AU9021598A - Nitrogen substituted imidazo{4,5-c}pyrazoles as corticotropin relea sing hormone antagonists - Google Patents

Description

WO 99/10350 PCT/US98/17049 TITLE NITROGEN SUBSTITUTED IMIDAZO[4,5-c]PYRAZOLES AS CORTICOTROPIN RELEASING HORMONE ANTAGONISTS. 5 FIELD OF THE INVENTION This invention relates to novel nitrogen substituted imidazo[4,5-c]pyrazole compounds and pharmaceutical compositions, and to methods for the treatment of psychiatric disorders and neurological 10 diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological, cardiovascular or heart related diseases and colonic hypersensitivity 15 associated with psychopathological disturbance and stress. In particular, the present invention relates to novel imidazopyrimidines and imidazopyridines, pharmaceutical compositions containing such compounds and their use in treating psychiatric disorders, 20 neurological diseases, immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress. 25 BACKGROUND OF THE INVENTION Corticotropin releasing hormone or factor (herein referred to as CRH or CRF), a 41 amino acid peptide, is the primary physiological regulator of 30 proopiomelanocortin(POMC) -derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, 35 immunohistochemical localization of CRF has -1- WO99/10350 PCT/US98/17049 demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent 5 with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G.F. Koob, Persp. Behav. Med. 2:39 (1985); E.B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant 10 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 15 role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's 20 disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E.B. De Souza, Hosp. Practice 23:59 (1988)]. 25 In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C.B. Nemeroff et al., Science 226:1342 (1984); C.M. Banki et al., Am. J. Psychiatry 144:873 (1987); R.D. 30 France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of 35 CRF [C.B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted -2- WO99/10350 PCTIUS98/17049 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 5 (1984); P.W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R.M. Sapolsky, 10 Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)]. 15 There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine / non benzodiazepine anxiolytics and CRF have been 20 demonstrated in a variety of behavioral anxiety 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 25 behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines [C.W. Berridge and A.J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, 30 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 35 of CRF in both the conflict test [K.T. Britton et al., Psychopharmacology 86:170 (1985); K.T. Britton et -3- WO 99/10350 PCT/US98/17049 al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N.R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Rol5-1788), which 5 was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K.T. Britton et al., Psychopharmacology 94:306 (1988)]. 10 The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is 15 observed in these disorders. Of particular 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"f effects 20 qualitatively similar to the benzodiazepines [for review see G.F. Koob and K.T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E.B. De Souza and C.B. Nemeroff eds., CRC Press p221 (1990)]. 25 Several publications describe corticotropin releasing factor antagonist compounds and their use to treat psychiatric disorders and neurological diseases. Examples of such publications include DuPont Merck PCT application US94/11050, Pfizer WO 95/33750, Pfizer WO 30 95/34563, Pfizer WO 95/33727 and Pfizer EP 778277 Al. European Patent Application Number 190457 Al discloses 3-methyl-imidazo [4,5-cl pyrazole derivatives which have the general formula shown 35 below. The compounds have an intense depressant -4- WO 99/10350 PCTIUS98/17049 activity on the central nervous system, including anticonvulsant, sedative, analgesic and hypothermizing.

CH

3 N N N/ R N N H 5 R Similar imidazo[4,5-c]pyrazole derivatives are disclosed in Tetrahedron, Vol. 46, pp. 5777-5788 10 (1990). European Patent Application Publication Number 407102A discloses angiotensin II antagonists having the general formula: 15 N A R6 - E-V N B I

(CH

2 )n R3a - R3b Y x

R

2 a R1

R

2 b 20 PCT Patent Application WO 91/11999 discloses angiotensin II antagonists having the general formula -5- WO99/10350 PCTIUS98/17049 shown below. These compounds also have utility as treatments for cognitive dysfunctions, depression, anxiety and dysphoric mental states. 5

A

3 -B N A4 -A5

CH

2

R

9

-

l RS R10 X Y R12 10 Insofar as is known, novel nitrogen substituted imidazo[4,5-c]pyrazoles, which are described in detail below, have not been previously reported as corticotropin releasing factor antagonist compounds useful in the treatment of psychiatric disorders and 15 neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity 20 associated with psychopathological disturbance and stress. SUMMARY OF THE INVENTION In accordance with one aspect, the present 25 invention provides novel compounds which bind to -6- WO99/10350 PCT/US98/17049 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 5 diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological 10 disturbance and stress in mammals. According to another aspect, the present invention provides novel compounds of formulae (I) and (II) (described below) which are useful as antagonists 15 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 20 such compounds of formulae (I) and (II), and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders. 25 According to yet another aspect, the present invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress 30 disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, 35 the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to -7- WO99/10350 PCT/US98/17049 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; 5 panic, phobias, obsessive-compulsive 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 10 depression, child abuse induced depression, and postpartum depression; dysthemiax bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as 15 Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by 20 psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; 25 head traumas; spinal cord trauma; ischemic neuronal damage (.ag , cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hear related disorders including hypertension, tachycardia and congestive 30 heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.a., stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, 35 sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary -8- WO99/10350 PCT/US98/17049 incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.a., dependencies on alcohol, ***e, heroin, 5 benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in mammals. According to a still further aspect of the 10 invention, the compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor. 15 DETAILED DESCRIPTION OF THE INVENTION [11] Thus, in a first embodiment, the present invention 20 provides novel compounds of Formulae (I) and (II):

R

2 R R 2 G N N RI ,N RI-\ , -Rio N N 1N R4 R4 (I) (II) 25 or isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salt forms thereof, wherein: 30 R1 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, where such haloalkyl is -9- WO 99/10350 PCT/US98/17049 substituted with 1-6 halogens, C3-C6 cycloalkyl,

C

4

-C

8 cycloalkylalkyl, Cl-C6 alkoxy, aryl, heteroaryl or heterocyclyl; 5 R 2 is CI-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl,

C

3 -C8 cycloalkyl, C4-C12 cycloalkylalkyl, where each group can be optionally substituted with 1 to 3 substituents independently selected at each occurrence from Cl-C6 alkyl, C3-Cl0 alkenyl, C3-C0O 10 alkynyl, C3-C6 cycloalkyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, NR 6

R

7 , OR 7 , thiol, S(O)nR 9 , COR 7 , C02R 7 , OC(O)R 9 , NR 8

COR

7 , NR 8

CONR

6

R

7 ,

NR

8 CO2R 9 , CONR 6

R

7 ; or 9 7 7 6 7 15 S(O)nR , COR 7 , CO 2 R , CONR 6 R ; or

C

1

-C

4 haloalkyl, where C 1

-C

4 haloalkyl may be substituted with 1-6 halogens; or 20 aryl or aryl(C1-C4 alkyl), heteroaryl or heteroaryl(Cl-C4 alkyl), heterocyclyl, or heterocyclyl(Cl-C4 alkyl), wherein Cl-C4 alkyl in aryl(Cl-C4 alkyl), heteroaryl(C1-C4 alkyl) or heterocyclyl(CI-C4 alkyl) is optionally substituted 25 with substituents selected from Cl-C8 alkyl, COR 7 , C02R 7 , S(O)nR 9 , cyano and aryl; n is independently at each occurrence 0, 1, or 2; 30 R 3 is H, Cl-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cl C6 haloalkyl, where such haloalkyl is substituted -10- WO99/10350 PCTIUS98/17049 with 1-6 halogens, C3-C6 cycloalkyl, C2-C0O alkoxyalkyl, Cl-C6 hydroxyalkyl, cyano, OR 6 , thiol, S(O)nR 9 , NR 6

R

7 , aryl, or heteroaryl; 5 R 4 is phenyl, pyridyl, pyrimidyl, triazinyl, furanyl, naphthyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, 2,3-dihydrobenzofuranyl, 2,3 10 dihydrobenzothienyl, 1,2-berzopyranyl, 3,4-dihydro 1,2-benzopyranyl or pyrazolyl, where each R 4 is attached via an unsaturated carbon atom and each R 4 may be optionally substituted with 1 to 4 R 5 groups; 15

R

5 is independently at each occurrence selected from Cl-C10 alkyl, C2-C10 alkenyl, C2-Cl0 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, where Cl-C10 alkyl, C 2 -C10 alkenyl, C 2 -C10 alkynyl, C3-C6 20 cycloalkyl, C4-C12 cycloalkylalkyl are optionally substituted with 1-3 substituents independently selected at each occurrence from Cl-C4 alkyl, nitro, halogen, cyano, NR 6

R

7 , NR 8

COR

7 , NR 8 CO2R 9 ,

COR

7 , OR 7 , CONR 6

R

7 , NR 8

CONR

6

R

7 , C02R 7 , thiol, or 25 S(O)nR 9 ; or nitro, halogen, cyano, Cl-C4 haloalkyl optionally substituted with 1-6 halogens, NR 6

R

7 , NR 8

COR

7 , NRSCO2R 9 , COR 7 , OR 7 , CONR 6

R

7 , NR 8

CONR

6

R

7 , C02R 7 , 30 thiol, or S(O)nR 9 ; -11- WO99/10350 PCT/US98/17049

R

6 and R 7 are independently at each occurrence selected from: (1) H; (2) CI-C0lo alkyl, C3-C0O alkenyl, C3-C0O alkynyl, 5 C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, or C4-C12 cycloalkylalkyl, each optionally substituted with 1-6 substituents independently selected at each occurrence from Cl-C6 alkyl, C3-C6 cycloalkyl, halogen, Cl-C4 haloalkyl, cyano, nitro, OR 12 , 10 thiol, S(O)nR 9 , COR 12 , CO2R1 2 , NR 8

COR

12 ,

NR

8 CONR11R 12 , NR 8 CO2R 9 , NR 11

R

12 , and CONR 11

R

12 ; (3) aryl, aryl(Cl-C4 alkyl), heteroaryl or heteroaryl(Cl-C4 alkyl), heterocyclyl, or heterocyclyl(Cl-C4 alkyl; 15

R

8 is independently at each occurrence selected from H, Cl-C4 alkyl, C3-C8 alkenyl, C3-C6 cycloalkyl, or C4-C7 cycloalkylalkyl; or 20 phenyl or phenyl(Ci-C4 alkyl), each optionally substituted with 1-3 substitutents selected from Cl-C4 alkyl, halogen, Cl-C4 haloalkyl optionally substituted with 1-6 halogens, Cl-C4 alkoxy, OH; 25 R 9 is independently at each occurrence selected from H, CI-C4 alkyl, C2-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl; or phenyl or phenyl(Cl-C4 alkyl), each optionally 30 substituted with 1-3 substitutents selected from Cl-C4 alkyl, halogen, Cl-C4 haloalkyl optionally substituted with 1-6 halogens, Cl-C4 alkoxy, OH; -12- WO 99/10350 PCT/US98/17049

R

10 is H, C1-C4 alkyl, Cl-C4 haloalkyl, C2-C8 alkoxyalkyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(Cl-C4 alkyl), heteroaryl, heteroaryl(Cl-C4 alkyl), heterocyclyl, 5 heterocyclyl(Cl-C4 alkyl), where Cl-C4 haloalkyl is optionally substituted with 1 to 6 halogens;

R

11 and R 12 are independently at each occurrence selected from H, Cl-C6 alkyl, C3-C6 cycloalkyl, C4 10 C7 cycloalkylalkyl, or Cl-C4 haloalkyl optionally substituted with 1-6 halogens; or phenyl or phenyl(Cl-C4 alkyl), each optionally substituted with 1-3 substitutents selected from 15 CI-C4 alkyl, halogen, Cl-C4 haloalkyl optionally substituted with 1-6 halogens, C1-C4 alkoxy, OH; aryl is phenyl or naphthyl, each optionally substituted with 1 to 5 substituents independently selected at 20 each occurrence from R 13 ; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, 25 benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, 2,3 dihydrobenzofuranyl, 2,3- dihydrobenzothienyl, or indazolyl, each optionally substituted with 1 to 4 substituents independently selected from at each 30 occurrence R13; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 -13- WO99/10350 PCTIUS98/17049 substituents independently selected at each occurrence from R1 3 ;

R

13 is independently at each occurrence selected from 5 C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl, where CI-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl are optionally substituted with 1-3 substituents independently 10 selected at each occurrence from Cl-C4 alkyl, nitro, halogen, cyano, NR 8

R

9 , NR 8

COR

9 , NR 8 CO2R 9 ,

COR

9 , OR 9 , CONR 8

R

9 , NR 8

CONR

8

R

9 , CO2R 9 , thiol, or S(O)nR 9 or 15 nitro, halogen, cyano, C1-C4 haloalkyl optionally substituted with 1-6 halogens, NR 8

R

9 , NR 8

COR

9 ,

NR

8 CO2R 9 , COR 9 , OR 9 , CONR 8

R

9,

NR

8

CONR

8

R

9 , CO2R 9 , thiol, or S(O)nR9; 20 [2] In a preferred embodiment, the present invention provides novel compounds of Formulae (I) and (II) wherein: R 4 is phenyl, pyridyl or pyrimidyl, each optionally substituted by 1 to 4 R 5 groups. 25 [3] In a more preferred embodiment, the present invention provides novel compounds of Formula (I) and (II), wherein: R 1 is selected from H, C1-C6 alkyl, C1 C6 haloalkyl, where such haloalkyl is substituted with 1-6 halogens, C3-C6 cycloalkyl, or aryl. 30 [4] In an even more preferred embodiment, the present invention provides novel compounds of Formulae (I) and -14- WO 99/10350 PCT/US98/17049 (II), wherein: R 1 is selected from H, C1-C6 alkyl, C1 C6 haloalkyl, where such haloalkyl is substituted with 1-6 halogens, C3-C6 cycloalkyl, or aryl and R 4 is phenyl, pyridyl or pyrimidyl, each optionally 5 substituted by 1 to 4 R 5 groups. [5] In an even further preferred embodiment, the present invention provides novel compounds of Formula (I) and (II), wherein the compound is selected from the 10 group: 1-(2-chloro-4-trifluoromethyl)phenyl-5-ethyl-3-methyl-4 [1- (1-methyl)butane]limidazo[4,5-c]pyrazole; 15 1-(2-chloro-4-trifluoromethyl)phenyl-5-ethyl-4-[1-(l ethyl)butane] -3-methylimidazo [4,5-c] pyrazole; 4-(n-butyl) -1- (2-chloro-4-bromo)phenyl-5-ethyl-3 methylimidazo[4,5-c]lpyrazole; 20 1-(2-chloro-4-bromo)phenyl-5-ethyl-3-methyl-4- [1- (1 methyl)butane] imidazo[4,5-c] pyrazole; 1-(2-chloro-4-bromo)phenyl-5-ethyl-4-[- (1 25 ethyl)butane] -3-methylimidazo[4,5-c]pyrazole; 5-ethyl-3-fluoromethyl-4- [1- (1-methyl)butane] -- (2,4,6 trichloro)phenylimidazo[4,5-c] pyrazole; 30 5-ethyl-4-[l-(1-methyl)butane]l--( 2

,

4 ,6 trichloro)phenylimidazo [4,5-c] pyrazole; 1-(2,6-dichloro-4-bromo)phenyl-5-ethyl-4- [1- (1 ethyl)butane] -3-methylimidazo[4,5-c] pyrazole; -15- WO 99/10350 PCT/US98/17049 1-(2,4-dichloro)phenyl-5-ethyl-4- [1- (l1-ethyl)butane] -3 methylimidazo[4,5-c] pyrazole; 5 1-(2,4-dichloro)phenyl-5-ethyl-3-methyl-4- [i-(l methyl)butane] imidazo[4,5-c] pyrazole; 1-(2,4-dichloro)phenyl-5-ethyl-3-methyl-4-[li-(1,3 dimethyl)butane] imidazo [4,5-c] pyrazole; 10 1-(2,6-dichloro-4-bromo)phenyl-5-ethyl-3-methyl-4- [1- (1 methyl)butane] imidazo[4,5-c] pyrazole; 5-ethyl-4- [1- (1-ethyl)butane] -3-methyl-l- (2,4,5 15 trichloro)phenylimidazo[4,5-clpyrazole; 5-ethyl-3-methyl-4- [1- (l-methyl)butane] -1-(2,4,5 trichloro)phenylimidazo [4,5-cl]pyrazole; 20 5-ethyl-4-[1-(1-methyl)pentane]-3-methyl-l-(2,4,6 trichloro)phenylimidazo[4,5-cl]pyrazole; 1-(2-bromo-4-isopropyl)phenyl-5-ethyl-4- [1- (1 ethyl)butanel]-3-methylimidazo[4,5-clpyrazole; 25 1-(2-bromo-4-isopropyl)phenyl-5-ethyl-3-methyl-4- [1- (1 methyl)butane] imidazo [4,5-c] pyrazole; 1-(2-bromo-4,6-dichloro)phenyl-5-ethyl-4-[1- (1 30 ethyl)butane] -3-methylimidazo[4,5-c]lpyrazole; 1-(2-bromo-4,6-dichloro)phenyl-5-ethyl-3-methyl-4-[1-l-( methyl)butanelimidazo[4,5-c] pyrazole; 35 4-(n-butyl)-- -(2,6-dichloro-4-bromo)phenyl-5-ethyl-3 methylimidazo[4,5-c] pyrazole; -16- WO 99/10350 PCTIUS98/17049 1-(2,6-dichloro-4-bromo)phenyl-5-ethyl-3-methyl-4- [1- (3 methyl)butane] imidazo[4,5-c] pyrazole; 5 1-(2,6-dichloro-4-bromo)phenyl-5-ethyl-4-[l-( 2 ethyl)butane] -3-methylimidazo[4,5-c]pyrazole; 4-benzyl--(2,6-dichloro-4-bromo)phenyl-5-ethyl-3 methylimidazo[4,5-c]pyrazole; and 10 1-(2,6-dichloro-4-bromo)phenyl-4-(3,4-difluorobenzyl)-5 ethyl-3-methylimidazo[4,5-c]pyrazole or a pharmaceutically acceptable salt form thereof. 15 [6, 7, 8, 9, 10] In another preferred embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of compounds of Formulae (I) and (II). 20 [11, 12, 13, 14, 15] In yet another preferred embodiment, the present invention provides a method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic 25 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 30 problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or 35 facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in -17- WO99/10350 PCTIUS98/17049 mammals, comprising: administering to the mammal a therapeutically effective amount of compounds of Formulae (I) and (II). 5 The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as 10 by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present 15 invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure 20 are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. 25 The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a 30 stable compound. When a substitent is keto (i.e., =0), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. The present invention is intended to include all isotopes of atoms occurring in the present compounds. 35 Isotopes include those atoms having the same atomic -18- WO 99/10350 PCT/US98/17049 number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14. 5 When any variable (e.g., R 6 ) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 10 R 6 , then said group may optionally be substituted with up to two R 6 groups and R 6 at each occurrence is selected independently from the definition of R 6 . Also, combinations of substituents and/or variables are permissible only if such combinations result in stable 15 compounds. When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via 20 which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable 25 compounds. As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited 30 to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or 35 more halogen (for example -CvFw where v = 1 to 3 and w = 1 to (2v+l)). Examples of haloalkyl include, but are -19- WO99/10350 PCT/US98/17049 not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an 5 oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. "Cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. 10 Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. "Alkynyl" is intended to include hydrocarbon 15 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 and propynyl. "Halo" or "halogen" as used herein refers to 20 fluoro, chloro, bromo, and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate. As used herein, "carbocycle" or "carbocyclic 25 residue" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7-to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, 30 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl. 35 As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5-to -20- WO99/10350 PCT/US98/17049 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms 5 independently selected from the group consisting of N, 0 and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be 10 attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may 15 optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1. As 20 used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group 25 consisting of N, 0 and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, 30 benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, 35 decahydroquinolinyl, 2H,6H-l,5,2-dithiazinyl, dihydrofuro[2,3-btetrahydrofuran, furanyl, furazanyl, -21- WO99/10350 PCT/US98/17049 imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, 5 isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, 10 phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, 15 pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5 thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 20 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3 triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4 triazolyl, and xanthenyl. Preferred heterocycles 25 include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl. Also included are fused 30 ring and spiro compounds containing, for example, the above heterocycles. The term "amino acid" as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are 35 natural amino acids (e.g., L-amino acids), modified and unusual amino acids (e.g., D-amino acids), as well as -22- WO99/10350 PCT/US98/17049 amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids,such as those disclosed in, for 5 example, Roberts and Vellaccio (1983) The Peotides, 5: 342-429, the teaching of which is hereby incorporated by reference. Natural protein occurring amino acids include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, 10 glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanin&, serine, threonine, tyrosine, tyrosine, tryptophan, proline, and valine. Natural non-protein amino acids include, but are not limited to arginosuccinic acid, citrulline, cysteine 15 sulfinic acid, 3,4-dihydroxyphenylalanine, homocysteine, homoserine, ornithine, 3-monoiodotyrosine, 3,5-diiodotryosine, 3,5,5'-triiodothyronine, and 3,3',5,5'-tetraiodothyronine. Modified or unusual amino acids which can be used to practice the invention 20 include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, 1-phenylproline, tert-leucine, 25 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 30 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid. The phrase "pharmaceutically acceptable" is 35 employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the -23- WO99/10350 PCT/US98/17049 scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate 5 with a reasonable benefit/risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable 10 salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the 15 quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; 20 and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, 25 toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by 30 conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, 35 nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of -24- WO 99/10350 PCTIUS98/17049 suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference. 5 Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc...) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended 10 to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. "Prodrugs" are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such 15 prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. 20 Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free 25 sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention. "Stable compound" and "stable structure" are meant 30 to indicate 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. "Substituted" is intended to indicate that one or 35 more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from -25- WO 99/10350 PCT/US98/17049 the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., =0) group, then 2 hydrogens 5 on the atom are replaced. "Therapeutically effective amount" is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms 10 of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of 15 the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can 20 be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components. The term "therapeutically effective amount" of a compound of this invention means an amount effective to 25 antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host. Synthesis 30 The novel substituted bicyclic imidazo[4,5 c]pyrazoles of Formulae (I) and (II) of this invention can be prepared by one of the general schemes outlined below, in particular Schemes 1-2. Compounds of Formula (I) of this invention may be 35 prepared as shown in Scheme 1. -26- WO 99/10350 PCT/US98/17049 SCHEME 1

R

3

R

3 (RICO) 2 0 1or

R

N H2 NC NH2 RICOC1 R- N H2N

R

4 (III)

R

3 R 3 N H R1 R4 R R4 (IV) (V) SR3 R N

R

2 -X N ~ R1-< N R1 N N R H R H (VI) (VII)

R

2

R

3 R1 N N N

R

4 (I) An appropriate hydrazine (R 4 NHNH2), either as the free base or as the corresponding mineral acid salt, may be 5 condensed with acrylonitrile compounds of formula

R

3

(NH

2 )C=C(CN)H to afford pyrazole compounds of formula -27- WO99/10350 PCT/US98/17049 (III). These cyclizations are preferrably conducted in aqueous media and at elevated temperatures up to boiling. When R 3 is hydrogen, 2-halogenoacrylonitrile compounds of formula CH 2 =CH(CN)Hal or 2,3 5 dihalogenopropionitrile compounds of formula Hal'CH 2 CH(CN)Hal may be cyclized with the hydrazines of formula R 4 NHNH2. Hal and Hal' may be independently selected from chlorine, bromine or iodine. One skilled in the art of heterocyclic chemistry will readily 10 understand the optimal combinations of conversions necessary to prepare a number of compounds of formula (III) with R 3 and R 4 variations and can refer to the review of Potts, K.T. (Comprehensive Heterocyclic Chemistry, Katritzky, A.R., et.al., Eds., Pergamon 15 Press, Oxford, 1984, 5, pg. 111-157) or Vicentini, et.al. (Tetrahedron, 1990, 46, 5777). Compounds of formula (III) may be readily condensed with compounds of formula (R 1

CO)

2 0 or R 1 COC1 to provide amides of formula (IV). The condensations may be 20 conducted neat or in the optional presence of cosolvent. The reactions are preferrably run at room temperature where R 1 is methyl and at elevated temperature up to the boiling point of the anhydride or cosolvent used where

R

1 is larger than methyl. Amides of formula (IV) may 25 then be converted, in the presence of a reducing agent, to the substituted amino pyrazoles of formula (V). Reducing agents include, but are not limited to, lithium aluminum hydride and borane. Reactions are generally run in ethereal solvents, for example tetrahydrofuran 30 and diethyl ether. The reductions are carried out for a period of time between 1 hour and 4 days, and at room temperature or elevated temperature up to reflux in order to effect the reaction. If borane is used, it may be employed as a complex, for example, but not limited -28- WO99/10350 PCT/US98/17049 to, borane-methyl sulfide complex, borane-piperidine complex, borane-pyridine complex, and borane tetrahydrofuran complex. In preparation for ring closure to the imidazole, 5 compounds of formula (V) may be nitrosated in the presence of acid and a suitable nitrosating agent such as, but not limited to, isoamyl nitrite in an alcoholic solvent such as methanol, ethanol, or isopropanol. The reactions are generally conducted at room temperature 10 and afford compounds of formula (VI) in high yield and purity after filtration or columrchromatography. Cyclization to imidazopyrazoles of formula (VII) may be accomplished by refluxing precursors of formula (VI) in the presence of a base such as, but not limited to, 15 pyridine or other non-nucleophilic organic base for a period of time between 1 hour and 3 days and at a temperature ranging from room temperature up to the boiling point of the base or co-solvent employed. Cosolvents such as, but not limited to, tetrahydrofuran 20 may be used, however, it may be preferrable to conduct the cyclizations in the absence of cosolvent. Compounds of formula (VII) are expected to exist as a mixture of imidazole tautomers, and one skilled in the art will immediately recognize this. 25 Finally, treatment of compounds of formula (VII) with a base and a compound of formula R 2 -X wherein X represents a leaving group may afford the desired imidazopyrazole compounds of formula (I). Leaving groups may include, but are not limited to, bromo, 30 chloro, iodo, cyano, alkoxy, methanesulfonyl, and p toluenesulfonyl. Possible bases include, but are not limited to, the sodium, lithium or potassium bis(trimethylsilyl)amides, sodium or potassium hydride, alkyl lithiums and alkyl grignards and inorganic bases 35 such as sodium, potassium and lithium hydroxide. The -29- WO99/10350 PCT/US98/17049 reactions are optionally conducted at room temperature or at elevated temperatures up to the boiling point of a cosolvent. A wide variety of inert solvents may be employed, for example, dimethylformamide, 5 dimethylsulfoxide, toluene, tetrahydrofuran, diethyl ether, and methylene chloride. The reactions may be successfully performed in glass reaction vessels or polypropylene wells, and one skilled in the art of organic chemistry will readily understand the optimal 10 combinations of above conditions for effecting this transformation, or can consult the text of Larock, R.C. (Comprehensive Organic Transformations, VCH Publishers, New York, 1989). Although regiomeric alkylation products are conceivably possible from tautomers of 15 formula (VII), the experimental conditions taught herein will selectively provide the desired regiomer represented by compounds of formula (I). Alternatively, compounds of formula (I) may be formed from compounds of formula (VII) by treatment with 20 a base and subsequent addition to the carbon-carbon double bond of an a,p-unsaturated carboxylic acid derivative, ketone, aldehyde, or nitrile; a process commonly accepted as the Michael reaction. Bases and optional inert cosolvents may be selected from those 25 identified (vide supra). One skilled in the art of organic synthesis will readily appreciate the utility of the Michael reaction, and may consult the teachings of House, H.O. (Modern Synthetic Reactions, W.A. Benjamin, Inc., Menlo Park, CA., 1972, p 595). 30 As shown in Scheme 2, compounds of formula (I) where R 3 is OH or SH may be transformed into compounds of formula (I) where R 3 is OR 6 or SR 6 or compounds of formula (II) where G is O or S and the pyrazole nitrogen is substituted as R i0 . -30- WO 99/10350 PCT/US98/17049 SCHEME 2

R

2

R

3 N R1 NJ N N N

R

4 2 R 3 (I); R 3 is OR 6 , SR 6 R1 1 -R1 (I); R 3 is OH, SH G N Rl-\ ;N-R1 0

R

4 (II); G is O, S Reactions to afford compounds of formula (I) where R 3 is

OR

6 or SR 6 may be preferably conducted with oxophilic 5 alkylating agents such as, but not limited to, the trialkyloxonium tetrafluoroborates and/or thiophilic alkylating agents such as, but not limited to, dialkyl sulfates. Reactions to afford compounds of formula (II), where G is O or S and the pyrazole nitrogen is 10 substituted (Scheme 2) as R 10 are more preferably effected by treatment of compounds of formula (I, R 3 is OH or SH) with a base such as, but not limited to, potassium hydroxide in a solvent such as acetone or other inert solvent with a reagent R 10 -X where X is a 15 leaving group (vide supra). These product compounds arise via the tautomeric nature of compounds of formula (I) where R 3 is OH or SH. In the described manner then, the novel substituted bicyclic imidazo[4,5-c]pyrazoles of formula (I) and (II) -31- WO 99/10350 PCT/US98/17049 of this invention can be prepared by one of the general schemes outlined above. See Schemes 1-2. Compounds of Formula (II) may also be prepared as outlined in Scheme 3. 5 SCHEME 3 R2 R2 O R20 S RNHNH 2 R1 N N-R10 RR 1N--\\ 0 N X (a) (b)

R

4 B (OH) 2

R

2 O or R 4 B(ORa) (ORb) N

R

1 -- \ IN- R10 N N

R

4 (II) Imidazoles of Formula (a) (where X = halogen, NH2, alkylamino (1-6 carbons), dialkylamino (2 - 12 carbons), 10 alkylthio (1 to 6 carbons) or alkylsulfonyl (1 to 6 carbons) may be reacted with a compound of the formula

R

10 NHNH2, in the presence or absence of a base, in an inert solvent to give intermediates of formula (b). Bases may include, but are not limited to, alkali metal 15 hydrides (preferably sodium hydride), alkali metal alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di isopropylamide), alkali metal bis(trialkylsilyl)amides 20 (preferably sodium bis(trimethylsilyl)amide), trialkyl -32- WO 99/10350 PCT/US98/17049 amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably 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 methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -20 to 1000C. 15 Intermediates (b) may then be treated with a boronic acid or a boronic acid ester of the formula

R

4 B(OH)2 or R 4 B(ORa)(ORb) (where Ra and Rb are lower alkyl( 1 to 6 carbons) or together R a and Rb are lower alkylene (2 to 12 carbons) in the presence of a metal 20 catalyst with or without a base in an inert solvent to give compounds of Formula (II). Metal catalysts include, but are not limited to salts or phosphine complexes of Cu, Pd or Ni (e.g. Cu(OAc)2, PdCl 2 (PPh 3 )2, NiCl 2 (PPh3)2). Bases may include, but are not limited 25 to, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, 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 -33- WO 99/10350 PCT/US98/17049 aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl 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 -800C to 150 0 C. 15 Alternatively, compounds of Formula (II) may be prepared as outlined in Scheme 4. SCHEME 4

R

2 0

CO

2 Et R 4

NHNH

2 N N go___ _ __ _ _ R 1 NH R R N N N x \ R (a) (c)

R

2 0 BASE, R 1 Y \N

R

1 --- N-R10 N N R' (II) -34- WO99/10350 PCTIUS98/17049 Imidazoles of Formula (a) (where X is defined above) may be treated with compounds of the formula R4NHNH 2 to yield intermediates (c) in the presence or absence of a base in an inert solvent. Bases may include, but are not 5 limited to, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal hydrides (preferably sodium hydride), alkali metal 10 alkoxides (1 to 6 carbons)(preferably sodium methoxide or sodium ethoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium di isopropylamide), alkali metal bis(trialkylsilyl)amides (preferably sodium bis(trimethylsilyl)amide), trialkyl 15 amines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine) or aromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl 20 ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethylformamide), N,N-dialkylacetamides (preferably d.methylacetamide), cyclic amides (preferably N methylpyrrolidin-2-one), dialkylsulfoxides (preferably 25 dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -80 0 C to 150 0 C. 30 Intermediates (c) may then be treated with a reagent of the Formula R 10 X to give compounds of Formula (II) in the presence or absence of a base in an inert solvent. Bases may include, but are not limited to, alkaline earth metal carbonates, alkaline earth metal 35 bicarbonates, alkaline earth metal hydroxides, alkali -35- WO99/10350 PCTIUS98/17049 metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, 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, lower alkanenitriles (1 to 6 carbons, preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 15 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 20 benzene or toluene) or haloalkanes of 1 to 10 carbons and 1 to 10 halogens (preferably dichloromethane). Preferred reaction temperatures range from -800C to 150 0 C. 25 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 30 illustrate and not to limit the invention. 35 -36- WO99/10350 PCT/US98/17049 Example 1 Preparation of 4-Cyclopropylmethyl-3,5 dimethyl-1- (2,4,6-trichloro)phenylimidazo[4,5 c]pyrazole: 5 Step A: -Aminocrotononitrile (14.68 g, 0.18 mol) was dissolved in 1.0N HC1 (500 ml) and treated with 2,4,6-trichlorophenylhydrazine (36 g, 0.17 mol). The reaction was refluxed 4h, cooled, and decanted into a 2 liter beaker. The solution was diluted with water (250 10 ml) and neutralized with 10% NaOH. The resultant precipitate was filtered and dried to constant weight to afford 44.71 g (95%) of the desired aminopyrazole as a white crystalline solid, mp 135.5-136.0OC. 1 H NMR (300 MHz, CDC13) 5 7.48 (s, 2H), 5.50 (s, 1H), 3.48 (bs, 2H), 15 2.25 (s, 3H). Anal. Calcd. for Co 10

H

8

N

3 C1 3 : C, 43.43; H, 2.92, N, 15.19. Found: C, 43.56; H, 2.92; N, 15.09. Step B: The product from Part A (14.0 g, 0.05 mol) was suspended in acetic anhydride (40 ml) and allowed to 20 stir at room temperature. The reaction became homogeneous after 20 minutes and was stirred 40 additional minutes, then transferred to a slurry of ice (600 ml). The resultant precipitate was stirred lh, filtered and dried to constant weight, affording 14.22 g 25 (88%) of acetylated product, mp 210.0-211.0 0 C. 1H NMR (300 MHz, CDC13) 8 7.50 (s, 2H), 6.81 (bs, 1H), 6.47 (s, 1H), 2.33 (s, 3H), 2.08 (s, 3H). Anal. Calcd. for C1 2 Ho10N 3 C1 3 01: C, 45.24; H, 3.16; N, 13.19. Found: C, 45.52; H, 3.18; N, 13.10. 30 e'p The product from Part B (16.63 g, 0.05 mmol) was dissolved in dry tetrahydrofuran (100 ml) under an atmosphere of nitrogen, and treated with borane/THF complex (156 ml, 0.15 mol) via addition -37- WO99/10350 PCT/US98/17049 funnel. Upon completion of addition, the reaction was brought to reflux for 48 hours. The reaction was cooled, treated with 10% NaOH (100 ml), and stirred lh. The heterogeneous mixture was diluted with water (400 5 ml) and diethyl ether (350 ml) and transferred to a separatory funnel. The mixture was partitioned and the aqueous layer reextracted with diethyl ether (2 X 100 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated 10 in-vacuo. Column chromatography on silica gel (450 g), eluting with hexanes/ethyl acetate (2/1) afforded the substituted amino pyrazole, 5.89 g (c. 40%) as a white crystalline solid, mp 81.5-83.5 0 C. 1 H NMR (300 MHz, CDC13) 8 7.47 (s, 2H), 5.38 (s, 1H), 3.14 (m, 2H), 3.03 15 (bs, 1H), 2.26 (s, 3H), 1.19 (t, 3H, J=7.0 Hz). Anal. Calcd. for C 12

H

12

N

3 C1 3 : C, 47.32; H, 3.97; N, 13.80. Found: C, 47.41; H, 4.01; N, 13.56. Ste D: The product from Step C (7.78 g, 25.54 mmol) was dissolved in ethanol (100 ml), cooled to 0OC, 20 and treated with 1.0N HC1 (0.5 ml) and isoamyl nitrite (3.42 ml, 25.54 mmol). The reaction was stirred 5 hours before final concentration in-vacuo to remove solvent. Purification via column chromatography (600 g) eluting with hexanes/ethyl acetate (1/2) yielded a violet 25 crystalline solid, 7.14 g (87%), mp 180.0-181.0 0 C. 1 H NMR (300 MHz, CDC13) 8 7.50 (s, 2H), 2.84 (m, 2H), 2.73 (s, 3H), 1.14 (t, 3H, J=7.3 Hz). Anal. Calcd. for

C

12

H

11

N

4 C1 3 01: C, 43.20; H, 3.32; N, 16.79. Found: C, 43.06; H, 3.26; N, 16.54. 30 Part E: The product from Part D (7.82 g, 0.023 mol) was dissolved in pyridine (50 ml) and the homogeneous solution refluxed 8 hours. The reaction was concentrated in-vacuo to remove pyridine and purified via column chromatography (600 g) eluting initially with -38- WO99/10350 PCT/US98/17049 ethyl acetate/hexanes (1/2) and then with ethyl acetate to afford desired imidazopyrazole, 1.71 g (c. 25%), mp 245 0 C (dec.). 1H NMR (300 MHz, CDC13) 8 9.20 (bs, 1H), 7.42 (s, 2H), 2.52 (s, 3H), 2.44 (s, 3H). MS (CI) 5 M+H=315. Part F:The product from Part E (0.10 g, 0.32 mmol) was charged to a dry flask, dissolved in anhydrous dimethylformamide (5.0 ml), and treated with sodium hydride (0.03 g, 0.70 mmol). After stirring 5 minutes, 10 the crimson reaction was quenched with cyclopropylmethylbromide (77 p1, 0.80 mmol). The reaction was heated to 100 0 C and allowed to stir 30 minutes, whereupon the reaction returned to a golden yellow color. After dilution with water (30 ml) the 15 reaction was extracted with ethyl acetate (4 X 15 ml). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in-vacuo. Purification on silica gel (30 g) eluting with ethyl acetate/hexanes (2/1) gave 50.3 mg of the title 20 compound, mp 190.0-192.0 0 C. 1 H NMR (300 MHz, CDC13) a 7.43 (s, 2H), 3.94 (d, 2H, J=7.5 Hz), 2.52 (s, 3H), 2.50 (s, 3H), 1.26 (m, 1H), 0.71 (m, 2H), 0.40 (m, 2H). HRMS calcd. for M+H (C 16

H

16

N

4 C1 3 ): 369.0441. Found: 369.0446. 25 Example 3 Preparation of 3,5-Dimethyl-4-[1-(2 ethyl)butane]-1-(2,4,6-trichloro) phenylimidazo[4,5-c]pyrazole: 30 The product from Example 1, Part E (61 mg, 0.19 minmol) was reacted with sodium hydride (19 mg, 0.48 mmol) and l-bromo-2-ethylbutane (108 p1, 0.77 mmol) in dimethylformamide (2.0 ml) as described for the -39- WO99/10350 PCT/US98/17049 preparation of Example 1, Part F. Title compound: mp 112.0-114.50C. 1 H NMR (300 MHz, CDC13) 6 7.44 (s, 2H), 3.89 (d, 2H, J=7.3 Hz), 2.51 (s, 3H), 2.48 (s, 3H), 1.8 (m, 1H), 1.39 (m, 4H), 0.95 (m, 6H). HRMS calcd. for 5 M+H (C 1 8

H

2 2

N

4 C1 3 ): 399.0910. Found: 399.0896. Examples 2 and 4-9 given in TABLE 1 may be prepared in the same manner as described for the preparation of Examples 1 and 3, starting with the product from Example 10 1, Part E and substituting the appropriate electrophile. Example 11 Preparation of 4-Benzyl-3,5-dimethyl-1-(2,4,6 trimethyl)phenylimidazo[4,5-c]pyrazole: 15 Ste A -Aminocrotononitrile (11.96 g, 0.15 mol) was dissolved in 1.0N HC1 (350 ml) and treated with 2,4,6-trimethylphenylhydrazine, hydrochloride (25.89 g, 0.14 mol). The reaction was refluxed 4h, cooled, and decanted into a 2 liter beaker. The solution was 20 diluted with water (250 ml) and neutralized with 10% NaOH. The resultant precipitate was filtered and dried to constant weight to afford 27.82 g (93%) of the desired aminopyrazole as a white crystalline solid, mp 127-1290C. 1H NMR (CDC13) 6 6.93 (s, 2H), 5.42 (s, 1H), 25 3.4 (bs, 2H), 2.31 (s, 3H), 2.23 (s, 3H), 2.02 (s, 6H). Ste B The product from Part A (10.0 g, 46.40 mmol) was suspended in acetic anhydride (35 ml) and allowed to stir at room temperature. The reaction became homogeneous after 20 minutes and was stirred 40 30 additional minutes, then transferred to a slurry of ice (500 ml). The resultant precipitate was stirred 2h, filtered and dried to constant weight, affording 8.14 g (68%) of acetylated product, 1H NMR (CDC13) 6 6.98 (s, -40- WO 99/10350 PCTIUS98/17049 2H), 6.78 (bs, 1H), 6.52 (s, 1H), 2.34 (s, 3H), 2.31 (s, 3H), 2.04 (s, 3H), 1.96 (s, 6H). Step C The product from Step B (8.1 g, 31.47 mmol) was dissolved in anhydrous THF (80 ml) and treated 5 with lithium aluminum hydride (63 ml, 62.94 mmol, 1.0 M/THF) under nitrogen at room temperature. The reaction was stirred 1.5 h at room temperature and 1.0 h at 500C, and quenched by the addition of 10% sodium hydroxide (10 ml). The heterogeneous slurry was filtered through 10 celite with copious diethyl ether washings. The filtrate was concentrated in-vacto and purified by column chromatography on silica gel (250 g), eluting with hexanes/ethyl acetate (1/1) to provide the desired product, 7.3 g (95%) as a crystalline solid. 15 Step The product from Step C (7.3 g, 29.99 mmol) was dissolved in ethanol (50 ml), cooled to 0OC, and treated with 1.0 N HCl (14 drops) and isoamyl nitrite (4.02 ml, 29.99 mmol). The reaction was stirred 10 minutes, warmed to room temperature, and stirred an 20 additional 5 hours. The reaction was concentrated in vacuo to remove ethanol and purified by column chromatography on silica gel (600 g) eluting with hexanes/ethyl acetate (2/1) to afford a violet crystalline solid, 7.14 g (87%). 1 H NMR (CDC13) 8 9.95 25 (bs, 1H), 6.94 (s, 2H), 2.70 (s, 3H), 2.69 (q, 2H, J=7.2 Hz), 2.33 (s, 3H), 2.10 (s, 6H), 1.03 (t, 3H, J=7.3 Hz). te E The product from Step D (7.14 g, 26.21 mmol) was dissolved in anhydrous pyridine (50 ml) and brought to reflux for 8 hours. The reaction was then 30 concentrated in-vacuo to dryness and directly purified by column chromatography on silica gel (600 g) eluting with ethyl acetate/hexanes (2/1) to afford a dark solid, 1.24 g (19%), mp 191-1930C. 1 H NMR (CDC13) 5 9.54 (bs, -41- WO 99/10350 PCT/US98/17049 1H), 6.87 (s, 2H), 2.39 (s, 3), 2.38 (s, 3H), 2.27 (s, 3H), 1.99 (s, 6H). Step F: The product from Part E (0.125 g, 0.49 mmol) was charged to a dry flask, dissolved in anhydrous 5 dimethylformamide (7.0 ml), and treated with sodium hydride (0.05 g, 1.22 mmol). After stirring 30 minutes, the dark reaction was quenched with benzylbromide (234 .1, 1.96 mmol). The reaction was heated to 500C and allowed to stir 1 hour, whereupon the reaction returned 10 to a golden yellow color. After dilution with water (40 ml) the reaction was extracted with ethyl acetate (4 X 15 ml). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in-vacuo. Purification on silica gel (40 g) eluting with ethyl 15 acetate/hexanes (1/1) gave 83.8 mg (50%) of the title compound, mp 88-890C. 1H NMR (300 MHz, CDC13) 6 7.4 (m, 3H), 7.15 (d, 2H, J=8.0 Hz), 6.90 (s, 2H), 5,24 (m, 2H), 2.47 (s, 3H), 2.29 (s, 3H), 2.20 (s, 3H), 2.01 (s, 3H). HRMS calcd. for M+H (C 22

H

25

N

4 ): 345.2079. Found: 20 345.2061. Examples 6-10 and 12-36 given in TABLE 1 may be prepared in the same manner as described for the preparation of Example 11, starting with the product 25 from Example 11, Part E, and substituting the appropriate electrophile. -42- WO 99/10350 PCT/US98/17049 TABLE 1 'R Me N Me N

NNR

4 2Rn R R5

R

3 Ex. R I

R

2

R

3

R

4

R

5 mp OC 1 CH 2 cPr C1 Cl Cl H 190-192 2 CH(CH 2

CH

3 2 Cl C1 C1 H 210-212 3 CH 2

CH(CH

2

CH

3

)

2 Cl C1 C1 H 112-114 4 benzyl C1 Cl C1 H Amorphous 5 n-butyl Cl C1 C1 H 176-177 6 4-fluorobenzyl Cl C1 C1 H 7 4-phenylbenzyl C1 Cl C1 H 8 CH 2 (2-tetrahydropyran) C1 C1 C1 H 9 CH 2

CH

2 0CH 2

CH

3 Cl Cl Cl H 10 CH 2 CH (CH 2

CH

3 ) 2 Me Me Me H Oil, MS 11 benzyl Me Me Me H 88-89 12 n-butyl Me Me Me H 122-123 13 CH 2 (2-tetrahydropyran) Me Me Me H 14 COPh Me Me Me H 15 CH 2 cPr C1 C1 H H 106-107 16 CH 2 cPr H C1 H H 130-134 17 benzyl C1 Cl Br H 18 benzyl Br Cl1 Br H 19 benzyl Cl1 OMe OMe H 20 benzyl Br OMe OMe H 21 n-butyl Et Br Et H 22 n-butyl Et Me Et H 23 CH 2 cPr Me OMe H H 24 CH 2 cPr Me C1 H H 25 CH (CH 2

CH

3 ) 2 Br iPr H H 26 CH(CH 2

CH

3

)

2 Br Br H H 27 CH(CH 2

CH

3

)

2 Cl1 OMe H H 28 CH(CH 2

CH

3

)

2 Cl Me Me H 29 benzyl C1 Me Me H 30 CH2CH2CH2CH3 C Me Me H 31 CH 2 cPr C1 C1 H Cl 32 CH(CH 2

CH

3 2 Me C1 H Cl 33 CH 2 CH (CH 2

CH

3

)

2 Br Me H Cl 34 benzyl C1 C1 H F 35 n-butyl Cl Me H F 36 CH(CH 3 ) CH 2

CH

2

CH

3 Me Me H F -43- WO99/10350 PCTIUS98/17049 Example 38 Preparation of 5-Ethyl-3-methyl-4-[1-(2 ethyl)butane]-1-(2,4,6-trichloro) phenylimidazo[4,5-c]pyrazole 5 Part A: The product from Example 1, Part A (15 g, 54.23 mmol) was suspended in propionic anhydride (40 ml) and allowed to stir at room temperature for 2 hours. The reaction was poured onto an ice slurry (500 ml) and stirred overnight. The resultant precipitate was 10 filtered and dried to constant weight to afford 16.02 g (89%) of desired amido pyrazole.' Part B The product from Part A (15.92 g, 47.86 mmol) was reduced with borane/THF complex (144 ml) in the same manner as described for the preparation of 15 Example 1, Part C to afford an oil, 5.65 g (56%, based on recovered starting material). 1 H NMR (300 MHz, CDC13) 6 7.47 (s, 2H), 5.36 (s, 1H), 3.08 (bs, 1H), 3.05 (m, 2H), 2.26 (s, 3H), 1.57 (m, 2H), 0.92 (s, 3H, J=7.8 Hz). 20 Part C: The product from Step B (10.50 g, 32.97 mmol) was dissolved in ethanol (75 ml), cooled to 0OC, and treated with 1.0N HC1 (0.5 ml) and isoamyl nitrite (4.41 ml, 32.97 mmol). The reaction was stirred 24 hours, cooled to 0 0 C and the resultant purple 25 precipitate filtered and dried to constant weight to afford 8.64 g (75%). 1 H NMR (300 MHz, CDC13) 8 7.51 (s, 2H), 2.74 (m, 2H), 2.3 (s, 3H), 1.48 (m, 2H), 0.85 (t, 3H, J=7.2 Hz). Part D: The product from Part C (8.47 g, 24.36 30 mmol) was dissolved in pyridine (140 ml) and the homogeneous solution refluxed 14 hours. The reaction was concentrated in-vacuo to remove pyridine and purified via column chromatography on silica gel (800 g) eluting initially with ethyl acetate/hexanes (1/1) to -44- WO99/10350 PCT/US98/17049 remove unreacted starting material, and then with ethyl acetate to afford desired imidazopyrazole, 2.87 g (36%), mp 221.0-223.0 0 C. 1 H NMR (300 MHz, CDC13) 8 8.82 (bs, 1H), 7.44 (s, 2H), 2.85 (q, 2H, J=7.8 Hz), 2.46 (s, 3H), 5 1.37 (t, 3H, J=7.5 Hz). Part E: The product from Part D (0.10 g, 0.30 mmol) was reacted with sodium hydride (30 mg, 0.75 mmol) and 1-bromo-2-ethylbutane (170 g1, 1.20 mmol) in dimethylformamide (2.0 ml) as described for the 10 preparation of Example 1, Part F. Title compound: mp 135.5-136.0 0 C. 1 H NMR (300 MHz, CDCl3) 8 7.44 (s, 2H), 3.89 (d, 2H, J=7.2 Hz), 2.77 (q, 2H, J=7.5 Hz), 2.51 (s, 3H), 1.80 (m, 1H), 1.38 (m, 7H), 0.94 (t, 3H, 7.5 Hz). 15 Example-40 Preparation of 4-Cyclopropylmethyl-5-ethyl-3 methyl-1-(2,4,6-trichloro) phenylimidazo[4,5 c]pyrazole The product from Example 38, Part D (0.02 g, 0.06 20 mmol) was reacted with sodium bis(trimethylsilyl)amide (152 p1, 0.09 mmol, 0.6M/toluene) and cyclopropylmethylbromide (11.8 p1, 0.12 mmol) in dimethylformamide (0.6 ml) in a 2.0 ml polypropylene well confined within a 96 well microtiter plate. The 25 reaction was agitated for 1 hour at room temperature, heated for 30 minutes at 60 0 C, then treated with aminomethylpolystyrene (180 mg, 0.180 mmol, Advanced ChemTech, 1.00 mmol/g loading, Lot # 13312) for 1 hour. The reaction was filtered, dried to constant weight, and 30 purified on a silica gel plug (0.70 g) eluting with a solvent gradient from hexanes/ethyl acetate (9/1) to hexanes/ethyl acetate (1/1) to afford title compound, 18.2 mg, mp 144.5-146.0OC. 1 H NMR (300 MHz, CDCl3) 8 7.44 -45- WO 99/10350 PCTIUS98/17049 (s, 2H), 3.94 (d, 2H, J=6.6 Hz), 2.79 (q, 2H, J=7.2 Hz), 2.52 (s, 3H), 1.59 (s, 6H), 1.35 (t, 3H, J=7.2 Hz), 1.26 (m, 1H), 0.66 (m, 2H), 0.40 (m, 2H). MS (CI) M+H=313.1. 5 Examle 105 Preparation of 5-Ethyl-3-methyl-4-[1-(1-n propyl)butane]-1-(2,4,6-trichloro) phenylimidazo[4,5-c]pyrazole: The product from Example 38, Part D (50 mg, 0.15 10 mmol) was reacted with sodium bis(trimethylsilyl)amide (630 p.l, 0.38 mmol, 0.6M/toluener and 4-bromoheptane (11.8 g1, 0.12 mmol) in dimethylformamide (1.5 ml). The reaction was heated to 60 0 C for 3 hours, then diluted with water (10 ml) and extracted with ethyl acetate (3 X 15 15 ml). The combined organic extracts were dried over anhydrous magnesium sulfate, concentrated in-vacuo and the crude product purified by column chromatography on silica gel (20 g) eluting with hexanes/ethyl acetate (1/1) to afford the title compound as a crystalline 20 solid, mp 113-114 0 C. 1H NMR (300 MHz, CDC13) 8 7.44 (s, 2H), 4.10 (m, 1H), 2.83 (q, 2H, J=7.3 Hz), 2.54 (s, 3H), 1.84 (q, 4H, J=7.7 Hz), 1.34 (t, 3H, J=7.2 Hz), 1.20 (m, 4H), 0.91 (t, 3H, J=7.4 Hz). HRMS calcd. for M+

(C

20

H

26

N

4 C13): 426.1145. Found: 426.1130. 25 Example 106 Preparation of 5-Ethyl-3-methyl-4-[1-(1 ethyl)pentane] -1- (2,4,6-trichloro) phenylimidazo[4,5-c]pyrazole 30 The product from Example 38, Part D (200 mg, 0.61 mmol) was reacted with sodium bis(trimethylsilyl)amide (2.50 ml, 1.52 mmol, 0.6M/toluene) and 3-bromoheptane (435 gg, 2.43 mmol) in dimethylformamide (6.0 ml) as -46- WO99/10350 PCT/US98/17049 described for the preparation of Example 99. Title compound was obtained as a crystalline solid, mp 121 122 0 C. 1 H NMR (300 MHz, CDC13) 8 7.44 (s, 2H), 3.99 (m, 1H), 2.81 (q, 2H, J=7.3 Hz), 2.53 (s, 3H), 1.88 (m, 4H), 5 1.35 (t, 3H, J=7.3 Hz), 1.29 (m, 4H), 0.86 (t, 3H, J=6.9 Hz), 0.84 (t, 3H, J=6.7 Hz). HRMS calcd. for M+ H

(C

20

H

26

N

4 C1 3 ): 427.1223. Found: 427.1213. Example 107 10 Preparation of 5-Ethyl-3-methyl-4-[1-(1 methyl)propane]-1-(2,4,6-trichloro) phenylimidazo[4,5-c]pyrazole: The product from Example 38, Part D (200 mg, 0.61 mmol) was reacted with sodium bis(trimethylsilyl)amide 15 (2.50 ml, 1.52 mmol, 0.6M/toluene) and 2-bromobutane (260 gi, 2.43 mmol) in dimethylformamide (6.0 ml) as described for the preparation of Example 105. Title compound was obtained as a crystalline solid, mp 113 114 0 C. 1 H NMR (300 MHz, CDC13) 8 7.45 (s, 2H), 4.2 (m, 20 1H), 2.83 (q, 2H, J=7.3 Hz), 2.56 (s, 3H), 1.91 (m, 2H), 1.57 (d, 3H, J=6.6 Hz), 1.33 (t, 3H, J=7.3 Hz), 0.86 (t, 3H, J=7.3 Hz). HRMS calcd. for M+H (C 17

H

20

N

4 C1 3 ): 385.0754. Found: 385.0743. 25 Examle 108 Preparation of 5-Ethyl-3-methyl-4-[1-(1 methyl)butane]-1-(2,4,6-trichloro) phenylimidazo[4,5-c]pyrazole The product from Example 38, Part D (200 mg, 0.61 30 mmol) was reacted with sodium bis(trimethylsilyl)amide (2.50 ml, 1.52 mmol, 0.6M/toluene) and 2-bromopentane (300 p1, 2.43 mmol) in dimethylformamide (6.0 ml) as described for the preparation of Example 105. Title -47- WO 99/10350 PCT/US98/17049 compound was obtained as a viscous oil. 1 H NMR (300 MHz, CDC13) 8 7.44 (s, 2H), 4.30 (m, 1H), 2.56 (s, 3H), 1.86 (m, 2H), 1.55 (d, 3H, J=6.9 Hz), 1.33 (t, 3H, J=7.3 Hz), 0.93 (t, 3H, J=7.3 Hz). HRMS calcd. for M+ H 5 (C 18

H

22

N

4 C1 3 ): 399.0910. Found: 399.0901. Example 113 Preparation of 5-Ethyl-4-methanesulfonylbenzyl-3 methyl-1- (2,4,6-trichloro) phenylimidazo[4,5 10 c]pyrazole: The product from Example 38, Part D (0.02 g, 0.06 immol) was reacted with sodium bis(trimethylsilyl)amide (152 gil, 0.09 mmol, 0.6M/toluene) and 4 methylsulfonylbenzyl chloride (121 p1, 0.12 mmol as a 15 1.0 M solution in DMF) in dimethylformamide (0.6 ml) in a 2.0 ml polypropylene well as described for the preparation of Example 40. Title compound was obtained as a crystalline solid, mp 194.0-196.0 0 C. 1 H NMR (300 MHz, CDC13) 8 7.98 (d, 2H, J=8.1 Hz), 7.46 (s, 2H), 7.32 20 (d, 2H, J=8.1 Hz), 5.36 s, 2H), 3.07 (s, 3H), 2.78 (q, 2H, J=7.7 Hz), 2.19 (s, i), 1.32 (t, 3H, J=7.7 Hz). HRMS calcd. for M+1 (C 21

H

20

N

4 0 2 C1 3

S

1 ): 497.0373. Found: 497.0343. 25 xamle 114 Preparation of 4-Benzoyl-5-ethyl-3-methyl-l (2,4,6-trichloro)phenylimidazo [4,5-c]pyrazole The product from Example 38, Part D (200 mg, 0.61 mmol) was dissolved with gentle heating in anhydrous 30 methylene chloride (5 ml) and treated with 4 dimethylaminopyridine (15 mg, 0.12 mmol), diisopropylethylamine (160 p.l, 0.92 mmol) and benzoyl -48- WO99/10350 PCT/US98/17049 chloride (78 g1, 0.67 mmol). The reaction was stirred 1.5 hours at room temperature, concentrated directly in vacuo and purified by column chromatography on silica gel (50 g) eluting with hexanes/ethyl acetate (2/1) to 5 afford desired product, 189 mg (71%) as a crystalline solid, mp 169.0-170.0OC. 1 H NMR (300 MHz, CDCl3) 8 7.85 (d, 2H, J=8.0 Hz), 7.75 (m, 1H), 7.59 (t, 2H, J=8.1 Hz), 7.48 (s, 2H), 3.10 (q, 2H, J=7.3 Hz), 1.54 (s, 3H), 1.38 (t, 3H, J=7.3 Hz). HRMS calcd. for M+ (C 20

H

15

N

4 C1 3 0 1 ): 10 432.0311. Found: 432.0291. Anal. Calcd. for

C

20

H

15

N

4 C1 3 0 1 : C, 55.39; H, 3.50; N, 12.92. Found: C, 55.65; H, 3.46; N, 12.52. ExamrDle 115 15 Preparation of 4-Benzenesulfonyl-5-ethyl-3 methyl-1-(2,4,6-trichloro)phenyl imidazo[4,5 c]pyrazole The product from Example 38, Part D (200 mg, 0.61 mmol) was dissolved with gentle heating in anhydrous 20 methylene chloride (5 ml) and treated diisopropylethylamine (160 p1, 0.92 mmol) and benzenesulfonyl chloride (86 p1, 0.67 mmol). The reaction was stirred 20 hours at room temperature, concentrated directly in-vacuo and purified by column 25 chromatography on silica gel (55 g) eluting with hexanes/ethyl acetate (2/1) to afford desired product, 150 mg (53%) as a crystalline solid, mp 189.0-190.0OC. 1H NMR (300 MHz, CDC13) 8 7.90 (d, 2H, J=8.8 Hz), 7.72 (m, 1H), 7.58 (t, 2H, J=8.1 Hz), 7.45 (s, 2H), 3.01 (q, 30 2H, J=7.3 Hz), 2.65 (s, 3H), 1.30 (t, 3H, J=7.3 Hz). HRMS calcd. for M+1 (C 19

H

16

N

4 0 2 C1 3

S

1 ): 469.0060. Found: 469.0035. Anal. Calcd. for C 19

H

15

N

4 C1 3 0 2

S

1 : C, 48.58; H, 3.23. Found: C, 48.93, H, 3.36. -49- WO99/10350 PCT/US98/17049 ExamDple 116 Preparation of 4-Diphenylmethyl-5-ethyl-3-methyl 1-(2,4,6-trichloro)phenylimidazo[4,5-c]pyrazole The compound prepared in Example 38, Part D (330 5 mg, 1.0 mmol) was dissolved in anhydrous dimethylformamide (10 mL), and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 4.17 mL, 2.5 mmol) was added. The solution was heated to 60 0 C for one hour, then bromodiphenylmethane (988 mg, 4.0 mmol) was 10 added and the reaction held at 100 0 C for 63 hours. The reaction was then cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness 15 in vacuo. The residue was purified by column chromatography (25% ethyl acetate/hexanes) to give the final product as a crystalline solid (183 mg, 37%), mp 'H NMR (300 MHz,CDC1 3 ) 8 7.44 (s, 2H), 7.39 (m, 6H), 7.14 (m, 4H), 6.69 (s, 1H), 2.85 (q, 2H, J=7.7 Hz), 1.38 (s, 20 3H), 1.29 (t, 3H, J=7.5 Hz). HRMS Calcd. for M+H

(C

26

H

22 C1 3

N

4 ): 495.0910. Found: 495.0883. Example 117 Preparation of 5-Ethyl-3-methyl-4-(1 25 phenylethyl)-1-(2,4,6 trichloro)phenylimidazo[4,5-c]pyrazole The compound prepared in Example Banana, Part D (200 mg, 0.61 mmol) was dissolved in anhydrous dimethylformamide (6 mL), and sodium 30 bis(trimethylsilyl)amide (0.6 M in toluene, 2.50 mL, 1.52 mmol) was added. The solution was heated to 60 0 C for one hour, then (l-bromoethyl)benzene (451 mg, 2.44 mmol) was added. The reaction was held at 100 0 C for 24 hours. The reaction was then cooled to room -50- WO 99/10350 PCT/US98/17049 temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified 5 by column chromatography (25% ethyl acetate/hexanes) to give the final product as a crystalline solid (135 mg, 31%), mp 1 H NMR (300 MHz,CDC1 3 ) 8 7.44 (s, 2H), 7.37 (m, 3H), 7.19 (m, 2H), 2.87 (dq, 2H, J=7.4 Hz, J=l.l Hz), 1.98 (s, 3H), 1.96 (d, 3H, J=7.0 Hz), 1.34 (t, 3H, J=7.5 10 Hz). HRMS Calcd. for M+H (C 21

H

20 C1 3

N

4 ): 433.0753. Found: 433.0763. Anal. Calcd. for C21HCl 3

N

4 : C, 58.15; H, 4.42; N, 12.92. Found: C, 58.05; H, 4.38; N, 12.73. Example 118 15 Preparation of 4-Cyclopentyl-5-ethyl-3-methyl-1 (2,4,6-trichloro)phenylimidazo[4,5-c]pyrazole The compound prepared in Example Banana, Part D (330 mg, 1.0 mmol) was dissolved in anhydrous dimethylformamide (10 mL), and sodium 20 bis(trimethylsilyl)amide (0.6 M in toluene, 4.17 mL, 2.5 mmol) was added. The solution was heated to 60 0 C for one hour, then bromocyclopentane (596 mg, 4.0 mmol) was added and the reaction held at 100 0 C for 63 hours. The reaction was then cooled to room temperature, and 25 diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by preparative thin layer chromatography (25% ethyl acetate/hexanes) to give 30 the final product as a crystalline solid (81 mg, 20%), mp 'H NMR (300 MHz,CDC1 3 ) 8 7.44 (s, 2H), 4.58 (m, 1H), 2.84 (q, 2H, J=7.6 Hz), 2.55 (s, 3H), 2.22 (m, 2H), 2.00 (m, 4H), 1.80 (m, 2H), 1.33 (t, 3H, J=7.7 Hz). HRMS Calcd. for M+H (C 18

H

20 C13N 4 ): 397.0753. Found: 397.0755. -51- WO99/10350 PCT/US98/17049 Anal. Calcd. for CH 1 ,Cl 3

N

4 : C, 54.36; H, 4.82; N, 14.09. Found: C, 54.37; H, 4.84; N, 13.82. Examle 152 5 Preparation of 4-(n-Butyl)-5-ethyl-3-ethyl-1 (2,4,6-trichloro)phenylimidazo[4,5-c]pyrazole Step A: Sodium hydride (60% in mineral oil, 6.30 g, 157 mmol) was rinsed free of oil with cyclohexane, fresh cyclohexane was added (200 mL), and this 10 suspension was heated to reflux. A solution of ethyl propionate (15.3 g, 150 mmol) and acetonitrile (6.77 g, 165 mmol) in cyclohexane (30 mL) was then added to the sodium hydride suspension over 10 minutes, the reaction was held at reflux for 16 hours, and cooled to room 15 temperature. The reaction was extracted with water, and the resulting aqueous solution acidified to pH 4 with 10% HC1. This solution was then extracted with ethyl acetate, and the organic solution dried over anhydrous magnesium sulfate and reduced in vacuo to leave the 20 cyanoketone as an amber oil (5.60 g, 38%). This oil was then dissolved in ethanol (500 mL), the reaction heated to 400C, and ammonium nitrate (2.3 g, 28.8 mmol) added. Anhydrous ammonia was bubbled through the solution for 24 hours, then water (200 mL) was added and the ethanol 25 removed in vacuo, then 0.3 N NaOH (200 mL) was added. The aqueous solution was extracted with diethyl ether, and the organic phase was dried over anhydrous magnesium sulfate and reduced in vacuo to leave the 9 aminoacrylonitrile (2.82 g, 29.3 mmol, 51%). To this 30 material was added 1N HC1 (95 mL) and 2,4,6 trichlorophenylhydrazine (4.13 g, 19.5 mmol), and this mixture was refluxed for three hours. The reaction was cooled to room temperature and the supernatant aqueous phase was decanted and neutralized with 10% NaOH, 35 producing an oil that solidifies upon stirring. The -52- WO 99/10350 PCT/US98/17049 amorphous solid was recovered by filtration to give the product (5.16 g, 91%). 'H NMR (300 MHz,CDC1 3 ) 6 7.47 (s, 2H), 5.52 (s, 1H), 3.49 (bs, 2H), 2.61 (q, 2H, J=7.7 Hz), 1.25 (t, 3H, J=7.7 Hz). HRMS Calcd. for M+H 5 (C11HuC1 3

N

3 ): 290.0018. Found: 289.9995. Anal. Calcd. for C1HI 0 C13N 3 : C, 45.47; H, 3.48; N, 14.46. Found: C, 45.58; H, 3.34; N, 14.30. Steu B: The compound prepared in Step A (5.16 g, 10 17.8 mmol) was suspended in propionic anhydride (11.4 mL, 88.8 mmol) at room temperature and allowed to stir for 2 hours, resulting in a homogeneous solution. Ice was added and the reaction stirred for 5 hours, causing a solid to form. The off-white solid was isolated by 15 filtration to leave the product (5.52 g, 90%), mp 145 1480C. 'H NMR (300 MHz,CDC1 3 ) 6 7.50(s, 2H), 6.70 (bs, 1H), 6.53 (bs, 1H), 2.70 (q, 2H, J=7.7 Hz), 2.30 (q, 2H, J=7.3 Hz), 1.29 (t, 3H, J=7.5 Hz), 1.15 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H (C4 4

H

1 5 C1 3

N

3 0): 346.0281. Found: 20 346.0280. Anal. Calcd. for C, 4 H,4C1 3

N

3 0: C, 48.51; H, 4.07; N, 12.12. Found: C, 48.51; H,3.96; N, 12.07. Ste.pQ C: The compound prepared in Step B (5.47 g, 15.8 mmol) was dissolved in anhydrous tetrahydrofuran 25 (50 mL). To this suspension was added borane/THF complex (47.3 mL, 47.3 mmol), and the reaction was refluxed for 16 hours. The reaction was cooled to room temperature and excess borane was quenched with 10% NaOH (15 mL) until off-gassing ceased. The reaction was 30 diluted with water and diethyl ether, the layers separated and the organic phase washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and reduced in vacuo to leave a white solid, mp 138 1400C. 'H NMR (300 MHz,CDC1 3 ) 8 7.52 (s, 2H), 5.43 (s, -53- WO 99/10350 PCT/US98/17049 1H), 3.41 (m, 1H), 3.12 (q, 2H, J=6.6 Hz), 2.80 (q, 2H, J=7.7 Hz), 1.58 (m, 2H), 1.29 (t, 3H, J=7.7 Hz), 0.92 (t, 3H, J=7.5 Hz). HRMS Calcd. for M+H (C1 4

H,

7 C1 3

N

3 ) 332.0488. Found: 332.0485. 5 Step D: The compound prepared in Step C was suspended in ethanol (30 mL), and 15 drops of 10% HCl were added. Upon addition of the HC1 significant off gassing occurred, and at the completion of the off 10 gassing the reaction mixture was homogeneous. Isoamyl nitrite (2.1 mL, 15.7 mmol) was then added, and the solution darkened upon addition. The solution was stirred at room temperature for 16 hours, then reduced to dryness in vacuo to give a dark oil. This residue 15 was purified by column chromatography (gradient elution of 25-50% ethyl acetate/hexanes) to give the final product as purple crystals (1.66 g, 29% from amide), mp 104-107oC. 'H NMR (300 MHz,CDCl 3 ) 8 10.46 (bs, 1H), 7.50 (s, 2H), 3.17 (q, 2H, J=7.7 Hz), 2.75 (m, 2H), 1.49 (q, 20 2H, J=7.0 Hz), 1.46 (t, 3H, J=7.7 Hz), 0.85 (t, 3H, J=7.5 Hz). HRMS Calcd. for M+H (C, 4 Hl 6 C1 3

N

4 0): 361.0390. Found: 361.0386. Anal. Calcd. for C, 4

H,

5 C1 3 lN 4 0: C, 46.50; H, 4.18; N, 15.49, Found: C, 46.78; H, 4.10; N, 15.50. 25 Step E: The compound prepared in Step D (1.56 g, 4.31 mmol) was dissolved in anhydrous pyridine (20 mL) and the solution heated to reflux for 16 hours. The solvent was removed in vacuo and the residue purified by column chromatography (50% ethyl acetate/hexanes) to 30 afford the product as a brown solid. This solid was washed with ethyl ether to leave the product as a tan solid (517 mg, 35%), mp 242-243.5 0 C. 'H NMR (300 MHz,CDC13) 8 8.60 (bs, 1H), 7.44 (s, 2H), 2.866 (q, 2H, J=7.6 Hz), 2.860 (q, 2H, J=7.5 Hz), 1.394 (t, 3H, J=7.7 -54- WO 99/10350 PCT/US98/17049 Hz), 1.386 (t, 3H, J=7.7 Hz). HRMS Calcd. for M+H

(C

14

H

1 4 C1 3

N

4 ): 343.0273. Found: 343.0284. Anal. Calcd. for C14H 13 C1 3

N

4 : C, 48.93; H, 3.81; N, 16.30. Found: C, 48.87; H, 3.61; N, 16.14. 5 Ste F: The compound prepared in Step E (80 mg, 0.23 mmol) was dissolved in anhydrous dimethylformamide (2.5 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 0.97 mL, 0.58 mmol) was added. The solution 10 was heated to 600C for one hour, then 1-bromobutane (0.10 mL, 0.92 mmol) was added. The reaction was held at 600C for one hour, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over 15 anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column chromatography (25% ethyl acetate/hexanes) to give the final product as a crystalline solid (53 mg, 58%), mp 101-104 0 C. 'H NMR (300 MHz,CDC1 3 ) 8 7.43 (s, 2H), 4.02 20 (t, 2H, J=7.5 Hz), 2.87 (q, 2H, J=7.7 Hz), 2.79 (q, 2H, J=7.3 Hz), 1.84 (m, 2H), 1.39 (m, 8H), 1.01 (t, 3H, J=7.3 Hz). 13C NMR (75 MHz,CDC1 3 ) 8 157.18, 152.16, 136.73, 136.14, 135.15, 133.77, 128.58, 120.94, 45.27, 33.45, 21.31, 21.25, 20.04, 14.14, 13.74, 12.72. HRMS 25 Calcd. for M+ (C 8

H

21 Cl 3

N

4 ): 398.0829. Found: 398.0832. Anal. Calcd. for C 8

H

21 Cl 3

N

4 : C, 54.08; H, 5.30; N, 14.02. Found: C, 54.45; H, 5.22; N, 13.86. Example 153 30 Preparation of 4-(3,4-Difluorobenzyl)-5-ethyl-3 ethyl-i- (2,4,6-trichloro)phenylimidazo [4,5 c] pyrazole The compound prepared in Step E, Example 152 (80 mg, 0.23 mmol) was dissolved in anhydrous -55- WO 99/10350 PCT/US98/17049 dimethylformamide (2.5 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 0.97 mL, 0.58 mmol) was added. The solution was heated to 60 0 C for one hour, then a-bromo-3,4-difluorotoluene (0.12 mL, 5 0.92 mmol) was added. The reaction was held at 60 0 C for one hour, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in 10 vacuo. The residue was purified by column chromatography (25% ethyl acetate/hexanes) to give the final product as a crystalline solid (74 mg, 68%), mp 100-1030C. 'H NMR (300 MHz,CDC1 3 ) 8 7.45 (s, 2H), 7.18 (m, 1H), 6.87 (m, 2H), 5.24 (s, 2H), 2.76 (q, 2H, J=7.7 15 Hz), 2.57 (q, 2H, J=7.6 Hz), 1.31 (t, 3H, J=7.6 Hz), 1.17 (t, 3H, J=7.5 Hz). HRMS Calcd. for M+H

(C

21

H

18 C1 3

F

2

N

4 ): 469.0550. Found: 469.0565. Anal. Calcd. for C 21 H,C13F2N 4 C, 53.69; H, 3.66; N, 11.93. Found: C, 53.85; H, 3.52; N, 11.49. 20 Example 154 Preparation of 4-[l-(1-Ethyl)butane]-5-ethyl-3 ethyl-i- (2,4,6-trichloro)phenylimidazo [4,5 c] pyrazole 25 The compound prepared in Step E, Example 152 (145 mg, 0.42 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 1.76 mL, 1.05 mmol) was added. The solution was heated to 60 0 C 30 for one hour, then 3-bromohexane (277 mg, 1.68 mmol) was added. The reaction was held at 60 0 C for 24 hours, then held at 80 0 C for an additional 24 hours. The reaction -56- WO99/10350 PCT/US98/17049 was then cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in 5 vacuo. The residue was purified by column chromatography (25% ethyl acetate/hexanes) to give the final product as a crystalline solid (22 mg, 12%), mp 96.5-98.0 0 C. 'H NMR (300 MHz,CDC13) 8 7.43 (s, 2H), 4.01 (m, 1H), 2.90 (q, 2H, J=7.3 Hz), 2.81 (q, 2H, J=7.7 Hz), 10 1.87 (m, 4H), 1.39 (t, 3H, J=7.5 Hz), 1.34 (t, 3H, J=7.5 Hz), 1.25 (m, 2H), 0.92 (t, 3H, J=7.3 Hz), 0.84 (t, 3H, J=7.5 Hz). HRMS Calcd. for M+ (C 20

H

25 C1 3

N

4 ) : 426.1130. Found: 426.1145. 15 Example 155 Preparation of 5-Ethyl-4-[1-(1-methyl)butane]-3 ethyl-l-(2,4,6-trichloro)phenylimidazo[4,5 c]pyrazole The compound prepared in Step E, Example 152 (145 20 mg, 0.42 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 1.76 mL, 1.05 mmol) was added. The solution was heated to 60 0 C for one hour, then 2-bromopentane (0.21 mL, 1.68 mmol) 25 was added. The reaction was held at 60 0 C for 24 hours, then held at 80 0 C for an additional 24 hours. The reaction was then cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried 30 over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column chromatography (25% ethyl acetate/hexanes) to give the final product as a crystalline solid (20 mg, 11%), mp -57- WO99/10350 PCT/US98/17049 87.5-89.5 0 C. 'H NMR (300 MHz,CDC1 3 ) 3 7.43 (s, 2H), 4.29 (m, 1H), 2.93 (q, 2H, J=7.3 Hz), 2.82 (q, 2H, J=7.7 Hz), 1.87 (m, 2H), 1.55 (d, 3H, J=6.6 Hz), 1.40 (t, 3H, J=7.5 Hz), 1.33 (t, 3H, J=7.5 Hz), 1.20 (m, 2H), 0.93 (t, 3H, 5 J=7.3 Hz). HRMS Calcd. for M+H (C19H 24 C1 3

N

4 ): 413.1066. Found: 413.1056. Example 156 Preparation of 4-(n-Butyl)-5-ethyl-3 10 methoxymethyl-1-(2,4,6 trichloro)phenylimidazo[4,5-c]pyrazole Step A* A solution of methoxyacetonitrile (16.3 g, 0.23 mol) and acetonitrile (8.21 g, 0.20 mol) in tetrahydrofuran (50 mL) was added slowly at room 15 temperature to potassium t-butoxide (IM in THF, 180 mL, 0.18 mol). A thick slurry resulted during the addition, and additional tetrahydrofuran (70 mL) was added. The reaction was heated to reflux for 24 hours, and was then slowly hydrolyzed with water (100 mL). This mixture was 20 then extracted with dichloromethane, and the organic phase was dried over anhydrous magnesium sulfate, filtered and reduced in vacuo to leave a brown oil. This oil was then purified by vacuum distillation to give the S-aminoacrylonitrile as a light yellow solid 25 (13.0 g, 116 mmol, 50%). To this solid was added IN HC1 (200 mL) and 2,4,6-trichlorophenylhydrazine (16.3 g, 77.0 mmol) and this mixture was heated at reflux for three hours. The reaction was cooled to room temperature and the supernatant aqueous phase was 30 decanted and neutralized with 10% NaOH, producing an oil that solidifies upon stirring. The solid was isolated by filtration, then redissolved in IN HCI and filtered to remove dark solids. The solution was neutralized to recover the product as a tan solid. The tarry residue 35 from the reaction was dissolved in ethyl acetate and -58- WO99/10350 PCT/US98/17049 extracted with IN HC1, and this extract was neutralized with 10% NaOH to leave a brown oil which solidifies upon standing to give the product (combined with earlier product, 5.71 g, 24%), mp 103.5-106 0 C. 'H NMR (300 5 MHz,CDC1 3 ) 8 7.49 (s, 2H), 5.72 (s, 1H), 4.42 (s, 2H), 3.58 (bs, 2H), 3.38 (s, 3H). HRMS Calcd. for M+H (CuHuC1 3 NO): 305.9970. Found: 305.9974. Anal. Calcd. for C11H, 0 Cl3N30: C, 43.10; H, 3.30; N, 13.71. Found: C, 43.09; H, 3.23; N, 13.70. 10 Ster : The compound prepared in Step A (5.61 g, 18.3 mmol) was suspended in propionic anhydride (11.7 mL, 91.5 mmol) at room temperature and allowed to stir for 20 hours, resulting in a homogeneous solution. Ice 15 was added and the reaction stirred for 5 hours, then diethyl ether was added and the phases were separated, the organic phase washed with saturated aqueous NaHCO 3 , then saturated aqueous Na 2

CO

3 , then dried over anhydrous magnesium sulfate and reduced in vacuo to leave an oil. 20 Ice was added to this oil and stirred for four hours, causing a solid to form. The solid was isolated by filtration to leave the product as an amorphous solid (5.42 g, 81%). 'H NMR (300 MHz,CDC1 3 ) 7.52(s, 2H), 6.72 (m, 2H), 4.51 (s, 2H), 3.40 (s, 3H), 2.31 (m, 2H), 1.15 25 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H (C, 4

H

1 C1 3

N

3 0 2 ): 362.0230. Found: 362.0223. Anal. Calcd. for C1 4H 1 4 C13N3O2: C, 46.37; H, 3.89; N, 11.59. Found: C, 46.51; H, 3.82; N, 11.55. 30 Step C: The compound prepared in Step B (5.32 g, 14.7 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL). To this suspension was added borane/THF complex (47.3 mL, 47.3 mmol), and the reaction was refluxed for 16 hours. The reaction was cooled to room 35 temperature and excess borane was quenched with 10% NaOH -59- WO99/10350 PCT/US98/17049 (15 mL) until off-gassing ceased. The reaction was diluted with water and diethyl ether, the layers separated and the organic phase washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, 5 and reduced in vacuo to leave an orange oil. This oil was purified by column chromatography (25% ethyl acetate/hexanes) to give a light yellow oil (3.75 g, 73%) 1 H NMR (300 MHz,CDC13) 8 7.48 (s, 2H), 5.59 (s, 1H), 4.44 (s, 2H), 3.40 (s, 3H), 3.10 (m, 3H), 1.58 (m, 10 2H), 0.92 (t, 3H, J=7.3 Hz).Anal. Calcd. for C 14

H

16 C1 3 NI0: C, 48.23; H, 4.64; N, 12.05. Found: C, 48.38; H, 4.50; N, 11.94. HRMS Calcd. for M+H (C 14

H

17 C1 3

N

3 0): 348.0437. Found: 348.0441. 15 Step D: The compound prepared in Step C was dissolved in ethanol (25 mL), and 15 drops of 10% HC1 were added. Isoamyl nitrite (1.7 mL, 12.6 mmol) was then added, and the solution darkened upon addition. The solution was stirred at room temperature for 16 hours, 20 and then reduced to dryness in vacuo to give a dark oil. This residue was purified by column chromatography (gradient elution of 25-50% ethyl acetate/hexanes) to give the final product as a dark blue oil (1.05 g, 26%). 1 H NMR (300 MHz,CDC13) 8 10.25 (bs, 1H), 7.55 (s, 2H), 25 5.04 (s, 2H), 3.56 (s, 3H), 2.76 (m, 2H), 1.49 (m, 2H), 0.86 (t, 3H, J=7.5 Hz). HRMS Calcd. for M+H (C4 H6C13 N402): 377.0339. Found: 377.0318. Ste E The compound prepared in Step D (1.05 g, 30 2.8 mmol) was dissolved in anhydrous pyridine (20 mL) and the solution heated to reflux for 16 hours. The solvent was removed in vacuo and the residue purified by column chromatography (50% ethyl acetate/hexanes) to afford the product as a brown solid. This solid was 35 recrystallized from diethyl ether/ethyl acetate to give -60- WO 99/10350 PCT/US98/17049 the product as a light tan solid (505 mg, 50%), mp 165.5-167.0 0 C. 1 H NMR (300 MHz,CDC1 3 ) 8 8.89 (bs, 1H), 7.46 (s, 2H), 4.68 (s, 2H), 3.44 (s, 3H), 2.86 (q, 2H, J=7.7 Hz), 1.37 (t, 3H, J=7.7 Hz). HRMS Calcd. for M+H 5 (C 14

H

14 C1 3

N

4 0): 359.0233. Found: 359.0242. Anal. Calcd. for C 14

H

15 C1N 4 : C, 61.20; H, 5.50; N, 20.39; Cl, 12.90. Found: C, 61.18; H, 5.90; N, 20.34; Cl, 12.78. Step F: The compound prepared in Step E (76 mg, 10 0.21 mmol) was dissolved in anhydrous dimethylformamide (3 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 0.88 mL, 0.53 mmol) was added. The solution was heated to 60 0 C for one hour, then 1-bromobutane (0.09 mL, 0.84 mmol) was added. The reaction was held at 60 0 C 15 for 1.5 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column 20 chromatography (10% ethyl acetate/hexanes) to give the final product as an orange solid (46 mg, 53%), mp 65.5 67.5 0 C. 'H NMR (300 MHz,CDC1 3 ) 8 7.45 (s, 2H), 4.67 (s, 2H), 4.08 (t, 2H, J=7.5 Hz), 3.41 (ws, 3H), 2.80 (q, 2H, J=7.7 Hz), 1.84 (m, 2H), 1.43 (m, 2H), 1.36 (t, 3H, 25 J=7.7 Hz), 1.00 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H

(C

18

H

22

CI

3

N

4 0): 415.0870. Found: 415.0859. Example 157 Preparation of 4-(3,4-Difluorobenzyl)-5-ethyl-3 30 methoxymethyl-1-(2,4,6-trichloro) phenylimidazo[4,5-c]pyrazole The compound prepared in Step E, Example 156 (76 mg, 0.21 mmol) was dissolved in anhydrous dimethylformamide (3 mL) and sodium -61- WO 99/10350 PCTIUS98/17049 bis(trimethylsilyl)amide (0.6 M in toluene, 0.88 mL, 0.53 mmol) was added. The solution was heated to 60 0 C for one hour, then a-bromo-3,4-difluorotoluene (0.11 mL, 0.84 mmol) was added. The reaction was held at 60 0 C for 5 1.5 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column 10 chromatography (10% ethyl acetate/hexanes) to give the final product as an orange solid (50 mg, 49%), mp 91.5 94.5 0 C. 'H NMR (300 MHz,CDC13) 8 7.47 (s, 2H), 7.16 (m, 1H), 6.90 (m, 2H), 5.30 (s, 2H), 4.45 (s, 2H), 3.30 (s, 3H), 2.77 (q, 2H, J=7.7 Hz), 1.31 (t, 3H, J=7.7 Hz). 13 C 15 NMR (75 MHz,CDC13) 8 158.28, 152.56, 151.48, 148.87, 148.34, 148.17, 136.05, 135.76, 133.92, 133.23, 132.97, 128.68, 122.36, 122.30, 122.22, 121.83, 117.93, 117.70, 115.67, 115.43, 67.75, 57.75, 48.09, 21.45, 12.36. HRMS Calcd. for M+H (C 21 H,C1 3

F

2

N

4 0): 485.0505. Found: 20 485.0514. Example 158 Preparation of 4-[1-(1-Ethyl)butane]-5-ethyl-3 methoxymethyl-1-(2,4,6-trichloro) 25 phenylimidazo[4,5-c]pyrazole The compound prepared in Step E, Example 156, (125 mg, 0.35 mmol) was dissolved in anhydrous dimethylformamide (4.0 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 1.45 mL, 30 0.87 mmol) was added. The solution was heated to 60 0 C for one hour, then 3-bromohexane (229 mg, 1.39 mmol) was added. The reaction was held at 60 0 C for 20 hours, -62- WO99/10350 PCT/US98/17049 cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The 5 residue was purified by column chromatography (10% ethyl acetate/hexanes) to give the final product as a white solid (27 mg, 17%), mp 117-119 0 C. 'H NMR (300 MHz,CDC1 3 ) 8 7.46 (s, 2H), 4.67 (d, 2H, J=1.4 Hz), 4.04 (m, 1H), 3.34 (s, 3H), 2.83 (q, 2H, J=7.3 Hz), 1.92 (m, 4H), 1.35 10 (t, 3H, J=7.5 Hz), 0.91 (t, 3H, =7.3 Hz), 0.82 (t, 3H, J=7.3 Hz). 13 C NMR (75 MHz,CDC1 3 ) 8 158.65, 153.50, 136.09, 135.62, 133.32, 131.87, 128.64, 67.93, 58.61, 56.77, 37.10, 28.38, 22.11, 19.88, 13.87, 12.84, 11.10. HRMS Calcd. for M+H (C 20

H

26 C1 3

N

4 0): 443.1161. Found: 15 443.1172. Examule 159 Preparation of 5-Ethyl-4-[1-(1-methyl)butane]-3 methoxymethyl-1-(2,4,6-trichloro) 20 phenylimidazo[4,5-c]pyrazole The compound prepared in Step E, Example 156 (125 mg, 0.35 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 0.97 mL, 25 0.58 mmol) was added. The solution was heated to 60 0 C for one hour, then 2-bromopentane (0.18 mL, 1.39 mmol) was added. The reaction was held at 60 0 C for 20 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the 30 organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column chromatography (10% ethyl acetate/hexanes) to give the final product as a -63- WO 99/10350 PCT/US98/17049 crystalline solid (34 mg, 23%), mp 100.0-101.5 0 C. 1H NMR (300 MHz,CDC1 3 ) 8 7.46 (s, 2H), 4.69 (s, 2H), 4.32 (m, 1H), 3.36 (s, 3H), 2.84 (q, 2H, J=7.7 Hz), 2.05 (m, 1H), 1.85 (mn, 1H), 1.58 (d, 3H, J=6.5 H), 1.34 (t, 3H, J=7.7 5 Hz), 1.18 (mn, 2H), 0.92 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H (C 19

H

24 C13N 4 0): 429.1017. Found: 429.1016. Example 161 Preparation of 5-Ethyl-3-hydroxymethyl-4- [1- (1 10 methyl)butane]-1-(2,4 ,6-trichloro) phenylimidazo[4,5-c] pyrazole This compound was obtained as the second eluting compound from the reaction described in Example 163 (see below) as a solid (1.51 g, 65%), mp 144-146 0 C. 'H NMR 15 (300 MHz,CDC1 3 ) 8 7.46 (s, 2H), 4.90 (d, 2H, J=5.8 Hz), 4.33 (m, 1H), 3.27 (bs, 1H), 2.84 (q, 2H, J=7.5 Hz), 1.97 (m, 1H), 1.88 (m, 1H), 1.56 (d, 3H, J=6.9 Hz), 1.34 (t, 3H, J=7.7 Hz), 1.25 (mn, 2H), 0.91 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+ (C, 7

H,

9 C1 3

N

4 0): 415.0859. Found: 20 415.0860. Examule 163 Preparation of 3-Bromomethyl-5-ethyl-4-[1-(1 methyl)butane] -1- (2,4,6-trichloro) 25 phenylimidazo[4,5-c]pyrazole The compound prepared in Example 159 (2.39 g, 5.56 mmol) was dissolved in dichloromethane and cooled to 78 0 C and BBr 3 (27.8 mL as 1.0 M in dichloromethane, 27.8 mmol) was added. The reaction was held at -78 0 C for one 30 hour, then warmed to room temperature for 16 hours. The reaction was quenched with water (100 mL) and diluted with dichloromethane. The layers were separated and the organic phase washed with saturated sodium chloride, -64- WO99/10350 PCT/US98/17049 dried over anhydrous magnesium sulfate, and reduced in vacuo. The residue was purified by column chromatography (gradient elution of 10-20% ethyl acetate/hexanes), the first eluting compound being the 5 title product as an amorphous solid (660 mg, 25%). 'H NMR (300 MHz,CDC1 3 ) 8 7.46 (s, 2H), 4.75 (s, 2H), 4.35 (m, 1H), 2.84 (q, 2H, J=7.5 Hz), 2.0 (mn, 2H), 1.63 (d, 3H, J=8.4 Hz), 1.35 (t, 3H, J=7.5 Hz), 1.25 (m, 2H), 0.96 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H 10 (C 1

,H

2 1Cl 3 BrN 4 ): 477.0016. Found: 477.0020. Example 164 Preparation of 4-Benzyl-5-isopropyl-3-methyl-1 (2,4,6-trichloro)phenyl-imidazo[4,5-c]pyrazole 15 Part A: The product from Example 1, Part A (9.96 g, 36.01 mmol) was suspended in isobutyric anhydride (25 ml), refluxed for 18 hours and allowed to stir at room temperature for 18 hours. The reaction was treated with water (200 ml) and 10% sodium hydroxide (100 ml) and 20 stirred 2 hours. The reaction was then extracted with diethyl ether (3 X 100 ml), and the combined organic extracts dried over anhydrous magnesium sulfate, and concentrated in-vacuo and dried to constant weight to afford an amorphous solid, 12.48 g (100%). 1 H NMR (300 25 MHz, CDC13) 8 7.51 (s, 2H), 6.71 (bs, 1H), 6.47 (bs, 1H), 2.39 (mn, 1H), 2.33 (s, 3H), 1.24 (d, 3H, J=7.0 Hz), 1.13 (d, 3H, J=7.0 Hz). Part B The product from Part A (12.48 g, 36.00 mmol) was reduced with borane/THF complex (100 ml) in 30 the same manner as described for the preparation of Example 1, Part C to afford an oil, 10.91 g (92%). 1 H NMR (300 MHz, CDCl3) 8 7.53 (s, 2H), 5.39 (s, 1H), 3.49 (m, 1H), 2.94 (t, 2H, J=4.5Hz), 2.39 (s, 3H). -65- WO 99/10350 PCT/US98/17049 Part C: The product from Step B (10.91 g, 32.80 mmol) was dissolved in ethanol (55 ml), cooled to 0 0 C, and treated with 1.0N HC1 (0.5 ml) and isoamyl nitrite (4.40 ml, 32.80 mmol). The reaction was stirred for 3 5 hours while exposed to air, then concentrated to dryness in-vacuo, and purified by column chromatography on silica gel (800 g) eluting with hexanes/ethyl acetate (1/1) to afford a violet crystalline solid, 8.56 g (72%), mp 100-1020C. . 1H NMR (300 MHz, CDC13) 8 10.53 10 (bs, 1H), 7.51 (s, 2H), 2.73 (s, 3H), 2.60 (t, 3H, J=6.3 Hz), 1.68 (m, 1H), 0.84 (d, 6H, J=7.2 Hz). Part D: The product from Part C (8.56 g, 23.67 mmol) was dissolved in pyridine (143 ml) and the homogeneous solution refluxed 20 hours. The reaction 15 was concentrated in-vacuo to remove pyridine and purified via column chromatography on silica gel (800 g) eluting initially with ethyl acetate/hexanes (1/1) and then hexanes/ethyl acetate (1/2) to afford desired imidazopyrazole, 1.49 g (18%), mp 139-139.50C. 1 H NMR 20 (300 MHz, CDC13) 6 8.81 (bs, 1H), 7.44 (s, 2H), 3.13 (m, 1H), 2.46 (s, 3H), 1.39 (d, 6H, J=7.0 Hz). Part E: The product from Part D (0.10 g, 0.29 mmol) was reacted with sodium hydride (30 mg, 0.75 mmol) and benzyl bromide (138 pl, 1.16 mmol) in 25 dimethylformamide (2.0 ml) as described for the preparation of Example 1, Part F. Title compound: mp 103-1050C. 1 H NMR (300 MHz, CDC13) 8 7.44 (s, 2H), 7.35 (m, 3H), 7.11 (d, 2H, J=6.6Hz), 5.29 (s, 2H), 3.07 (m, 1H), 2.15 (s, 3H), 1.32 (d, 6H, J=7.0 Hz). HRMS calcd. 30 for M+ (C 21

H

20

N

4 C1 3 ): 432.0675. Found: 432.0660. Anal. Calcd. for C 21

H

20

N

4 C1 3 : C, 58.14; H, 4.42; N, 12.92. Found: C, 58.30; H, 4.29; N, 12.70. -66- WO99/10350 PCTIUS98/17049 Example 165 Preparation of 4-(n-Butyl)-5-isopropyl-3-methyl 1-(2,4,6-trichloro)phenyl imidazo[4,5-c]pyrazole The product from Example 164, Step D (100 mg, 0.29 5 mmol) was reacted with sodium hydride (30 mg, 0.75 mmol) and n-butyl bromide (125 p1, 1.16 mmol) in dimethylformamide (2.0 ml) as described for the preparation of Example 1, Part F. Title compound: mp 85.0-86.0 0 C. 1 H NMR (300 MHz, CDC13) 8 7.43 (s, 2H), 10 4.03 (t, 2H, J=7.3 Hz), 3.05 (m, IH), 2.51 (s, 3H), 1.84 (m, 2H), 1.45 (m, 2H), 1.36 (d, 6H, J=7.6 Hz), 1.01 (t, 3H, J=7.3 Hz). HRMS calcd. for M+ (C 18

H

21

N

4 C1 3 ): 398.0832. Found: 398.0819. 15 Example 166 Preparation of 5-Isopropyl-3-methyl-4-[1-(3 methyl)butane]-1-(2,4,6-trichloro)phenyl imidazo[4,5-c]pyrazole The product from Example 164, Step D (100 mg, 0.29 20 mmol) was reacted with sodium hydride (30 mg, 0.75 mmol) and l-bromo-2-ethylbutane (160 pl, 1.16 mmol) in dimethylformamide (2.0 ml) as described for the preparation of Example 1, Part F. Title compound: mp 88.0-91.0oC. 1 H NMR (300 MHz, CDC13) 8 7.43 (s, 2H), 25 3.92 (d, 2H, J=6.6 Hz), 3.03 (m, 1H), 2.50 (s, 3H), 2.78 (m, 1H), 1.35 (d, 6H, J=7.0 Hz), 1.40-1.25 (m, 4H), 0.94 (t, 6H, J=7.3 Hz). HRMS calcd. for M+ (C 20

H

25

N

4 C1 3 ): 426.1145. Found: 412.1143. 30 -67- WO99/10350 PCT/US98/17049 Example 167 Preparation of 5-Isopropyl-3-methyl-4-[1-(3 methyl)butane]-1-(2,4,6-trichloro)phenyl imidazo[4,5-c]pyrazole 5 The product from Example 164, Step D (100 mg, 0.29 mmol) was reacted with sodium hydride (30 mg, 0.75 mmol) and 1-bromo-3-methylbutane (140 il, 1.16 mmol) in dimethylformamide (2.0 ml) as described for the preparation of Example 1, Part F. Title compound: mp 10 87.0-89.0OC. 1 H NMR (300 MHz, CDC13) 8 7.43 (s, 2H), 4.04 (mn, 2H), 3.02 (m, 1H), 2.52 (s, 3H), 1.76 (mn, 3H), 1.36 (d, 6H, J=7.0 Hz), 1.23 (m, 2H), 1.03 (d, 6H, J=6.2 Hz). HRMS calcd. for M+ (C 19

H

23

N

4 C1 3 ): 412.0988. Found: 412.0988. Anal. Calcd. for C 19

H

23

N

4 C1 3 : C, 15 55.15; H, 5.60; N, 13.54. Found: C, 55.44; H, 5.50; N, 13.17. Example 238 Preparation of 5-Ethyl-3-formyl-4-[1-(1 20 methyl)butane]-1-(2,4,6-trichloro) phenylimidazo[4,5-c]pyrazole Dess-Martin periodinane (1.84 g, 4.33 mmol) was dissolved in anhydrous acetonitrile (3 mL), and to this was added the compound prepared in Example 161 (1.50 g, 25 3.61 mmnol) suspended in anhydrous acetonitrile (60 mL). The reaction was stirred at room temperature for 30 minutes, and was then diluted with diethyl ether. The reaction was quenched with 0.5 N NaOH and the phases were separated, the organic phase was washed with 30 saturated sodium chloride, dried over anhydrous magnesium sulfate, and reduced in vacuo. The residue was purified by column chromatography (25% ethyl acetate/hexanes) to give the product as an amophous white solid (1.43 g, 96%). 'H NMR (300 MHz,CDC1 3 ) 6 9.97 -68- WO 99/10350 PCT/US98/17049 (s, 1H), 7.52 (s, 2H), 4.43 (m, 1H), 2.88 (q, 2H, J=7.5 Hz), 2.16 (m, 1H), 1.95 (m, 1H), 1.66 (d, 3H, J=7.0 Hz), 1.36 (t, 3H, J=7.5 Hz(), 1.27 (m, 1H), 1.11 (m, 1H), 0.89 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H 5 (C 18

H

2 oC1 3

N

4 0): 413.0703. Found: 413.0704. Exame~le 243 Preparation of 5-Ethyl-3-(1-hydroxyethyl)-4-[1 (1-methyl)butane] -1- (2,4,6-trichloro) 10 phenylimidazo[4,5-c]pyrazole The compound prepared in ExAmple 238 (1.38 g, 3.33 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) and cooled to -780C. To this solution was added methylmagnesium bromide (2.11 mL, 3.0 M in diethyl 15 ether, 6.33 mmol) and the reaction was held at -78 0 C for one hour, then the temperature was gradually increased to room temperature. After three hours at room temperature, the reaction was quenched with 15% aqueous ammonium chloride and diethyl ether was added. The 20 organic phase was dried over anhydrous magnesium sulfate and reduced in vacuo. The residue was purified by chromatography (20% ethyl acetate/hexanes) to give the desired mixture of diastereomers as a white solid (950 mg, 66%), mp 182.0-184.0 oC. 'H NMR (300 MHz,CDC1 3 ) 8 25 7.45 (s, 2H), 5.15 (m, 1H), 4.40 (m, 1H), 2.83 (q, 2H, J=7.5 Hz), 2.28 (d, 0.5H, J=7.7 Hz), 2.23 (d, 0.5H, J=7.7 Hz), 2.0 (m, 2H), 1.72 (d, 1.5H, J=6.6 Hz), 1.72 (d, 1.5H, J=6.6 Hz), 1.56 (m, 3H), 1.34 (t, 3H, J=7.7 Hz), 0.93 (t, 1.5H, J=7.3 Hz), 0.921 (t, 1.5H, J=7.3 30 Hz). HRMS Calcd. for M+H (C 19

H

24

CI

3

N

4 0): 429.1016. Found: 429.1010. Anal. Calcd. for (CuH 23

CI

3

N

4 0): C, 53.10; H, 5.39; N, 13.04. Found: C, 53.11; H, 5.41; N, 12.64. -69- WO99/10350 PCT/US98/17049 Example 251 Preparation of 3-Acetyl-5-ethyl-4-[1-(1 methyl)butane]-1-(2,4,6-trichloro) phenylimidazo[4,5-c]pyrazole 5 Dess-Martin periodinane (1.12 g, 2.65 mmol) was suspended in anhydrous dichloromethane (5 mL) and to this solution was added the compound prepared in Example 243 (950 mg, 2.21 mmol) in anhydrous dichloromethane (100 mL). The reaction was held at room temperature for 10 two hours, and was then quenched with 0.5 N NaOH (200 mL). Diethyl ether was added and the organic phase was dried over anhydrous magnesium sulfate and reduced in vacuo. The residue was purified by chromatography (gradient elutions with 10-20% ethyl acetate/hexanes) to 15 give the final product as a white solid (768 mg, 81%), mp 50.0-52.00C. 'H NMR (400 MHz,DMSO-d 6 , 120 0 C) 8 7.88 (s, 2H), 4.66 (m, 1H), 2.85 (q, 1H, J=7.5 Hz), 2.84 (q, 1H, J=7.4 Hz), 2.05 (m, 1H), 1.90 (m, 1H), 1.57 (d, 3H, J=6.8 Hz), 1.28 (m, 4H, includes 1.26 (t, 3H, J=7.5 Hz), 20 1.09 (m, 1H), 0.83 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H (C 1 9

H

22 C1 3

N

4 0): 427.0859. Found: 427.0853. Anal. Calcd. for C 19

H

21 C1N 4 0: C, 53.35; H, 4.96; N, 13.10. Found: C, 53.55; H, 4.91; N, 13.11. 25 The Examples in Table 2 may be prepared as exemplified above for the preparation of Examples 38, 40, 105-108, 113-118, 152-159, 161, 163-167, 238, 243, and 251. 30 -70- WO 99/10350 PCT/US98/17049 TABLE 2 2 R R3 N N cl ci Ex. R I

R

2

R

3 mp oC 37 Et CH 2 Ph Me 129-131 38 Et CH 2 CH(Et) 2 Me 135-136 39 Et CH 2

CH

2 CH (Me) 2 Me 109-110 40 Et CH 2 cPr Me 144-146 41 Et n-butyl Me 115-117 42 Et n-propyl Me 110-113 43 Et CH(Et) 2 Me 110-111 44 Et CH 2

CH

2

CH

2 CN Me Oil, MS 45 Et CH 2

CH

2 CN Me 192-194 46 Et 4-methoxybenzyl Me 134-136 47 Et 3-methoxybenzyl Me Oil, MS 48 Et 2-methylbenzyl Me 135-137 49 Et 3-methylbenzyl Me 155-156 50 Et 4-methylbenzyl Me 133-134 51 Et 2,4-dimethylbenzyl Me Oil, MS 52 Et 2,5-dimethylbenzyl Me 130-133 53 Et 3,4-dimethylbenzyl Me 125-127 54 Et 3,5-dimethylbenzyl Me 157-157 55 Et 4-tertbutylbenzyl Me 104-105 56 Et 2-phenylbenzyl Me 126-127 57 Et 4-phenylbenzyl Me 140-141 58 Et 2-bromobenzyl Me 151-153 59 Et 3-bromobenzyl Me 147-148 60 Et 4-bromobenzyl Me 192-194 61 Et 2-chlorobenzyl Me 158-159 62 Et 3-chlorobenzyl Me 140-141 63 Et 4-chlorobenzyl Me 193-195 64 Et 2,4-dichlorobenzyl Me 194-195 65 Et 2,6-dichlorobenzyl Me 130-132 66 Et 3,4-dichlorobenzyl Me 187-188 67 Et 2-chloro-6-fluorobenzyl Me 146-147 68 Et 2-fluorobenzyl Me 127-129 69 Et 3-fluorobenzyl Me 136-137 70 Et 4-fluorobenzyl Me 130-132 71 Et 2,4-difluorobenzyl Me 151-152 -71- WO 99/10350 PCT/US98/17049 TABLE 2 (Continued) Ex. R 1

R

2 R mp °C 72 Et 2,5-difluorobenzyl Me 162-163 73 Et 3,4-difluorobenzyl Me 154-155 74 Et 3,5-difluorobenzyl Me 139-140 75 Et 2-trifluoromethylbenzyl Me 177-178 76 Et 3-trifluoromethylbenzyl Me 176-178 77 Et 4-trifluoromethylbenzyl Me 167-168 78 Et 2,4-bis(trifluoromethyl)benzyl Me 150-151 79 Et 3,5-bis(trifluoromethyl)benzyl Me 144-145 80 Et 3,5-dimethoxybenzyl Me 139-140 81 Et 4-methoxy-3-methylbenzyl Me 149-150 82 Et 4-benzyloxybenzyl Me 115-117 83 Et 2-cyanobenzyl Me 220-221 84 Et 3-cyanobenzyl Me 149-152 85 Et 4-cyanobenzyl Me 205-206 86 Et 3-trifluoromethoxybenzyl Me 93-96 87 Et 4-trifluoromethoxybenzyl Me 79-81 88 Et 2-nitrobenzyl Me >250 89 Et 3-nitrobenzyl Me >250 90 Et 4-nitrobenzyl Me >250 91 Et 2-methyl-3-nitrobenzyl Me >250 92 Et 4-acetamidobenzyl Me Oil, MS 93 Et CH 2

CH

2 CH(OiPr)4-methylphenyl Me Oil, MS 94 Et CH 2

CH

2 CH(OMe)4-chlorophenyl Me Oil, MS 95 Et CH 2

CH

2

CH

2

CF

3 Me 138-140 96 Et geranyl Me 151-152 97 Et CH 2 CH=CHPh Me Oil, MS 98 Et CH 2 (cyclohexyl) Me 149-150 99 Et CH 2 CH(Me) 2 Me 131-132 100 Et CH 2

CH

2

CH

2 CCH Me 145-146 101 Et nPentyl Me 142-143 102 Et CH2CH 2

OCH

2

CH

3 Me 195-196 103 Et CH 2 (2-tetrahydropyran) Me Oil, MS 104 Et CH 2

CH(CH

3

)CH

2

CH

3 Me 118-120 105 Et CH (CH 2

CH

2

CH

3

)

2 Me 113-114 106 Et CH (CH 2

CH

3 ) CH 2

CH

2

CH

2

CH

3 Me 121-122 107 Et CH(CH 3

)CH

2

CH

3 Me 113-114 108 Et CH (CH 3 ) CH 2

CH

2

CH

3 Me 93-95 109 Et CH (CH 3 ) CH 2

CH

2

CH

2

CH

3 Me Oil, MS 110 Et CH (CH 3 ) CH 2 CH (CH 3 ) 2 Me 119-120 111 Et CH (CH 2

CH

3 ) CH 2 CH2CH 3 Me Oil, MS 112 Et 4-methylcyclohexyl Me Oil, MS -72- WO 99/10350 PCT/US98/17049 TABLE 2 (Continued) Ex. R I

R

2

R

3 mp C 113 Et 4-methanesulfonylbenzyl Me 194-196 114 Et COPh Me 169-170 115 Et SO 2 Ph Me 189-190 116 Et CH(phenyl) 2 Me 170-172 117 Et CH (CH 3 ) phenyl Me 166-168 118 Et cyclopentyl Me 125-128 119 Et cyclohexyl Me 120 Et CH 2 (2-tetrahydrofuran) Me 121 Et CH 2 CH2COPh Me 122 Et CH 2

CH

2 CO(4-fluorophenyl) Me 123 Et CH 2

CH

2

COCH

2

CH

3 Me 124 Et CH 2

CH

2 CH2COCH 3 Me 125 Et CH 2

CH

2 NHCOPh Me 126 Et 2,4,6-trimethylbenzyl Me 127 Et 2-picolyl Me 128 Et 3-picolyl Me 129 Et 4-picolyl Me 130 Et 2-methylquinoline Me 131 Et n-butyl H 80-82 132 Et benzyl H 86-89 133 Et 3,4-difluorobenzyl H 145-147 134 Et CH 2 CH (CH 2

CH

3 ) 2 H Oil, MS 135 Et CH 2

CH

2 CH (CH 3 ) 2 H Oil, MS 136 Et CH 2 -2-tetrahydropyranyl H Oil, MS 137 Et CH (CH 2

CH

3 ) CH 2

CH

2

CH

3 H Oil, MS 138 Et CH (CH 3 ) CH 2 CH (CH 3 ) 2 H 90-92 139 Et CH (CH 3 ) CH 2

CH

2

CH

3 H Oil, MS 140 n-Pr n-butyl H Oil, MS 141 n-Pr CH (CH 2

CH

3 ) CH 2

CH

2

CH

3 H Oil, MS 142 n-Pr CH (CH 3 ) CH 2 CH (CH 3 ) 2 H Oil, MS 143 n-Pr CH (CH 3 ) CH 2

CH

2

CH

3 H Oil, MS 144 n-Pr n-butyl Me 94-95 145 n-Pr CH(CH 2

CH

3 ) CH 2

CH

2

CH

3 Me 91-93 146 n-Pr CH (CH 3 ) CH 2 CH (CH 3 ) 2 Me 113-115 147 n-Pr CH (CH 3 ) CH 2

CH

2

CH

3 Me 98-100 148 c-Pr n-butyl Me 91-93 149 c-Pr CH (CH 2

CH

3 ) CH 2

CH

2

CH

3 Me 120-122 150 c-Pr CH (CH 3 ) CH 2 CH (CH 3 ) 2 Me 152-155 151 c-Pr CH (CH 3 ) CH 2

CH

2

CH

3 Me 102-105 152 Et n-butyl Et 101-104 153 Et 3,4-difluorobenzyl Et Oil, MS -73- WO 99/10350 PCT/US98/17049 TABLE 2 (Continued) Ex. R I R2 R 3 mp C 154 Et CH(CH 2

CH

3

)CH

2

CH

2

CH

3 Et 96-98 155 Et CH(CH 3

)CH

2

CH

2

CH

3 Et 88-90 156 Et n-butyl CH 2

OCH

3 66-68 157 Et 3,4-difluorobenzyl CH 2

OCH

3 Oil, MS 158 Et CH(CH 2

CH

3

)CH

2

CH

2

CH

3

CH

2

OCH

3 117-119 159 Et CH(CH 3

)CH

2

CH

2

CH

3

CH

2

OCH

3 100-102 160 Et n-butyl CH 2 0H 163-165 161 Et CH (CH 3 ) CH 2

CH

2

CH

3

CH

2 OH 144-146 162 Et CH(CH 3

)CH

2

CH

2

CH

3

CH

2 F Oil, MS 163 Et CH (CH 3 ) CH 2

CH

2

CH

3

CH

2 Br Oil, MS 164 i-Pr benzyl Me 103-105 165 i-Pr n-butyl Me 85-86 166 i-Pr CH 2 CH (CH 2

CH

3 ) 2 Me 88-91 167 i-Pr CH 2

CH

2 CH (CH 3 ) 2 Me 87-89 168 i-Pr n-butyl H 169 i-Pr benzyl H 170 i-Pr CH 2 CH (CH 2

CH

3 ) 2 H 171 i-Pr CH 2

CH

2 CH (CH 3 ) 2 H 172 n-Bu n-butyl Me 173 n-Bu benzyl Me 174 n-Bu CH 2 CH (CH 2

CH

3 ) 2 Me 175 n-Bu CH 2

CH

2 CH (CH 3 ) 2 Me 176 Ph n-butyl Me 177 Ph CH (CH 2

CH

3 ) CH 2

CH

2

CH

3 Me 178 Ph CH (CH 3 ) CH 2 CH (CH 3 ) 2 Me 179 Ph CH(CH 3

)CH

2

CH

2

CH

3 Me 180 Ph CH (CH 3 ) CH 2 CH (CH 3 ) 2 Me 181 Ph CH (CH 3 ) CH 2

CH

2

CH

3 Me 182 CF 3 n-butyl Me 183 CF 3 CH (CH 2

CH

3 ) CH 2

CH

2

CH

3 Me 184 CF 3 CH (CH 3 ) CH 2 CH (CH 3 ) 2 Me 185 CF 3 CH (CH 3 ) CH 2

CH

2

CH

3 Me 186 CF 3 CH (CH 3 ) CH 2 CH (CH 3 ) 2 Et 187 CF 3 CH (CH 3 ) CH 2

CH

2

CH

3 Et 188 Et n-butyl CF 3 189 Et CH (CH 2

CH

3 ) CH 2

CH

2

CH

3

CF

3 190 Et CH (CH 3 ) CH 2 CH (CH 3 ) 2

CF

3 191 Et CH (CH 3 ) CH 2

CH

2

CH

3

CF

3 192 Et n-butyl CHF 2 193 Et benzyl CHF 2 194 Et CH(CH 3

)CH

2

CH

2

CH

3

CHF

2 -74- WO 99/10350 PCT/US98/17049 TABLE 2 (Continued) Ex. R 1

R

2 R mp °C 195 Et CH (CH 3 ) CH 2

CH

2

CH

3

CH

2

CF

3 196 Et CH 2

CH

2

SCH

2

CH

3 Me 197 Et CH 2

CH

2 0Ph Me 198 Et CH 2 CH (CH 3 ) CN Me 199 Et (CH 2

)

4 CN Me 200 Et 2-methoxybenzyl Me 201 Et 2-methoxy-5-nitrobenzyl Me 202 Et 2-hydroxy-5-nitrobeqzyl Me 203 Et CH 2

CH

2 Ph Me 204 Et (CH 2

)

3 Ph Me 205 Et CH 2

CH

2 N(i-Pr) 2 Me 206 Et CH 2

CH

2 -morpholino Me 207 Et 5-methyl-2-nitrobenzyl Me 208 Et 2-pentanone Me 209 Et 2,4,6-trifluorobenzyl Me 210 Et CH (COphenyl) CH 3 Me 211 Et CH (COphenyl) CH (CH 3 ) 2 Me 212 Et CH(COphenyl)phenyl Me 213 Et CH(COphenyl)benzyl Me 214 Et CH (CO 2

CH

3 ) phenyl Me 215 Et CH (CO 2

CH

3 ) CH 2

CH

2

CH

3 Me 216 Et CH (COCH 3 ) CH 3 Me 217 Et CH 2 CH (OH) CH 2 phenyl Me 218 Et CH 2 CH (OH) phenyl Me 219 Et CH 2 CH (OH) benzyl Me 220 Et CH 2 CH (OH) CH 2

CH

2

CH

3 Me 221 Et CH 2

COCH

2

CH

2

CH

3 Me 222 Et CH 2 CObenzyl Me 223 Et CH 2 CH (OMe) benzyl Me 224 Et CO(4-chlorophenyl) Me 225 Et CO(2-methoxyphenyl) Me 226 Et COCH(CH 2

CH

3 )phenyl Me 227 Et CO 2

CH

2

CH

3 Me 228 Et CO 2 phenyl Me 229 Et CON(CH 3 )phenyl Me 230 Et COmorpholino Me 231 Et SO 2 (2-thiophene) Me 232 Et SO 2 benzyl Me 233 Et SO 2

CH

2

CH

2

CH

3 Me 234 Et CON(CH 3 )phenyl H 235 Et COmorpholino CF 3 -75- WO 99/10350 PCT/US98/17049 TABLE 2 (Continued) Ex. R I

R

2 R mp °C 236 Et SO 2 (2-thiophene) CF 3 237 Et n-butyl CHO 238 Et CH (CH 3 ) CH 2

CH

2

CH

3 CHO Oil, MS 239 Et benzyl CHO 240 Et CH 2 cPr

CH(CH

3 )OH 241 Et n-butyl

CH(CH

3 )OH 242 Et benzyl

CH(CH

3 )OH 243 Et CH (CH 3 ) CH 2

CH

2

CH

3

CH(CH

3 )OH 182-184 244 Me benzyl CH(Ph)OH 245 Et CH (CH 3 ) CH 2

CH

2

CH

3 CH(Ph)OH 246 Et n-butyl

CO

2 H 247 Et CH (CH 3 ) CH 2

CH

2

CH

3

CO

2 H 248 Et CH (CH 3 ) CH 2

CH

2

CH

3

CO

2 Et 249 Et n-butyl

CO

2 Et 250 Et benzyl COMe 251 Et CH (CH 3 ) CH 2

CH

2

CH

3 COMe 50-52 252 Et n-butyl COMe 253 Et 3,4-difluorobenzyl COMe 254 Et 4-fluorobenzyl COMe 255 Et cyclopentyl COMe 256 Et CH (CH 3 ) CH 2

CH

2

CH

3

CH

2

NH

2 257 Et benzyl CH 2

NH

2 258 Et CH 2 cPr

CH

2 NHMe 259 Et n-butyl

CH

2 NHMe 260 Et benzyl CH 2 NMe 2 261 Et CH (CH 3 ) CH 2

CH

2

CH

3

CH

2 NMe 2 Example 263. Preparation of 4-Benzyl-5-ethyl-3-methyl-1 5 (2,4,6-trimethyl)phenyl-imidazo[4,5-c]pyrazole Ste A The product from Example 11, Part A (10 g, 46.44 mmol) was suspended in propionic anhydride (30 ml) and allowed to stir at room temperature for 2 hours. The reaction was poured onto an ice slurry (500 ml) and 10 stirred overnight. The resultant precipitate was filtered and dried to constant weight to afford 11.92 g (95%) of desired amido pyrazole, mp 171.5-173oC. 1 H -76- WO 99/10350 PCT/US98/17049 NMR (300 MHz, CDC13) 5 6.98 (s, 2H), 6.74 (bs, 1H), 6.54 (s, 1H), 2.34 (s, 3H), 2.31 (s, 3H), 2.24 (q, 2H, J=7.3 Hz), 1.96 (s, 3H), 1.13 (t, 3H, J=7.3 Hz). Ste B: The product from Step A (11.5 g, 42.37 5 mmol) was reduced with lithium aluminum hydride (84.75 ml, 84.74 mmol, 1.0 M/THF) as described for the preparation of Example 11, Step C. The product was obtained as a clear viscous oil, 10.81 g (99%). 1 H NMR (300 MHz, CDC13) 8 6.93 (s, 2H), 5.31 (s, 1H), 3.02 (m, 10 3H), 2.31 (s, 3H), 2.24 (s, 3H), 1.99 (s, 6H), 1.53 (m, 2H), 0.88 (t, 3H, J=7.3 Hz). te C The product from Step B (10.81 g, 41.99 mmol) was treated with isoamyl nitrite (5.62 ml, 41.99 mmol) as described for the preparation of Example 11, 15 Step D to afford a purple crystalline solid, 9.59 g (80%). 1 H NMR (300 MHz, CDC13) 6 10.07 (bs, 1H), 6.94 (s, 2H), 2.70 (s, 3H), 2.62 (q, 2H, J=6.8 Hz), 2.36 (s, 3H), 2.09 (s, 6H), 1.36 (m, 2H), 0.77 (t, 3H, J=7.3 Hz). Ste D: The product from Step C (9.59 g) was 20 refluxed in pyridine (60 ml) for 16 hours, as described for the preparation of Example 11, Step E. Chromatography on silica gel (700 g) eluting with hexanes/ethyl acetate (1/1) yielded recovery of 2.38 g of starting material, while elution with ethyl acetate 25 alone afforded the desired product, 3.41 g (50% based on recovered starting material). 1 H NMR (300 MHz, CDC13) 6 9.67 (bs, 1H), 6.86 (s, 2H), 2.71 (q, 2H, J=7.8 Hz), 2.38 (s, 3H), 2.27 (s, 3H), 1.99 (s, 6H), 1.28 (t, 3H, J=7.8 Hz). 30 Ste E: The product from Step D (0.25 g, 0.93 mmol) was treated with sodium hydride (93 mg, 2.32 mmol) and benzyl bromide (443 gl, 3.7 mmol) in anhydrous dimethylformamide (15 ml) as described for the -77- WO99/10350 PCT/US98/17049 preparation of Example 11, Step F. Title compound: 200.0 mg (60%), mp 96.5-98 0 C, 1 H NMR (300 MHz, CDC13) 3 7.35 (m, 3H), 7.14 (d, 2H, J=6.6 Hz), 6.90 (s, 2H), 5.26 (s, 2H), 2.77 (q, 2H, J=7.7 Hz), 2.29 (s, 3H), 2.16 (s, 5 3H), 2.02 (s, 6H), 1.29 (t, 3H, J=7.7 Hz). Example 325 Preparation of 4-(n-Butyl)-5-ethyl-3-methyl-1-(2 chloro-4-bromo)phenylimidazo[4,5-c]pyrazole 10 Step A: P-Aminocrotononitrile (8.62 g, 0.10 mol) was dissolved in 1.0N HC1 (275 ml) and treated with 2 chloro-4-bromophenylhydrazine (0.1 mol). The reaction was refluxed 4h, cooled, and decanted into a 2 liter beaker. The solution was diluted with water (250 ml) 15 and neutralized with 10% NaOH (125 ml). The resultant precipitate was filtered and dried to constant weight to afford 22.71 g (79%) of the desired aminopyrazole as a white crystalline solid, mp 125.0-126.0 0 C. 1 H NMR (300 MHz, CDC13) 8 7.69 (d, 1H, J=2.0 Hz), 7.51 (dd, 1H, 20 J=2.0, 7.0 Hz), 7.34 (d, 1H, J=7.0 Hz), 5.46 (s, 1H), 3.58 (bs, 2H), 2.23 (s, 3H). Step B: The compound prepared in Step A (4.0g, 14.0 mmol) was suspended in propionic anhydride (9.0 mL, 25 69.8 mmol) at room temperature and was allowed to stir for 16 hours. Ice was then added and the reaction stirred for 5 hours. Diethyl ether was added and the phases were separated. The organic phase was washed with saturated sodium chloride, dried over anhydrous 30 magnesium sulfate and reduced in vacuo to leave a thick oil. This residue was purified by column chromatography (50% ethyl acetate/hexanes) to give the final product as a solid (4.2 g, 88%), mp 107-110 0 C. 'H NMR (300 -78- WO 99/10350 PCT/US98/17049 MHz,CDC1 3 ) 8 7.71 (d, 1H, J=2.2 Hz), 7.54 (dd, 1H, J=8.4 Hz, J=2.2 Hz), 7.35 (d, 1H, J=8.4 Hz), 6.91 (bs, 1H), 6.44 (s, 1H), 2.31 (s, 3H), 2.28 (m, 2H), 1.14 (m, 3H). 13C NMR (75 MHz,CDC1 3 ) 8 150.61, 137.18, 134.68, 133.02, 5 132.62, 131.39, 123.73, 99.01, 29.82, 14.04, 9.30. Anal. Calcd. for C 13

H,

3 BrC1N 3 0O: C, 45.57; H, 3.82; N, 12.26. Found: C, 45.76; H, 3.83; N, 12.26. Stn C: The compound prepared in Step B (4.1 g, 10 12.0 mmol) was suspended in tetrahydrofuran (30 mL). To this suspension was added borane/THF complex (36.0 mL, 36.0 mmol), and the reaction refluxed for 3 hours. The reaction was cooled to room temperature and excess borane was quenched with 10% NaOH (10 mL) until off 15 gassing ceased and the reaction was diluted with water and diethyl ether. The layers were separated and the organic phase was washed with saturated sodium chloride, dried over anhydrous anhydrous magnesium sulfate, and reduced in vacuo. This residue was purified by column 20 chromatography (25% ethyl acetate/hexanes) to provide the final product as a white solid (3.46 g, 88%), mp 140-141.5 0 C. 'H NMR (300 MHz,CDC1 3 ) 8 7.75 (d, 1H, J=2.2 Hz), 7.59 (dd, 1H, J=8.5 Hz, J=2.2 Hz), 7.31 (d, 1H, J=8.4 Hz), 5.39 (s, 1H), 3.43 (t, 1H, J=5.9 Hz), 3.07 25 (m, 2H), 2.38 (s, 3H), 1.57 (m, 2H), 0.90 (t, 3H, J=7.5 Hz). 1C NMR (75 MHz,CDC1 3 ) 8 149.79, 149.42, 135.79, 133.45, 133.33, 131.34, 130.94, 125.56, 87.10, 46.66, 22.51, 14.01, 11.15. 30 Ste D The compound prepared in Step C (2.76 g, 8.40 mmol) was suspended in ethanol (20 mL), and 15 drops of 10% HC1 were added. Upon addition of the HC1 significant off-gassing occurred, and at the completion of the off-gassing the reaction mixture was homogeneous. 35 Isoamyl nitrite (1.35 mL, 10.1 minmol) was then added, and -79- WO 99/10350 PCT/US98/17049 the solution darkened upon addition. The solution was stirred at room temperature for 16 hours, and then reduced to dryness in vacuo. The residue was purified by column chromatography (gradient elution of 25-50% ethyl 5 acetate/hexanes) to give the final product as purple crystals (2.16 g, 72%), mp 118.5-119.50C. 'H NMR (300 MHz,CDC1 3 ) 8 10.30 (bs, 1H), 7.72 (d, 1H, J=2.2 Hz), 7.57 (dd, 1H, J=8.5 Hz, J=2.2 Hz), 7.40 (d, 1H, J=8.5 Hz), 2.72 (mn, 2H), 2.70 (s, 3H), 1.45 (m, 2H), 0.82 (t, 3H, 10 J=7.3 Hz). 1 3 C NMR (75 MHz,CDC1 3 ) 8 152.98, 149.91, 149.01, 135.40, 134.37, 132.92, 131.23, 131.01, 124.69, 43.90, 22.76, 11.45, 10.95. Anal Calcd. for C,3H, 4 BrClN40: C, 43.66; H, 3.95; N, 15.67. Found: C, 43.85; H, 3.96; N, 15.69. 15 tep E The compound prepared in Step D (2.06 g, 5.76 mmol) was dissolved in anhydrous pyridine (30 mL) and the solution heated to reflux for 16 hours. The solvent was removed in vacuo and the residue was 20 purified by column chromatography (50% ethyl acetate/hexanes) to recover the product as a brown solid (0.83 g, 42%). This product was used in further reactions directly, however a sample was further purified for analytical purposes by washing briefly with 25 50% diethyl ether/hexanes to remove a brown oily residue, leaving the final product as an off-white solid, mp 175.5-178.5 0 C. 'H NMR (300 MHz,CDC1 3 ) 8 8.69 (bs, 1H), 7.67 (d, 1H, J=1.8 Hz), 7.45 (m, 2H), 2.87 (q, 2H, J=7.5 Hz), 2.45 (s, 3H), 1.38 (t, 3H, J=7.7 Hz). 3 C 30 NMR (75 MHz,CDC1 3 ) 157.73, 152.93, 136.01, 133.16, 130.80, 130.59, 128.94, 121.14, 120.31, 23.29, 12.91, 12.55. tep F: The compound prepared in Step E (500 mg, 35 1.47 mmol) was dissolved in anhydrous dimethylformamide -80- WO 99/10350 PCT/US98/17049 (15 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 6.1 mL, 3.68 mmol) was added. The solution was heated to 60 0 C for one hour, then 1-bromobutane (0.63 mL, 5.88 mmol) was added. The reaction was held at 60 0 C for 5 4 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column 10 chromatography (33% ethyl acetate/hexanes) to give the final product as an oil (303 mg, 52%). 'H NMR (300 MHz,CDC1 3 ) 5 7.67 (d, 1H, J=1.8 Hz), 7.44 (m, 2H), 4.01 (t, 2H, J=7.4 Hz), 2.79 (q, 2H, J=7.6 Hz), 2.51 (s, 3H), 1.83 (m, 2H), 1.43 (m, 2H), 1.35 (t, 3H, J=7.5 Hz), 1.00 15 (t, 3H, J=7.3 Hz). 13C NMR (75 MHz,CDC1 3 ) 8 157.15, 136.17, 133.25, 130.64, 130.53, 128.88, 120.82, 44.89, 33.54, 21.24, 19.99, 13.74, 12.99, 12.80. Example 326 20 Preparation of 4-(3,4-Difluorobenzyl)-5-ethyl-3 methyl-1-(2-chloro-4-bromo) phenylimidazo[4,5 c]pyrazole The product from Step E, Example 325 (50 mg, 0.15 mmol) was dissolved in anhydrous dimethylformamide (1 25 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 0.61 mL, 0.37 mmol) was added. The solution was heated to 60 0 C for one hour, then a-bromo-3,4 difluorotoluene (0.075 mL, 0.59 mmol) was added. The reaction was held at 60 0 C for 4 hours, cooled to room 30 temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase was washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column chromatography (33% ethyl -81- WO 99/10350 PCT/US98/17049 acetate/hexanes) to give the final product as a solid (30 mg, 13%), mp 114-116 0 C. 1H NMR (300 MHz,CDC1 3 ) 8 7.68 (d, 1H, J=1.5 Hz), 7.46 (m, 2H), 7.21 (m, 1H), 6.95 (m, 2H), 5.21 (s, 2H), 2.79 (q, 2H, J=7.5 Hz), 2.19 (s, 3H), 5 1.32 (t, 3H, J=7.5 Hz). " 3 C NMR (75 MHz,CDC1 3 ) 6 157.62, 135.96, 133.29, 130.75, 130.61, 128.96, 122.23, 121.13, 118.20, 117.97, 115.54, 115.30, 47.44, 21.38, 12.65, 12.54. 10 Example 327 Preparation of 4-[l-(1-Ethyl)butane]-5-ethyl-3 methyl-1-(2-chloro-4-bromo) phenylimidazo[4,5 c] pyrazole The product from Step E, Example 325 (110 mg, 0.32 15 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 1.3 mL, 0.8 mmol) was added. The solution was heated to 60 0 C for one hour, then 3-bromohexane (211 mg, 1.28 mmol) was added. The reaction was held at 100 0 C for 20 64 hours, then cooled to room temperature and diluted with water and diethyl ether. The layers were separated and the organic phase was washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column 25 chromatography (33% ethyl acetate/hexanes) to give the final product as an oil (19 mg, 14%). 'H NMR (300 MHz,CDC1 3 ) 8 7.67 (t, 1H, J=1.l Hz), 7.46 (d, 2H, J=l.1 Hz), 4.01 (m, 1H), 2.82 (q, 2H, J=7.5 Hz), 2.53 (s, 3H), 1.86 (m, 4H), 1.35 (t, 3H, J=7.5 Hz), 1.26 (m, 2H), 0.92 30 (t, 3H, 7.2 Hz), 0.85 (t, 3H, J=7.3 Hz). 3 C NMR (75 MHz,CDC1 3 ) 8 157.85, 152.75, 136.08, 133.29, 130.72, 130.66, 130.52, 128.92, 120.84, 119.95, 58.19, 38.40, 29.47, 22.32, 21.94, 19.83, 15.43, 13.87, 12.91, 11.14. -82- WO99/10350 PCT/US98/17049 Example 328 Preparation of 5-Ethyl-4-[1-(1-methyl)butane]-3 methyl-1-(2-chloro-4-bromo) phenylimidazo[4,5 c]pyrazole 5 The product from Step E, Example 325 (110 mg, 0.32 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 1.3 mL, 0.8 mmol) was added. The solution was heated to 600C for one hour, then 2-bromopentane (0.16 10 mL, 1.28 mmol) was added. The reaction was held at 1000C for 64 hours, then cooled to room temperature and diluted with water and diethyl ether. The layers were separated and the organic phase was washed with water, dried over anhydrous magnesium sulfate, and reduced to 15 dryness in vacuo. The residue was purified by column chromatography (33% ethyl acetate/hexanes) to give the final product as an oil (27 mg, 20%). 'H NMR (300 MHz,CDC1 3 ) 8 7.67 (d, 1H, J=1.4 Hz), 7.45 (m, 2H), 4.31 (m, 1H), 2.83 (q, 2H, J=7.7 Hz), 2.56 (s, 3H), 1.84 (m, 20 2H), 1.54 (d, 3H, J=6.6 Hz), 1.33 (t, 3H, J=7.5 Hz), 1.25 (m, 2H), 0.93 (t, 3H, J=7.3 Hz). 13C NMR (75 MHz,CDC1 3 ) 6 156.94, 152.63, 136.07, 133.26, 130.65, 130.60, 130.53, 128.92, 120.85, 120.07, 51.77, 39.77, 22.30, 22.00, 19.87, 15.50, 13.78, 12.98. 25 Example 329 Preparation of 4-(n-Butyl)-5-ethyl-3-methyl-1-(2 chloro-4-methyl) phenylimidazo[4,5-c]pyrazole Step A: P-Aminocrotonitrile (4.53 g, 0.06 mol) was 30 dissolved in 1.0N HC1 (90 ml) and treated with 2-chloro 4-methylhydrazine (8.66 g, 0.06 mol). The reaction was allowed to reflux for 6h, cooled, and decanted into a 2 liter beaker. The solution was diluted with water (250 ml) and neutralized with 10% NaOH. The resulting -83- WO99/10350 PCT/US98/17049 solution was extracted with Et 2 0 (4 x 30 ml) and the combined organic extracts were dried over MgSO, filtered and concentrated in-vacuo to afford 2.29 g (17.2%) of the desired aminopyrazole as a red oil. 'H NMR (300 Mhz, 5 CDC1 3 ) 57.34 (m, 2H), 7.19 (m, 1H), 5.46 (s, 1H), 3.56 (bs, 2H), 2.39 (s, 3H), 2.24 (s, 3H). Ste p : The compound prepared in Step A (0.97 g, 4.37 mmol) was suspended in propionic anhydride (2.8 mL, 10 21.9 mmol) at room temperature and allowed to stir for 16 hours. Ice was added and the reaction stirred for 24 hours. Diethyl ether was added and the phases separated. The organic phase was washed with saturated sodium chloride and dried over anhydrous magnesium sulfate and 15 reduced in vacuo to leave a thick oil. This residue was purified by column chromatography (50% ethyl acetate/hexanes) to give the final product as a solid (1.0 g, 85%), mp 115-116.5 0 C. 1H NMR (300 MHz,CDCl 3 ) 7.33 (m, 2H), 7.21 (d, 1H, J=8.0 Hz), 6.91 (bs, 1H), 20 6.48 (s, 1H), 2.42 (s, 3H), 2.32 (s, 3H), 2.27 (q, 2H, J=7.5), 1.14 (t, 3H, J=7.5 Hz). '3C NMR (75 MHz,CDCl 3 ) S 149.99, 141.42, 137.22, 132.64, 131.25, 130.72, 129.95, 128.83, 97.88, 29.87, 21.03, 14.05, 9.30. Anal. Calcd. for C1 4

H,

6 C1N 3 0: C, 60.54; H, 5.82; N, 15.13. Found: C, 25 60.60; H, 5.79; N, 15.10. SteD C: The compound prepared in Step B (0.94 g, 3.4 mmol) was suspended in anhydrous tetrahydrofuran (20 mL). To this suspension was added borane/THF complex 30 (10.2 mL, 10.2 mmol), and the reaction was refluxed for 1.5 hours. The reaction was cooled to room temperature and excess borane was quenched with 10% NaOH (10 mL) until off-gassing ceased and the reaction was diluted with water and diethyl ether. The layers were separated -84- WO 99/10350 PCT/US98/17049 and the organic phase was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and reduced in vacuo. This residue was purified by column chromatography (25% ethyl acetate/hexanes) to provide 5 the final product as a white solid (0.76 g, 85%), mp 100.5-101.5 0 C. 'H NMR (300 MHz,CDC1 3 ) 8 7.39 (d, 1H, J=0.8 Hz), 7.31 (d, 1H, J=8.4 Hz), 7.24 (dd, 1H, J=8.1 Hz, J=l.l Hz), 5.38 (s, 1H), 3.43 (t, 1H, J=5.6 Hz), 3.07 (m, 2H), 2.43 (s, 3H), 2.38 (s, 3H), 1.55 (m, 2H), 10 0.89 (t, 3H, J=7.4 Hz). 1C NMR (75 MHz,CDC1 3 ) 8 149.46, 149.13, 142.88, 134.16, 131.77, 131.06, 129.00, 128.69, 86.85, 46.63, 22.54, 21.25, 14.04, 11.14. Step D: The compound prepared in Step C (0.69 g, 15 2.62 mmol) was suspended in ethanol (10 mL), and 15 drops of 10% HC1 were added. Upon addition of the HC1 significant off-gassing occurred, and at the completion of the off-gassing the reaction mixture was homogeneous. Isoamyl nitrite (0.42 mL, 3.14 mmol) was then added, and 20 the solution darkened upon addition. The solution was stirred at room temperature for 16 hours, and then reduced to dryness in vacuo. The residue was purified by column chromatography (gradient elution of 25-50% ethyl acetate/hexanes) to give the final product as purple 25 crystals (0.37 g, 48%), mp 83-85 0 C. 'H NMR (300 MHz,CDC1 3 ) 8 10.28 (bs, 1H), 7.38 (d, 1H, J=8.1 Hz), 7.34 (d, 1H, J=l.9 Hz), 7.20 (dd, 1H, J=8. Hz, J=2.2 Hz), 2.72 (m, 2H), 2.70 (s, 3H), 1.42 (m, 2H), 0.78 (t, 3H, J=7.5 Hz). " 3 C NMR (75 MHz,CDC1 3 ) 8 152.51, 142.33, 30 139.08, 130.52, 129.62, 128.55, 43.63, 22.82, 21.13, 11.45, 10.94. Anal. Calcd. for C, 4

H

17 C1N 4 0: C, 57.44; H, 5.85; N, 19.14. Found: C, 57.51; H, 5.83; N, 19.03. Ste E: The compound prepared in Step D (0.34 g, 35 1.15 mmol) was dissolved in anhydrous pyridine (5 mL) -85- WO 99/10350 PCT/US98/17049 and the solution heated to reflux for 16 hours. The solvent was removed in vacuo and the residue purified by column chromatography (75% ethyl acetate/hexanes) to afford the product as a brown solid (0.2 g, 60%). This 5 product was used in further reactions directly, however a sample was further purified for analytical purposes by washing briefly with diethyl ether to remove a brown oily residue, leaving the final product as an off-white solid, mp 178-180oC. 'H NMR (300 MHz,CDC1 3 ) 8 9.46 (bs, 10 1H), 7.39 (d, 1H, J=8.1 Hz), 7.28 (d, 1H, J=1.l Hz), 7.09 (dd, 1H, J=8.0, J=1.1), 2.80 (q, 2H, J=7.7 Hz), 2.41 (s, 3H), 2.34 (s, 3H), 1.32 (t, 3H, J=7.7 Hz). 3 C NMR (75 MHz,CDC13) 8 157.73, 153.03, 139.18, 134.15, 130.78, 129.92, 129.74, 128.07, 127.89, 120.13, 23.23, 15 20.85, 12.86, 12.58. Anal. Calcd. for C, 4 H1 C1N 4 : C, 61.20; H, 5.50; N, 20.39; Cl, 12.90. Found: C, 61.18; H, 5.9; N, 20.34; Cl, 12.78. Step F: The compound prepared in Step E (50 mg, 20 0.18 mmol) was dissolved in anhydrous dimethylformamide (1.5 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 0.75 mL, 0.45 mmol) was added. The solution was heated to 60 0 C for one hour, then 1-bromobutane (0.078 mL, 0.73 mmol) was added. The reaction was held 25 at 60 0 C for 2 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column 30 chromatography (33% ethyl acetate/hexanes) to give the final product as an oil (45 mg, 75%). 'H NMR (300 MHz,CDC1 3 ) 8 7.41 (d, 1H, J=8.1 Hz), 7.31 (d, 1H, J=l.1 Hz), 7.10 (dd, 1H, J=8.1 Hz, J=1.1 Hz) 4.01 (t, 2H, J=7.5 Hz), 2.79 (q, 2H, J=7.3 Hz), 2.51 (s, 3H), 2.36 -86- WO 99/10350 PCT/US98/17049 (s, 3H), 1.83 (m, 2H), 1.43 (m, 2H), 1.34 (t, 3H, J=7.7 Hz), 0.99 (t, 3H, J=7.3 Hz). " 3 C NMR (75 MHz,CDC1 3 ) 5 156.98, 152.05, 138.85, 134.31, 130.87, 129.69, 129.64, 128.05, 127.91, 121.98, 44.85, 33.55, 21.26, 20.85, 5 19.99, 13.75, 13.01, 12.87. Example 330 Preparation of 5-Ethyl-4-[1-(1-methyl)butane]-3 methyl-l- (2-chloro-4-methyl) phenylimidazo[4,5 10 c] pyrazole The product from Step E, Example 329 (116 mg, 0.42 mmol) was dissolved in anhydrous dimethylformamide (3.5 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 1.75 mL, 1.05 mmol) was added. The solution 15 was heated to 60 0 C for one hour, then 2-bromopentane (0.21 mL, 1.69 mmol) was added. The reaction was held at 100 0 C for 40 hours, then cooled to room temperature and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, 20 dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column chromatography (33% ethyl acetate/hexanes) to give the final product as an oil (23 mg, 16%). 1 H NMR (300 MHz,CDC1 3 ) 8 7.41 (d, 1H, J=8.1 Hz), 7.32 (s, 1H), 7.12 25 (d, 1H, J=8.1 Hz) 4.28 (m, 1H), 2.83 (q, 2H, J=7.5 Hz), 2.57 (s, 3H), 2.36 (s, 3H), 1.85 (m, 2H), 1.54 (d, 3H, J=6.6 Hz), 1.33 (t, 3H, J=7.5 Hz), 1.29 (m, 2H), 0.92 (t, 3H, J=7.0 Hz). 13C NMR (75 MHz,CDC13) 8 156.77, 152.76, 138.86, 134.23, 130.91, 129.74, 129.67, 128.05, 30 127.95, 119.73, 51.69, 39.79, 22.31, 22.02, 20.85, 19.87, 15.51, 13.80, 13.07. -87- WO99/10350 PCTIUS98/17049 Example 331 Preparation of 4-(n-Butyl)-5-ethyl-3-methyl-1-(2 chloro-4-trifluoromethyl)phenylimidazo[4,5 c]pyrazole 5 Step A -Aminocrotonitrile (8.39 g, 0.10 mol) was dissolved in 1.0N HC1 (350 ml) and treated with 2 chloro-4-trifluoromethylhydrazine (21.52 g, 0.10 mol). The reaction was allowed to reflux for 2.5h, cooled, and decanted into a 2 liter beaker. The solution was 10 diluted with water (250 ml) and neutralized with 10% NaOH. The resulting precipitate was filtered and dried to constant weight to afford 23.61 g (83%) of the desired aminopyrazole as a white crystalline solid, mp 158.0-160.0 0 C. 'H NMR (300 Mhz, CDC1 3 ) 57.80 (s, 1H), 15 7.64 (m, 2H), 5.50 (s, 1H), 3.62 (bs, 2H), 2.25 (s, 3H). Step B: The compound prepared in Step A (4.0 g, 14.5 mmol) was dissolved in propionic anhydride (9.3 mL, 72.5 mmol) at room temperature and was allowed to stir 20 for 16 hours. Ice was then added and the reaction stirred for 5 hours. The solid product was removed by filtration, washed with water, and dried in vacuo to leave the final product as a yellow solid (3.75 g, 78%), mp 135-138 0 C. 'H NMR (300 MHz,CDC1 3 ) 8 7.81 (s, 1H), 7.66 25 (m, 2H), 6.93 (bs, 1H), 6.43 (s, 1H), 2.32 (s, 3H), 2.28 (q, 2H, J=7.7 Hz), 1.13 (t, 3H, J=7.7 Hz). "C NMR (75 MHz,CDC13) 6 170.92, 151.05, 138.79, 137.13, 132.02, 130.94, 127.64, 125.03, 124.57, 99.79, 29.82, 14.05, 9.27. Anal. Calcd for C, 4 H1ClF3NO: C, 50.69; H,3.95; N, 30 12.67. Found: C, 51.00; H, 4.05; N, 12.27. Step C The compound prepared in Step B (3.63 g, 10.9 mmol) was suspended in tetrahydrofuran (30 mL). To this suspension was added borane/THF complex (32.8 mL, -88- WO 99/10350 PCTIUS98/17049 32.8 mmol), and the reaction refluxed for one hour, then held at room temperature for 16 hours. Excess borane was quenched with 10% NaOH (10 mL) until off-gassing ceased and the reaction was diluted with water and 5 diethyl ether. The layers were separated and the organic phase as washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and reduced in vacuo. This residue was purified by column chromatography (25% ethyl acetate/hexanes) to provide 10 the final product as a white solid (2.73 g, 79%), mp 139-140 0 C. 'H NMR (300 MHz,CDC13) 8 7.85 (d, 1H, J=l.9 Hz), 7.72 (dd, 1H, J=8.1 Hz, J=1.5 Hz), 7.60 (d, 1H, J=8.4 Hz), 5.43 (s, 1H), 3.42 (t, 1H, J=5.6 Hz), 3.10 (m, 2H), 2.40 (s, 3H), 1.57 (m, 2H), 0.91 (t, 3H, J=7.5 15 Hz). 13C NMR (75 MHz,CDC1 3 ) 8 150.25, 149.43, 135.64, 135.10, 133.08, 127.91, 127.86, 124.95, 124.90, 87.32, 46.70, 22.49, 13.99, 11.14. te D: The compound prepared in Step C (2.83 g, 20 8.91 mmol) was suspended in ethanol (22 mL), and 15 drops of 10% HC1 were added. Upon addition of the HC1 significant off-gassing occurred, and at the completion of the off-gassing the reaction mixture was homogeneous. Isoamyl nitrite (1.4 mL, 10.7 mmol) was then added, and 25 the solution darkened upon addition. The solution was stirred at room temperature for 16 hours, and then reduced to dryness in vacuo. Hexanes were added to the residual oil and a yellow precipitate formed. This solid was removed by filtration and washed with hexanes, 30 and was later identified as the hydrochloride salt of the desired product (0.51 g, 17%). The filtrate was reduced in vacuo and the residual oil was purified by column chromatography (gradient elution with 25-50% ethyl acetate/hexanes) to give the final product as 35 reddish purple crystals (2.03 g, 66%), mp 95-97 0 C. iH -89- WO 99/10350 PCT/US98/17049 NMR (300 MHz,CDC13) 8 10.34 (bs, 1H), 7.83 (s, 1H), 7.70 (m, 2H), 2.73 (s, 3H), 2.70 (m, 2H), 1.45 (m, 2H), 0.81 (t, 3H, J=7.3 Hz). 13C NMR (75 MHz,CDC1 3 ) 8 153.31, 149.87, 139.45, 139.01, 134.13, 133.84, 130.65, 127.49, 5 127.44, 124.92, 124.88, 44.10, 22.73, 11.48, 10.89. Anal Calcd. for C, 4

H

14 C1F 3

N

4 0: C, 48.50; H, 4.08; N, 16.16. Found: C, 48.53; H, 4.11; N, 16.04. Sten E: The compound prepared in Step D (1.92 g, 10 5.55 mmol) was dissolved in anhydrous pyridine (30 mL) and the solution heated to reflux for 16 hours. The solvent was removed in vacuo and the residue purified by column chromatography (50% ethyl acetate/hexanes) to afford the product as a brown solid (0.74 g, 41%). This 15 product was used in further reactions directly, however a sample was further purified for analytical purposes by washing briefly with 50% diethyl ether/hexanes to remove a brown oily residue, leaving the final product as an off-white solid, mp 155.5-158 0 C. 'H NMR (300 MHz,CDC1 3 ) 8 20 8.76 (bs, 1H), 7.78 (d, 1H, J=l.5 Hz), 7.76 (d, 1H, J=8.4 Hz), 7.59 (dd, 1H, J=8.4 Hz, J=l.5 Hz), 2.88 (q, 2H, J=7.6 Hz), 2.47 (s, 3H), 1.38 (t, 3H, J=7.5 Hz). 13C NMR (75 MHz,CDC1 3 ) 8 157.50, 152.94, 139.71, 131.59, 130.85, 130.40, 129.96, 129.39, 128.13, 128.08, 127.74, 25 124.92, 124.37, 124.33, 121.32, 120.63, 23.28, 12.90, 12.52. Anal. Calcd. for C, 4

H,

2 C1F 3

N

4 : C, 51.15; H, 3.69; N, 17.04; Cl, 10.79; F, 17.34. Found: C, 51.37; H, 3.77; N, 16.92; Cl, 10.96; F, 16.98. 30 te F* The compound prepared in Step E (160 mg, 0.49 mmol) was dissolved in anhydrous dimethylformamide (5 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 2.0 mL, 1.22 mmol) was added. The solution was heated to 60'C for one hour, then 1-bromobutane (0.21 mL, -90- WO 99/10350 PCT/US98/17049 1.96 mmol) was added. The reaction was held at 600C for 1.5 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over 5 anhydrous sodium sulfate, and reduced in vacuo. The residue was purified by preparative thin layer chromatography (33% ethyl acetate/hexanes) to give the final product as an oil (83 mg, 44%). 'H NMR (300 MHz,CDC1 3 ) 5 7.78 (d, 1H, J=l.5 Hz), 7.73 (d, 1H, J=8.4 10 Hz), 7.58 (dd, 1H, J=8.4 Hz, J=l.5 Hz), 4.00 (t, 2H, J=7.5 Hz), 2.80 (q, 2H, J=7.5 Hz), 2.52 (s, 3H), 1.81 (m, 2H), 1.44 (m, 2H), 1.36 (t, 3H, J=7.7 Hz), 1.00 (t, 3H, J=7.3 Hz). 13C NMR (75 MHz,CDC1 3 ) 8 157.22, 151.95, 139.84, 131.45, 130.06, 129.61, 129.23, 128.24, 128.18, 15 127.58, 125.02, 124.34, 124.29, 122.62, 44.92, 33.56, 21.24, 19.99, 13.73, 13.01, 12.76 Example-332 Preparation of 4-(3,4-Difluorobenzyl)-5-ethyl-3 20 methyl-l- (2-chloro-4-trifluoromethyl) phenylimidazo[4,5-c]pyrazole The product from Step E, Example 331 (160 mg, 0.49 mmol) was dissolved in anhydrous dimethylformamide (5 mL) and sodium bis(trimethylsilyl)amide (0.6 M in 25 toluene, 2.0 mL, 1.22 mmol) was added. The solution was heated to 600C for one hour, then a-bromo-3,4 difluorotoluene (0.25 mL, 1.96 mmol) was added. The reaction was held at 600C for 2.5 hours, cooled to room temperature, and diluted with water and diethyl ether. 30 The layers were separated and the organic phase washed with water, dried over anhydrous sodium sulfate, and reduced to dryness in vacuo. The residue was purified by column chromatography (33% ethyl acetate/hexanes) followed by recrystallization from diethyl ether/hexanes -91- WO 99/10350 PCT/US98/17049 to give the final product (30 mg, 13%), mp 108-1100C. 1H NMR (300 MHz,CDC1 3 ) 8 7.80 (d, 1H, J=1.5 Hz), 7.75 (d, 1H, J=8.4 Hz), 7.61 (dd, 1H, J=8.4 Hz, J=1.5 Hz), 7.19 (m, 1H), 6.93 (m, 2H), 5.22 (s, 2H), 2.81 (q, 2H, J=7.5 5 Hz), 2.21 (s, 3H), 1.33 (t, 3H, J=7.5 Hz). 1 3 C NMR (75 MHz,CDC1 3 ) 8 157.67, 151.98, 151.69, 139.65, 133.27, 131.52, 130.33, 129.89, 129.33, 128.25, 128.21, 127.71, 124.99, 124.39, 124.35, 122.54, 122.29, 122.20, 118.24, 118.01, 115.55, 115.30, 47.46, 21.39, 12.62, 12.58. 10 Example 333 Preparation of 4-[1-(1-Ethyl)butane]-5-ethyl 3-methyl-1-(2-chloro-4-trifluoromethyl) phenylimidazo[4,5-c] pyrazole 15 The product from Step E, Example 331 (150 mg, 0.45 mmol) was dissolved in anhydrous dimethylformamide (5 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 1.9 mL, 1.14 mmol) was added. The solution was heated to 60 0 C for one hour, then 3-bromohexane (300 mg, 20 1.82 mmol) was added. The reaction was held at 80 0 C for 64 hours, then cooled to room temperature and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in 25 vacuo. The residue was purified by column chromatography (33% ethyl acetate/hexanes) to give the final product as an oil (31 mg, 16%). 'H NMR (300 MHz,CDC1 3 ) 8 7.77 (m, 2H), 7.59 (dd, 1H, J=8.4 Hz, J=l.5 Hz), 4.02 (mn, 1H), 2.83 (q, 2H, J=7.5 Hz), 2.55 (s, 3H), 30 1.85 (m, 4H), 1.36 (t, 3H, J=7.7 Hz), 1.27 (m, 2H), 0.92 (t, 3H, J=7.2 HZ), 0.86 (t, 3H, J=7.3 Hz). 3 C NMR (75 MHz,CDC13) 8 157.91, 152.73, 139.73, 131.50, 130.06, 129.62, 129.31, 128.26, 128.22, 127.60, 125.03, 124.32, -92- WO99/10350 PCT/US98/17049 124.27, 121.43, 120.26, 58.24, 38.41, 37.35, 29.48, 21.94, 19.83, 15.47, 13.87, 12.88, 11.14. Examhe 334 5 Preparation of 5-Ethyl-4-[l-(1-methyl)butane]-3 methyl-l-(2-chloro-4-trifluoromethyl) phenylimidazo[4,5-c]pyrazole The product from Step E, Example 501 (150 mg, 0.45 mmol) was dissolved in anhydrous dimethylformamide (5 mL) and 10 sodium bis(trimethylsilyl)amide (0.6 M in toluene, 1.9 mL, 1.14 mmol) was added. The solution was heated to 60'C for one hour, then 2-bromopentane (0.22 mL, 1.82 mmol) was added. The reaction was held at 80 0 C for 64 hours, then cooled to room temperature and diluted with 15 water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced to dryness in vacuo. The residue was purified by column chromatography (gradient elution with 33-50% ethyl 20 acetate/hexanes) to give the final product as an oil (37 mg, 21%). 'H NMR (300 MHz,CDC1 3 ) 8 7.79 (d, 1H, J=l.5 Hz), 7.75 (d, 1H, J=8.1 Hz), 7.59 (dd, 1H, J=8.4 Hz, J=l.5 Hz), 4.30 (m, 1H), 2.84 (q, 2H, J=7.5 Hz), 2.58 (s, 3H), 1.86 (m, 2H), 1.55 (d, 3H, J=6.6 Hz), 1.34 (t, 25 3H, J=7.5 Hz), 1.22 (m, 2H), 0.93 (t, 3H, J=7.3 Hz). 3 C NMR (75 MHz,CDC1 3 ) 8 157.01, 139.73, 131.43, 129.31, 128.24, 128.20, 127.63, 124.32, 124.27, 120.40, 51.83, 39.77, 22.29, 21.99, 19.86, 15.52, 13.77, 12.93. 30 Examle 353 Preparation of 4-(n-Butyl)-5-ethyl-3-methyl-1-(2 chloro-4-methoxy)phenylimidazo[4,5-c]pyrazole This compound was obtained as the second eluting compound from the reaction described in Example 355 (see 35 below) (12 mg, 8%) as a yellow oil. 'H NMR (300 -93- WO 99/10350 PCT/US98/17049 MHz,CDC1 3 ) 8 7.42 (d, 1H, J=8.8 Hz), 7.03 (d, 1H, J=2.6 Hz), 6.86 (dd, 1H, J=8.8 Hz, J=2.5 Hz), 4.01 (t, 2H, J=7.3 Hz), 3.82 (s, 3H), 2.79 (q, 2H, J=7.7 Hz), 2.51 (s, 3H), 1.73 (m, 2H), 1.44 (m, 2H), 1.34 (t, 3H, 5 J=7.5), 1.00 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H

(C

18

H

24 CO10N 4 ): 347.1638. Found: 347.1642. Example 354 Preparation of 4-(n-Butyl)-5-ethyl-3-methyl-1 10 (2,4-dimethoxy)phenylimidazo[4,5-c]pyrazole This compound was obtained as the third eluting compound from the reaction described in Example 520 (29 mg, 19%) as a yellow oil. 1 H NMR (300 MHz,CDC1 3 ) 8 7.35 (d, 1H, J=8.8 Hz), 6.57 (d, 1H, J=2.5 Hz), 6.52 (dd, 1H, 15 J=8.6 Hz, J=2.7 Hz), 3.99 (t, 2H, J=7.3 Hz), 3.82 (s, 3H), 3.80 (s, 3H), 2.77 (q, 2H, J=7.7 Hz), 2.50 (s, 3H), 1.82 (m, 2H), 1.43 (m, 2H), 1.33 (t, 3H, J=7.5 Hz), 0.99 (t, 3H, J=7.5 Hz). HRMS Calcd. for M+H (C 19

H

27 CO2N 4 ): 343.2134. Found: 343.2117. 20 Preparation of 4-(n-Butyl)-5-ethyl-3-methyl-l-(2 methoxy-4-bromo)phenylimidazo[4,5-c]pyrazole The compound prepared in Step F, Example 325 (178 25 mg, 0.45 mmol) was dissolved in anhydrous dimethylformamide (2.2 mL). To this solution was added CuBr (9.7 mg, 0.0676 mmol), followed by sodium methoxide (25% in methanol, 0.29 mL, 1.35 mmol). This solution was heated to 155 0 C for 30 minutes, cooled to room 30 temperature, and diluted with diethyl ether. This solution was shaken with a 20% solution of NH40H in saturated aqueous NH 4 Cl, and the ethereal phase was dried over anhydrous magnesium sulfate and reduced in vacuo to leave a brown oil. This residue was purified by column 35 chromatography (gradient elution with 50-75% ethyl -94- WO99/10350 PCT/US98/17049 acetate/hexanes), the first eluting compound being the title product as a yellow oil (27 mg, 15%). Further elution provided Examples 521 and 522, described below. 'H NMR (300 MHz,CDC1 3 ) 8 7.37 (m, 1H), 7.15 (m, 2H), 3.99 5 (t, 2H, J=7.3 Hz), 3.86 (s, 3H), 2.78 (q, 2H, J=7.7 Hz), 2.50 (s, 3H), 1.82 (m, 2H), 1.43 (m, 2H), 1.35 (t, 3H, J=7.5 Hz), 0.99 (t, 3H, J=7.5 Hz). HRMS Calcd. for M+H

(C,

8

H

24 BrON 4 ): 391.1134. Found: 391.1133. 10 Example 356 Preparation of 5-Ethyl-4-[1- (1-methyl)butane]-3 methyl-l-(2,6-dichloro-4-methoxy) phenylimidazo[4,5-c]pyrazole The compound prepared in Example 102 (296 mg, 0.74 15 mmol) was dissolved in anhydrous dimethylformamide (3.5 mL). To this solution was added CuBr (16 mg, 0.11 mmol), followed by sodium methoxide (25% in methanol, 0.25 mL, 1.11 mmol). This solution was heated to 75 0 C for 30 minutes, then additional sodium methoxide (0.050 20 mL, 0.22 mmol) was added and the reaction was heated to 100 0 C for two hours. The reactionw as cooled to room temperature and and diluted with diethyl ether. This solution was shaken with a 20% solution of NH40H in saturated aqueous NH 4 C1, and the ethereal phase was dried 25 over anhydrous magnesium sulfate and reduced in vacuo to leave a yellow oil. This residue was purified by column chromatography (gradient elution with 25-50% ethyl acetate/hexanes), the first eluting compound being the title product as an oil (39 mg, 13%). Further elution 30 provided Example 524, described below. 'H NMR (300 MHz,CDC13) 8 6.95 (s, 2H), 4.28 (m, 1H), 3.82 (s, 3H), 2.82 (q, 2H, J=7.7 Hz), 2.56 (s, 3H), 1.877 (m, 2H), 1.55 (d, 3H, J=7.0 Hz), 1.33 (t, 3H, J=7.5 Hz), 0.92 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H (C 1H25C1 2 0N 4 ): 35 395.1405. Found: 395.1406. -95- WO99/10350 PCT/US98/17049 Example 357 Preparation of 5-Ethyl-4-[1-(1-methyl)butane]-3 methyl-l-(2,4-dichloro-6-methoxy) phenylimidazo[4,5-c]pyrazole 5 This compound was obtained as the second eluting compound from the reaction described in Example 523 as an oil (27 mg, 9%). 'H NMR (300 MHz,CDC1 3 ) 8 7.11 (d, 1H, J=2.2 Hz), 6.90 (d, 1H, J=2.2 Hz), 4.28 (m, 1H), 3.76 (s, 3H), 2.81 (q, 2H, J=7.6 Hz), 1.88 (m, 2H), 1.55 (d, 10 3H, J=7.0 Hz), 1.32 (t, 3H, J=7.5 Hz), 0.92 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H (C 19

H

25 C1 3 0N 4 ): 395.1405. Found: 395.1397. Example 396 15 Preparation of 4-(n-Butyl)-5-ethyl-3-methyl-l-(2 methyl-4-bromo)phenylimidazo[4, 5 -c]pyrazole St A To 2-methyl-4-bromoaniline (30.0 g, 161 mmol) at 10 0 C was added concentrated HC1 (400 mL), and to this solution was added sodium nitrite (13.4 g, 193 20 mmol) in water (125 mL), maintaining an internal temperature of -10°C during the addition. The reaction was stirred for an hour at 0-5 0 C, then tin (II) chloride (90.9 g, 403 mmol) in concentrated HC1 (395 mL) was added so as to keep the temperature between 5-8 0 C; 25 significant foaming occurred during addition. The orange solid was isolated by filtration and dried to give the hydrazine hydrochloride. This compound was dissolved in 1N HC1 (500 mL) and 3-aminocrotonitrile (13.2 g, 161 mmol) was added and the reaction was heated 30 to reflux for 16 hours. It was cooled to room temperature and the supernatant aqueous phase was decanted and neutralized with 50% NaOH, extracted with ethyl acetate, and the organic solution dried over anhydrous magnesium sulfate and reduced in vacuo to -96- WO 99/10350 PCT/US98/17049 leave the crude product. This was purified by column chromatography (gradient elution of 25-50% ethyl acetate/hexanes) to give the product (11.7 g). The residue from the reaction was dissolved in ethyl acetate 5 and extracted with 1N HC1, and this acidic extract was neutralized with 10% NaOH and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and reduced in vacuo to leave the crude product. This was purified by column 10 chromatography (gradient elution of 25-50% ethyl acetate/hexanes) to recover additional pyrazole as a light yellow solid (total of 13.8 g, 32%), mp 89.5-92 0 C. 'H NMR (300 MHz,CDC1 3 ) 8 7.47 (d, 1H, J=l.8 Hz), 7.41 (dd, 1H, J=8.5 Hz, J=2.2 Hz), 7.18 (d, 1H, J=8.4 H), 5.42 (s, 15 1H), 3.49 (bs, 2H), 2.22 (s, 3H), 2.15 (s, 3H). HRMS Calcd. for M+H (C 11 H1 3 BrN 3 ): 266.0293. Found: 266.0309. Anal. Calcd. for CuH, BrN: C, 49.64; H, 4.54; N, 15.79. Found: C, 49.92; H, 4.53; N, 15.67. 20 Step The compound prepared in Step A (13.8 g, 51.7 mmol) was dissolved in propionic anhydride (33.2 mL, 259 mmol) and was allowed to stir for 16 hours at room temperature. Ice was then added and the reaction stirred for 5 hours, then diethyl ether was added and 25 the phases were separated. The organic phase was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and reduced in vacuo to leave a thick oil. This residue was purified by column chromatography (50% ethyl acetate/hexanes) to give the final product as 30 an off-white solid (13.9 g, 83%), mp 119-121 0 C. 'H NMR (300 MHz,CDC13) 8 7.51 (s, 1H), 7.43 (dd, 1H, J=8.0 Hz, J=l.8 Hz), 7.12 (d, 1H, J=8.4 Hz)6.91 (bs, 1H), 6.47 (s, 1H), 2.29 (s, 3H), 2.25 (q, 2H, J=7.5 Hz), 2.08 (s, 3H), 1.13m (t, 3H, J=7.5 Hz). HRMS Calcd. for M+H 35 (C,4H 17 BrN 3 0): 322.0555. Found: 322.0567. Anal. Calcd. -97- WO 99/10350 PCT/US98/17049 for C, 4

H

16 BrN30: C, 52.19; H, 5.02; N, 13.04. Found: C, 51.94; H, 4.98; N, 12.85. Sten C The compound prepared in Step B (13.9 g, 5 43.0 mmol) was suspended in tetrahydrofuran (150 mL). To this suspension was added borane/THF complex (129 mL, 129 mmol), and the reaction refluxed for 16 hours. Excess borane was quenched with 10% NaOH (50 mL) until off-gassing ceased and the reaction was diluted with 10 water and diethyl ether. The layers were separated and the organic phase was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and reduced in vacuo to leave the product as a white solid (13.7 g, 103%). mp 116-119 0 C. 'H NMR (300 MHz,CDC1 3 ) 5 15 7.54 (d, 1H, J=l.8 Hz), 7.49 (dd, 1H, J=8.5 Hz, J=2.2 Hz), 7.14 (d, 1H, J=8.5 Hz), 5.38 (s, 1H), 3.38 (t, 1H, J-5.7 Hz), 3.05 (q, 2H, J=6.7 Hz), 2.37 (s, 3H), 2.03 (s, 3H), 1.53 (m, 2H), 0.88 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H (C14H , 9 BrN 3 ) : 308.0763. Found: 308.0754. 20 Step D The compound prepared in Step C (13.6 g, 44.3 mmol) was suspended in ethanol (110 mL), and one mL of 10% HC1 was added. Upon addition of the HC1 significant off-gassing occurred, and at the completion 25 of the off-gassing the reaction mixture was homogeneous. Isoanyl nitrite (7.1 mL, 53.2 mmol) was added, and the solution darkened upon addition. The solution was stirred at room temperature for 16 hours, and then a few drops of triethylamine were added to neutralize the HC1. 30 The reaction was reduced to dryness in vacuo and the residue was dissolved in dichloromethane and the insoluble triethylamine hydrochloride was removed by filtration. The reaction was reduced to dryness again and diethyl ether was added, causing a precipitate to 35 form. This solid was isolated by filtration and rinsed -98- WO 99/10350 PCT/US98/17049 with hexanes to leave the product as a purple solid (11.4 g, 76%), mp 120-121.50C. 'H NMR (300 MHz,CDC1 3 ) 8 10.11 (bs, 1H), 7.50 (d, 1H, J=l.8 Hz), 7.45 (dd, 1H, J=8.5 Hz, J=1.8 Hz), 7.21 (d, 1H, J=8.4 Hz), 3.10 (q, 5 1H, J=7.3 Hz), 2.70 (s, 3H), 2.66 (m, 2H), 2.17 (s, 3H), 1.42 (m, 3H), 0.79 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H (C, 4 HiBrN 4 0): 337.0664. Found: 337.0662. Anal. Calcd. for C 14

H,

7 BrN 4 0: C, 49.86; H, 5.08; N, 16.61. Found: C, 49.90; H, 4.92; N, 16.50. 10 Ste E: The compound prepared in Step D (11.3 g, 33.5 mmol) was dissolved in anhydrous pyridine (100 mL) and the solution heated to reflux for 16 hours. The solvent was removed in vacuo and the residue purified by 15 column chromatography (50% ethyl acetate/hexanes) to afford the product as a tan solid (7.3 g, 68%) mp 136 1380C. 'H NMR (300 MHz,CDC13) 8 8.81 (bs, 1H), 7.44 (m, 1H), 7.35 (m, 2H), 2.83 (q, 2H, J=7.7 Hz), 2.43 (s, 3H), 2.37 (s, 3H), 1.36 (t, 3H, J=7.5 Hz). HRMS Calcd. for 20 M+H (C 14 H 16 BrN 4 ): 319.0559. Found: 319.0555. Anal. Calcd. for C14H 15 BrN 4 : C, 52.68; H, 4.75; N, 17.55. Found: C, 52.53; H, 4.61; N, 17.42. Ste F: The compound prepared in Step E (130 mg, 25 0.41 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 1.7 mL, 1.02 mmol) was added. The solution was heated to 600C for one hour, then 1-bromobutane (0.17 mL, 1.63 mmol) was added. The reaction was held at 600C for 30 16 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced in vacuo. The residue was purified by column chromatography (15% ethyl -99- WO 99/10350 PCT/US98/17049 acetate/hexanes) to give the final product as an oil (120 mg, 79%). 'H NMR (300 MHz,CDC1 3 ) 8 7.43 (m, 1H), 7.36 (m, 2H), 4.01 (t, 2H, J=7.5 Hz), 2.78 (q, 2H, J=7.5 Hz), 2.49 (s, 3H), 2.38 (s, 3H), 1.82 (m, 2H), 1.43 (m, 5 2H), 1.35 (t, 3H, J-7.5 Hz), 1.00 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H (C, 8

H

24 BrN 4 ): 375.1185. Found: 375.1185. Anal. Calcd. for C18H 23 BrN 4 : C, 57.60; H, 6.19; N, 14.93. Found: C, 57.63; H, 6.00; N, 14.74. 10 Examle 397 Preparation of 4-(3,4-Diflu orobenzyl)-5-ethyl-3 methyl-1-(2-methyl-4-bromo)phenylimidazo[4,5 c] pyrazole The compound prepared in Step E, Example 396, (130 15 mg, 0.41 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 1.7 mL, 1.02 mmol) was added. The solution was heated to 60 0 C for one hour, then a-bromo-3,4-difluorotoluene (0.21 mL, 1.63 20 mmol) was added. The reaction was held at 60 0 C for 16 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced in vacuo. The 25 residue was purified by column chromatography (15% ethyl acetate/hexanes) to give the final product as a crystalline solid (125 mg, 69%), mp 127-129 0 C. 'H NMR (300 MHz,CDCl 3 ) 8 7.45 (s, 1H), 7.37 (m, 2H), 7.17 (m, 1H), 6.90 (m, 2H), 5.21 (s, 2H), 2.78 (q, 2H, J=7.5 Hz), 30 2.9 (s, 3H), 1.57 (s, 3H), 1.32 (t, 3H, J=7./7 Hz). HRMS Calcd. for M+H (C 21

H

20 BrF 2

N

4 ): 445.0840. Found: 445.0845. Anal. Calcd. for C 21

H,

9 BrF 2

N

4 : C, 56.64; H, 4.30; N, 12.58. Found: C, 56.46; H, 4.21; N, 12.22. -100- WO 99/10350 PCT/US98/17049 Example 398 Preparation of 5-Ethyl-4-[1-(1-methyl)butane]-3 methyl-i- (2-methyl-4-bromo)phenylimidazo[4,5 c] pyrazole 5 The compound prepared in Step E, Example 396, (5.38 g, 16.8 mmol) was dissolved in anhydrous dimethylformamide (170 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 70.2 mL, 42.1 mmol) was added. The solution was heated to 60 0 C 10 for one hour, then 2-bromopentane (8.3 mL, 67.2 mmol) was added. The reaction was held at 80 0 C for 16 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous 15 magnesium sulfate, and reduced in vacuo. The residue was purified by column chromatography (gradient elution with 10-50% ethyl acetate/hexanes) to give the final product as an oil (1.68 g, 26%). 1 H NMR (300 MHz,CDC1 3 ) 8 7.44 (m, 1H), 7.36 (m, 2H), 4.28 (m, 1H), 2.83 (q, 2H, 20 J=7.5 Hz), 2.55 (s, 3H), 2.39 (s, 3H), 1.85 (m, 2H), 1.54 (d, 3H, J=6.6 Hz), 1.34 (t, -3H, J=7.5 Hz), 1.20 (m, 2H), 0.92 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H

(C

19

H

26 BrN 4 ): 389.1341. Found: 389.1341. Anal. Calcd. for C,9H 25 BrN 4 : C, 58.61; H, 6.47; N, 14.39. Found: C, 25 58.88; H, 6.36; N, 14.33. Examle 399 Preparation of 4-[1-(1-Ethyl)butane]-5-ethyl-3 methyl-1- (2-methyl-4-bromo) phenylimidazo[4, 5 30 c] pyrazole The compound prepared in Step E, Example 396, (319 mg, 1.0 mmol) was dissolved in anhydrous dimethylformamide (10 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 4.2 mL, 2.5 -101- WO99/10350 PCT/US98/17049 mmol) was added. The solution was heated to 600C for one hour, then 3-bromohexane (660 mg, 4.0 mmol) was added. The reaction was held at 800C for 16 hours, cooled to room temperature, and diluted with water and diethyl 5 ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced in vacuo. The residue was purified by column chromatography (15% ethyl acetate/hexanes) to give the final product as an oil (37 mg, 9%). 'H NMR 10 (300 MHz,CDC13) 8 7.44 (m, 1H), 7 37 (m, 2H), 4.02 (m, 1H), 2.80 (q, 2H, J=7.5 Hz), 2.52 (s, 3H), 2.38 (s, 3H), 1.83 (m, 4H), 1.35 (t, 3H, J=7.5 Hz), 1.26 (m, 2H), 0.91 (t, 3H, J=7.3 Hz), 0.84 (t, 3H, J=7.5 Hz). HRMS Calcd. for M+H (C 20

H

28 BrN 4 ): 403.1498. Found: 403.1494. 15 Example 400 Preparation of 4-(n-Butyl)-5-ethyl-3-methyl-1-(2 trifluoromethyl-4-bromo)phenylimidazo[ 4 ,5 c]pyrazole 20 Step A: To 2-trifluoromethyl-4-bromoaniline (38.4 g, 160 mmol) was added concentrated HC1 (400 mL), and to this solution was cooled to 50C. To this was added sodium nitrite (13.25 g, 192 nmmol) in water (125 mL), maintaining an internal temperature of -10°C with 25 additional cooling. The reaction was stirred for an hour at 0-5 0 C, then tin (II) chloride (95.0 g, 400 mmol) in concentrated HC1 (400 mL) was added so as to keep the temperature between 5-8°C; significant foaming occurred during addition. The orange solid was recovered by 30 filtration and dried to give the hydrazine hydrochloride (34.9 g, 120 mmol, 75%). This compound was suspended in 1N HC1 (500 mL), 3-aminocrotonitrile (9.84 g, 120 mmol) was added and the reaction heated to reflux for 3 hours. -102- WO 99/10350 PCT/US98/17049 It was cooled to room temperature and the supernatant aqueous phase was decanted, filtered to remove a small amount of dark solids, and neutralized with 10% NaOH to give a fine off-white solid. This solid was recovered 5 by filtration and dried to give the product (27.4 g, 71%), mp 117-119 0 C. 'H NMR (300 MHz,CDC1 3 ) 8 7.94 (d, 1H, J=2.2 Hz), 7.80 (dd, 1H, J=8.4 Hz, J=2.2 Hz), 7.33 (d, 1H, J=8.4 Hz), 5.44 (s, 1H), 3.44 (bs, 1H), 2.21 (s, 3H). HRMS Calcd. for M+H (C,,HloBrF 3

N

3 ): 320.0011. Found: 10 320.0005. Anal. Calcd. for C,,HgBrF 3

N

3 : C, 41.27; H, 2.83; N, 13.13. Found: C, 41.33; H, 2.56; N, 12.96. Ste B: The compound prepared in Step A (27.3 g, 85.4 mmol) was dissolved in propionic anhydride (54.8 15 mL, 427 mmol) and was allowed to stir for 2 hours at room temperature. Ice was then added and the reaction stirred for 16 hours, providing the product as a solid. The product was isolated by filtration and dried to leave an off-white solid (29.8 g, 93%), mp 165.5-167.5 0 C. 20 'H NMR (300 MHz,CDCl 3 ) 8 7.94 (d, 1H, J=2.2 Hz), 7.80 (dd, 1H, J=8.2 Hz, J=2.0 Hz), 7.33 (d, 1H, J=8.2 Hz), 6.86 (bs, 1H), 6.34 (s, 1H), 2.29 (s, 3H), 2.21 (q, 2H, J=7.5 Hz), 1.08 (t, 3H, J=7.5 Hz). HRMS Calcd. for M+H (C1 4 H1 4 BrF 3

ON

3 ): 376.0273. Found: 376.0267. Anal. Calcd. 25 for C1 4

H

3 BrF 3

ON

3 : C, 44.70; H, 3.48; N, 11.17. Found: C, 44.47; H, 3.27; N, 11.02. Step C: The compound prepared in Step B (29.8 g, 79.1 mmol) was suspended in anhydrous tetrahydrofuran 30 (220 mL). To this suspension was added borane/THF complex (237 mL, 237 mmol), and the reaction refluxed for 16 hours. Excess borane was quenched with 10% NaOH (100 mL) until off-gassing ceased, and the reaction was filtered through Celite. Diethyl ether was added and 35 the layers were separated, the organic phase was washed -103- WO 99/10350 PCT/US98/17049 with saturated sodium chloride, dried over anhydrous magnesium sulfate, and reduced in vacuo to leave the product as a white solid (28.4 g, 99%). 1H NMR (300 MHz,CDC1 3 ) 8 7.94 (d, 1H, J=2.2 Hz), 7.79 (dd, 1H, J=8.4 5 Hz, J=2.2 Hz), 5.31 (s, 1H), 3.10 (bs, 1H), 3.01 (m, 2H), 2.23 (s, 3H), 1.54 (m, 2H), 0.90 (t, 3H, J=7.5 Hz). HRMS Calcd. for M+H (Cl4H 6 BrF3N3): 362.0480. Found: 362.0470. 10 SteD D: The compound prepared in Step C (28.3 g, 78.1 mmol) was suspended in ethanol (200 mL), and one mL of 10% HC1 was added. Upon addition of the HC1 significant off-gassing occurred, and at the completion of the off-gassing the reaction mixture was homogeneous. 15 Isoamyl nitrite (12.6 mL, 93.8 mmol) was then added, and the solution darkened upon addition. The solution was stirred at room temperature for 16 hours, and then a few drops of triethylamine were added to neutralize the HC1. The reaction was reduced to dryness in vacuo and the 20 residue was dissolved in dichloromethane and the insoluble triethylamine hydrochloride was removed by filtration. The reaction was again reduced to dryness and hexanes was added, causing a red precipitate to form. This solid was isolated by filtration and rinsed 25 with hexanes to leave the product as a red solid (18.2 g, 60%). 'H NMR (300 MHz,CDC1 3 ) 8 10.34 (bs, 1H), 7.97 (d, 1H, J=l.8 Hz), 7.85 (dd, 1H, J=8.5 Hz, J=2.2 Hz), 7.38 (d, 8.5 Hz), 2.70 (s, 3H), 2.65 (m, 2H), 1.44 (m, 2H), 0.82 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H 30 (C, 4

H,

5 BrON 4 ): 391.0382. Found: 391.0380. Anal. Calcd. for C, 4 Hu 4 BrON 4 : C, 42.98; H, 3.62; N, 14.32. Found: C, 3.22; H, ; N, 14.09. Step E: The compound prepared in Step D (18.1 g, 35 46.2 mmol) was dissolved in anhydrous pyridine (200 mL) -104- WO 99/10350 PCT/US98/17049 and the solution heated to reflux for 16 hours. The solvent was removed in vacuo and the residue purified by column chromatography (gradient elution with 25-50% ethyl acetate/hexanes) to afford the product as a tan 5 solid (13.1 g, 76%) mp 158-160.50C. 'H NMR (300 MHz,CDC1 3 ) 8 8.65 (bs, 1H), 7.92 (d, 1H, J=2.2 H), 7.73 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 7.52 (d, 1H, J=8.4 Hz), 2.85 (q, 2H, J=7.5 Hz), 2.43 (s, 3H), 1.38 (t, 3H, J=7.7 Hz). HRMS Calcd. for M+H (C, 4

H,

3 BrN 4 ): 373.0276. Found: 10 373.0281. Anal. Calcd. for C, 4 H1 2 BrN 4 C, 45.06; H, 3.24; N, 15.01. Found: C, 44.70; H, 3.00; N, 14.59. Step F: The compound prepared in Step E (153 mg, 0.41 mmol) was dissolved in anhydrous dimethylformamide 15 (4 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 1.7 mL, 1.02 mmol) was added. The solution was heated to 60 0 C for one hour, then 1-bromobutane (0.17 mL, 1.63 mmol) was added. The reaction was held at 60 0 C for 16 hours, cooled to room temperature, and diluted with 20 water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced in vacuo. The residue was purified by column chromatography (gradient elution with 15-25% ethyl acetate/hexanes) to give the 25 final product as a crystalline solid (68 mg, 39%), mp 78-80 0 C. 1H NMR (300 MHz,CDC1 3 ) 8 7.91 (d, 1H, J=2.2 Hz), 7.72 (dd, 1H, J=8.5 Hz, J=2.2 Hz), 7.55 (d, 1H, J=8.4 Hz), 4.01 (t, 2H, J=7.3 Hz), 2.78 (q, 2H, J=7.5 Hz), 2.48 (s, 3H), 1.83 (m, 2H), 1.42 (m, 2H), 1.35 (t, 3H, 30 J=7.7 Hz), 1.00 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H

(CH

21 BrF 3

N

4 ): 429.0902. Found: 429.0894. Anal. Calcd. for C 18

H

20 BrF 3

N

4 : C, 50.36; H, 4.71; N, 13.05. Found: C, 50.70; H, 4.58; N, 12.91. -105- WO 99/10350 PCT/US98/17049 Example 401 Preparation of 4-(3,4-Difluorobenzyl)-5-ethyl-3 methyl-- -(2-trifluoromethyl-4-bromo) phenylimidazo[4,5-c] pyrazole 5 The compound prepared in Step E, Example 400, (153 mg, 0.41 mmol) was dissolved in anhydrous dimethylformamide (4 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 1.7 mL, 1.02 mmol) was added. The solution was heated to 60 0 C for one 10 hour, then a-bromo-3,4-difluorotoluene (0.21 mL, 1.63 mmol) was added. The reaction was held at 60 0 C for 16 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over 15 anhydrous magnesium sulfate, and reduced in vacuo. The residue was purified by column chromatography (25% ethyl acetate/hexanes) to give the final product as a crystalline solid (74 mg, 36%), mp 105-107 0 C. 'H NMR (300 MHz,CDC13) 8 7.93 (d, 1H, J=2.2 Hz), 7.75 (dd, 1H, 20 J=8.8 Hz, J=2.2 Hz), 7.57 (d, 1H, J=8.4 Hz), 7.18 (m, IH), 6.90 (m, 2H), 5.21 (s, 2H), 2.77 (q, 2H, J=7.5 Hz), 2.18 (s, 3H), 1.32 (t, 3H, J=7.7 Hz). HRMS Calcd. for M+H (C 21

H,

7 BrF 5

N

4 ): 499.0557. Found: 499.0558. Anal. Calcd. for C 21

H,

6 BrF 5

N

4 : C, 50.52; H, 3.23; N, 11.22. 25 Found: C, 50.98; H, 3.19; N, 11.01. 30 -106- WO 99/10350 PCT/US98/17049 ExamDle 402 Preparation of 5-Ethyl-4-[1-(1-methyl)butane]-3 methyl-i- (2-trifluoromethyl-4 bromo)phenylimidazo[4,5-c]pyrazole 5 The compound prepared in Step E, Example 400, (3.4 g, 9.16 mmol) was dissolved in anhydrous dimethylformamide (100 mL) and sodium bis(trimethylsilyl)amide (0.6 M in toluene, 38.2 mL, 22.9 mmol) was added. The solution was heated to 60 0 C 10 for one hour, then 2-bromopentane (4.5 mL, 36.6 mmol) was added. The reaction was held at 80 0 C for 16 hours, cooled to room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous 15 magnesium sulfate, and reduced in vacuo. The residue was purified by column chromatography (gradient elution with 10-20% ethyl acetate/hexanes) to give the final product as a crystalline solid (829 mg, 20%), mp 51-53 0 C. 'H NMR (300 MHz,CDC13) 8 7.92 (d, 1H, J=2.2 Hz), 7.73 (dd, 20 1H, J=8.4 Hz, J=2.2 Hz), 7.58 (d, 1H, J=8.4 Hz), 4.29 (m, 1H), 2.81 (q, 2H, J=7.5 Hz), 2.53 (s, 3H), 1.85 (m, 2H), 1.54 (d, 3H, J=6.6 Hz0< 1.34 (t, 3H, J=7.5 Hz), 0.92 (t, 3H, J=7.3 Hz). HRMS Calcd. for M+H (C,19H 23 BrF 3

N

4 ): 443.1059. Found: 443.1064. Anal. Calcd. 25 for C, 9

H

22 BrF 3

N

4 : C, 51.48; H, 5.00; N, 12.64. Found: C, 51.84; H, 4,.99; N, 12.56. Example 403 Preparation of 5-Ethyl-4-[1-(l-ethyl)butane]-3 30 methyl-1-(2-trifluoromethyl-4-bromo) phenylimidazo[4,5-c]pyrazole The compound prepared in Step E, Example 400, (373 mg, 1.0 mmol) was dissolved in anhydrous dimethylformamide (10 mL) and sodium -107- WO 99/10350 PCT/US98/17049 bis(trimethylsilyl)amide (0.6 M in toluene, 4.2 mL, 2.5 mmol) was added. The solution was heated to 60 0 C for one hour, then 3-bromohexane (660.mg, 4.0 mmol) was added. The reaction was held at 80 0 C for 16 hours, cooled to 5 room temperature, and diluted with water and diethyl ether. The layers were separated and the organic phase washed with water, dried over anhydrous magnesium sulfate, and reduced in vacuo. The residue was purified by column chromatography (15% ethyl acetate/hexanes) to 10 give the final product as an oil (50 mg, 11%). 'H NMR (300 MHz,CDC1 3 ) 8 7.91 (d, 1H, J=2.2 Hz), 7.73 (dd, 1H, J=8.5 Hz, J=2.2 Hz), 7.61 (d, 1H, J=8.8 Hz), 4.00 (m, 1H), 2.80 (q, 2H, J=7.5 Hz), 2.51 (s, 3H), 1.83 (m, 4H), 1.35 (t, 3H, J=7.5 Hz), 1.23 (m, 2H), 0.91 (t, 3H, J=7.3 15 Hz), 0.83 (t, 3H, J=7.5 Hz). HRMS Calcd. for M+H

(C

2 0

H

25 BrF 3

N

4 ): 457.1215. Found: 457.1223. Example 408 Preparation of 5-Ethyl-4-[1-(1-methyl)butane]-3 20 methyl-1-(2-methyl-4-acetyl)phenyllmidazo[ 4 ,5 c]pyrazole The compound prepared in Example 396 (492 mg, 1.26 mmol) was dissolved in anhydrous toluene (5 mL) and dichlorobis (triphenylphosphine)palladium(II) (18 mg, 25 0.025 minmol) was added, followed by tributyl(l ethoxyvinyl)tin (548 mg, 1.52 mmol), and the solution was heated to reflux for 2.5 hours. The reaction was cooled to room temperature and quenched with 1N HC1 (10 mL) and diethyl ether. After stirring for 30 minutes 30 the layers were separated and the organic phase was washed with saturated aqueous sodium chloride, filtered through Celite, dried over anhydrous magnesium sulfate and reduced to dryness in vacuo. The crude product was purified by column chromatography (gradient elution with 35 10-20% ethyl acetate/hexanes) to give the final product -108- WO 99/10350 PCT/US98/17049 as a yellow oil (225 mg, 51%). 1 H NMR (300 MHz,CDC1 3 ) 8 7.91 (m, 1H), 7.85 (dd, 1H, J=8.4 Hz, J=1.8 Hz), 7.68 (d, 1H, J=8.1 Hz), 4.30 (m, 1H), 2.83 (q, 2H, J=7.5 Hz), 2.61 (s, 3H), 2.57 (s, 3H), 2.56 (s, 3H), 1.86 (m, 2H), 5 1.54 (d, 3H, J=6.6 Hz), 1.35 (t, 3H, J=7.5 Hz), 1.21 (t, 3H, J=7.1 Hz). HRMS Calcd. for M+H (C21H290N4): 353.2341. Found: 353.2344. Anal. Calcd. for C21 H 28 N40: C, 71.56; H, 8.02; N, 15.90. Found: C, 71.39; H, 7.97; N, 15.55. 10 The Examples in Table 3 may be prepared as amply exemplified above for the preparation of Examples 325 334, 353-357, 396-403, and 408. -109- WO 99/10350 PCT/US98/17049 TABLE 3 ,mN N N N2

R

4

R

2 / \

R

3 Ex.

R

I

R

2

R

3

R

4 X Mp C 262 CH 2

C(CH

2

CH

3

)

2 Me Me Me C Oil, MS 263 benzyl Me Me Me C 97-98 264 n-butyl Me Me Me C 81-83 265 2-phenylbenzyl Me Me Me C 266 4-phenylbenzyl Me Me Me C 267 CH 2

CH

2

OCH

2

CH

3 Me Me Me C 268 CH 2

C(CH

2

CH

3

)

2 Me Me Me N 269 benzyl Me Me Me N 270 n-butyl Me Me Me N 271 4-fluorobenzyl Br iPr H C 107-108 272 2-phenylbenzyl Br iPr H C Oil, MS 273 4-phenylbenzyl Br iPr H C 135-136 274 n-pentyl Br iPr H C 132-135 275 benzyl Br iPr H C Oil, MS 276 n-butyl Br iPr H C 76-69 277 CH 2 cPr Br iPr H C Oil, MS 278 CH 2 CH(Et) 2 Br iPr H C Oil, MS 279 CH(Et) 2 Br iPr H C Oil, MS 280 CH 2

CH

2 CH (Me) 2 Br iPr H C Oil, MS 281 CH (Et) CH 2

CH

2

CH

3 Br iPr H C Oil, MS 282 CH (Me) CH 2

CH

2

CH

3 Br iPr H C Oil, MS 283 CH 2

CH

2

OCH

2

CH

3 Br iPr H C 284 CH 2

CH

2

SCH

2

CH

3 Br iPr H C 285 4-picolyl Br iPr H C 286 CH(cPr) 2 Br iPr H C 287 CH(ethyl)n-butyl Br iPr H C 288 CH(CH 2 OMe) 2 Br iPr H C 289 benzyl Br OMe OMe C 290 n-butyl Br OMe OMe C 291 4-fluorobenzyl Br OMe OMe C 292 2-phenylbenzyl Br OMe OMe C 293 4-phenylbenzyl Br OMe OMe C 294 n-pentyl Br OMe OMe C 295 CH(cPr) 2 Br OMe OMe C -110- WO 99/10350 PCT/US98/17049 TABLE 3 (Continued) Ex. R1 R 2

R

3

R

4 X mp °C 296 benzyl Br Cl C1 C 125-127 297 n-butyl Br Cl C1 C 111-112 298 CH 2 cPr Br C1 Cl C 128-129 299 CH 2 CH (ethyl) 2 Br Cl C1 C 127-128 300 CH 2

CH

2 CH (CH 3

)

2 Br Cl Cl C 88-89 301 4-fluorobenzyl Br Cl Cl C 110-113 302 4-phenylbenzyl Br C1 Cl C 131-134 303 n-pentyl Br Cl C1 C 135-136 304 CH (Et) CH 2

CH

2

CH

3 Br C1 Cl C 116-118 305 CH (Me) CH 2

CH

2

CH

3 Br C1 C1 C Oil, MS 306 benzyl Br C1 Br C 117-124 307 n-butyl Br C1 Br C 112-113 308 CH 2 cPr Br Cl Br C 122-123 309 CH 2 CH (CH 2

CH

3 ) 2 Br C1 Br C 124-126 310 CH 2

CH

2 CH (CH 3 ) 2 Br Cl Br C 67-69 311 4-fluorobenzyl Br C1 Br C Oil, MS 312 4-phenylbenzyl Br C1 Br C 124-125 313 n-pentyl Br C1 Br C 124-125 314 n-butyl C1 Br C1 C 111-112 315 CH 2

CH

2 CH (CH 3 ) 2 C1 Br C1 C 115-116 316 CH 2 CH (CH 2

CH

3 ) 2 C1 Br C1 C 142-144 317 benzyl Cl Br Cl C 136-137 318 3,4-difluorobenzyl Cl Br Cl C 136-138 319 CH 2 -(2-tetrahydropyran) Cl Br Cl C 136-138 320 CH (Et) CH 2

CH

2

CH

3 C1 Br C1 C 132-133 321 CH (CH 3 ) CH 2 CH (CH 3 ) 2 C1 Br Cl C Oil, MS 322 CH (CH 3 ) CH 2

CH

2

CH

3 C1 Br C1 C 95-98 323 n-butyl C1 CN H C 163-165 324 n-butyl C1 CN CN C 151-153 325 n-butyl C1 Br H C Oil, MS 326 3,4-difluorobenzyl C1 Br H C 114-116 327 CH (Et) CH 2

CH

2

CH

3 C1 Br H C Oil, MS 328 CH (CH 3 ) CH 2

CH

2

CH

3 Cl Br H C Oil, MS 329 n-butyl C1 Me H C Oil, MS 330 CH (CH 3 ) CH 2

CH

2

CH

3 Cl Me H C Oil, MS 331 n-butyl C1 CF 3 H C Oil, MS 332 3,4-difluorobenzyl Cl CF 3 H C 108-110 333 CH (Et) CH 2

CH

2

CH

3 C1 CF 3 H C Oil, MS 334 CH (CH 3 ) CH 2

CH

2

CH

3 Cl CF 3 H C Oil, MS 335 CH (Et) CH 2

CH

2

CH

3 Cl C1 H C Oil, MS 336 CH(CH 3

)CH

2

CH

2

CH

3 C1 C1 H C 105-107 -111- WO 99/10350 PCT/US98/17049 TABLE 3 (Continued) Ex. RI R 2

R

3

R

4 X mp °C 337 n-butyl Cl Cl H C Oil, MS 338 CH 2

CH

2 CH (CH 3 ) 2 C1 C1 H C Oil, MS 339 CH 2 CH (CH 2

CH

3 ) 2 Cl C1 H C Oil, MS 340 benzyl C1 Cl H C Oil, MS 341 3,4-difluorobenzyl Cl C1 H C 124-125 342 CH 2 -(2-tetrahydropyran) Cl Cl H C 100-101 343 CH(CH3)CH2CH(CH3)2 Cl C1 H C Oil, MS 344 n-butyl Et Br Et C 54-55 345 CH 2

CH

2 CH (CH 3 ) 2 Et Br Et C Oil, MS 346 CH 2 CH (CH 2

CH

3 ) 2 Et Br Et C Oil, MS 347 benzyl Et Br Et C Oil, MS 348 3,4-difluorobenzyl Et Br Et C Oil, MS 349 CH 2 -(2-tetrahydropyran) Et Br Et C Oil, MS 350 CH (Et) CH 2

CH

2

CH

3 Et Br Et C 70-72 351 CH (CH 3 ) CH 2 CH (CH 3 ) 2 Et Br Et C 91-93 352 CH (CH 3 ) CH 2

CH

2

CH

3 Et Br Et C 82-84 353 n-butyl C1 OMe H C Oil, MS 354 n-butyl OMe OMe H C Oil, MS 355 n-butyl OMe Br H C Oil, MS 356 CH (CH 3 ) CH 2

CH

2

CH

3 C1 OMe C1 C Oil, MS 357 CH (CH 3 ) CH 2

CH

2

CH

3 OMe Cl C1 C Oil, MS 358 CH (CH 3 ) CH 2

CH

2

CH

3 Br OMe H C 359 CH (CH 3 ) CH 2

CH

2

CH

3 Br OMe Cl C 360 CH (CH 3 ) CH 2

CH

2

CH

3 Br OMe OMe C 361 CH (CH 3 ) CH 2

CH

2

CH

3 Me OMe H C 362 CH (CH 3 ) CH 2

CH

2

CH

3 Me OMe C1 C 363 CH (CH 3 ) CH 2

CH

2

CH

3 C1 OMe OMe N 364 benzyl H OMe OMe N 365 n-butyl H OMe OMe N 366 CH 2 cPr H OMe OMe N 367 CH 2 CH (CH 2

CH

3 ) 2 H OMe OMe N 368 CH (CH 3 ) CH 2

CH

2 CH3 H OMe OMe N 369 3,4-difluorobenzyl H OMe OMe N 370 CH 2 cPr Me Me Me N 371 CH 2 CH (CH 2

CH

3

)

2 Me Me Me N 372 CH (CH 3 ) CH 2

CH

2

CH

3 Me Me Me N 373 3,4-difluorobenzyl Me Me Me N 374 CH 2 cPr Me Me H N 375 CH 2 CH (CH 2

CH

3

)

2 Me Me H N 376 CH (CH 3 ) CH 2

CH

2

CH

3 Me NMe 2 H N 377 3,4-difluorobenzyl Me NMe 2 H N -112- WO 99/10350 PCT/US98/17049 TABLE 3 (Continued) Ex. RI R2 R3 R4 X mp °C 378 n-pentyl Et Me Et C 379 benzyl Et Me Et C 380 n-pentyl H Me Me N 381 benzyl H Me Me N 382 n-pentyl H NMe 2 Me N 383 benzyl H NMe 2 Me N 384 n-pentyl CF 3 NMe 2 H C 385 benzyl CF 3 NMe 2 H C 386 n-pentyl Me NMe 2 H C 387 benzyl Me NMe 2 H C 388 n-pentyl Br NMe 2 H C 389 benzyl Br NMe 2 H C 390 n-pentyl Br iPr OMe C 391 benzyl Br iPr OMe C 392 n-pentyl Br SMe H C 393 benzyl Br SMe H C 394 n-pentyl Br SOMe H C 395 benzyl Br SO 2 Me H C 396 n-butyl Me Br H C Oil, MS 397 3,4-difluorobenzyl Me Br H C 127-129 398 CH (CH 3 ) CH 2

CH

2

CH

3 Me Br H C Oil, MS 399 CH(Et)CH 2

CH

2

CH

3 Me Br H C Oil, MS 400 n-butyl

CF

3 Br H C 78-80 401 3,4-difluorobenzyl CF 3 Br H C 105-107 402 CH (CH 3 ) CH 2

CH

2

CH

3

CF

3 Br H C 51-53 403 CH (Et) CH 2

CH

2

CH

3

CF

3 Br H C Oil, MS 404 n-butyl Br Me F C 405 3,4-difluorobenzyl Br Me H C 406 CH (CH 3 ) CH 2

CH

2

CH

3 OMe Me H C 407 CH (Et) CH 2

CH

2

CH

3 COMe Me H C 408 n-butyl Me COMe H C 409 3,4-difluorobenzyl Me COMe Me C 410 CH (CH 3 ) CH 2

CH

2

CH

3 C1 COMe H C 411 CH (Et) CH 2

CH

2

CH

3 Cl COMe C1 C 412 n-butyl Cl Ph H C 413 3,4-difluorobenzyl Cl Ph OMe C 414 CH (CH 3 ) CH 2

CH

2

CH

3 C1 CO 2 Me Cl C 415 CH (Et) CH 2

CH

2

CH

3 C1 OCOMe Cl C -113- WO99/10350 PCT/US98/17049 Examples 416-452 given in TABLE 4 may be prepared from compounds of formula R 3

(NH

2 )C=C(CN)H where R 3 is Me and the appropriate hydrazine of formula R 4

NHNH

2 , where

R

4 corresponds to the substitutions exemplified in Table 5 4 to give initially compounds of formula (III). Conversion to compounds of formula (I) may then follow the preparation detailed for Examples 38 and 164. -114- WO 99/10350 PCT/US98/17049 TABLE 4 'R N N3 sR R3 Ex. R 1

R

2 R R 3

R

5 rMp oC 416 n-butyl Cl H Cl H Oil, MS 417 CH 2

CH

2

CH(CH

3 ) 2 C1 H Cl H Oil, MS 418 CH 2

CH(CH

2

CH

3

)

2 C1 H C1 H Oil, MS 419 benzyl Cl H C1 H 113-114 420 3,4-difluorobenzyl C1 H C1 H Oil, MS 421 CH 2 -(2-tetrahydropyran) C1 H C1 H 125-126 422 CH(CH 2

CH

3

)(CH

2

CH

2

CH

3 ) C1 H Cl H Oil, MS 423 CH(CH 3

)CH

2

CH(CH

3 ) 2 Cl H C1 H Oil, MS 424 CH(CH 3

)CH

2

CH

2

CH

3 C1 H C1 H Oil, MS 425 n-butyl H C1 C1 C1 Oil, MS 426 CH 2

CH

2

CH(CH

3 ) 2 H Cl Cl C1 Oil, MS 427 CH 2

CH(CH

2

CH

3

)

2 H C1 C1 C1 Oil, MS 428 benzyl H C1 C1 Cl Oil, MS 429 3,4-difluorobenzyl H C1 C1 C1 Oil, MS 430 CH 2 -(2-tetrahydropyran) H C1 C1 C1 Oil, MS 431 n-butyl Cl C1 C1 H Oil, MS 432 CH 2

CH

2

CH(CH

3

)

2 Cl Cl C1 H Oil, MS 433 CH 2

CH(CH

2

CH

3

)

2 C1 Cl Cl H Oil, MS 434 benzyl Cl C1 C1 H 153-155 435 3,4-difluorobenzyl C1 C1 C1 H Oil, MS 436 CH 2 -(2-tetrahydropyran) C1 C1 C1 H Oil, MS 437 CH (CH 2

CH

3 ) (CH 2

CH

2

CH

3 ) Cl Cl Cl H Oil, MS 438 CH(CH 3

)CH

2

CH(CH

3

)

2 Cl C1 C1 H Oil, MS 439 CH (CH 3 ) CH 2

CH

2

CH

3 C1 C1 C1 H Oil, MS 440 benzyl Br Me F H 441 CH(CH 3

)CH

2 CH (CH 3

)

2 Br Me F H 442 CH(CH 3

)CH

2

CH

2

CH

3 Me Br F H 443 benzyl Me Me F Me 444 CH (CH 3 ) CH 2 CH (CH 3

)

2 Cl Me F Me 445 CH (CH 3 ) CH 2

CH

2

CH

3 Cl Cl F H 446 benzyl Me Br C1 H 447 CH(CH 3 ) CH 2

CH(CH

3 ) 2 Me Me Me H 448 CH (CH 3 ) CH 2

CH

2

CH

3 C1 Me Me H 449 benzyl Cl Br Me H 450 CH(CH 3

)CH

2

CH(CH

3

)

2 Me Cl Me H 451 CH (CH 3 ) CH 2

CH

2

CH

3 H OMe Me Me 452 benzyl Cl NO 2 C1 H -115- WO 99/10350 PCT/US98/17049 Examples 453-471 given in TABLE 5 may be preferably prepared by treatment of compounds of formula (I, R 3 is OH or SH) with a base such as, but not limited to, potassium hydroxide in a solvent such as acetone or 5 other inert solvent with a reagent R 10 -X where X is a leaving group (vide supra). These product compounds arise via the tautomeric nature of compounds of formula (I) where R 3 is OH or SH. 10 TABLE 5 O N 'R- 1N-Rio N N

R

4 Example R I Rio R 3 mp oC 453 Me H 2,4,6-trimethylphenyl 454 Me Me 2,4,6-trichlorophenyl 455 Me CH 2 cPr 4-chloro-2,6-dibromophenyl 456 Me COPh 2-bromo-4,6-dichlorophenyl 457 Et H 2,4,6-trimethylphenyl 458 Et Me 2,4,6-trichlorophenyl 459 Et Et 2,4,6-trichlorophenyl 460 Et i-Pr 2,4,6-trichlorophenyl 461 Et c-Pr 2,4,6-trichlorophenyl 462 Et n-Pr 2,4,6-trichlorophenyl 463 Et CH 2 cPr 2,4,6-trichlorophenyl 464 Et c-pentyl 2,4,6-trichlorophenyl 465 Et CH 2 cPr 4-chloro-2,6-dibromophenyl 466 Et COPh 2-bromo-4,6-dichlorophenyl 467 Et Me 2,4,6-trimethylphenyl 468 Et Me 4-chloro-2,6-dibromophenyl 469 Et Me 2-bromo-4,6-dichlorophenyl 470 Ph Me 2,4,6-trimethylphenyl 471 Ph CH 2 cPr 2,4,6-trichlorophenyl 15 -116- WO99/10350 PCT/US98/17049 Utility CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity 5 The following is a description of the 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. 10 Messenger RNA was isolated from human hippocampus. The mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from start to stop codons The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from whence the insert was 15 reclaimed using XhoI + XbaI and cloned into the XhoI + XbaI sites of vector pm3ar ( which contains a CMV promoter, the SV40 't' splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker). The resulting expression 20 vector, called phchCRFR was transfected in 293EBNA cells and cells retaining the episome were selected in the presence of 400 pM hygromycin. Cells surviving 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for 25 the binding assay described below. Individual aliquots containing approximately 1 x 108 of the suspended cells were then centrifuged to form a pellet and frozen. For the binding assay a frozen pellet described above containing 293EBNA cells transfected with hCRFR1 30 receptors is homogenized in 10 ml of ice cold tissue buffer ( 50 mM HEPES buffer pH 7.0, containing 10 mM MgC12, 2 mM EGTA, 1 gg/l aprotinin, 1 gg/ml leupeptin and 1 gg/ml pepstatin). The homogenate is centrifuged at 40,000 x g for 12 min and the resulting pellet -117- WO99/10350 PCTIUS98/17049 rehomogenized in 10 ml of tissue buffer. After another centrifugation at 40,000 x g for 12 min, the pellet is resuspended to a protein concentration of 360 gg/ml to be used in the assay. 5 Binding assays are performed in 96 well plates; each well having a 300 pl capacity. To each well is added 50 p.l of test drug dilutions (final concentration of drugs range from 10

-

10 - 10 -5 M), 100 gl of 1 25 ovine-CRF ( 125 I-o-CRF) (final concentration 150 pM) and 10 150 p.l of the cell homogenate described above. Plates are then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (presoaked with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed 2 times 15 with ice cold assay buffer before removing individual filters and assessing them for radioactivity on a gamma counter. Curves of the inhibition of 125 I-o-CRF binding to cell membranes at various dilutions of test drug are 20 analyzed by the iterative curve fitting program LIGAND [P.J. Munson and D. Rodbard, Anal. Biochem. 107:220 (1980), which provides Ki values for inhibition which are then used to assess biological activity. A compound is considered to be active if it has a 25 Ki value of less than about 10000 nM for the inhibition of CRF. Inhibition of CRF-Stimulated Adenvlate Cvclase 30 Inhibition of CRF-stimulated adenylate cyclase activity can be performed as described by G. Battaglia et al. Synapse 1:572 (1987). Briefly, assays are carried out at 370 C for 10 min in 200 ml of buffer -118- WO99/10350 PCT/US98/17049 containing 100 mM Tris-HC1 (pH 7.4 at 370 C), 10 mM MgC12, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 5 mM guanosine 5'-triphosphate, 100 nM oCRF, antagonist peptides (concentration range 10 -9 to 10

-

6 m) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions are initiated by the addition of 1 mM ATP/ 32 P]ATP (approximately 2-4 mCi/tube) and 10 terminated by the addition of 100 ml of 50 mM Tris HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 p1l of

[

3 H]cAMP (approximately 40,000 dpm) is added to each tube prior to separation. The separation of [ 32 PlcAMP 15 from [ 32 P]ATP is performed by sequential elution over Dowex and alumina columns. In vivo Biological Assay The in vivo activity of the compounds of the 20 present invention can be assessed using any one of the biological assays available and accepted-within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models 25 useful for the testing of compounds of the present invention have been outlined in C.W. Berridge and A.J. Dunn Brain Research Reviews 15:71 (1990). Compounds may be tested in any species of rodent or small mammal. 30 Compounds of this invention have utility in the treatment of inbalances associated with abnormal levels of corticotropin releasing factor in patients suffering treating psychiatric disorders and 35 neurological diseases including major depression, -119- WO99/10350 PCT/US98/17049 anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity 5 associated with psychopathological disturbance and stress. Compounds of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent's site of 10 action in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, 15 but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. The dosage administered will vary depending on 20 the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and 25 desired effect. For use in the treatment of said diseases or conditions, the compounds of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in 30 divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect. Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg 35 of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be -120- WO 99/10350 PCT/US98/17049 present in an amount of about 0.5 to 95% by weight based on the total weight of the composition. The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and 5 powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations. Gelatin capsules can be used to contain the 10 active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained 15 release products to provide for continuous release of medication over a period of time. Compressed tablets 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 20 disintegration of the tablet in the gastrointestinal tract. Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance. 25 In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral 30 administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are 35 suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral -121- WO99/10350 PCTIUS98/17049 solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in 5 "Remington's Pharmaceutical Sciences", A. Osol, a standard reference in the field. Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: 10 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 15 lactose, 50 mg cellulose, and 6 mg magnesium stearate. Soft Gelatin CaDsules A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is 20 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. 25 Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of 30 microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption. -122- WO99/10350 PCT/US98/17049 The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease. 5 Although the present invention has been described and exemplified in terms of certain preferred embodiments, other embodiments will be apparent to those skilled in the art. The invention is, therefore, not limited to the particular embodiments 10 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. -123-

Claims (7)

1-6 substituents independently selected at each 25 occurrence from C1-C6 alkyl, C3-C6 cycloalkyl, halogen, C1-C4 haloalkyl, cyano, nitro, OR 12 , thiol, S(O)nR 9 , COR 12 , CO2R 12 , NR 8 COR 12 , NRSCONR 11 R 1 2 , NR 8 C02R 9 , NR 11 R 12 , and CONR 11 R 12 ; (3) aryl, aryl(C1-C4 alkyl), heteroaryl or 30 heteroaryl(C1-C4 alkyl), heterocyclyl, or heterocyclyl(C1-C4 alkyl; -126- WO 99/10350 PCT/US98/17049 R 8 is independently at each occurrence selected from H, C1-C4 alkyl, C3-C8 alkenyl, C3-C 6 cycloalkyl, or C4-C7 cycloalkylalkyl; 5 or phenyl or phenyl(Cl-C4 alkyl), each optionally substituted with 1-3 substitutents selected from C1-C4 alkyl, halogen, Cl-C4 haloalkyl optionally substituted with 1-6 halogens, C1-C4 alkoxy, OH; 10 R 9 is independently at each occurrence selected from H, Cl-C4 alkyl, C2-C4 alkoxyalkyl, C3-C6 cycloalkyl, C4-C7 cycloalkylalkyl; or 15 phenyl or phenyl(Cl-C4 alkyl), each optionally substituted with 1-3 substitutents selected from Cl-C4 alkyl, halogen, C1-C4 haloalkyl optionally substituted with 1-6 halogens, C1-C4 alkoxy, OH; 20 R1 0 is H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C8 alkoxyalkyl, C 3 -C6 cycloalkyl, C4-C12 cycloalkylalkyl, aryl, aryl(Cl-C4 alkyl), heteroaryl, heteroaryl(C1-C4 alkyl), heterocyclyl, heterocyclyl(Cl-C4 alkyl), where C1-C4 haloalkyl is 25 optionally substituted with 1 to 6 halogens; R 11 and R 12 are independently at each occurrence selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, C4 C7 cycloalkylalkyl, or CI-C4 haloalkyl optionally 30 substituted with 1-6 halogens; or phenyl or phenyl(Cl-C4 alkyl), each optionally substituted with 1-3 substitutents selected from -127- WO99/10350 PCT/US98/17049 C1-C4 alkyl, halogen, C1-C4 haloalkyl optionally substituted with 1-6 halogens, C1-C4 alkoxy, OH; aryl is phenyl or naphthyl, each optionally substituted 5 with 1 to 5 substituents independently selected at each occurrence from R 13 ; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, 10 thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, 2,3 dihydrobenzofuranyl, 2,3- dihydrobenzothienyl, or indazolyl, each optionally substituted with 1 to 4 15 substituents independently selected from at each occurrence R13; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 20 substituents independently selected at each occurrence from R 13 ; R 13 is independently at each occurrence selected from Cl-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 25 cycloalkyl, C4-C12 cycloalkylalkyl, where C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C6 cycloalkyl, C4-C12 cycloalkylalkyl are optionally substituted with 1-3 substituents independently selected at each occurrence from Cl-C4 alkyl, 30 nitro, halogen, cyano, NR 8 R 9 , NR 8 COR 9 , NR 8 CO2R 9 , COR 9 , OR 9 , CONR 8 R 9 , NR 8 CONR 8 R 9 , CO2R 9 , thiol, or S(O)nR 9 or -128- WO99/10350 PCT/US98/17049 nitro, halogen, cyano, C1-C4 haloalkyl optionally substituted with 1-6 halogens, NR 8 R 9 , NR 8 COR 9 , NR 8 C02R 9 , COR 9 , OR 9 , CONR 8 R 9 , NR 8 CONR 8 R 9 , C02R 9 , thiol, or S(O)nR 9 ; 5

2. A compound of claim 1 and and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts thereof wherein: R 4 is phenyl, pyridyl 10 or pyrimidyl, each optionally substituted by 1 to 4 R 5 groups.

3. A compound of claim 2 and isomers thereof, stereoisomeric forms thereof, or mixtures of 15 stereoisomeric forms thereof, and pharmaceutically acceptable salts thereof wherein: R 1 is selected from H, CI-C6 alkyl, C1-C6 haloalkyl, where such haloalkyl is substituted with 1-6 halogens, C3-C6 cycloalkyl, or aryl. 20

4. A compound of claim 3 and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts thereof wherein: R 1 is selected from 25 H, C1-C6 alkyl, C1-C6 haloalkyl, where such haloalkyl is substituted with 1-6 halogens, C3-C6 cycloalkyl, or aryl and R 4 is phenyl, pyridyl or pyrimidyl, each optionally substituted by 1 to 4 R 5 groups. 30 5. A compound of claim 1 and and isomers thereof, stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, and pharmaceutically acceptable salts thereof, selected from the group -129- WO 99/1 0350 PCTIUS98/1 7049 1- (2-chloro-4-trifluorornethyl)phenyl-5-ethyl-3-methyl-4 [1-(l-methyl)butanelirnidazo[4,5-clpyrazole; 5 1- (2-chloro-4-trifluoromethyl)phenyl-5--ethyl-4-[1- (1 ethyl)butane] -3-methylimidazo[4, 5-clpyrazole; 4- (n-butyl) -1-(2-chloro-4-bromo)phenylL-5-ethyl-3 methylirnidazo [4, 5-c] pyrazole; 10 1- (2-chloro-4-bromo)phenyl-5-ethyl-3-methyl-4-[1- (1 methyl) butane] imidazo [4, 5-c] pyrazole; 1-(2-chloro-4-brorno)phenyl-5-ethyl-4-[1- (1 15 ethyl)butane] -3-inethylimidazo [4, 5-c] pyrazole;

5-ethylL-3-fluoroinethyl-4- [1- (1-rethyl)butane -1- (2,4,6 trichioro) phenyllinidazo [4, 5-c] pyrazole; 20 5-ethyl-4-[1-Cl-methyl)butane]-l-(2,4,6 trichioro) phenylimidazo [4, 5-c] pyrazole; 1- (2, 6-dichloro--4-broro)phenyl-5-ethyl-4-[1- (1 ethyl)butane] -3-inethylimidazo[4, 5-clpyrazole; 25 1- (2,4-dichloro)phenyl-5-ethyl-4- [1-(l-ethyl)butane] -3 methylimidazo [4, 5-c] pyrazole; 1- (2,4-dichloro)phenyl-5-ethyl-3-methyl-4-[1- (1 30 iethyl)butane] iridazo[14, 5-c] pyrazole; 1- (2,4-dichloro)phenyl-5-ethyl-3-methyl-4-[l-(l,3 diinethyl)butane] iiidazo[4, 5-cipyrazole; 35 1- (2,6-dichloro-4-bromo)phenyl-5-ethyl-3-methyl-4-[l-(l methyl) butane] imidazo [4, 5-c] pyrazole; -130- WO 99/10350 PCT/US98/17049 5-ethyl-4-[l-(l-ethyl)butane]-3-methyl-1-(2,4,5 trichloro)phenylimidazo[4,5-c]lpyrazole; 5 5-ethyl-3-methyl-4-[-(1-methyl)butane]-l-(2,4,5 trichloro)phenylimidazo[4,5-c] pyrazole; 5-ethyl-4- [1- (1-methyl)pentane] -3-methyl-l- (2,4,6 trichloro)phenylimidazo[4,5-c]pyrazole; 10 1-(2-bromo-4-isopropyl)phenyl-5-ethyl-4- [1- (1 ethyl)butane] -3-methylimidazo[4,5-c]lpyrazole; 1-(2-bromo-4-isopropyl)phenyl-5-ethyl-3-methyl-4- [1- (1 15 methyl)butanel imidazo[4,5-c]pyrazole; 1-(2-bromo-4,6-dichloro)phenyl-5-ethyl-4 -[1- (1 ethyl)butane] -3-methylimidazo[4,5-c] pyrazole; 20 1-(2-bromo-4,6-dichloro)phenyl-5-ethyl-3-methyl-4-[- (1 methyl)butane] imidazo[4,5-c] pyrazole; 4-(n-butyl) -1- (2,6-dichloro-4-bromo)phenyl-5-ethyl-3 methylimidazo[4,5-c] pyrazole; 25 1-(2,6-dichloro-4-bromo)phenyl-5-ethyl-3-methyl-4-[l-(3 methyl)butane] imidazo[4,5-c] pyrazole; 1-(2,6-dichloro-4-bromo)phenyl-5-ethyl-4- [1- (2 30 ethyl)butane] -3-methylimidazo[4,5-c] pyrazole; 4-benzyl-1- (2,6-dichloro-4-bromo)phenyl-5-ethyl-3 methylimidazo[4,5-c] pyrazole; and 35 1-(2,6-dichloro-4-bromo)phenyl-4-(3,4-difluorobenzyl)-5 ethyl-3-methylimidazo[4,5-c] pyrazole. -131- WO99/10350 PCT/US98/17049

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claims 5 1, 2, 3, 4 or 5.

7. A method of treating affective disorder, anxiety, depression, headache, irritable bowel syndrome, post traumatic stress disorder, supranuclear palsy, immune 10 suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency 15 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, 20 including but not limited to disorders induced or facilitated by CRF, in mammals, comprising: administering to the mammal a therapeutically effective amount of a compound of claims 1, 2, 3, 4 or 5. 25 -132-