s(0)nr13, cor15, c02r15, 0c(0)r13, n^8cor15, n (cor15) 2, 20 r9c0nr15r15, NR8cofer13, n!r15R15, conr16r15, aryl, heteroaryl or heterocyclyl. 25 24. A compound lof claiJm 16 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric /forms ohereof, and pharmaceutically acceptable salt or prp-drug forms thereof wherein Ar is phenyl, pyridyl or 2/3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, and R3 is NRpaR7a or/OR7 . 25. A compound off claim 24 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt pr pro-drug forms thereof wherein 35 R^a is independently selected from: -Hi 30 -187- Printed from Mimosa WO 98/03510 PCT/US97/13072 10 15 20 25 30 -Ci-Cio alkyl, C3-C10 alkenyl, C^-tiQ alkynyl, C1-C10 haloalkyl with /i-10 halogens, C2-C3 alkoxyalkyl, c3-c5 cwcloalkjl, c4-c12 cycloalkylalkyl,/C5-C].g cycloalkenyl, or C6-C14 eye loalkeayl alky/1, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from c/-c5 aVkyl, c3-C6 cycloalkyl, hallo, C3/-C4 haloalkyl, cyano, OR15, SH,/ S(O)nf13, COR15, CO2R15, 0C(0)R13, NR8COR15, N yCOR15) 2, NR8CONR16R15, NR8C02R13, NRifR15, qONR16R15, aryl, heteroaryl orfheterokyclyl, -ary 1, aryl (C1-C4 /alkyl) j, heteroaryl, heteroaryl(C/-C4 aVkyl), heterocyclyl or heterocyclyl alkyl) ; R7a is independently /selected at each occurrence from: -H, -C5-C10 alkyl,/C3-CiQf alkenyl, C3-C3.0 alkynyl, C1-C10 haloalkyfi. with 1-10 halogens, C2-Cg alkoxyalkyl, Cn-C6 cycloalkyl, C4-Cl2 cygloalkylalkyl, C5-C10 cycloalkenyl, or C6~/Cl4 cycloalkenylalkyl, each optionally substituted with 1 to 3 substfituentp independently selected at each occurrence/from C1-C6 alkyl, C3-C5 ybycloalAyl, halo, C1-C4 haloalkyl, cy*no, od5, SH, S(0)nR'''3/ COR15, C02R^ 5, 0</(0)R13/ NR®COR15, N (COR15)2, NR8C0NR16R15, ^8C02r/3, NRi6R15, CONR1^R15, aryl, leteroafryl or heterocyclyl, -ary/, arylflCi-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl), 35 -188- Printed from Mimosa WO 98/03510 PCT/US97/13072 alternatively, NR^R7 and NR^at^a are independently piperidine, pyrrolidine, piparazine, N+ methylpiperazine, morpholine/ or thiomorpholine, each optionally substituted with/l-3 C1-C4/alkyl groups. 26. A compound of claim 2« and isomers thereof, stereoisomeric forms theraof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms /thereof wherein r6* 10 and R7a are identical ank are selected from: -C1-C4 alkyl or C3-/C6 cycloalkyl, each optionally substituted with 1 to/3 substituents independent J7y selected at each occurrence from Ci-Cg alkyl/ C3-C6 cycloalkyl, halo, C1-C4 15 haloalkyl, /cyano, ORIS, SH, S(0)nR13, -CORlS, C02R15/ 0c/0)Rl3, NR8COR15, N(CORl5)2, NR8CONRl6ttl5, NR8CO2R13, NR16R15, CONRISRIS, aryl, heyeroaryl pr heterocyclyl, and -aryl or heteroaryl. / 20 27. A compound of claim £4 and isomers thereof, stereoisomeric farms thereof, or mixtures of stereoisomeric forms thefreof, and pharmaceutically acceptable salt lor pro-drug forms thereof wherein R6a 25 and R7a are identical apd are -C1-C4 alj/yl, each such C1-C4 alkyl optionally /substituted with 1 to 3 sufcsstituents independently selected at each occurrence from Ci,-C6 alkyl, C3-C6 cycloalkyl, 30 halo, C1-C4 haloalkyl, cyano, OR15, SH, s/o)nR13/ -COR15, CO2R15, 0C(0)R13, NR8COR15, M(COR15)/2, NR8CONR1-6R15, NR8CO2R13, NRISRIS, CONRl6fyl5( aryl, heteroaryl or heterocyclyl. -189- Printed from Mimosa WO 98/03510 PCT/US97/13072 28. A compound of claim 2 4 And isomers thereof, stereoisomeric forms thereof/, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms t/hereof wherein 5 RSa is selected from: -H, -Ci-Cio alkyl, c3-c1 h alkeny/L, c3-c10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, Cn-Cg cygloalkyl, c4-10 C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or Cg-C14 cyqfloalkenwlalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci~t6 alkyl, c3-15 C 6 cycloalwyl, ha id, C1-c4 haloalkyl, cyano, OR1?, SH, s/(0)nR13, COR15, co2r15, OC (0) R13, WRSCOR1^, N (COR15) 2, NR8C0NR1&R15, NR8C02R13/ NRl6P-lP, CONR16R15, aryl, heteroaryl or heterocyclyl, 20 -aryl, aryl (C/ — C4 alk#/l) , heteroaryl, heteroaryl (C1 —C A alkyl), heterocyclyl or heteroqyclyl alkyl) ; R7a is : -C1-c4 alky£ and eafch such c1-c4 alkyl is 25 substituted with 1-3 substituents independently selected at each occurrence from Cj-C/ alkyl,/C3-C6 cycloalkyl, halo, C1-C4 haldalky1, iyano, ORIS, SH, S(0)nR13, COR15, CO2B15, OC (L>) R^-3, NR0CORX5, N I COR15) 2, 30 NRfCONRi^R^p, NR8CO2R13, NR^RlS, CONRl-SR1^, arfyl, heteroaryl or heterocyclyl. 29. A compound of /claim 24 and isomers thereof, stereoisomeric forms thereof, or mixtures of 35 stereoisomeric foams thereof, and pharmaceutically -190- Printed from Mimosa wmrn WO 98/03510 PCT/US97/13072 10 15 acceptable salt or pro-drug f^rms thereof wherein one of R6a and R7a is selected from: -Cj~Cg cycloalkyl, each/such C^-ps cycloalkyl optionally substituted wirni 1-3 substituents independently selected at/each occurrence from Ci~Cs alkyl, C^-k^ cycloatLkyl, halo, C1-C4 haloalkyl, cyano, OR15, £H, S(O)nR13, COR15, CO2R15, OC(0)R/3, NR8COH15, N(C0R15)2, NR8C0NR16R15, ^r8C02R13/ NR16R15, C0NR16r15, aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, and the other of R^y and R7a ^s unsubstituted C1-C4 alkyl. 30. A compound of claim 2m and isomers thereof, stereoisomeric fopcms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically 20 acceptable salt/or pro-drug forms thereof wherein R^a and R7a are independently H or C1-C10 alkyl, each such ci-c/o alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence tJom Ci-Cg alkyl, C3-C6 cycloalkyl, 25 halo, C1-C4 maloalkyl/ cyano, OR15, SH, S(0)nRl3f COR15, C02 *f5, OC (O) PI13, NReCOR15, N (COR15) 2, R8CONR16R1/, HR8C02^3, NR15R15, CONR16R15, aryl, heteroary^f or heterocyclyl, 30 31. A compound off claim 16 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically accept/able salt for pro-drug forms thereof wherein -Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, 35 / and each Ar is optionally substituted with 1 to i R4 substituents, -191- Printed from Mimosa WO 98/03510 -R3 is NR6aR7a or OR7 and -R1 and R^ are independen 'ly selected from H, C1-C4 alkyl, c3-c6 cycloaj yl, Cl-ClQ cycloalkylalkyl. 10 15 20 25 30 35 PCT7US97/13072 nd isomers thereof, or i|Lxturss of , and/pharmaceutically forma thereof wherein f rpm: 32. A compound of claim 31 stereoisomeric forms thereof stereoisomeric forms therec acceptable salt or pro-druj R®a is independently sel< -H, -Ci-C'10 alkyl, C3-C/1.O alkrfnyl, C3-C10 alkynyl, C1-C10 haloalkyl wit/h 1-10 halogens, C2~Cg alkoxyalkyl, /C3-C6 /cycloalkyl, C4-c12 eye 1 oa 1 kr/la 1 kyl, C5-C10 cycloalkenyl, or C6-Ci4 c/'cloall/enylalkyl, each optionally /substituted with 1 to 3 substituen/ts independently selected at each occurrence from/Ci~C5 alkyl, C3-C6 cycloalkyl, /halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, CO2R15, OC (0) R1/, NR0(7OR15, N (COR15) 2, NRSCONR1 6R15, NR8c02^A3, NIjA ^R15, CONR1^15, aryl, I heteroaryl ok heterocyclyl, -aryl, ary|(Ci-Cl alkyl)-, heteroaryl, heteroaryl/C1-C4 alkyl), heterocyclyl or hetei-ocycM'l (C1-C4 alkyl); R7a is indepei/dentl/ selected at each occurrence from: -H, -Cs-Cio/alkyi/ C3-C10 alkenyl, C3-C10 alkynyl, C/-C10 naloalkyl with 1-10 halogens, C2-C8 Lkoxyalkyl, C3-C6 cycloalkyl, c4--12 cycloalkylalkyl, C5-C10 cycloalkenyl, for Cg/Ci4 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each 192- Printed from Mimosa * MMm? WO 98/03510 PCT/US97/13072 10 15 20 25 30 35 occurrence from Ci/Cg alkyl/ C3-Cg cycloalkyl, haVo, C1-C4/haloalkyl, cyano, or15, sh, k (0) nr13/cor15, CO2R15, 0c(0)r13, nr8cor#5, n (corP) 2, nr8conr16r15, nr8c02r13, nr16h15, CONr/6R15, aryl, heteroaryl or bfeterocyclyl, -aryl, aryl (C1-C4 aJLky 1) , heteroaryl, heteroaryl(C1/C4 alkyl/, heterocyclyl or heterocyclyl yCi—C4 aljtyl) , alternatively, NR°R7 ind are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine/or thiomorpholine, each optionally substituted with/l-3 C1-C4 alkyl groups. 33. A compound off claim 3/1 and isomers thereof, stereoisomeric fojrms thereof, or mixtures of stereoisomeric fdrms thereof, and pharmaceutically acceptable salt for pro-drug forms thereof wherein R6a and R7a are identical amd are selected from: -C1-C4 alMyl or C-/-Cg cycloalkyl, each optionally substituted/with 1 to 3 substituents independently selected at each occurrence from CifCg alkyl, C3-C6 cycloalkyl, halo, C1-C4 iloalkylj cyano, OR15, SH, S(0)nR13» -COR15, ^>2R15, yC (0) R13, NR0COR15, N (COR15) 2, JR8CONR?6Rl5, NR8CO2R13, NR^R15, CONR^R15, aryl, rfeteroaryl or heterocyclyl, and -ar/1 or heteroaryl. 34. A Compound of claim 31 and isomers thereof, stereo/somerig forms thereof, or mixtures of stereoisomer:^ forms thereof, and pharmaceutically acceptable shit or pro-drug forms thereof wherein R6a and R7a are/identical and are -193- Printed from Mimosa WO 98/03510 / / PCT/US97/13072 -C1-C4 alkyl, each such a1-C4 alkj optionally substitnted with/1 to 3 substituents independently/selected at each occurrence from (/-Cg alkyl, C3-C6 cycloalkyl, 5 halo, C1-C4 haloalkyl, cyano, OR15, SH, S (0) nR13r -CORlJ, C02R15 Joe (O) R13, NR8COR15, N(COR15)2, NR8(X)NR16R15 /NR8C02R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl. 10 15 20 25 30 35. A compound of claim 31 and/isomers thereof, stereoisomeric forms t/hereof, gr mixtures of stereoisomeric forms /thereof, /and pharmaceutically acceptable salt or pyto-drug fjbrms thereof wherein r6s is selected froi] -H, -C1-C10 alkyl, C3-C10/alkenyl, C3-C10 alkynyl, Ci-Cio /haloalkyy with 1-10 halogens, C2~Cg alkoxyalkyl, Cy-CQ cycloalkyl, C4-c12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C/5-C14 cycloalkenylalkyl, each optionally substituted with i to 3 sufc/stituentsf independently selected at each occurrence from C3.-C6 alkyl, C3-Cfi cycloalkyl, halo, C1-C4 haloalkyl, fyano, OR?5, SH, S(0)nR13, COR15, CO2R15, 5C(0)R13,/NR8C0R15, N(C0R15) 2» NR8CONR1^R15, NR8C02R1r, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, -a/yl, aryl/c1-c4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl); R7a i: 35 -C1-C4 alkyl and each such c1-c4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from /x~Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 -194- Printed from Mimosa WO 98/03510 PCT/US97/13072 haloalkyl, cyani, OR15, tin, S(O)nR13, COR15, c02r15r oc (o) Rl/, NRBCORp, N(corl5)2, NR8CONR16R15, N/(8C02R13, /nr!6R15, C0NR16R15, aryl, heteroaryl or het/erocyclyl. 36. A compound of clajjm 31 and/isomers thereof, stereoisomeric forms thereof, of mixtures of stereoisomeric forms thereof, afrid pharmaceutically acceptable salt or prp-drug fopms thereof wherein one of 10 R6a and R7a is selected from: -Cj-Cq cycloalkyl, each £uch C3-C5 cycloalkyl optionall# substituted with 1-3 substituents independently selected at each occurrence from Ci-Cg alrfy1, C3-Crf cycloalkyl, halo, C1-C4 15 haloalkyl, cyano/ ORIS, SH, S(0)nR13, CORlS, C02R15, /OC(0)R13/ NRBC0R15, N(COR1S)2, NR0CONm6Rl5, NR/C02R13, NR16r15, CONR16r15, aryl, /leteroar^/l or heterocyclyl, -aryl, 20 -heteroaryl or -heterocyalyl, and the other of R6a anA R7a is unsubstituted C1-C4 alkyl. 25 37. A compound of clfeim 31 and isomers thereof, stereoisomerac forms /thereof, or mixtures of stereoisomeric forms/thereof, and pharmaceutically acceptable /salt or nro-drug forms thereof wherein R®a and R7? are independently H or C]_-Cio alkyl, 30 each such IC1-C10 alkyl optionally substituted with 1 to 3 supstituentys independently selected at each occurrence from Cf-Cg alkyl, C3-C6 cycloalkyl, halo, C1/-C4 haloalkyl, cyano, OR15, SH, S (O) nR^3f COR15, 202R15, OC(0)R13, NR8COR15, N(COR15)2, 35 R8CONR1^R15, NR7C02R13, NR16R15, CONR16R15, aryl, heteroiryl or hfeterocyclyl. -195- Printed from Miiriosa WaMIM! WO 98/03510 PCT/US97/13072 38. A compound of claim 31 pf Formula (50) N"^ AN N 4«f >4a >4b FORMULAf (50) and isomers thereof,/stereoisomeric forms thereof, or 10 mixtures of stereoisomeric fprms thereof, and pharmaceutically acceptable /salt or pro-drug forms thereof, selected fftrom the hroup consisting of: 15 a compound of Formula (50)/wherein R3 is -NHCH(n-Pr)2, H; a compound of Formula (50) wherein R3 is -N(Et)(n-Bu)r R4a is Cl, /R4b is If, R4c is Cl, R4d is H and R4e is 20 H; 25 a compound of formula tf50) wherein R3 is -(n- Pr)(ch2cpt), r4a /s Cl, R4b is H, R4c is Cl, R4d is H and R J is H; a compound of/Formula/ (50) wherein R3 is -N(CH2CH20Me)2, H; 30 a compound if Formula (50) wherein R3 is -NHCH(Et)(n- -196- Printed from Mimosa WO 98/03510 PCT/US97/13072 10 15 a compound of Formula (50)iwherein R3 is -NHCH (Et) (CH2OMe) , R4 is Cl, k4b is H, R4c is Cl, R4d is H and R4e is 5 a compound of Formula (501 wherein! R3 is -NHCH(CH20Me)2, R4a is Cl, R4b is H,/ R4c is </l, R4d is H and R4e is H; a compound of Formula (50) wheredin R3 is -N (Et) 2, r4a is Cl, R4b is H, R4c ils Cl, R4f is H and R4e is H; a compound of Formula (SO) wherein R3 is -NHCH(CH20Et)2, R4a is Cl, R4b is jti, R4c i| Cl, R4d is H and R4e is H; a compound of Formula J( 50) whejtein R3 is -NHCH (Et) 2, R4a R4d is H and R4e is H; a compound of Formula/(50) wherein R3 is -N(Me)(Ph) , r4s 20 a compound of Formula (50) wfcerein R3 is -N(n-Pr)2, r . - , ^ r\4a R4? is/ Cl, R4d is H and R4e is H; 25 30 35 40 a compound of Formula (50) ^herein R3 is -NHCH(Et)(n- >r), ,4e . Pr) , r4a is Cl I R4b ij/ H, R4c is Cl, R4d is H and R is H; a compound of Formila (50)/ wherein R3 is -NHCH(CH20Me)2, R4a is Me, R4f is H,jR4c is Me, R4d is H and R4e is Me; a compound of Formula (50) wherein R3 is -NHCH(CH20Me)2, /, R4c is Me, R4d is H and R4e is H; a compound of Formula (60) wherein R3 is -N(CH2CH20Me)2, R4ais Me, /R4b is|H, R4c is Me, R4d is H and R4e is H; a compound of Formula 1(50) wherein R3 is -NHCH(Et) |cH20Mel, R4a is Me, R4b is H, R4c is Me, 45 a compound of Formula (50) wherein R3 is -NHCH (Et)2, R4a is Me, Rfb is H, R4c is Me, R4d is H and R4e is H; -197- Printed from Mimosa if mm WO 98/03510 PCT/US97/13072 a compound of Formula (50) wherein R-f is -OEt R4a is 5 a compound of Formula (50) J»herein a3 is -N (Et)2, R4a i< 10 15 20 25 H and R4e is H; a compound of Formula (50)/ where in/ R3 is -N (ch2cn) 2, R4a is Me, R4b is H, R4c/ is Me, i/4d is H and R4e is H; R3 is a compound of Formula (50) where: -NHCH(Me)(CH2OMe), 4 4a is R4b is H> R4c is Me? R4d is H and R4e i/ H; a compound of Formula p0) where in R3 is -OCH (Et) (C H 2 OMe) ,/R4a is f/e, R4b is H, R4c is Me, R4d is H and R4e lis H ; a compound of Formula/(50) wherein R3 is -N(n-Pr)(CH2cPr), r4| iS Me, H and R 4e 4b is H, R4c is Me, R4d is is H;j a compound of Formula (50) wherein R3 is -NHCH (Me) (CH2N|(Me) 2) , /4a is Me, R4b is H, R4c is H; Me, R4d is H </nd R4e a compound of Forrmila (50)/wherein R3 is -N(cPr)(ch2ca2CN)/ Rfa is Me, R4b is H, R4c is Me, 30 a compound of Formula (5(3) wherein R3 is -N (n- Pr) (CH2CH2q^J) , R4a /is Me, R4b is H, R4c is Me, R4d is H and Rfe is H; 35 a compound of formula (150) wherein R3 is -N (n- Bu)(ch2cni, R4a i| Me, R4b is H, R4c is Me, R4d is H and R47 is H; 40 a compound of/ Formula/ (50) wherein R3 is -NHCH(Etf)(CH2OM«f), r4a is Me, R4b is H, R4c is Me, 45 a compound pf Formula (50) wherein R3 is -nhch(et)2, R4a is Me/ R4b is /h, R4c is Me, R4d is h and R4e is Me; -198- Printed from Mimosa f'ViV'd 'Jh'ifiif1'[j WO 98/03510 PCT/US97/13072 a compound of Formula (50)/wherein is -N (CH2CH20Me) 2, R4a is Me, R4b is H,/R4c is Mfe, R4d is H and R4e is Me; 5 a compound of Formula (5^) wherei/i r3 is -NHCH(CH2OMe)2, R4a is Br, R4b is is H; R4c is/OMe, R4d is H and R4e a compound of Formula U50) wherein R3 is 10 -NHCH(Et)(CH20Me)/ R4a is/sr, R4b is H, R4c is OMe, R4d is H and R4e /is H; 15 a compound of Formulp (50) wherein R3 is -NHCH<CH2OEt)2, R4a is Me, R4b/is H, Me; ic is Me, R4d is H and R4e is 20 a compound of Formula (50/ wherein R3 is -NHCH(CH2CH2C/Me) (CH/0Me)2, R4a is Me, R4b is H, R4c 25 30 35 is Me, R 4d H and/ R40 is Me; a compound of Formula (80) wherein R3 is morpholinor R4a is Me, R4b lis H, H4c is Me, R4d is H and R4e is H; a compound of Fprmula /(50) wherein R3 is -N(CH2CH20Me)2, R4a is Br/ R4b is H; H, R4c is OMe, R4d is H and R4e a compound of/Formuya (50) wherein R3 is -NHCH (Et)2, R4a is Br, 3rb is h, R4c is OMe, R4d is H and R4e is H; a compound op Formula (50) wherein R3 is -N(Et)2, R4a is a compound/of Fotfmula (50) wherein r3 is -NH(c-Pr), R4a is Me/ R4b /is H, R4c is Me, R4d is H and R4e is H; 40 a compound of Formula (50) wherein R3 is -NHCH(CH20Me)2, R4a /is CN/ R4b is H, R4c is OMe, R4d is H and R4e is a compound of/Formula (50) wherein R3 is -N(c-45 Pr/ (CH2p2CN) , R4a is Me, R4b is H, R4c is Me, R4d ig H ar/d R4e is Me; -199- Printed from Mimosa MtMmm WO 98/03510 PCT/US97/13072 a compound of Formula (501) wherein R3 is -NCH (CH20Me) 2, R4 H; R4a is Me, R4b is HJ PAc is kr, R4d is H and R4e is a compound of Formula (5/0) wherein R3 is -NHCH(CH2OMe) (CH2Ci2OMe); d* is me, r4b is h, R4c 10 a compound of Formula u50) wherein R3 is -NHCH(CH20Me)2 R4a i, is H; a compound of Formula 1(50) wherein R3 is -N(CH2CH2OMe)2 R4a i is H; 15 20 25 R4a is Me, R4b iI H, R4c lis OMe, R4d is Me and R4e a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is Hf R4c isfOMe, R4d is Me and R4e is H; a compound of FormuJa (50) wherein a compound of Formula (50) wherein RP is -N(Ht)2, R4a is Me, R4b is H, a compound of Formula (50) /wherein R3 is -NHCH(CH20Me)2, R4a is Cl, R4f is H, |4c is Me, R4d is H and R4e is H; 30 a compound of Formula (50)1 wherein R3 is -NHCH(Et)(CHfcOMe), R?a is Cl, R4b is H, RHU is Me, ,4c • 35 40 45 a compound of Formula (50) wherein R3 is -N(CH2CH2QMe)2, R4a is Cl, jR4b is H| R4c is Me, R4d is H and R4e is H; a compound of Formula (SO) wherein R3 is -NHCH(CH2CWe)(CH2CH20Me), r4a is Cl, R4b is H, R4c a compound of Formula A50) wherein R3 is -N(c- Pr) (CH2CH2CN) ( R-ya is Mg/ R4b is R4c is 0Me? R4d is Me anl R4e is|H; -200- Printed from Mimosa WO 98/03510 PCT/US97/13072 a compound of Formula (50) wfterein/R3 is -N (c- Pr)(CH2CH2CN), R4a is gi( is H and R4e is H; is H, R4c is Cl, R4d a compound of Formula <50)/wherein R3 is IS)- NHCH(CH2OMe) (CH2CH20Me), r4A is Cl, R4b is H, R4c a compound of Formula (5®) whenein R3 is 10 -NHCH (CH2OMe) (CH2Cf/2OMe) ,/R4a is Cl, R is Cl, R4d is H an/a R4e #s H; 4b is H, R4c 15 a compound of Formula /50) whJerein R3 is -NHCH (Et)2 f R 4a is Me, R4b is H, ,4c is/B r, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2/ R4a is Me, R4b As H, H; !c is Br, R4d is H and R4e is 20 a compound of Formula Me, R is H/and R 7 is H; (50)/ wherein R3 is r: 4« -NH(CH2OMe)(Cft2-iPr)/ R4a is Me, R4b is H, R4c is >4d 25 a compound of Formula (5p) wherein R3 is -N(CH2CH2OMe)2, is H, R4d is H and R4e is R4a is Me, jR4b is H; ,4c 30 a compound of Ejbrmula /50) wherein R3 is -N (CH2CH2OMe) 2, R4a is is H; Mel R4b i^ H, R4c is NMe2, R4d is H and R4e 35 a compound off Formula (50) wherein R3 is -NHCH (Cft2OMe) (rfPr), R4a is Me, R4b is H, R4c is Me, R is H amd R 4e is H; a compound jot Formula (50) wherein R3 is -NHCH«CH2OEt)WEt), r4a is Me, R4b is H, R4c is Me, >4d ts H and /R4e is H; 40 a compound of Formula (50) wherein R3 is -NH£H(CH2CW) (CH2CH2OMe) f R4a is Me, R4b is H, R4c is/NMe2, R / is H and R4e is H; 45 a compound of Formula (50) wherein R3 is -N(Et)2> r 4a is -201- Printed from Mimosa WO 98/03510 PCT/US97/13072 a compound of Formula (50) wMerein R-y is -NHCH (Et) 2, R4a 10 20 a compound of Formula (50) where in jP is -N' (CH2CH20Me) 2 R4' " H; a compound of Formula (50A whereii R3 is -NHCH(CH20Me)2, R4' H; R4a is Me, R4b is h/ R4c is a compound of Formula (50) wherein R3 is -N(Et)2, R4a is a compound of FormuJ/a (50) wherein R3 is -NHCH (Et) 2, R4a is Cl, R4b is a compound of Formflla (50) /wherein R3 is -NHCH(Et)2, R4a is Me, R4b id H, R4c /is NMe2, R4d is H and R4e is H; 25 a compound of Formula (5Cf) wherein R3 is (S) - NHCH(CH2OMf)(CH2CHaDMe), R4a is Me, R4b is H, R4c 30 35 40 a compound of Formula /50) wherein R3 is -NHCH(CH/OMe)(CH^tH20Me), R4a is Me, R4b is H, R4c is Me, /OMe) Id is H Lnd R4e is H; a compound of Formula (50) wherein R3 is (S) - NHCH (Cp20Me) (CH?2CH20Me) , R4a is Me, R4b is H, R4c l20Me) is ClJ R4d is and R4e is H; a compound/ of Formula (50) wherein R3 is -NHC/MCH20Metf(CH2CH20Me), R4a is Me, R"d is H, R ,4b ,4c is ,4d H and R 4e is H; a compoi/nd of Formula (50) wherein R3 is -N(c- Pri(CH2CH2fN), r4a is Me, R4b is H, R4c is Cl, R4d H and is H; -202- Printed from Mimosa * 1 / ' WO 98/03510 a compound of Formula (50) wf/erein R3 R4' H; PCT/US97/13072 -NH(Et) (CH2CN), ld is H and R4e is 5 a compound of Formula (50) /wherein R-f is -N (Et) 2, R a is >4b ,4c . 4d Me, R'11*' is Me, R"11" is/ OMe, R"*u As H and R4e is H; a compound of Formula (50/ wherein R3 is -N(CH2ch20Me)(CH2Ch/oh), r4a L Ql> R4b i3 H> R4c 10 15 a compound of Formula (60) wherein r3 is -N(CH2CH20Me)2 R4a i is H; R4a is Me, R4b is/Me, R4c iI OMe, R4d is H and R4e a compound of Formula/ (50) wherein R3 is -NHCH(Et)2, R 4a H; 20 a compound of Formula (50) wtherein R3 is -N (CH2c-Pr) (n-Pr), R4a is Mfe, R4b is H, R4c is Cl, R4d is H and 25 30 40 45 R4e is H; a compound of Foymula (50) wherein R3 is -N(c-Pr) (CH2CH2CN) /R4a is Me/ R4b is Me, R4c is OMe, R4d is H and R?e is H; compound of formula (50 wherein R3 is -NHCH (Et)2' R4a is Cm, R4b is 'J, R4c is OMe, P.4d is H and R 4e is H; a compound of Formula /50) wherein R3 is -N (Et)2, R4a is 35 a compound jot Formulal (50) wherein R3 is -N (CH2CH20Me) 2, R4a ih Cl, R4b Is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(Et) (CH2pMe) , R4a is Cl, R4b is H, R4c is OMe, R4t is H and/R4e is H; a compound of Formula (50) wherein R3 is -N (Et)2, R4a i« -203- Printed from Mimosa ';H 'S'j 20 •5< 39. A corr.pour.d of cial.T. 31 ar.d/ isomers tr.ereof, 3t3raci3cmeric forms trieraof, ^/r .x'.xtures of stersc.i3crr.eri: :c rrns ' -IS-TwOif/ ind sharsacau::: accec; icie salt or pr/c-crug srms nersoi vr.erem 3- ( 2-.Tiqfchoxyet .iy 1} amine) -2, 3a id compound is 4- d i ma t h v i - 3 - ( 2 - me t h y y- 4 - me t ho/c y p he r. y 1) - ; 1, 5 - a j -pvraioio-1, 3,5-t ria/fcir.e 4C . A compound oif claim 3/-. and isomers therec: 30 stereoisomeric totns thereof, or mixtures of stereoisomeric fgrns thereof, ana pharmaceutically acceptabie salt fcr pro-dfug forms thereof, wnerein said compound ia 4-(5 :s| ( 2-methoxyet hy 1) amino) -2, 7 • dirnethyi-3- (2, 5bdi.nec.H-y/l-4-methoxyphenyl) - i 1, 5-a ] 35 pyrazolo-i, 3, 5/-C ria2ir.j 41. A compound of cl/aim 4 and isomers thereof, stereoisomerLc forms/thereof, or mixtures of 3tereo:somerfic forma thereof, and pharmaceutically -204- K.EPLACEME>!T SHEET amended sheet :f'm mmi WO 98/03510 PCT/US97/13072 acceptable salt or pro-drug/forms thereof wherein A is CR. 42. A compound of Formulaf (2) of cfaim 41 and isomers 5 thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms theneof, and pharmaceutically acceptable salt or pro-d/rug forms/thereof. 43- A compound of claifn 42 and /isomers thereof, 10 stereoisomeric forms tnereof, 0/ mixtures of stereoisomeric forms t/iereof, qfnd pharmaceutically acceptable salt or prd-drug fqfrms thereof wherein Ar is phenyl, pyridyl or 2,B-dihydr£benzofuranyl and each Ar is optionally substituted wifh 1 to 4 R4 substituents. 15 44. A compound of ilaim 42/and isomers thereof, stereoisomeric forit\|s thereof, or mixtures of stereoisomeric f ornfts thereof, and pharmaceutically acceptable salt or/ pro-dr/ig forms thereof wherein R3 is 20 NR6aR7a or OR7. 45. A compound £>f cla^m 42 and isomers thereof, stereoisomeric ffarms tnereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically 25 acceptable salt/ or pao-drug forms thereof wherein Ar is phenyl, pyridyl or 2A 3-dihydrobenzofuranyl, and each Ar is optionally /substituted with 1 to 4 R4 substituents, and R3 is NRSfR7* or OR7. 30 46. A compound op Formula (1) of claim 41 and isomers thereof, stareaisomeric forms thereof, or mixtures of stereoisomeric norms thereof, and pharmaceutically acceptable/salt/or pro-drug forms thereof wherein Z is CR2 . 35 -205- Printed from Mimosa C'W OSSI flsgip WO 98/03510 PCT/US97/13072 47. A compound of claim 46 and/isomers chereof, stereoisomeric forms thereof, ar mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug firms thereof wherein Ar is 5 phenyl, pyridyl or 2,3-dihydtfobenzofuranyl and each Ar is optionally substituted wifh 1 tg 4 R4 substituents. 48. A compound of claim 46f and isomers thereof, stereoisomeric forms thereof, or mixtures of 10 stereoisomeric forms thereof, anfl pharmaceutically acceptable salt or pro-dr/jg for/s thereof wherein r3 is NR6aR7a or OR7. 49. A compound of claijh 4 6 a/id isomers thereof, 15 stereoisomeric forms thfereof J or mixtures of stereoisomeric forms thereof/, and pharmaceutically acceptable salt or pro-drug/forms thereof wherein Ar is phenyl, pyridyl or 2,C-dihydrobenzofuranyl, and each Ar is optionally substituted faith 1 to 4 R4 substituents, 20 and R3 is NR6aR7a or /OR7. 50. A compound of/clairrf 49 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms tnereof, and pharmaceutically 25 acceptable salt gr prgf-drug forms thereof wherein R^a and R7a are Independently H or Ci-Cio alkyl, and each such Cf-Cio/alkyl is optionally substituted with 1 go 3 substituents independently selected at each occurrence from Ci~C6 alkyl, c3-30 c5 cycloalkyl,/ hale, C1-c4 haloalkyl, cyano, or15, sh, S(O)nH13jCOR#5, C02R15, OC(0)R13, NR^COR15, N (COR15) 2/ R8£ONRA6R15, NR8C02R13, NRi6R15, conr16r15, afryl,/heteroaryl or heterocyclyl. 35 51. A compound of claim 4 6 and isomers thereof, stereoisor forms thereof, or mixtures of -206- Printed from Mimosa JEN WO 98/03510 PCT/US97/13072 10 15 20 stereoisomeric forms thereof, aAd pharmaceutically acceptable salt or pro-drug forms therepf wherein -Ar is phenyl, pyridyl or 2, 3-dihydrobenzofuranyl, and each Ar is opt/onally s/bstituted with 1 to 4 R4 substituerfts, -R3 is NR6aR7a or OR7 a/d -R1 and R2 are independently selected from H, C1-C4 alkyl, C3-C6 cycloalkyl, /C4-C10 cycloalkylalkyj 52. A compound of claiin 51 and isomers thereof, stereoisomeric forms thereof, or/mixtures of stereoisomeric forms /hereof, amd pharmaceutically acceptable salt or p/o-drug fooms thereof wherein R^a and R7a are independent ly ti or C1-C10 alkyl, and each such C\-C\Jq alkyl is/optionally substituted with 1/to 3 substfituents independently selected at each occurrence /from Ci-Cg alkyl, C5-C6 cycloalkyl, haflo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, Ccfe15, c02R17, 0C<0)R13, NR8COR15, N(COR15) 2 > R8COHR16R15, NRPCO2R13, NR16R15, CONR^^R^-5, ary/, heteroaryl or heterocyclyl. 25 53. A compound of claim 51 of Formula (51) R 'N N -207- Printed from Mimosa WO 98/03510 PCT/US97/13072 and isomers thereof, stereoisomeric farms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable/salt or pro-drug forms thereof selected from the group consisting of: 10 20 25 30 35 a compound of Formula (5li wherein/R3 is -NHCH(n-Pr)2, R4a is Me, R4b is H; R4c is Me, R4d is H and R4e is a compound of Formula /51) whereAn R3 is -NHCH (CH20Me)2 R4a is Me, R4b i/ H, R4c ifi Me, R4d is H and R4e is H; 15 a compound of Formula (51) wherein R3 is -N (CH2CH20Me)2, R4a is Me, R4b/is H, R4c/ is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -N(c- Pr) <CH2CH2CNjf, r4a is /!e, R4b is H, R4c is Me, R4d is H and RAr is H; a compound of Formula (51/ wherein R^ is -N (CH2CH20Me) 2, R4a is Cl/ R4b is H; R4c is Me, R4d is H and R4e is a compound of Formula (pi) wherein R3 is -NHCH (CH20Me) 2, R4a is, H; R4b is/H, R4c is Me, R4d is H and R4e is a compouncy of Formula (51) wherein R3 is -NHCH(Et)2, R4a is C/l, R4b is ij, R4c is Me, R4ci is H and R4e is H; a compound of Formu&a (51) wherein R3 is -N(Et)2, R4a is R4b is H,/R4c is Me, R4d is H and R4e is H; 40 a compound of Formula (51) wherein R3 is -N(n- 'r) <CH2CH2Cf/) , R4a is Me, R4b is H, R4c is Me, R lis H and RJe is H; a compound of Hormula (51) wherein R3 is -N(n- 4d Bu) (CH2CH|CN) , R4ia is Me, R4b is H, R""~ is Me, R is H and/R4e is H; 4c • ,4d -208- Printed from Mimosa msifii > r<' WO 98/03510 PCT/US97/13072 a compound of Formula (51) wherein R^ is t^IHCH (n- Pr) (CH2OMe) , R4a is Me,/R4b is H, R4/ is Me, R4d i« H and R4e is H; 5 a compound of Formula (51)/ wherein R3 is -NHCH (Et)2, R4a is Me, R4b is H, R4 7 is OMe, R4d/is H and R4e is H; a compound of Formula (31) wherein RP is -NHCH(CH20Me)2, ,4a ,4b ,4c ,4d , 10 R™ is Me, R is/H, R is Otfe, R™ is H and R is H; a compound of Formula (51) where® R3 is (S) -NH(CH2CH2OMe)c/2OMe, R4a i/ Me, R4b is H, R4c is 4e 15 a compound of Formula (51) wharein R3 is -NH(CH2CH2OMef)CH2OMe, r¥ is Me, R4b is H, R4c is Me, R4d is j and R4e isf H; 20 a compound of Formula (51)/wherein R3 is -N (CH2CH2OMe)2, R4a is Me/ R4b is H,/r4c is Cl, R4d is H and R4e is H; . a compound off Formula (pi) wherein R3 is -NH(Et), R4a is 25 Me, R4y is H, R4CJ is Me, R4d is H and R4e is H; a compound/of Formula! (51) wherein R3 is -NHCH (n-Pr) 2, R4a is Me, R4b/is H, R4c is Cl, R4d is H and R4e is 30 H; a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2/ Rr is Me, /4b is H, R4c is Cl, R4d is H and R4e is 35 a confound of formula (51) wherein R3 is (S) -NH(CH2aC2OMe)CH20Me, R4a is Me, R4b is H, R4c is Cl, R4<y is H and R4e is H; a compound lot Formula (51) wherein R3 is 40 / -NH<y(l2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is Cl,yR4d is H and R4e is H; ■a. compo/nd of Formula (51) wherein R3 is -N(n- p/) (CH2CH2CN) , R4a is Me, R4b is H, R4c is OMe, R4d 45, Ls H and R4e is H; -209- Printed from Mimosa assii WO 98/03510 PCT/US97/13072 a compound of Formula /(51) wherein R/ is -N (Et) 2, R4a is Me, R4b is H, R4( is OMe, R4d fs H and R4e is H; a compound of Formula (51) wherein /R3 is (S) -NH(CH2CH2OMe)C^2OMe, R4a is R4b ig H> R4c -s Me, R4d is H an R4e is H; 10 a compound of Formufla (51) whereyn R3 is -NH(CH2CH2OMejfCH2OMe, R4a ii Cl, R4b is H, R4c is Me, R4d is H 'and R4e is H; a compound of Forifnula (51) whene in R3 is -N(Et)2, R4a i; Cl, R4b is R4c is Me, JR4d is H and R4e is H; 15 a compound of Ffrmula (51) :rein RJ is -N(c- Pr) (CH2CH2CN) , R4a is Kef, RHO is H, R4C is OMe, R is H and R4e is H; 4b ,4c ,4d 20 25 a compound of/Formula (51) wherein R3 is -N(c- Pr) (CH2C«2CN) , R4a is/Cl, R4b is H, R4c is Me, R4d is H ana R4e is H; a compound of Formula (51/ wherein P.3 is -NHCH (n- Pr)(CH^OMe), r4a is/Me, R4b is H, R4c is OMe, R4d is H ind R4e is H; a compound of Formula (pi) wherein R3 is -NHCH (n- Pr)(£H20Me), R4a /s Cl, R4b is H, R4c is Me, R4d is H aad R4e is H; a compoifnd of Formula (51) wherein R3 is -NHCH (Et) 2, R4a 1J, R4c is OMe, R4d is OMe and R4e is Hj* 35 a comppund of Formula (51) wherein R3 is -NHCH(Et)2, R4a .s Br, R4b is/H, R4c is OMe, R4d is H and R4e is H; 30 40 45 a compound of Formula (51) wherein R3 is -N (CH2CH20Me)2( ,4a R"*" is Br, is H; ^4b is H, R4c is OMe, R4d is H and R4e a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2, R4a is Br/ R4b is H; is H, R4c is OMe, R"*u is H and R 4d , ,4e -210- Printed from Mimosa -kks WO 98/03510 PCTYUS97/13072 a compound of Formula (51) wherein Ry is -N(Et)2, r 4a Me, R4b is H, R4c Cl, R4d is/ H and R4e is H; is 10 a compound of Formula #51) wherein R3 is -N(Et)2, R4a is Cl, R4b is H, R4c/ is OMe, R4d/is OMe and R4e is H; a compound of Formula/(51) wherein R3 is -NHCH(Et)2, R4a is Cl, R4b is H/ R4c is OMe,/ R4d is OMe and r4e is H; a compound of Formula (51) whersin R3 is -N(CH2CH20Me) 2, R4 H; Cl, R4d is H and R4e is 15 a compound of Formula (51) wherein R3 is -NHCH (CH20Me)2, R4a is Cl, f4b is H, R47 is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is 20 -N(Pr) (CH2£H2CN) , R4a/is ci, R4b is H, R4c is Cl, R4d is H and R4e is 25 35 40 a compound of/Formula (5l/ wherein R3 is -N(Bu)(Et)( r is Cl, a compound of Formula (/l) wherein R3 is -NHCH R4d is/ H and R4e Is H; 4a 30 a compound/of Formula/(51) wherein R3 is -NHCH(Et)2, R4a is CL, R4b is h/ R4c is Cl, R4d is H and R4e is H; compoui/d of Formula (51) wherein R3 is -NHCH (Et) 2, R4a R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NHCH (Et)2, R4a ii Cl, R4b if H, R4c is Me, R4d is H and R4e is H; a compound of Fojrmula (51) wherein R3 is -NHCH (Et) 2, R4a lis Me, R4b a compound of Rormula (51) wherein R3 is -NEt2, R4a is ,4b H, R4c is OMe, R4d is H and R4e is H; 45 -211- Printed from Mimosa WO 9 a compound of Formula (51) wherein RJ is -N(Pr) (CH2CH2CN) , R4a/is Me, R4b iSj R4d is H and R4e is \ 4 f gp7/l3b72/ H, R4c is OMe, 10 54. A compound of claim/51 and isomer^ thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro/drug forms thereof, wherein said compound is 7-(3Hpentylamino)-J, 5-dimethyl-3-(2-methyl-4-methoxyphenyi)-[1,5-a]-pyrazoiopyrimidine. 55. A compound of c/laim 51 and and isomers thereof, stereoisomeric forms thereof, or mixtures of 15 stereoisomeric forms thereof, and! pharmaceutically acceptable salt or/ pro-drug forms thereof, wherein said compound is 7-(Diethylamino)-2,5-dimethy1-3-(2-methyl-4-methoxynhenyl-[1,5-a]Vpyrazolopyrimidine. 20 56. 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) -25 2, 5-dimethyIf3-(2,4-dimettyylphenyl)-[1,5-a, pyrazoiopyrimidine. 30 57. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effect/ive amount of/a compound of anyone of claims 1 1 to 56. -212- itSSsH y 58. A method of treating affective disorder, anxiety, depression headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer^ 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 4 disorder the treatment of which can be effected or facilitated by antagonizing CRF, including out not limited to disorders induced or facilitated by CRF, in non-human/nammals comprising administering to the mammal a therapeutically effective amount of a compound according to any one of claims A to 7 of 12 to 56 or a composition according jo any one of claims 8 to 10 or 57. 59. The use of a compound of Formulae (1) or (2): as defined in any one of claims 4 t® 11 or 12 to 56 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or p/odrug forms thereof for preparation of medicament 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 immunodefiaiency 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 inducedjor facilitated by CRF. 30. A method according to any one of claims 1 to 3 substantially as hereinbefore described with reference to any one of the examples. / 61. A compound according to any one of claims 4 to 11 or 12 to 56 substantially as hereinbefore described with reference to any one of the examples. -213- 07/03/00,gcop657.spe.doc, 2§3 62. A composition acco/ding to one any of claims 8 to 10 or 57 substantially as hereinbefore described with referei/ce to any one of the examples. 63. A method according to claim 58 substantially as hereinbefore described with reference to any one of the examples. 64. The use according to claim 59 substantially as hereinbefore described with reference to any one of the examples. Dated this 7th day of March, 2000. THE DU PONT MffRCK PHARMACEUTICAL COMPANY By their Registered New Zealand At^rneys: CALLiNAN LAWRIE CKi/U f.H i 214 RECr: . * >657. s8e.doc, 214 s smm 333777 5 The claims defining the invention are as follows: 1. A method of treating affective disorder, anxiety, depression, headache, irritable bowel 10 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, 15 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 20 can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in non-human mammals comprising administering to the mammal a therapeutically effective amount of a compound of Formulae (1) or 25 (2) : O Ar Ar (1) (2) -169- ^ Mmm 333777 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; 10 Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 15 indanyl, 1,2-benzopyranyl, 3,4-dihydro-l,2- benzopyranyl, tetralinyl, each Ar optionally substituted with 1 to 5 R^ groups and each Ar is attached to an unsaturated carbon atom; 20 R is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl; 25 R1 is independently selected at each occurrence from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl, C2_Ci2 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR^R^O, Ci~ 30 C4 alkyl-NR9R10, NR9COR10, OR11, SH or S (0) ; 35 R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN, -17 0- ;y. " C:; f j v ~ 333777 -NR6R7, NR9COR10, -NR6S(0)nR7, S(0)nNR5R7, Ci~ C4 haloalkyl, -OR7, SH or -S(0)nR12; r3 is selected from: 5 OR7, SH, S(0)nR13/ COR7, CO2R7, OC(0)R13, NR8COR7, N(COR7)2, NR8CONR6R7, NR8C02R13, NR6R7, NR6aR7a, N(OR7)R6, CONR^R7, aryl, heteroaryl and heterocyclyl; or .10 — Cl—Cl0 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C8 cycloalkyl, C5-C3 cycloalkenyl, C4-Cl2 cycloalkylalkyl or C6-C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents 15 independently selected at each occurrence from Ci-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR1^, SH, S(0)nR13/ COR15, C02R15, 0C(0)R13, NR8COR15, N(C0R15)2, NR8CONR16R15, 20 NR8C02R13, NR16R15, CONR16R15, aryl, heteroaryl and heterocyclyl; R4 is independently selected at each occurrence from: C1-C10 alkyl, C2"Cio alkenyl, C2-25 C10 alkynyl, C3-C6 cycloalkyl, C4- C12 cycloalkylalkyl, NO2, halo, CN, Ci~ C4 haloalkyl, NR6R7 , NR8COR7, NR8C02R7, COR7, OR7, CONR6R7, CO(NOR9)R7, CO2R7, or S(0)nR7, where each such C1-C10 alkyl, C2-C10 alkenyl, 30 C2-C10 alkynyl, C3-C6 cycloalkyl and C4- C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, N02, halo, CN, NR6R7, NR8COR7, NR8C02R7, COR7, OR7, 35 CONR6R7, CO2R7, CO(NOR9)R7, or S(0)nR7; -171- ilfii; 333777 and R7, R^a and R7a are independently selected at each occurrence from: -H, 5 -Ci-Cio alkyl, C3-C10 alkenyl, C3-C10 alkynyl, Cl-Cio haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-Cl2 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each 10 optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-Cq cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, CO2R15, 15 OC (0) R13 , NR8COR15/ N(C0R15) 2,NR8CONR15R15, NR8C02R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(Ci-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or 20 heterocyclyl(C1-C4 alkyl); alternatively, NR^r7 and NR^aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each 25 optionally substituted with 1-3 C1-C4 alkyl groups; R8 is independently selected at each occurrence from H or C1-C4 alkyl; 30 R9 and R1(^ are independently selected at each occurrence from H, C1-C4 alkyl, or C3-C6 cycloalkyl; R11 is selected from H, C1-C4 alkyl, C1-C4 35 haloalkyl, or C3-C6 cycloalkyl; -172- « mmm R12 is C1-C4 alkyl or C1-C4 haloalkyl; 333777 R1^ is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl)-; R14 is selected from C1-C10 alkyl, C3-C10 alkenyl, c3_c10 alkynyl, C3-C8 cycloalkyl, or C4-Cl2 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C±-C4 haloalkyl, cyano, OR15, SH, S(0)nR15, COR15, C02R15, OC(0)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R15, NR16R15, CONR16R15, and Ci-Cg alkylthio, Ci-Cg alkyisuifinyl and C1-C6 alkyisuifonyl; R15 and R1® are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C4-C16 cycloalkylalkyl, except that for S(0)nR^5* R15 cannot be H; aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR15/ COR15, C02R15, 0C(0)R15, NR8C0R15, N(COR15)2, NR8CONR16R15, NR8C02R15, NR16R15, and CONR16R15; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, pyranyl, quinolinyl, isoquinolinyl, -173- 1 ^ mmmi thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, 2,3-dihydrobenzothienyl or 2,3-dihydrobenzofuranyl, 5 each being optionally substituted with 1 to 5 substituents independently selected at each occurrence from Ci-Cs alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR15, -COR15, CO2R15, 0C(0)R15, NR8COR15, 10 N(COR15)2, NR8CONR16R15, NR8C02R15, NR16R15, and CONR16R15; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 15 substituents independently selected at each occurrence from C1-C5 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR15, COR15, C02R15, 0C(0)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R15, NR15R16, and 20 C0NR16R15; n is independently at each occurrence 0, 1 or 2; provided that R1 is not H or OR11 when A is CR and Z 25 is CR2; and further provided that: (1) when R1 is - (C^C., alkylene)-0-(C^C,, alkyl) or 30 - (C1-C2 alkylene) -OH, then at least one of the following conditions (i), (ii) and (iii) is true : (i) the compound is a compound of formula (2); (ii) Ar is selected from optionally substituted 35 naphthyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3- -174- 30 sS SiMtt 333777 dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-l,2 -benzopyranyl, and tetralinyl; (iii) R3 is selected from H, SH, S(0)nR13 wherein 5 n = 1, C02R7, 0C(0)R13, NR8COR7, N(COR7)2, NR8CONR6R7, NR8C02R13, N(0R7)Rs, CONR6R7, aryl other than optionally substituted phenyl, heteroaryl other than (a) optionally substituted pyrazinyl, (b) optionally 10 substituted pyrimidyl or (c) optionally substituted pyridazinyl, or heterocyclyl; and (2) when R3 is C5-C8 cycloalkenyl or C6-C10 cylcoalkenylalkyl, then at least one of the 15 following conditions (i), (ii) and (iii) is true: (i) the compound is a compound of formula (2); (ii) Ar is selected from optionally substituted naphthyl, triazinyl, furanyl, thienyl, 20 benzothienyl, benzofuranyl, 2,3- dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-l,2-benzopyranyl, and tetralinyl; (iii) R1 is selected from C2-C4 alkenyl, C2-C4 25 alkynyl, CN, Cx-C4 haloalkyl, C3-C12 hydroxyalkyl- , C4-C12 alkoxyalkyl other than - (Cx-C2 alkylene)-0- (Cj-Cj alkyl), C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9R16, C1-Ci alkyl-NR9R10, NR9COR16, OR11, SH or S(0) R1 2. A method of claim 1 wherein, in the compound of Formulae (1) or (2), Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 R^ substituents. 35 -175 ft. 333777 3. A method of claim 1 wherein, in the compound of Formulae (1) or (2) , A is N, Z is CR2, Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R1 and R2 are CH3, and R3 is 5 NR6aR7a.
4. A compound of Formulae (1) or (2): (1) (2) and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and 15 pharmaceutically acceptable salt or pro-drug forms thereof wherein: A is N or CR; 20 Z is N or CR2 ; Ar is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-25 dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-l,2-benzopyranyl, tetralinyl, each Ar optionally -176- 8i$8j 333777 substituted with 1 to 5 groups and each Ar is attached to an unsaturated carbon atom; R is independently selected at each occurrence from 5 H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl, halo, CN, C1-C4 haloalkyl; R1 is independently selected at each occurrence from 10 H, C1-C4 alkyl, C2--C4 alkenyl, C2-C4 alkynyl, halo, CN, C1-C4 haloalkyl, C1-C12 hydroxyalkyl, C2-C12 alkoxyalkyl, C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9RlO, Ci~ C4 alkyl-NR9R10, NR9COR10, OR11, SH or 15 S (0) ; R2 is selected from H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, C1-C4 hydroxyalkyl, halo, CN, 20 -NR6R7, NR9COR10, -NR6S(0)nR7, S(0)nNR6R7, Cl~ C4 haloalkyl, -OR7, SH or -S(0)nR12; R3 is selected from: OR7, SH, S(0)nR13/ COR7, C02R7, 25 OC(0)R13 , NR8COR7, N(COR7)2, NR8CONR6R7, NR8C02R13, NR6R7, NR6aR7a, N(OR7)R6, CONR^R7, aryl, heteroaryl and heterocyclylr Qr -C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, 30 C3-C8 cycloalkyl, C5-C8 cycloalkenyl, C4- Cl2 cycloalkylalkyl or C6-C10 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence 35 from C1-C6 alkyl, C3-C6 cycloalkyl, halo, -17 7- 333777 C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, C02R15, 0C(0)R13, NR8COR15, N(C0R15)2, NR8C0NR16R15, NR8C02R13, NR16R15, C0NR16R15, aryl, 5 heteroaryl and heterocyclyl; R4 is independently selected at each occurrence from: C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-10 C12 cycloalkylalkyl, NO2, halo, CN, Ci~ C4 haloalkyl, NR6R7, NR8COR7, NR8C02R7, COR7, OR7, CONR6R7, CO(NOR9)R7, C02R7, or S(0)nR7, where each such C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C5 cycloalkyl and C4-15 C12 cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C4 alkyl, NO2, halo, CN, NR6R7, NR8COR7, NR8C02R7, COR7, OR7, CONR6R7, C02R7, CO(NOR9)R7, or S(0)nR7; 20 R^ and R7, R^a and R7a are independently selected at each occurrence from: -H, -C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, 25 C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-Cl2 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 30 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-Cg cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S<0)nR13, COR15, CO2R15, 0C(0)R13, NR8COR15, N(COR15)2, 35 NR8CONR16R15, NR8C02R13, NR16R15, -178- 10 20 ISWI 333777 conr-^r15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(Ci-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl), alternatively, NR^R7 and NR^aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups; R8 is independently selected at each occurrence from H or C1-C4 alkyl; R9 and R1^ are independently selected at each 15 occurrence from H, C1-C4 alkyl, or C3-C6 cycloalkyl; R11 is selected from H, C1-C4 alkyl, C1-C4 haloalkyl, or C3-C6 cycloalkyl; r!2 is C1-C4 alkyl or C1-C4 haloalkyl; R18 is selected from C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-Cg cycloalkyl, C4™ 25 C12 cycloalkylalkyl, aryl, aryl(C1-C4 alkyl)-, heteroaryl or heteroaryl(C1-C4 alkyl)-; R14 is sel ected from C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, or C4-30 C12 cycloalkylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, Ci-C4 haloalkyl, cyano, OR^5, SH, S(0)nR^5^ COR^5, 35 C02R15, OC(O)R15, NR8COR15, N(COR15)2, -179- 333777 NR8CONR16R15, NR8C02R15, NR16R15, CONR16R15, and C1-C6 alkylthio, Ci-Cg alkyisuifinyl and C1-C5 alkyisuifonyl; R15 and R1^ are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C4-C16 cycloalkylalkyl, except that for S(0)nR"^/ R15 cannot be H; aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR15, COR15, C02R15, 0C(0)R15, NR8COR15, N(COR15)2/ NR8CONR16R15, NR8C02R15, Nr16r15/ and CONR16R15; 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 C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR15, -COR15, C02R15, 0C(0)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R15, NR16R15, and CONR16R15; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each -180- « aiiiiH 333777 10 occurrence from Ci~C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR15, COR15, C02R15, OC(0)R15, NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R15, NR15R16, and CONR16R15; n is independently at each occurrence 0, 1 or 2, with the provisos that: (1) when A is N, Z is CR2, R2 is H, R3 is -OR7 or -0C0R13, and R7 is H, then R1 is not H, OH or SH; 15 (2) when A is N, Z is CR2, R1 is H, SH, SCH3, CH3 or C2H5( R2 is H, and R3 is OH, H, CH3, C2H5, C6H5, n-C3H7, i-C3H7, SH, SCH3, nhc4h9, or N(C2H5)2; then Ar is not phenyl, m-Cl-phenyl, or m-CH3-phenyl. 20 (3) when Z is CR2, R2 is H, R1 is H or C1-C4 alkyl and Ar is pyridyl or unsubstituted pyrimidinyl then R3 is not -NH2, -NR8COR7 wherein R7 is C1-C5 alkyl, NR8CONR6R7 wherein R6 25 and R7 are each independently selected from H and C1-C5 alkyl, provided that at least one of r6 and r7 is H, or nr6ar7a, wherein r6a and r7a are independently selected from H and C1-C5 alkyl; 30 (4) when A is N, Z is CR2, and R2 is S02NR6R7, then R3 is not OH or SH; (5) when A is CR and Z is CR2, then R2 is not- 35 NR6S02R7 or -S02NR6R7; -181- mm-. 1/ 333777 (6) when A is N, Z is CR2 and R2 is -NR6S02R7 or -S02NR6R7, then R3 is not OH or SH; (7) when A is N, Z is CR2, R1 is methyl or ethyl, R2 5 is H, and R3 is H, OH, CH3, C2H5, C6H5, n-C3H7, iso-C3H7, SH, SCH3, NH(n-C4H9)/ or N(C2H5)2, then Ar is not unsubstituted phenyl or m-methylphenyl; 10 (8) when A is CR, when R is H, and Z is CR2, Ar is not phenyl or substituted phenyl (9) when A is CH, Z is CR2, R1 is OR11, R2 is H, R3 is OR7, and R7 and R11 are both H, then Ar is 15 not phenyl, p-Br-phenyl, p-Cl-phenyl, p-NHCOCH3- phenyl, p-CH3-phenyl, pyridyl or naphthyl; (10) when R1 is - (C1-C2 alkylene) -0- (C1-C2 alkyl) or - (C1-C2 alkylene)-OH, then at least one of the 20 following conditions (i), (ii) and (iii) is true: (i) the compound is a compound of formula (2); (11) Ar is selected from optionally substituted naphthyl, triazinyl, furanyl, thienyl, 25 benzothienyl, benzofuranyl, 2,3- dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-l,2- benzopyranyl, and tetralinyl; iii) R3 is selected from H, SH, S(0)nR13 wherein n 30 1, COjR7, OC (0) R13, NR8COR7, N(C0R7),, NR8CONR6R NR8C02R13, N(OR7)R6, CONR6R7, aryl other than optionally substituted phenyl, heteroaryl other than (a) optionally substituted pyrazinyl, (b) optionally substituted pyrimidyl or (c) 35 optionally substituted pyridazinyl, or heterocyclyl; and -182- aa 333777 (11) when R3 is C5-C8 cycloalkenyl or C6-C10 cylcoalkenylalkyl, then at least one of the following conditions (i), (ii) and (iii) is true: 5 (i) the compound is a compound of formula (2); (ii) Ar is selected from optionally substituted naphthyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 10 indanyl, 1,2-benzopyranyl, 3,4-dihydro-l,2 - benzopyranyl, and tetralinyl; (iii) R1 is selected from C2-C4 alkenyl, C2-C4 alkynyl, CN, C1-C4 haloalkyl, C3-C12 hydroxyalkyl-,C4-C12 alkoxyalkyl other than - (C1-C2 alkylene)- 15 0- (Cj^-Cj alkyl), C2-C10 cyanoalkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl, NR9R16, C1-C4 alkyl-NR9R10, NR9COR16, OR11, SH or S(0)nR12-
5. A compound of claim 4 and isomers thereof, 20 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof with the additional provisos that: (1) when A is N, R1 is H, C1-C4 alkyl, halo, CN, C1-C12 hydroxyalkyl, C1-C4 25 alkoxyalkyl or SO2(C1-C4 alkyl), R^ is NR^aR7a and R6a is unsubstituted C1-C4 alkyl, then R7a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, benzofuranyl, benzothiazolyl, indolyl or C3-C6 cycloalkyl; and (2) 30 A is N, R1 is H, C1-C4 alkyl, halo, CN, C1-C12 hydroxyalkyl, C1-C4 alkoxyalkyl or SC>2 (C1-C4 alkyl), R3 is NR^aR7a and R7a is unsubstituted C1-C4 alkyl, then R^a is not phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, furanyl, 35 benzofuranyl, benzothiazolyl, indolyl or C3-C6 cycloalkyl. -183- mmw 333777
6. A compound of claim 4 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically 5 acceptable salt or pro-drug forms thereof wherein Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, each optionally substituted with 1 to 4 substituents.
7. A compound of claim 6 and isomers thereof, 10 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein A is N, Z is CR2, Ar is 2,4-dichlorophenyl, 2,4-dimethylphenyl or 2,4,6-trimethylphenyl, R1 and R2 15 are CH3, and R3 is NR6aR7a.
8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 20 4.
9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 25 6.
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 30 7 .
11. A compound of claim 4 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically 35 acceptable salt or pro-drug forms thereof wherein A is N. -184 - sis /siSHiitji 333777
12. A compound of Formula (2) of claim 11 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically 5 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 10 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^ substituents.
14. A compound of claim 12 and isomers thereof, 15 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R3 is NR6aR7a Qr OR7. 20
15. 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 25 is optionally substituted with 1 to 4 R^ substituents, and R3 is NR6aR7a or OR7 .
16. A compound of Formula (1) of claim 11 and isomers thereof, stereoisomeric forms thereof, or mixtures of 30 stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Z is CR2 .
17. A compound of claim 16 and isomers thereof, 35 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically -185- H: 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 R4 substituents. 5
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 R3 is NR6aR7a or OR7 . 10
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 15 R^a is independently selected from: -H, -Ci-Cio alkyl, C3-C10 alkenyl, C3-C10 alkynyl, Ci-Cio haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-20 C12 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C]_-C6 alkyl, C3-25 Cg cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, CO2R15, OC (0) R13 , NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R13, NR16R15, CONR1®r15, aryl, heteroaryl or 30 heterocyclyl, -aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl)-, heterocyclyl or heterocyclyl (C3.-C4 alkyl)-; and R7a is independently selected at each occurrence from: 35 -H, -186- ■s mm* 333777 -C5-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, Cl~Cio haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-Cl2 cycloalkylalkyl, C5-C10 cycloalkenyl, 5 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, 10 cyano, OR15, SH, S(0)nR13, COR15, CO2R15, 0C(0)R13, NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R13, NR16R15, CONR-^R15, aryl, heteroaryl or heterocyclyl, 15 -aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl); alternatively, NR^R7 and NR^aR7a are independently 20 piperidine, pyrrolidine, piperazine, N- methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups.
20. A compound of claim 18 and isomers thereof, 25 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a and R7a are identical and are selected from: -C1-c4 alkyl or C3-C6 cycloalkyl, each optionally 30 substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-c4 haloalkyl, cyano, OR15, SH, S(0)nRl3/ -CORlS, C02R15, 0C(0)Rl3, NR8COR15, N(CORl5)2, -187- ;fs mmm 333777 NR8CONRl6Rl5, NR8CO2R13 , NR16R15, CONR^R15, aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl. 5
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 R6a is selected from: 10 -H, -Ci-Cio alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C1-C10 haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, 15 or C5-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, 20 cyano, OR15, SH, S(0)nR13, COR15, CO2R15, OC (0) R13 , NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R13, NR16R15, CONR-^r15, aryl, heteroaryl or heterocyclyl, 25 -aryl, aryl(Ci-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl); R7a is selected from: -C1-c4 alkyl and each such C1-C4 alkyl is 30 substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-c4 haloalkyl, cyano, ORIS, SH, S(0)nRl3, CORlS, CO2R15, OC (0) RI3 , NR8C0Rl5, N(CORl5)2, -188 m Mil# 333777 NR8CONR16R15, NR8C02R13 / NR16R15, CONR1^^, aryl, heteroaryl or heterocyclyl.
22. A compound of claim 18 and isomers thereof, 5 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R6a and R7a is selected from: -C3-C6 cycloalkyl, each such C3-C6 cycloalkyl 10 optionally substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-c4 haloalkyl, cyano, ORl5, SH, S(0)nRl3, CORI5, CO2R15, 0C(0)R13, NR8COR15, N(CORl5)2, 15 nr8conr16r15, NR8CO2R13, nr16r15, conr!6r15, aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, 20 and the other of R6a and R7a is unsubstituted C1-c4 alkyl.
23. A compound of claim 18 and isomers thereof, stereoisomeric forms thereof, or mixtures of 25 stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^a and R7a are independently H or C1-C10 alkyl, each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each 30 occurrence from C1-C5 alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13/ COR15, C02R15, OC(0)R13 , NR8COR15, N(COR15)2, R8CONR16R15, NR8C02 R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl. 35 -189- 333777
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 5 phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 substituents, and R3 is NR6aR7a or OR7.
25. A compound of claim 24 and isomers thereof, 10 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a j_s independently selected from: -H, 15 -Ci-Cio alkyl, C3-C10 alkenyl, C3-C10 alkynyl, Ci-Cio 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 Ci-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, CO2R15, OC(0)R13 , NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R13, NR16R15, CONR^r15, aryl, heteroaryl or heterocyclyl, 20 25 30 -aryl, aryl(C1-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl); R7a is independently selected at each occurrence from: -H, 35 ~C5-Cio alkyl, C3-C10 alkenyl, C3-C10 alkynyl, Ci-Cio haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4- -190 as sifsiw; 333777 Cl2 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at 5 each occurrence from C1-C6 alkyl, C3- C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, CO2R15, OC(O)R13 , NR8COR15, N{COR15)2, NR8CONR16R15, NR8C02R13, NR16R15, 10 CONR1^r15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(Ci-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl), 15 alternatively, NR^R7 and NR^aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups. 20
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 R6a 25 and R7a are identical and are selected from: -C1-c4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C]_-C6 alkyl, C3-C6 cycloalkyl, halo, C1-C4 30 haloalkyl, cyano, ORIS, sh, S(0)nR13, -COR15, CO2R15, OC (0) R13 , NR8COR15, N(CORl5)2, NR8CONR16Rl5, NR8CO2R13, NR16Rl5 ( CONRiSRlS, aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl. 35 -191 « mmim- 333777
27. 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 Rga 5 and R7a are identical and are -C1-c4 alkyl, each such C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, 10 halo, C1-c4 haloalkyl, cyano, OR15, SH, S (0) nR13 / -C0R15, CO2R15, 0C(0)R13, NRSCOR15, N(CORl5)2, NR8CONR16R15, NR8CO2R13, NR16R15/ CONR16r15 , aryl, heteroaryl or heterocyclyl. 15
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 R6a is selected from: 20 -H, —C1 — C]_0 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, Ci-Cio haloalkyl with 1-10 halogens, C2~C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, C5-C10 cycloalkenyl, 25 or C6-C14 cycloalkenylalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-Cq cycloalkyl, halo, C1-C4 haloalkyl, 30 cyano, OR15, SH, S(0)nR13, COR15, CO2R15, OC(0)R13 , NR8COR15, N(COR15 ) 2 < NR8CONR16R15, NR8C02R13, NR15R15, CONR1®r15, aryl, heteroaryl or heterocyclyl, -192- 333777 -aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl); R7a is: 5 -C1-C4 alkyl and each such C1-C4 alkyl is substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, C1-c4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, 10 CO2R15, OC (0) R13, NR8COR15, N (COR15 ) 2 , nrsconrisrls, nr8c02r13, nr16rl51 com^r^, aryl, heteroaryl or heterocyclyl.
29. A compound of claim 24 and isomers thereof, 15 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R6a and R7a is selected from: -C3-C6 cycloalkyl, each such C3-C6 cycloalkyl 20 optionally substituted with 1-3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halo, c1-c4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, CO2R15, OC (O) R13 , NR8COR15, N(COR15)2, 25 NR8CONR16R15, NR8C02R13, NR^R15, CONR^RlS, aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, 30 and the other of R6a and R7a is unsubstituted C1-c4 alkyl.
30. A compound of claim 24 and isomers thereof, stereoisomeric forms thereof, or mixtures of -193 ^ ^ ^ j* ^ Ij^l f. ^ I 333777 stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^a and R7a are independently H or Ci-Cio alkyl, each such Ci-Cio alkyl optionally substituted with 5 1 to 3 substituents independently selected at each occurrence from C±-Cq alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR^3' COR15, C02R15, OC(O)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8C02R13, NR16R15, CONR16R15, aryl, 10 heteroaryl or heterocyclyl.
31. A compound of claim 16 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^ substituents, -R3 is NR6aR7a or OR7 and 20 -R1 and R2 are independently selected from H, C±- C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.
32. A compound of claim 31 and isomers thereof, 25 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R6a j_s independently selected from: -H, 30 -C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, Cl-Cio haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-Cl2 cycloalkylalkyl, C5-C10 cycloalkenyl, or C6-C14 cycloalkenylalkyl, each 35 optionally substituted with 1 to 3 substituents independently selected at -194- * mm 333777 each occurrence from C]_-C6 alkyl, C3-Cs cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, CO2R15, OC (0) R13 , NR8COR15, N(COR15)2, 5 NR8CONR16R15, NR8C02R13, NR16R15, CONR16r15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(Ci-C4 alkyl)-, heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or 10 heterocyclyl(C1-C4 alkyl); R7a is independently selected at each occurrence from: -H, -C5-C10 aikyi, C3-C10 alkenyl, C3-C10 alkynyl, Cl-Cio haloalkyl with 1-10 halogens, C2-C8 15 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 20 each occurrence from C1-C6 alkyl, C3- Cq cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, CO2R15, OC(0)R13 , NR8COR15, N(COR15 ) 2 / NR8CONR16R15, NR8C02R13, NR16R15, 25 CONR-L^R15, aryl, heteroaryl or heterocyclyl, -aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl), 30 alternatively, NR^R7 and NR6aR7a are independently piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine, each optionally substituted with 1-3 C1-C4 alkyl groups. 35 -195 Alfiiirfjf 33
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 R6a 5 and R7a are identical and are selected from: -C1-c4 alkyl or C3-C6 cycloalkyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-Cg alkyl, C3~Cg cycloalkyl, halo, C1-c4 10 haloalkyl, cyano, OR15, SH, S(0)nRi3, -C0R15, CO2R15, 0C(0)Rl3, NR8COR15, N(CORl5)2, NR8CONR16R15, NR8CO2R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl, and -aryl or heteroaryl. 15
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 R6a 20 and R7a are identical and are -C1-c4 alkyl, each such C1-C4 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, 25 halo, C1-c4 haloalkyl, cyano, OR15, SH, S (0) nR13, -C0R15, CO2R15, 0C(0)Rl3, NRSCORIS, N(CORl5)2, NR8C0NR16R15, NR8CO2R13 , NR16R15, CONR16r15 ; aryl, heteroaryl or heterocyclyl. 30
35. 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 R6a is selected from: 35 -H, -196- ft /!»»: 333777 -Cl"Cio alkyl, C3-C10 alkenyl, C3-C10 alkynyl, Ci-Cio haloalkyl with 1-10 halogens, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-Cl2 cycloalkylalkyl, C5-C10 cycloalkenyl, 5 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, 10 cyano, OR15, SH, S(0)nR13, COR15, CO2R15, OC(0)R13 , NR8COR15, N(COR15)2, NR8CONR16R15, NR8C02R13, NR16R15, CONR^R15, aryl, heteroaryl or heterocyclyl, 15 -aryl, aryl(C1-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl or heterocyclyl(C1-C4 alkyl); R7a is : -C1-c4 alkyl and each such C1-C4 alkyl is 20 substituted with 1-3 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-C6 cycloalkyl, halo, C1-c4 haloalkyl, cyano, ORIS, SH, S(0)nRl3, C0R15, CO2R15, 0C(0)R13, NR8COR15, N(CORl5)2, 25 NR8CONR16R15; NR8C02R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl.
36. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of 30 stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein one of R6a and R7a is selected from: -C3-C6 cycloalkyl, each such C3-C6 cycloalkyl optionally substituted with 1-3 substituents 35 independently selected at each occurrence from -197- « Ml % 333777 a IIeJ? Ci~C6 alkyl, C3-C6 cycloalkyl, halo, C1-c4 haloalkyl, cyano, OR15, SH, S(0)nRl3, COR15, CO2R15, 0C(0)R13, NRSCORiS, N(CORl5)2, NRSCONRiSRlS, NR8CO2R13, NR16R15, CONR16R15 , 5 aryl, heteroaryl or heterocyclyl, -aryl, -heteroaryl or -heterocyclyl, and the other of R6a and R7a is unsubstituted C1-c4 10 alkyl.
37. A compound of claim 31 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically 15 acceptable salt or pro-drug forms thereof wherein R6a ancj j>7a are independently H or C1-C10 alkyl, each such C1-C10 alkyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from Ci-Cg alkyl, C3-C6 cycloalkyl, 20 halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR"'"3/ COR15, CO2R15, OC(0)R13 , NR8COR15, N(COR15)2, R8CONR16R15, NR8C02R13, NR16R15, CONR16R15, aryl, heteroaryl or heterocyclyl. 25
38. A compound of claim 31 of Formula (50) -198- m mmm* 333777 R4C FORMULA (50) 5 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 R3 is -NHCH(n-Pr)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(Et)(n-Bu) 15 R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(n-Pr)(CH2cPr), R4a is Cl, R4b is H, R4c is Cl, 20 R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; 25 a compound of Formula (50) wherein R3 is -NHCH(Et)(n-Bu), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; -199- « nmm 333777 a compound of Formula (50) wherein R3 is -NHCH(Et)(CH20Me), R4a is C1, R4b is H, R4c is Cl, R4d is H and R4e is H; 5 a compound of Formula (50) wherein R3 is -NHCH(CH20Me)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(Et)2/ r4a 10 is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(CH2OEt)2t R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; 20 a compound of Formula (50) wherein R3 is -N(Me)(Ph)r R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(n-Pr)2/ r4a 25 is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(Et)(n-Pr), R4a is Cl, R4b is H, R4c is Cl, 15 30 R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(CH20Me)2; R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me; 35 a compound of Formula (50) wherein R3 is -NHCH(CH20Me)2; R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is 40 -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; -200- 30 ■sis mmn 333777 a compound of Formula (50) wherein R3 is -NHCH(Et)(CH2OMe), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -OEt; R4a is H; is 10 cl, R4b is H, R4c is Cl, R4d is H and R4e a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; 15 a compound of Formula (50) wherein R3 is -N(CH2CN)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is 20 -NHCH(Me)(CH2OMe)r R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -OCH(Et)(CH20Me), R4a is Me, R4b is H, R4c is Me, 25 R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(n-Pr)(CH2cPr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(Me)(CH2N(Me)2), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; 35 a compound of Formula (50) wherein R3 is -N(cPr)(CH2CH2CN); R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is 40 -N(n-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; -201 20 mum 333777 a compound of Formula (50) wherein R3 is -N(n-Bu)(CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; 5 a compound of Formula (50) wherein R3 is -NHCH(Et)(CH20Me)r R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me; a compound of Formula (50) wherein R3 is -NHCH(Et)2, 10 R4a is Me, R4b is H, R4c is Me, R4d is H and R4e i s Me ; a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Me, 15 R4d is H and R4e is Me; a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2/ R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(Et)(CH20Me), R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H; 4a 25 a compound of Formula (50) wherein R3 is -N(Et)2| R is Me, R4b is H, R4c is Me, R4d is H and R4e is Me; a compound of Formula (50) wherein R3 is 30 -NHCH(CH20Et)2; R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me; a compound of Formula (50) wherein R3 is -NHCH(CH2CH20Me)(CH20Me), R4a is Me, R4b is H, R4c 35 is Me, R4d is H and R4e is Me; 40 a compound of Formula (50) wherein R3 is morpholino, R4a i is H; R4a is Me, R4b is H, R4c is Me, R4d is H and R4e -202- 333777 15 a compound of Formula (50) wherein R3 is - N(CH2CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H; 5 a compound of Formula (50) wherein R3 is -NHCH(Et)2/ R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(Et)2/ r4a 10 is Br, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NH(c-Pr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2, R4a is CN, R4b is H, R4c is OMe, R4d is H and R4e is H; 20 a compound of Formula (50) wherein R3 is -N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is Me; a compound of Formula (50) wherein R3 is -NCH(CH2OMe)2; 25 r4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c 30 is Br, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2/ R4a is Me, R4b is H, R4c is OMe, 35 R4d is Me and R4e is H; a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H; 40 a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a i is H; R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e -203- SI! 333777 a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Me, R4b is H, R4c is OMe, R4d is Me and R4e is H; 5 a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; 10 a compound of Formula (50) wherein R3 is -NHCH(Et)(CH20Me), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is 15 -N(CH2CH20Me)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)(CH2CH2OMe), R4a is Cl, R4b is H, R4c 20 is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(c-Pr)(CH2CH2CN), R4a is Me, R4b is H, R4c is Ar\ , . 4p « OMe, R is Me and R xs H; a compound of Formula (50) wherein R3 is -N(c-Pr)(CH2CH2CN), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; 30 a compound of Formula (50) wherein R3 is (S)-NHCH(CH20Me)(CH2CH2OMe), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is 35 -NHCH(CH20Me)(CH2CH2OMe); R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; 25 40 a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a i is H; R4a is Me, R4b is H, R4c is Br, R4d is H and R4e -204- as fflJMB!. 333777 35 a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NH(CH20Me)(CH2-iPr), R4a is Me, R4b is H, R4 Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is c is 4d 10 -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is H, R is H and R4e is H; a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is NMe2, 15 R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)(n-Pr), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; 20 a compound of Formula (50) wherein R3 is -NHCH(CH2OEt)(Et); R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; 25 a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is NMe2, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(Et)2/ R4a 30 is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 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 R3 is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; -205- 333777 10 a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Me, R4b is H, R4c is Br, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; 15 a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a i is H; R4a is Me, R4b is H, R4c is NMe2, R4d is H and R4e a compound of Formula (50) wherein R3 is 20 (£)-NHCH(CH2OMe)(CH2CH2OMe); R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(CH20Me)(CH2CH2OMe); R4a is Me, R4b is H, R4c 25 is Me, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is (S)-NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; 30 a compound of Formula (50) wherein R3 is -NHCH(CH2OMe)(CH2CH2OMe), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; 35 a compound of Formula (50) wherein R3 is -N(c-Pr)(CH2CH2CN); R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is 40 -NHCH(Et)(CH2CN), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; -206- 20 333777 a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H; 5 a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)(CH2CH2OH); R4a is Cl, R4b is H; R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is 10 -N(CH2CH2OMe)2, R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is Me, R4c is OMe, R4d 15 is H and R4e is H; a compound of Formula (50) wherein R3 is -N(CH2C-Pr) (n-Pr), R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(c-Pr) (CH2CH2CN); R4a is Me, R4b is Me, R4c is OMe, R4d is H and R4e is H; 25 a compound of Formula (50) wherein R3 is -NHCH (Et)2/ R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(Et)2, R4a 30 is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -N(CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is OMe, 35 R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(Et)(CH2OMe), R4a is Cl, OMe, R4d is H and R4e is H; R4b is H, R4c is 40 -207 S3 SMB.) a compound of Formula (50) wherein R3 is -N(Et)2, R4a is Cl, R4b is H, R4c is CN, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is 5 -N(c-Pr)(CH2CH2CN), R4a is Cl, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (50) wherein R3 is -NHCH(CH2OH)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e 10 is H; and a compound of Formula (50) wherein R3 is N(CH2CH20Me)2, R4a j_s Me< R4b j_s H? r4c 0Me, r4d is H and R4e is H. 15
39. 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 20 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, 25 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]-30 pyrazolo-1,3,5-triazine.
41. A compound of claim 4 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically 35 acceptable salt or pro-drug forms thereof wherein A is CR. -208- 333777
42. A compound of Formula (2) of claim 41 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof. 5
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 10 phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R4 substituents.
44. A compound of claim 42 and isomers thereof, stereoisomeric forms thereof, or mixtures of 15 stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R3 is NR6aR7a or OR7.
45. A compound of claim 42 and isomers thereof, 20 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 R4 substituents, 25 and R3 is NR6aR7a Qr OR7 .
46. A compound of Formula (1) of claim 41 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically 30 acceptable salt or pro-drug forms thereof wherein Z is CR2 .
47. A compound of claim 46 and isomers thereof, stereoisomeric forms thereof, or mixtures of 35 stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein Ar is -209- M ('ilfllfji' 333777 phenyl, pyridyl or 2,3-dihydrobenzofuranyl and each Ar is optionally substituted with 1 to 4 R4 substituents.
48. A compound of claim 46 and isomers thereof, 5 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R3 is NR6aR7a Qr OR7 . 10
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 15 is optionally substituted with 1 to 4 R4 substituents, and R3 is NR6aR7a or OR7.
50. A compound of claim 49 and isomers thereof, stereoisomeric forms thereof, or mixtures of 20 stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^a and R7a are independently H or Ci-Cio alkyl, and each such Ci-Cio alkyl is optionally substituted with 1 to 3 substituents independently 25 selected at each occurrence from Ci-Cg alkyl, C3-C6 cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, C02R15, OC(0)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8C02R13, NR16R15, CONR-^R15, aryl, heteroaryl or heterocyclyl. 30
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 -210 333777 -Ar is phenyl, pyridyl or 2,3-dihydrobenzofuranyl, and each Ar is optionally substituted with 1 to 4 R4 substituents, -R3 is NR6aR7a or OR7 and 5 -R1 and R2 are independently selected from H, Ci~ C4 alkyl, C3-C6 cycloalkyl, C4-C10 cycloalkylalkyl.
52. A compound of claim 51 and isomers thereof, 10 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof wherein R^a and R7a are independently H or Cl-Cio alkyl, and each such C1-C10 alkyl is optionally 15 substituted with 1 to 3 substituents independently selected at each occurrence from C±-Cq alkyl, C3-Cq cycloalkyl, halo, C1-C4 haloalkyl, cyano, OR15, SH, S(0)nR13, COR15, C02R15, 0C(0)R13, NR8COR15, N(COR15)2, R8CONR16R15, NR8C02R13, NR16R15, 20 CONR-L^R15, aryl, heteroaryl or heterocyclyl.
53. A compound of Formula (51) FORMULA (51) 25 -211 AS 5 10 15 20 25 30 35 40 mmm \ 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 is -NHCH(n-Pr)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R^ is -NHCH(CH20Me)2, R4a is Me, R4b is H, R4c is Me, R4d ^s H and R4e H. a compound of Formula (51) wherein R^ is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R^ is -N(c-Pr) (CH2CH2CN) , R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R8 is -N(CH2CH2OMe)2, R4a is cl^ R4b is H^ R4c ±s Me# R4d is H and R4e is H; a compound of Formula (51) wherein R8 is -NHCH(CH2OMe)2, R4a is C1, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R8 is -NHCH(Et)2/ R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H ; a compound of Formula (51) wherein R^ is -N(Et)2/ R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R^ is -N(n-Pr) (CH2CH2CN) , R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; -212- 20 35 mmm 333777 a compound of Formula (51) wherein R3 is -N(n-Bu) (CH2CH2CN) t R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; 5 a compound of Formula (51) wherein R8 is -NHCH(n-Pr)(CH20Me), R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NHCH(Et)2/ 10 R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2, R4a is Me, R4b is H, R4c is OMe, 15 R4d is H and R4e is H; a compound of Formula (51) wherein R^ is (S) -NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c AH , A is Me, R is H and R is H; a compound of Formula (51) wherein R^ is -NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; 25 a compound of Formula (51) wherein R^ is -N(CH2CH2OMe)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein r3 is -NH(Et), R4a 30 is Me, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NHCH(n-Pr)2r R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2/ R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; -213- iis MMBii 333777 a compound of Formula (51) wherein R3 is (S) -NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; 5 a compound of Formula (51) wherein R3 is -NH(CH2CH2OMe)CH2OMe, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is 10 -N(n-Pr) (CH2CH2CN)t R4a is Me, R4b is H, R4c is 15 20 35 OMe, R4d is H and R4e is H; 4a a compound of Formula (51) wherein R3 is -N(Et)2/ r is Me, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is (S) -NH(CH2CH2OMe)CH2OMe, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NH(CH2CH2OMe)CH2OMe, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; 25 a compound of Formula (51) wherein R3 is -N(Et)2/ R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -N(c-Pr) (CH2CH2CN) ; R4a is Me, R4b is H, R4c is 30 OMe, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -N(c-Pr) (CH2CH2CN) , R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NHCH (n-Pr)(CH20Me), R4a is Me, R4b is H, R4c is OMe, R4d is H and R4e is H; -214- 20 35 is feiBCSf® 333777 a compound of Formula (51) wherein R3 is -NHCH (n-Pr)(CH2OMe), R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; 5 a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Br, R4b is H, R4c is OMe, R4d is OMe and R4e is H; a compound of Formula (51) wherein R3 is -NHCH(Et)2, 10 R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -N(CH2CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, 15 R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2, R4a is Br, R4b is H, R4c is OMe, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -N(Et)2; r4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -N(Et)2/ r4a 25 is Cl, R4b is H, R4c is OMe, R4d is OMe and R4e is H; a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a i 30 R4e is H; R4a is Cl, R4b is H, R4c is OMe, R4d is OMe and a compound of Formula (51) wherein R3 is -N (CH2CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NHCH(CH2OMe)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; -215- 333777 a compound of Formula (51) wherein R3 is -N(Pr) (CH2CH2CN), R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; 5 a compound of Formula (51) wherein R3 is -N(Bu)(Et)t R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is 10 -NHCH(Et)CH2OMe; R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Cl, R4b is H, R4c is Cl, R4d is H and R4e 15 is H; a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is H, R4c is Me, R4d is H and R4e is H; 20 a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Cl, R4b is H, R4c is Me, R4d is H and R4e is H; 25 a compound of Formula (51) wherein R3 is -NHCH(Et)2, R4a is Me, R4b is H, R4c is Cl, R4d is H and R4e is H; a compound of Formula (51) wherein R3 is -NEt2, R4a is 30 Me, R4b is H, R4c is OMe, R4d is H and R4e is H; and a compound of Formula (51) wherein R3 is -N(Pr) (CH2CH2CN) , R4a is Me, R4b is H, R4c is OMe, 35 r4d is H and R4e is H.
54. A compound of claim 51 and isomers thereof, stereoisomeric forms thereof, or mixtures of 40 stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein said compound is 7-(3-pentylamino)-2,5-dimethyl-3- -216- «MW 333777 (2-methyl-4-methoxyphenyl)-[1,5-a]- pyrazoiopyrimidine.
55. A compound of claim 51 and and isomers thereof, 5 stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt or pro-drug forms thereof, wherein said compound is 7-(Diethylamino)-2,5-dimethyl-3-(2-methyl-4-methoxyphenyl-[1,5-a]-pyrazoiopyrimidine. 10
56. 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 15 said compound is 7-(N-(3-cyanopropyl)-N- propylamino)-2,5-dimethyl-3-(2,4-dimethylphenyl)-[1,5-a]-pyrazoiopyrimidine.
57. A pharmaceutical composition comprising a 20 pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 11 to 56.
58. A method of treating affective disorder, 25 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 30 alcohol withdrawal symptoms, inflammatory diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, 35 hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, -217-