CA2291115A1 - Substituted pyrazoles as p38 kinase inhibitors - Google Patents

Substituted pyrazoles as p38 kinase inhibitors Download PDF

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CA2291115A1
CA2291115A1 CA002291115A CA2291115A CA2291115A1 CA 2291115 A1 CA2291115 A1 CA 2291115A1 CA 002291115 A CA002291115 A CA 002291115A CA 2291115 A CA2291115 A CA 2291115A CA 2291115 A1 CA2291115 A1 CA 2291115A1
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pyrazol
methyl
alkyl
pyridine
fluorophenyl
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Ashok Anantanarayan
Michael Clare
Paul W. Collins
Joyce Zuowu Crich
Rajesh Devraj
Daniel L. Flynn
Lifeng Geng
Gunnar J. Hanson
Francis J. Koszyk
Shuyuan Liao
Richard A. Partis
Shashidhar N. Rao
Shaun Raj Selness
Michael S. South
Michael A. Stealey
Richard M. Weier
Xiangdong Xu
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GD Searle LLC
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Abstract

A class of pyrazole derivatives is described for use in treating p38 kinase mediated disorders. Compounds of particular interest are defined by Formula (I) wherein R1, R2, R3 and R4 are as described in the specification.

Description

DEMANDES OU BREVETS VOLUMtNEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET
COMPREND PLUS D'UN TOME.
CECI EST LE TOME ~-DE -NOTE. Pour les tomes additionels, veuillez contacier le Bureau canadien des brevets -' TNIS SECTION OF THE APPL1CAT10N1PATE3YT CONTAINS MORE
THAiV ONE VOLUME
THIS IS VOLUME ~ OF ~_ f110TE: For additional voi~rmes~please contact 'the Canadian Patent Office -SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS
Cross-Reference to Related Application This application claims priority from U.S.
Provisional Application Serial No. 60/047,570 filed May 22, 1997.
Field of the Invention This invention relates to a novel group of pyrazole compounds, compositions and methods for treating p38 kinase mediated disorders.
Background of the Invention Mitogen-activated protein kinases (MAP) is a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. The kinases are activated by a variety of signals including nutritional and osmotic stress, W light, growth factors, endotoxin and inflammatory cytokines. The p38 MAP kinase group is a MAP family of various isoforms, including p38a, p38~i and p38y, and is responsible for phosphorylating and activating transcription factors (e. g. ATF2, CHOP and MEF2C) as well as other kinases (e.g. MAPKAP-2 and MAPKAP-3). The p38 isoforms are activated by bacterial lipopolysaccharide, physical and chemical stress and by pro-inflammatory cytokines, including tumor necrosis factor (TNF-a) and interleukin-1 (IL-1). The products of the p38 phosphorylation mediate the production of inflammatory cytokines, including TNF
and IL-1, and cyclooxygenase-2.
TNF-a is a cytokine produced primarily by activated monocytes and macrophages. Excessive or unregulated TNF
production has been implicated in mediating a number of diseases. Recent studies indicate that TNF has a causative role in the pathogenesis of rheumatoid WO 98/52940 PC1'/US98/10436 arthritis. Additional studies demonstrate that inhibition of TNF has broad application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.
TNF has also been implicated in viral infections, such as HIV, influenza virus, and herpes virus including .
herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.
IL-8 is another pro-inflammatory cytokine, which is produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes, and is associated with conditions including inflammation.
IL-1 is produced by activated monocytes and macrophages and is involved in the inflammatory response.
IL-1 plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption.
TNF, IL-1 and IL-8 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines by inhibition of the p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states.
Various pyrazoles have previously been described.
U.S. Patent No. 4,000,281, to Beiler and Binon, describes 4,5-aryl/heteroaryl substituted pyrazoles with antiviral activity against both RNA and DNA viruses such as myxoviruses, adenoviruses, rhinoviruses, and various viruses of the herpes group. WO 92/19615, published November 12, 1992, describes pyrazoles as novel fungicides. U. S. Patent No. 3,984,431, to Cueremy and Renault, describes derivatives of,pyrazole-5-acetic acid as having anti-inflammatory activity. Specifically, [1-isobutyl-3,4-diphenyl-1H-pyrazol-5-yl]acetic acid is described. U. S. Patent No. 3,245,093 to Hinsgen et al, describes a process for preparing pyrazoles. WO
' 83/00330, published February 3, 1983, describes a new process for the preparation of diphenyl-3,4-methyl-5-pyrazole derivatives. WO 95/06036, published Ldarch 2, 1995, describes a process for preparing pyrazole derivatives. US patent 5,589,439, to T. Goto, et al., describes tetrazole derivatives and their use as herbicides. EP 515,041 describes pyrimidyl substituted pyrazole derivatives as novel agricultural fungicides.
Japanese Patent 4,145,081 describes pyrazolecarboxylic acid derivatives as herbicides. Japanese Patent 5,345,772 describes novel pyrazole derivatives as inhibiting acetylcholinesterase.
Pyrazoles have been described for use in the treatment of inflammation. Japanese Patent 5,017,470 describes synthesis of pyrazole derivatives as anti- ' inflammatory, anti-rheumatic, anti-bacterial and anti-viral drugs. EP 115640, published Dec 30, 1983, describes 4-imidazolyl-pyrazole derivatives as inhibitors of thromboxane synthesis. 3-(4-Isopropyl-1-methylcyclohex-1-yl)-4-(imidazol-1-yl)-1H-pyrazole is specifically described. WO 97/01551, published Jan 16, 1997, describes pyrazole compounds as adenosine antagonists. 4-(3-Oxo-2,3-dihydropyridazin-6-yl)-3-phenylpyrazole is specifically described. U.S. Patent No. 5,134,142, to Matsuo et al. describes 1,5-diaryl pyrazoles as having anti-inflammatory activity.
U.S. Patent No. 5,559,137 to Adams et al, describes novel pyrazoles (1,3,4,-substituted) as inhibitors of cytokines used in the treatment of cytokine diseases.
Specifically, 3-(4-fluorophenyl)-1-(4-methylsulfinylphenyl)-4-(4-pyridyl)-SH-pyrazole is described. WO 96/03385, published February 8, 1996, describes 3,4-substituted pyrazoles, as having anti-StIBS~T~E SHEET (~1L~ ~

WO 98/52940 PCT/US98l10436 inflammatory activity. Specifically, 4-(1-ethyl-4-(4-pyridyl?-S-trifluoromethyl-1H-pyrazol-3-yl]benzenesulfonamide is described.
The invention's pyrazolyl compounds are found to show usefulness as p38 kinase inhibitors.
Description of the Invention A class of substituted pyrazolyl compounds useful in treating p38 mediated disorders is defined by Formula I:

R '~
s z N
N

R (I) wherein R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, -arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylaryiene, ' aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, 5 alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or R1 has the formula a25 ~ A26 -C-CCHZ) ~-IC-N
~R2~
(II) wherein:
i is an integer from 0 to 9;
R~5 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and RZ' is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkyiarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene,~
alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, .
arylcarbonylalkylene, alkoxycarbonylarylene, aryioxycarbanylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or R2' is -CHR~eR29 wherein RZe is alkoxycarbonyl, and R~9 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or R~6 and R~' together with the nitrogen atom to which they are attached form a heterocyele, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and - alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy;
and RZ is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl;
wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or R~ has the formula:
t pap hl R32 -C-~CH2)~- C 'N
~R33 R3~ R3 '" (III) wherein:
j is an integer from 0 to 8; and m is 0 or 1; and R3° and R31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R'~ is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
R" is selected from hydrogen, alkyl, -C (O) R35, -C (O) OR35, -SO~R'6, -C {O) NR3'R38, and -SOzNR39R'°, wherein R35, R3s ~ R3' ~ R3e r R39 and R'° are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R" is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or RZ is -CR'1R'2 wherein R" is aryl, and R'~ is hydroxy;
and R' is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, ,~o N , and 0 \R"3 N 0 ' (IV) (V) wherein R" is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;
and wherein the R' pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl,~cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR"R'S wherein R" is alkylcarbonyl or amino, and R'5 is alkyl or aralkyl; and R' is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R' is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy;
provided R' is not 2-pyridinyl when R' is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido; further provided RZ is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R' is hydrido; and further provided R' is not 5 methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof.
Compounds of Formula I would be useful for, but not 10 limited to, the treatment of any disorder or disease state in a human, or other mammal, which is excacerbated or caused by excessive or unregulated TNF or p38 kinase production by~such mammal. Accordingly, the present invention provides a method of treating a cytokine-mediated disease which comprises administering an effective cytokine-interfering amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
Compounds of Formula I would be useful for, but not limited to, the treatment of inflammation in a subject, and for use as antipyretics for the treatment of fever.
Compounds of the invention would be useful to treat arthritis, including but not limited to, rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis, gouty arthritis and other arthritic conditions. Such compounds would be useful for the treatment of pulmonary disorders or lung inflammation, including adult respiratory distress syndrome, pulmonary sarcoisosis, asthma, silicosis, and chronic pulmonary inflammatory disease. The compounds are also useful for the treatment of viral and bacterial infections, including sepsis, septic shock, gram negative sepsis, malaria, meningitis, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS)-, AIDS, ARC (AIDS
related complex), pneumonia, and herpesvirus. The WO 98/529d0 PC'T/US98/1Q436 compounds are also useful for the treatment of bone resorption diseases, such as osteoporosis, endotoxic shock, toxic shock syndrome, reperfusion injury, autoimmune disease including graft vs. host reaction and allograft rejections, cardiovascular diseases including ' atherosclerosis, thrombosis, congestive heart failure, and cardiac reperfusion injury, renal reperfusion injury, liver disease and nephritis, and myalgias due to infection. The compounds are also useful for the treatment of influenza, multiple sclerosis, cancer, diabetes, systemic lupus erthrematosis (SLE), skin-related conditions such as psoriasis, eczema, burns, dermatitis, keloid formation, scar tissue formation, and angiogenic disorders. Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, uveitis, ocular photophobia, and of acute injury to the eye tissue. Compounds of the invention also would be useful for treatment of angiogenesis, including neoplasia; metastasis; ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemaginomas, including invantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; diabetic nephropathy and cardiomyopathy; and disorders of the female reproductive system such as endometriosis. The compounds of the invention may also be useful for preventing the production of cyclooxygenase-2.
Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
The present compounds may also be used in co-therapies, partially or completely, in place of other conventional anti-inflammatories, such as together with steroids, cyclooxygenase-2 inhibitors, DMARD's, immunosuppressive agents, NSAIDs, 5-lipoxygenase inhibitors, LT84 antagonists and LTA4 hydrolase inhibitors.
As used herein, the term "TNF mediated disorder"
refers to any and all disorders and disease states in which TNF plays a role, either by control of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disorder mediated by TNF.
As used herein, the term "p38 mediated disorder"
refers to any and all disorders and disease states in which p38 plays a role, either by control of p38 itself, or by p38 causing another factor to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to p38, would therefore be considered a disorder mediated by p38.
As TNF-(3 has close structural homology with TNF-a (also known as cachectin) and since each induces similar biologic responses and binds to the same cellular receptor, the synthesis of both TNF-a and TNF-a are inhibited by the compounds of the present invention and ' thus are herein referred to collectively as "TNF" unless specifically delineated otherwise.
A preferred class of compounds consists of those compounds of Formula I wherein ' Rl is selected from hydrido, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower ' heterocyclyl, lower cycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower aralkyl, lower alkoxyalkyl, lower mercaptoalkyl, lower alkylthioalkylene, amino, lower alkylamino, lower arylamino, lower alkylaminoalkylene, and lower heterocyclylalkylene; or Rv has the formula R25 ~ F26 -C-~ CH2~ ,' IC-Pd ~~,27 cII>
wherein:
i is 0, 1 or 2; and R~5 is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, lower phenoxyalkylene, lower aminoalkyl, lower alkylaminoalkyl, lower phenoxyaminoalkyl, lower alkylcarbonylalkylene, lower phenoxycarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene; and R~6 is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkoxycarbonylalkylene, and lower alkylaminoalkyl; and R~' is selected from lower alkyl, lower cycloalkyl, lower alkynyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower cycloalkylalkylene, lower cycloalkenylalkylene, lower cycloalkylarylene, lower cycloalkylcycloalkyl, lower heterocyclylalkylene, lower alkylphenylene, lower alkylphenylalkyl, lower phenylalkylphenylene, lower alkylheterocyclyl, lower alkylheterocyclylalkylene, lower alkylheterocyclylphenylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl, lower alkoxyheterocyclyl, lower alkoxyalkoxyphenylene, lower phenoxyphenylene, lower phenylalkoxyphenylene, lower alkoxyheterocyclylalkylene, lower phenoxyalkoxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonylalkylene, lower aminoalkyl, lower alkylaminoalkylene, lower phenylaminocarbonylalkylene, lower alkoxyphenylaminocarbonylalkylene, lower aminocarbonyl~.lkylene, arylaminocarbonylalkylene, lower alkylaminocarbonylalkylene, lower phenylcarbonylalkylene, lower alkoxycarbonylphenylene, lower phenoxycarbonylphenylene, lower alkylphenoxycarbonylphenylene, lower phenylcarbonylphenylene, lower alkylphenylcarbonylphenylene, lower alkoxycarbonylheterocyclylphenylene, lower alkoxycarbonylalkoxylphenylene, lower heterocyclylcarbonylalkylphenylene, lower alkylthioalkylene, cycloalkylthioalkylene, lower alkylthiophenylene, lower phenylalkylthiophenylene, lower heterocyclylthiophenylene, lower phenylthioalklylphenylene, lower phenylsulfonylaminoalkylene, lower alkylsulfonylphenylene, lower alkylaminosulfonylphenylene; wherein said lower alkyl, lower cycloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower heterocyclylalkylene, lower alkylheterocyclylphenylene, lower alkoxyphenylene, lower phenoxyphenylene, lower phenylaminocarbonylalkylene, lower phenoxycarbonylphenylene, lower phenylcarbonylphenylene, lower alkylthiophenylene, lower heterocyclylthiophenylene, lower phenylthioalklylphenylene, and lower alkylsulfonylphenylene groups are optionally substituted ' with one or more radicals independently selected from 5 lower alkyl, halo, lower haloalkyl, lower alkoxy, keto, ~ amino, nitro, and cyano; or RZ' is -CHR'6R" wherein R'6 is lower alkoxycarbonyl , and R" is selected from lower phenylalkyl, lower phenylalkoxyalkylene, lower heterocyclylalkylene, lower 10 alkylheterocyclylalkylene, lower alkoxycarbonylalkylene, lower alkylthioalkylene, and lower phenylalkylthioalkylene; wherein said phenylalkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from lower alkyl 15 and nitro; or R~6 and R~' together with tY~e nitrogen atom to which they are attached form a 4-8 membered ring heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenoxyalkylene, lower alkoxyphenylene, lower alkylphenoxyalkylene, lower alkylcarbonyl, lower alkoxycarbonyl, lower phenylalkoxycarbonyl, lower alkylamino and lower alkoxycarbonylamino; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclylalkylene and lower phenoxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, lower alkyl and lower alkoxy; and RZ is~selected from hydrido, halogen, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, lower haloalkyl, lower hydroxyalkyl, 5- or 6-membered .
heterocyclyl, lower alkylheterocyclyl, lower heterocyclylalkyl, lower alkylamino, lower alkynylamino, phenylamino, lower heterocyclylamino, lower WO 98/52940 PCTlUS98I10.~3G
heterocyclylalkylamino, lower phenylalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkylaminoalkylamino, lower cycloalkyl, lower alkenyl, lower alkoxycarbonylalkyl, lower cycloalkenyl, lower -carboxyalkylamino, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonyl, alkoxycarbonylalkyl, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylsulfonyl, lower heterocyclyloxy, and lower heterocyclylthio; wherein the aryl, heterocylyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, lower alkyl, lower alkynyl, phenyl, 5- or 6-membered heterocyclyl, lower phenylalkyl, lower heterocyclylalkyl, lower epoxyalkyl, carboxy, lower alkoxy, lower aryloxy, lower phenylalkoxy, lower haloalkyl, lower alkylamino, lower alkylaminoalkylamino, lower alkynylamino, lower amino(hydroxyalkyl), lower heterocyclylalkylamino, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, and phenylsulfonyl; or RZ has the formula:

-C-~ CH2) ~ - C -N
p3~ R3 ~R33 "' (III) wherein:
j is 0, 1 or 2; and m is 0;
R'° and R'1 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R'Z is selected from hydrogen, alkyl, aralkyl, WO 98/52940 PC'TIUS98/10436 heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and ' heterocyclylcarbonylaminoalkylene; and S R33 is selected from hydrogen, alkyl, -C (O) R's, -C (O) OR'S, -SOZR'6, -C (O) NR"R'8, and -SOZNR39R.o;
wherein R'S is selected from alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl, cycloalkenylalkylene, heterocyclylalkylene, alkylarylene, alkylheterocyclyl, arylarylene, arylheterocyclyl, alkoxy, alkenoxy, alkoxyalkylene, alkoxyaralkyl, alkoxyarylene, aryloxyalkylene, aralkoxyalkylene, cycloalkyloxyalkylene, alkoxycarbonyl, heterocyclylcarbonyl, alkylcarbonyloxyalkylene, alkylcarbonyloxyarylene, alkoxycarbonylalkylene, alkoxycarbonylarylene, aralkoxycarbonylheterocyclyl, alkylcarbonylheterocyclyl, arylcarbonyloxyalkylarylene, and alkylthioalkylene;
wherein said aryl, heterocyclyl, aralkyl, alkylarylene, arylheterocyclyl, alkoxyarylene, aryloxyalkylene, cycloalkoxyalkylene, alkoxycarbonylalkylene, and alkylcarbonylheterocyclyl groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; or R'S is CFiR'eR'9 wherein R'e is arylsulfonylamino or alkylarylsulfonylamino, and R'9 is selected from aralkyl, amino, alkylamino, and aralkylamino; or R'S is -NRS°R51 wherein RS° is alkyl, and R51 is aryl;
and wherein R'6 is selected from alkyl, haloalkyl, aryl, heterocyclyl, cycloalkylalkylene, alkylarylene, alkenylarylene, arylarylene, aralkyl, aralkenyl, heterocyclylheterocyclyl, carboxyarylene, alkoxyarylene, alkoxycarbonylarylene, alkylcarbonylaminoarylene, alkylcarbonylaminoheterocyclyl, arylcarbonylaminoalkylheterocyclyl, alkylaminoarylene, alkylamino, alkylaniinoarylene, alkylsulfonylarylene, alkylsulfonylaralkyl, and arylsulfonylheterocyclyl;
wherein said aryl, heterocyclyl, cycloalkylalkylene, aralkyl, alkylcarbonylaminoheterocyclyl, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and wherein R" is selected from hydrogen and alkyl; and wherein R'e is selected from hydrogen, alkyl, alkenyl, aryl, heterocyclyl, aralkyl, alkylarylene, arylcycloalkyl', arylarylene, cycloalkylalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, aryloxyarylene, arylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylene, alkoxycarbonylarylene, alkylcarbonylcarbonylalkylene, alkylaminoalkylene, alkylaminoaralkyl, alkylcarbonylaminoalkylene, alkylthioarylene, alkylsulfonylaralkyl, and aminosulfonylaralkyl; wherein said aryl, heterocyclyl, aralkyl, and heterocyclylalkylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; or R'e is -CRS~RS' wherein R5~ is alkoxycarbonyl, and RS' is alkylthioalkylene; or R" and R'e together with the nitrogen atom to which they are attached form a heterocycle; and R'9 and R'° have the same definition as R~6 and R2' in claim 1; or R2 is -CRS'R55 wherein RS' is phenyl and R55 is hydroxy;
or R~ is selected from the group consisting of R57 N_ R56 I
N N
and ~Hp~k I 0 \~ CH2)k_ ~CH2~k _ (VI) (VII) (VIII) wherein k is an integer from 0 to 3; and R56 is. hydrogen or lower alkyl; and RS' is hydrogen or lower alkyl; or R56 and RS' form a lower alkylene bridge; and R58 is selected from hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, -C (O) R59, -S02R6°, and -C (O) NHR61;
wherein R59 is selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl; wherein said aryl, heterocyclyl, and aralkyl groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, vitro, and cyano; and wherein R6° is selected from alkyl, aryl, heterocyclyl, alkylarylene, alkylheterocyclyl, aralkyl, heterocyclylheterocyclyl, alkoxyarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, and arylsulfonylheterocyclyl; wherein said aryl, heterocyclyl, and aralkyl groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, vitro, and cyano; and s~rms~s~rc~~

wherein R61 is selected from alkyl, aryl, alkylarylene, and alkoxyarylene; wherein said aryl group is optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, 5 haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and R' is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, and N
~Ra3 (IV) 10 wherein R" is selected from hydrogen, lower alkyl, lower aminoalkyl, lower alkoxyalkyl, lower alkenoxyalkyl and lower aryloxyalkyl; and wherein the R' pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or 15 more radicals independently selected from lower alkylthio, lower alkylsulfonyl, aminosulfonyl, halo, lower alkyl, lower aralkyl, lower phenylalkenyl, lower phenylheterocyclyl, carboxy, lower alkylsulfinyl, cyano, lower alkoxycarbonyl, aminocarbonyl, lower 20 alkylcarbonylamino, lower haloalkyl, hydroxy, lower alkoxy, amino, lower cycloalkylamino, lower alkylamino, lower alkenylamino, lower alkynylamino, lower aminoalkyl, arylamino, lower aralkylamino, nitro, halosulfonyl, lower alkylcarbonyl, lower alkoxycarbonylamino, lower alkoxyphenylalkylamino, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyphenylalkylamino, hydrazinyl, lower alkylhydrazinyl, or -NR6~R6' wherein R6Z is lower alkylcarbonyl or amino, and R6' is lower alkyl or lower WO 98/52940 PC?/US98/10436 phenylalkyl; and R' is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, aryl selected from phenyl, biphenyl, and naphthyl, and 5- or 6- membered heterocyclyl; wherein the lower cycloalkyl, lower cycloalkenyl, aryl and 5-10 membered heterocyclyl groups of R' are optionally substituted with one or more radicals independently selected from lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl, halo, lower alkyl, lower alkynyl, lower alkoxy, lower aryloxy, lower aralkoxy, lower heterocyclyl, lower haloalkyl, amino, cyano, vitro, lower alkylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof .
A class of compounds of particular interest consists of these compounds of Formula I wherein R1 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methylthiomethyl; and R~ is selected from hydrido, chloro, fluoro, bromo, sua~rrns~s~r~rc~~~
methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, phenyl, biphenyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, ' difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxymethyl, hydroxyethyl, pyridinyl, isothiazolyl, isoxazolyl, thienyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, N-methylpiperazinyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-rnethylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-n-propylamino, N,N-dimethylamino, N-methyl-N-phenylamino, N-phenylamino, piperadinylamino, N-benzylamino, N-propargylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, N,N-dimethylaminoethylamino, N,N-dimethylaminopropylamino, morpholinylethylamino, morpholinylpropylamino, carboxymethylamino, methoxyethylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1,1-dimethylethoxycarbonyl, 1,1-dimethylethoxycarbonylaminoethylamino, 1,1-dimethylethoxycarbonylaminopropylamino, piperazinylcarbonyl, and 1,1-dimethylethoxycarbonylpiperazinylcarbonyl; wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, isopropyl, tert-butyl, isobutyl, benzyl, carboxy, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, dimethylamino, methoxycarbonyl, ethoxycarbonyl, and 1,1- ' dimethylethylcarbonyl; or R~ is -CRS'RSS wherein RS' is phenyl and RSS is hydroxy;
and R' is selected from pyridinyl, pyrimidinyl, and purinyl; wherein R' is optionally substituted with one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylainino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methyl-hydrazinyl, or -NR6~R6' wherein R6~ is methyl carbonyl or amino, and R6' is methyl, ethyl or phenylmethyl; and R' is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, $U~STITUTESi~'tR~Il.EQ6) biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoguinolinyl, imidazolyl, benzimidazolyl, furyl, ' pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, -benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R4 are optionally substituted with one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, vitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof.
Another class of compounds of particular interest consists of these compounds of Formula I wherein R1 is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl;
R~ is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, methoxycarbonylethyl, N,N-dimethylamino, N-phenylamino, piperidinyl, piperazinyl, pyridinyl, N-methylpiperazinyl, and piperazinylamino;
wherein the phenyl, piperidinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, methyl, ethyl, and trifluoromethyl;
R3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R' is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl;
R' is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, 5 dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R' are optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, 1C benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof.
15 A class of compounds of specific interest consists of those compounds of Formula I wherein Rl is hydrido or methyl;
RZ is selected from hydrido, methyl or ethyl;
R' is selected from pyridinyl, pyrimidinyl or 20 quinolinyl; wherein R' is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, 25 amino, hydroxy, and methylcarbonyl;
R' is selected from phenyl which is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof .
Still another class of compounds of particular interest consists of those compounds of Formula I wherein R1 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, -ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methylthiomethyl; and R2 has the formula:
R3p H R32 -C-~CH2)~- C -N
\x,33 q3~ R3 "' (III) wherein:
j is 0, 1 or 2; and m is 0; and R'° and R'1 are independently selected from hydrogen and lower alkyl;
R'~ is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, aryloxyalkylene, aminoalkyl, lower alkylaminoalkyl, lower phenylaminoalkyl, lower alkylcarbonylalkylene, lower phenylcarbonylalkylene, and -lower heterocyclylcarbonylaminoalkylene;
R" is selected from hydrogen, lower alkyl, -C(O)R'S, .
-C (O) OR'S, -SOzR36, -C (O) NR"R'e, and -SOzNR39R'°;
wherein R'S is selected from lower alkyl, lower cycloalkyl, lower haloalkyl, lower alkenyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower phenylcycloalkyl, lower cycloalkenylalkylene, lower heterocyclylalkylene, lower alkylphenylene, lower alkylheterocyclyl, phenylphenylene, lower phenylheterocyclyl, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower alkoxyphenylalkyl, lower alkoxyphenylene, lower phenoxyalkylene, lower phenylalkoxyalkylene, lower cycloalkyloxyalkylene, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkylcarbonyloxyalkylene, lower alkylcarbonyloxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower phenylalkoxycarbonylheterocyclyl, lower alkylcarbonylheterocyclyl, lower phenylcarbonyloxyalkylphenylene, and lower alkylthioalkylene; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylheterocyclyl, lower alkoxyphenylene, lower phenoxyalkylene, lower cycloalkoxyalkylene, lower alkoxycarbonylalkylene, and lower alkylcarbonylheterocyclyl groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano;
or R'S is CFiR'eR'9 wherein R'e is phenylsulfonylamino or lower alkylphenylsulfonylamino, and R'9 is selected from lower phenylalkyl, amino, lower alkylamino, and lower phenylalkylamino; or R's is -NRS°RS1 wherein RS° is lower alkyl, and R51 is aryl selected from phenyl, biphenyl and naphthyl; and wherein R'6 is selected from, lower alkyl, lower haloalkyl, aryl selected from phenyl, biphenyl and 8U8S~CmJTE Sl~i' (RIjLE 26~
naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower alkylphenylene, lower alkenylphenylene, phenylphenylene, lower phenylalkyl, lower phenylalkenyl, lower heterocyclylheterocyclyl, carboxyphenylene, lower -alkoxyphenylene, lower alkoxycarbonylphenylene, lower alkylcarbonylaminophenylene, lower -alkylcarbonylaminoheterocyclyl, lower phenylcarbonylaminoalkylheterocyclyl, lower alkylaminophenylene, lower alkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene, lower alkylsulfonylphenylalkyl, and lower phenylsulfonylheterocyclyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkylcarbonylaminoheterocyclyl, and lower alkylsulfonylphenylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, vitro, and cyano;
and wherein R" is selected from hydrogen and lower alkyl; and wherein R38 is selected from hydrogen, lower alkyl, lower alkenyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylcycloalkyl, phenylphenylene, lower cycloalkylalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower phenoxyphenylene, phenylcarbonyl, lower alkoxycarbonyl, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower alkylcarbonylcarbonylalkylene, lower alkylaminoalkylene, lower alkylaminophenylalkyl, lower alkylcarbonylaminoalkylene, lower alkylthiophenylene, ' lower alkylsulfonylphenylalkyl, and lower aminosulfonylphenylalkyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, and lower heterocyclylalkylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; or R'e is -CRS~RS' wherein RS~ is lower alkoxycarbonyl, and R53 is lower alkylthioalkylene; or R" and R'e together with the nitrogen atom to which they are attached form a 4-8 membered ring heterocycle;
R39 and R'° have the same definition as R~6 and Rz' in claim 2; or R~ is selected from the group consisting of N N
J
a nd C~HZ~k i 0 ~[CHZ)k_ CCH2~k _ (VI) (VII) (VIII) wherein k is an integer from 0 to 2; and R56 is hydrogen or lower alkyl; and RS' is hydrogen or lower alkyl; and Rse is selected from hydrogen, lower alkyl, lower phenylalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower heterocyclylalkyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, lower phenylsulfonyl, -C(O)RS', -S02R6°, and -C (O) NHR61;
wherein R59 is selected from lower alkyl, lower haloalkyl, lower cycloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower WO 98152940 PC'TIUS98/10436 alkylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower alkoxy, lower alkenoxy, loewr phenylalkoxy, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl; wherein said 5 aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, and lower phenylalkyl groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, 10 nitro, and cyano; and wherein R6° is selected from lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl,~lower alkylphenylene, lower alkylheterocyclyl, lower phenylalkyl, lower 15 heterocyclylheterocyclyl, lower alkoxyphenylene, lower alkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene, and lower phenylsulfonylheterocyclyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, 20 and lower phenylalkyl groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano;
and 25 wherein R61 is selected from lower alkyl, aryl selected from phenyl, biphenyl and napthyl, lower alkylphenylene, and lower alkoxyphenylene; wherein said aryl group is optionally substituted with one or more radicals independently selected from lower alkyl, halo, 30 hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and R' is selected from pyridinyl, pyrimidinyl, and purinyl; wherein R' is optionally substituted with one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, ' aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, t isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino,' benzylamino, phenethylamino, cyclopropylamino, vitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methyl-hydrazinyl, or -NR6~R6' wherein R62 is methylcarbonyl or amino, and R6' is methyl, ethyl or phenylmethyl; and R' is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of. R' are optionally substituted with one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, .
fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof.
Still another class of compounds of particular interest consists of those compounds of Formula I wherein R1 is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl;
RZ has the formula:

-C-[ CH2) ~ - C -N
a3i R3 \R33 '" (III) wherein:
j is 0, 1 or 2; and m is 0; and R'° is hydrogen; and R31 is selected from hydrogen and lower alkyl; and R32 is selected from hydrogen and lower alkyl; and R" is selected from lower alkyl, -C (O) R35, -C (O) OR's, -SOzR'6, -C(O)NR3'R'8, and -SOzNR'9R'°~
wherein R35 is selected from lower alkyl, lower cycloalkyl, phenyl, lower heterocyclyl, lower alkylphenylene, lower alkoxy, lower alkenoxy, lower -alkoxyalkylene, lower phenoxyalkylene, and lower phenylalkoxyalkylene; wherein said phenyl and lower phenoxyalkylene groups are optionally substituted with ~ET(RUt.EQ6) one or more radicals independently selected from lower alkyl, halo, and lower haloalkyl; and wherein R'6 is selected from lower alkyl, phenyl, lower heterocyclyl, lower alkylphenylene, phenylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene, and lower alkylamino; wherein said phenyl and lower heterocyclyl groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and wherein R" is hydrogen; and wherein R'8 is selected from lower alkyl, phenyl, and lower alkylphenylene;
wherein R'9 and R'° have the same definition as RZ6 and RZ' in claim 2 ; or R2 is selected from the group consisting of R5 N F756 ~' N
and c~
(C~..~Z~k- i 0 CCHZ)k_ ~CH~~k _ (VI) (VII) (VIII) wherein k is an integer from 0 or 1; and R56 is hydrogen; and RS' is hydrogen; and R58 is selected from -C (0) R59 and -SOzR6o;
wherein R59 is selected from lower alkyl, lower cycloalkyl, phenyl, lower alkylphenylene, and lower alkoxyalkylene; wherein said phenyl group is optionally substituted with one or more radicals independently gtl~~~) selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and wherein R6° is selected from lower alkyl; and R' is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R' is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and R' is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R' are optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof .
Still another class of compounds of specific interest consists of those compounds of Formula I wherein R1 is hydrido or methyl; and R' is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R' is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and R' is selected from phenyl which is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, 8~~1 ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof.

In one embodiment of the present invention, the compounds of Formula I satisfy one or more of the following conditions:
Rl is hydrido or lower alkyl; more preferably, R' is 10 hydrido or methyl; and still more preferably, R1 is hydrido;
RZ is hydrido or lower alkyl; more preferably, R~ is hydrido or methyl; and still more preferably, RZ is hydrido;
15 R' is substituted or unsubstituted pyridinyl; and preferably, the pyridinyl is a 4-pyridinyl; or R4 is substituted or unsubstituted phenyl; and preferably, R° is phenyl substituted with halo.
In addition, where R3 is substituted pyrimidinyl, 20 preferably at least one R3 substitutent is attached to the carbon atom positioned between two nitrogen atoms of the pyrimidinyl ring.
A family of specific compounds of particular 25 interest within Formula I consists of compounds, tautomers and pharmaceutically-acceptable salts thereof as follows:
4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
30 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
4-[5-methyl-3-(2-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-methyl-3-(4-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[5-methyl-3-[4-(methylthio)phenyl]-1H-pyrazol-4-35 yl]pyridine;
4-[3-(4-chlorohpenyl)-5-methyl-1H-pyrazol-4-yl)pyridine;
4-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[5-(2,5-dimethylphenyl)-3-methyl-1H-pyrazol-4 yl ] pyridine ;
4-(5-(1,3-benzodioxol-5-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-(4-phenoxyphenyl)-1H-pyrazol-4-yl]pyridine;
4-[5-[(1,1'-biphenyl)-4-yl]-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-[3-(phenoxyphenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-[3-(phenylmethoxy)phenyl]-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-[2-(phenylmethoxy)phenyl]-1H-pyrazol-4-yl]pyridine;
2-[3-methyl-4-(4-pyridinyl)-1H-pyrazol-4-yl]phenol;
3-[3-methyl-4-(4-pyridinyl)-1H-~pyrazol-4-yl]phenol;
1-hydroxy-4-(3-methyl-5-phenyl-IH-pyrazol-4-yl]pyridinium;
5-(4-fluorophenyl)-N, N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
5-(4-fluorophenyl)-N-phenyl-4-(4-pyridinyl)-1H-pyrazol-3-amine; 4-[5-(4-fluorophenyl)-3-phenyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)pyridine;4-[3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]pyridine;
4-(5-cyclohexyl)-3-methyl-1H-pyrazol-4-yl)pyridine;
4-(5-(3-fluoro-5-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl ] pyridine ;
4-[5-(3-methylphenyl)-3-propyl-1H-pyrazol-4-yl]pyridine;
4-[(3-methyl-5-phenyl-1H-pyrazol-4-yl)methyl]pyridine;
4-[3,5-bis(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[4-methyl-2-(2-trifluorophenyl)-1H-pyrazol-4-yl ] pyridine ;
4-(3-(2-chlorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-methyl-3-(2,4-dimethylphenyl)-1H-pyrazol-4-c~~~

WO 98152940 PC'f/US98I10436 yl]pyridine;
4-[5-(4-chlorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3,5-dimethylphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3,5-dimethoxyphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-methyl-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine;
N,N-dimethyl-4-[5-methyl-4-(4-pyridinyl)-1H-pyrazol-3 yl ] benzenamine ;
4-[3-(2,3-dihydrobenzofuran-5-yl)-5-methyl-1H-pyrazol-4-yl ] pyridine ;
4-[3-(4-bromophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(2-fluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3-fluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine;
4-(3-ethyl-4-phenyl-1H-pyrazol-4-yl)pyridine;
4-[5-(3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl}pyridine;
4-[3-ethyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[5-(3,4-difluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-ethoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4- [3-methyl-5- [4- (trifluoromethyl)phenyl] -1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-(3-thienyl)-1H-pyrazol-4-yl]pyridine;
4-[5-(2,4-dichlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-chloro-4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
ethyl 3-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazole-5-propanoate;
4-[3-(4-fluorophenyl)-1-methyl-pyrazol-4-yl]pyridine;

WO 98/52940 PCTlUS98/10436 5-[5-(3-chlorophenyl)-3-methyl-IH-pyrazol-4-yl]pyrimidin-2-amine;
5-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine;
5-[3-methyl-5-(2-methylphenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine; -5-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
5-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
5-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
5-[5-(3-chloi'ophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-Q-yl]pyridin-2-amine;
4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
2-methoxy-5-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
2-methoxy-5-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
2-methoxy-4-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4- ' yl]pyridine;
2-methoxy-4-[3-methyl-5-(2-methylphenyl)-1H-pyrazol-4-yl] pyridine;
4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
2-methoxy-4-[3-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl] pyridine;
5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-0l;
4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
4-I5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
4-[5-(2-methylphenyl)-3-methyl-IH-pyrazol-4-yl]pyridin-2-ol;
4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-0l;
4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-0l;
5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
40 PCT/US98/1Od36 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
5 4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-l0 2-carboxamide;
4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
15 4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(4-fluoro-3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl)pyridine;
4-[5-(4-chloro-3-methoxyphenyl)-3-methyl-1H-pyrazol-4-20 yl]pyridine;
4-[5-(2,3-dihydrobenzofuran-6-yl)-3-methyl-1H-pyrazol-4-yl] pyridine;
4-[5-(benzofuran-6-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-fluoro-5-methoxyphenyl)-3-methyl-1H-pyrazol-4-25 yl]pyridine;
4-[5-(3-chloro-5-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl ] pyridine ;
4-[5-(1-cyclohexyen-1-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
30 4-[5-(1,3-cyclohexadien-1-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(5,6-dihydro-2H-pyran-4-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-(5-cyclohexyl-3-methyl-1H-pyrazol-4-yl)pyridine;
35 4-[5-(4-methoxy-3-methylphenyl)-3-methyl-1H-pyrazol-4 yl]pyridine;

WO 98!52940 PCTIUS98J10436 4-[5-(3-methoxy-4-methy!phenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-methoxy-5-methy!phenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-fury!)-3-methyl-1H-pyrazol-4-yl]pyridine;
2-methyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
2-methoxy-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
methyl 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyri-dine-2-carboxylate;
4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxamide;
1-[4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridin-2-yl]ethanone; ' N,N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazol-2-yl)pyridin-2-amine;
3-methyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
3-methoxy-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
methyl 4-(3-methyl-5-phenyl-1H-pyrazol-4y1)pyridine-3-carboxylate;
4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;
1-[4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridin-3-yl]ethanone;
3-bromo-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
N,N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazol-2-yl)pyridin-3-amine;
2-methyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidine;
4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidine;
2-methoxy-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidine;
4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidin-2-amine;
N,N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidin-2-amine;
4-(5,6-dihydro-2H-pyran-4-yl)-3-methyl-5-phenyl-1H-pyrazole;
3-methyl-5-phenyl-4-(3-thienyl)-1H-pyrazole;
BV

WO 98152940 PC'T/US98110436 4-(3-furyl)-3-methyl-5-phenyl-1H-pyrazole;
3-methyl-5-phenyl-4-(2-thienyl)-1H-pyrazole;
4-(2-furyl)-3-methyl-5-phenyl-1H-pyrazole;
4-(3-isothiazolyl)-3-methyl-5-phenyl-1H-pyrazole 4-(3-isoxazolyl)-3-methyl-5-phenyl-1H-pyrazole;
4-(5-isothiazolyl)-3-methyl-5-phenyl-1H-pyrazole;
4-(5-isoxazolyl)-3-methyl-5-phenyl-1H-pyrazole;
3-methyl-5-phenyl-4-(5-thiazolyl)-1H-pyrazole;
3-methyl-4-(5-oxazolyl)-5-phenyl-1H-pyrazole;
4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
2-methyl-4-[3-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyridine;
4-(3-phenyl-1H-pyrazol-4-yl)pyridine;
2-methyl-4-(3-phenyl-1H-pyrazol-4-yl)pyridine;
4-[3-(3-chlorophenyl)-1-methyl-pyrazol-4-yl]pyridine;
4-[3-(4-chlorophenyl)-1-methyl-pyrazol-4-yl]pyridine;
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-2-methylpyridine;
4-(3-(3-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
4-(3-(3-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
4-(3-(3-chlorophenyl)-1-methyl-pyrazol-4-yl]-2-methylpyridine;
5-(4-chlorophenyl)-N-phenyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
5-(4-chlorophenyl)-N-methyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
5-(4-chlorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine dihydrate;
5-(3-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
N,N-dimethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine;
N-methyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine;
N-ethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-WO 98/529d0 PCT'/US98/10436 amine;
N,N-diethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine;
5-(4-chlorophenyl)- N,N-diethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
- 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]morpholine;
5-(4-chlorophenyl)-N-propyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
5-(4-chlorophenyl)-N-(phenylmethyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine hydrate (2:1);
5-(4-chlorophenyl)-N-(2-methoxyethyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine monohydrate;
1,1-dimethylethyl 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate;
1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine trihydrochloride;
1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4- ' methylpiperazine;
1,1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate;
1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine trihydrochloride;
1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine;
N- [5- (4-chlorophenyl) -4- [2- (phenylmethyl) amino] -4-pyridinyl]-1H-pyrazol-3-yl]-1,3-propanediamine, trihydrochloride;
1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(phenylmethyl)piperazine;
4-[3-(4-fluorophenyl)-5-(1-piperazinyl)-1H-pyrazol-4-yl]pyrimidine, dihydrochloride;
1,1-dimethylethyl [3-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]propyl]carbamate;
N-[5-[4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,3-propanediamine, trihydrochloride monohydrate;

WO 98/529d0 PCTIUS98110436 1, 1-dimethylethyl [2- [ [5- (4-chlorophenyl) -4- (4-pyridinyl)-1H-pyrazol-3-yl]amino]ethyl]carbamate;
1,1-dimethylethyl 4-[5-(4-chlorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate;
1,1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4-pyrimidinyl>-1H-pyrazol-3-yl]-1-piperazinecarboxylate;
1, 1-dimethylethyl [3- [ (5- (4-chlorophenyl) -4- (2-fluoro-4-pyridinyl)-1H-pyrazol-3-yl]amino]propyl]carbamate;
1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-ethylpiperazine;
N-(5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2-ethanediamine;
4-[3-(2,6-difluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3-ethylphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3-chlorophenyl)-5-ethyl-1H-pyrazol-4-yl]pyridine;
4-(3-ethyl-5-(3-ethylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-chlorophenyl)-5-(1-methylethyl)-1H-pyrazol-4-yl]pyridine;
4-[3-cyclopropyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-fluorophenyl)-5-(trifluoromethyl)-IH-pyrazol-4-yl] pyridine;
4-[5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
5-cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol;
3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol;
4- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl]-2(1H)-pyridinone;
1-acetyl-4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2(1H)-pyridinone;
Ethyl 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]cyclopropanecarboxylate;

WO 98/52940 PCT/US98110s36 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyi)-1H-pyrazol-5-yl]cyclopropaneca=boxylic acid;
3-(4-fluorophenyl)-5-(4-imidazolyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol;
5 4-[3-(4-chloro-3-methylphenyl)-1H-pyrazol-4-yl]pyridine 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid;
5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-methanol;
10 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine;
1,1-dirnethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate;
4-(1,5-dimethyl-3-:henyl-1H-pyrazol-4-yl)pyridine;
15 4-(1,3-dimethyl-5-phenyl-1H-pyrazol-4-yl]pyridine;
4-[3-(4-chlorophenyl)-1,5-dimethyl-1H-pyrazol-4-yl]pyridine;
4-[5-(4-chlorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl] pyridine;
20 4-[5-ethyl-1-methyl-3-(3-methylphenyl)-1H-pyrazol-4-yl ] pyridine ;
4-[3-ethyl-1-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-chlorophenyl)-1-ethyl-5-methyl-IH-pyrazol-4-25 yl]pyridine;
4-[3-(4-chlorophenyl)-2-ethyl-5-methyl-1H-pyrazol-4-yl ] pyridine ;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(2-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
30 3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol;
3-(4-fluorophenyl)-4-(4-pyrimidinyl)-1H-pyrazole-1-ethanol;
4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-35 pyridinyl]amino]-1-butanol;
4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-SV~~~~~~

WO 98/52940 PC'T/US98110436 yl]pyridine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarbonitrile;
4- (2- [3- (4-fluorophenyl) -4- (4-pyridinyl) -1H-pyrazol-1-yl]ethyl]morpholine;
3-(4-fluorophenyl)-1-methyl-a-phenyl-4-(4-pyridinyl)-1H-pyrazole-5-methanol;
N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-morpholineethanamine;
4- (3- (3-chlorophenyl) -1H-pyrazol-4-yl] -2 (1H) -pyridinone hydrazone;
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyridinamine;
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-(phenylethyl)-2-pyridinamine;
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-ethyl-2-pyridinamine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxamide;
Methyl 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate;
4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyridinecarboxamide;
4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylic acid;
4-[3-(3-fluorophenyl}-1H-pyrazol-4-yl]pyridine;
4-[3-(1,3-benzodioxol-5-yl)-1H-pyrazol-4-yl]pyridine4-[3-(3-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(1,3-benzodioxol-5-y)-1-methyl-1H-pyrazol-4-yl]pyrid ine;
4-[3-(4-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-methylp yridine; 4-[5-(3-chlorophenyl)-1-methyl-1H-pyrazol-4 -yl]-2-methylpyridine;
4-[3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
S

4-[5-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
2-methyl-4-[1-methyl-3-(3-methylphenyl)-1H-pyrazol-4 -yl ] pyridine ;
2-methyl-4-[1-methyl-5-(3-methylphenyl)-1H-pyrazol-4 -yl]pyridine;
4-(3-phenyl-1H-pyrazol-4-yl)pyridine;
4-[3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine 4-[1-methyl-3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl ]pyridine;
4-[3-(3,4-difluorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-fluoropyridine;
4-[3-(4-bromophenyl)-1H-pyrazol-4y1]pyridine;
4-[3-(3,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridi ne;
4-[3-(4-bromophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
(E) -4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2- (2-phenyleth enyl)pyridine;
(S)-4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-(2-methylbut yl)- 2-pyridinamine;
4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxy-phenyl)methyl]- 2-pyridinamine;
N-[4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-2-pyridinemethanamine;
N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-2-pyridinemethanamine;
2-fluoro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-iodophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-iodophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
4-[1-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl ]pyridine;
N- [1- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -1H-pyra zol-4-yl]-2-pyridinamine;
N- [ (3-fluorophenyl)methyl] -4- [3- (4-fluorophenyl) -1H-pyraz ol-4-yl]-2-pyridinamine;
4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-(1-methylhydrazino)pyridine;
2-fluoro-4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]p yridine;
4-[3-(3,4-difluorophenyl)-1H-pyrazol-4-yl]-2-fluoro-pyridine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-3-methylpyridine;
4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-3-methyl-pyridine;
4-[3-(3,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-flu oropyridine;
3-(4-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazo le-1-ethanamine;
2- [2- (4-fluoraphenyl) ethyl] -4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yI]pyridine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[1-(phenylmethyl)-4-piperidinyl]-2-pyridinamine;
N' - [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -N,N-dimethyl-1,2-ethanediamine;
2,4-bis[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
N- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -4-morpholineethanamine;
3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazole-1-ethanol;
4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N- [2- (1H-imidazol-1-yl)ethyl]-2-pyridinamine;
4- [2- [3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) -1H-pyrazol-1-yl]ethyl]morpholine;
(E) -3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethenyl] -4-pyridinyl]-1H-pyrazole-1-ethanol;
3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-N,N-dimethyl-1H-pyrazole-1-ethanamine;
3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4-pyridinyl]-1H-pyrazole-1-ethanol;
4-[1-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N,N-dimethyl-2-pyridinamine;
4- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -1H-pyrazol-4-yl]-N-[(4-fluorophenyl)methyl]-2-pyridinamine;
3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4-pyridinyl]-N,N-dimethyl-1H-pyrazole-1-ethanamine;
N- ( (4-fluorophenyl)methyl] -4- (3 (or 5) - (4-fluorophenyl) -1-[[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl]-2-pyridinamine;
4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-4-piperadinyl-2-pyridinamine;
N,N-diethyl-3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazole-1-ethanamine;
4-[1-(2-(diethylamino)ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-fluorophenyl)methyl]-2-pyridinamine;
2- [ (4- [3- (4- (fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl]amino]ethanol;
2-I[4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-pyridinyl]amino]ethanol;
3- [ [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl]amino]-1-propanol;
3- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl)methyl] amino] -4-pyridinyl]-1H-pyrazole-1-ethanol;
5- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl)methyl] amino] -4-pyridinyl]-1H-pyrazole-1-ethanol;
N,N-diethyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanamine;
N-[(4-fluorophenyl)methyl]-4-(3-(4-fluorophenyl)-1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl]-2-pyridinamine;
N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-morpholinepropanamine;
N'-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-dimethyl-1,3-propanediamine;
5-(4-fluorophenyl)-N-2-propynyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
3- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl) methyl] amino] -4-pyridinyl]-1H-pyrazole-1-ethanol;
5- (4-fluorophenyl) -4- [2- [ ( (4-fluorophenyl)methyl] amino] -4-pyridinyl]-1H-pyrazole-1-ethanol;

'4- [3- [ (4-fluorophenyl) -1H-pyrazol-4-yl] quinoline;
N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]glycine methyl ester;
N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-5 yl]glycine;
4-[3-(4-fluorophenyl)-I-(2-propynyl)-1H-pyrazol-4-yl]pyridine;
4-[5-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazol-4-yl] pyridine;
10 4,4'-(1H-pyrazole-3,4-diyl)bis[pyridine];
4-[3-(3,4-dichlorophenyl)-1H-pyrazol-4-yl]pyridine;
N-(5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl)-4-piperidinamine;
2-Chloro-4-(3-(4-fluorophenyl)-1H-pyrazol-4-15 yl]pyrimidine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2(1H)-pyrimidinone hydrazone;
4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl)-N,N-dimethyl-2-pyrimidinamine;
20 4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl)-N-methyl-2-pyrimidinamine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyrimidinamine;
N-cyclopropyl-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl)-2-25 pyrimidinamine;
4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N- [ (4-methoxyphenyl)methyl]-2-pyrimidinamine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine;
N- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinyl] -30 N-(phenylmethyl)acetamide;
Ethyl [4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl)carbamate;
4-[3-(3-methylphenyl)-1H-pyrazol-4-yl]pyrimidine; ' 4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyrimidine;
35 4-[3-(3-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine; and -4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine.

Within Formula I there is another subclass of compounds of high interest represented by Formula IX:

N~~
J~

Ra s z/ N
N/
i R (IX) wherein Z represents a carbon atom or a nitrogen atom; and R' is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower heterocycyl, lower aralkyl, lower aminoalkyl and lower alkylaminoalkyl; and RZ is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl.and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and sues~s~c~~

heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or RZ is -CRS'RSS wherein RS' is phenyl and R55 is hydroxy;
and R' is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl, 5- or 6-membered heterocyclyl, and aryl selected from phenyl, biphenyl, naphthyl; wherein R° is optionally substituted at a substitutable~position with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and RS is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR6zR6' wherein R6~ is lower alkylcarbonyl or amino, and R6' is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof.
A preferred class of compounds consists of those compounds of Formula IX
R1 is selected from hydrido, methyl, ethyl, WO 98/52940 PCTIUS98/1p436 hydroxyethyl and propargyl; and R2 is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethyIcarbonylaminopropylamino, (1,1-dimethyl) ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dirnethyl-ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or ' more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl; and R' is selected from cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R' is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and RS is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, BI~STtTUTE~i' (RULE2f>) ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or -NR62R6' wherein R62 is methylcarbonyl or amino, and R6' is =methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof .
Within Formula I there is another subclass of compounds of high interest represented by Formula X:
RS , N i s Z N

N
R (X) wherein Z represents a carbon atom or a nitrogen atom; and R1 is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and RZ is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower ' haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, 5 lower alkylamino, lower alkylaminoalkyl, phenylamino, - lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower amit~.oalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower 10 heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower 15 alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower 20 heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or Rz is -CRS'Rss wherein RS' is phenyl and R55 is hydroxy;
and R' is selected from 5- or 6-membered heteroaryl, and 25 aryl selected from phenyl, biphenyl, and naphthyl;
wherein R' is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, vitro, hydroxy; and 30 RS is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower 35 arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR62R6' wherein R6~ is lower alkylcarbonyl or amino, and R6' is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof .
A preferred class of compounds consists of those compounds of Formula X
R1 is selected from methyl, ethyl, hydroxyethyl and propargyl; and RZ is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, piperadinyiamino, dimethylaminoethylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, N-methylpiperazinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, and 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl; and R' is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R' is ' optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, - bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, vitro, dimethylamino, and hydroxy; and RS is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, propargylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylrnethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydra.zinyl, and 1-methylhydrazinyl, or -NR6~R6' wherein R62 is methyl carbonyl or amino, and R6' is methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof .
Within Formula I there is another subclass of compounds of high interest represented by Formula XI:

N~i/
Rz Z /

s z N -Ra N
~xI) wherein Z represents a carbon atom or a nitrogen atom; and R1 is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and R~ is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or S R~ is -CRS'R55 wherein RS' is phenyl and R55 is hydroxy;
. and R' is selected from 5- or 6-membered heteroaryl, and aryl selected from phenyl, biphenyl, and naphthyl;
wherein R' is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, vitro, hydroxy; and RS is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR6~R63 wherein R62 is lower alkylcarbonyl or amino, and R6' is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof.
A preferred class of compounds consists of those compounds of Formula XZ
R1 is selected from methyl, ethyl, hydroxyethyl and propargyl; and RZ is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-WO 98/52940 PC'flUS98110436 ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, 5 morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, 10 piperazinylcarbonyl, 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein the phenyl, --piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, 15 bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl;
R' ~s selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, 20 dihydrobenzofuryl, and benzodioxolyl; wherein R' is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and 25 - hydroxy; and RS is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, 30 methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, 35 phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ~~~~~'t~Itl3~Et~R'~1.EE~

ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or -NR62R6' wherein R6~ is methyl carbonyl or amino, and R6' is methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof.
A preferred class of compounds consists of those compounds of Formula IX wherein Z represents a carbon atom or a nitrogen atom;
and R1 is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and R~ is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or R2 is -CRS'Rss wherein RS' is phenyl and R55 is hydroxy;
and R' is phenyl that is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and RS is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino,~lower alkoxycarbonyl, Lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, Lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR6'R6' wherein R62 is lower alkylcarbonyl or amino, and R6' is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer . thereof .
A class of compounds of specific interest consists of those compounds of Formula IX wherein Rl is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
RZ is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, -aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl;
Rq is phenyl that is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and RS is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or -NR6~R6' wherein R6z is methyl carbonyl or amino, and R6' is methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof .
Another class of compounds of specific interest consists of those compounds of Formula IX wherein Z represents a carbon atom or a nitrogen atom;
and R1 is selected from hydrido, lower alkyl, lower hydroxyalkyl and lower alkynyl; and RZ is selected from hydrido and lower alkyl; and R' is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more halo radicals; and.
RS is selected from hydrido, halo and alkylhydrazinyl; or a pharmaceutically-acceptable salt or tautomer thereof.
Still another class of compounds of specific interest consists of those compounds of Formula IX
wherein Z represents a carbon atom; and R1 is selected from hydrido, methyl, hydroxyethyl, propargyl; and Rz is hydrido; and R' is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more radicals independently selected from chloro, fluoro and bromo; and RS is selected from hydrido, fluoro, and 1-methylhydrazinyl; or a pharmaceutically-acceptable salt or tautomer thereof .
A preferred class of compounds of specific interest -consists of those compounds of Formula IX wherein ~g~G~~~

WO 98/52940 PC?IUS98110436 Z represents a carbon atom; and R1 is selected from hydrido and methyl; and R2 is hydrido; and R' is selected from phenyl that is optionally 5 substituted with one or more radicals independently selected from chloro, fluoro and bromo; and Rsis selected from hydrido and fluoro; or a pharmaceutically-acceptable salt or tautomer thereof .
The term "hydrido" denotes a single hydrogen atom (H). This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two hydrido radicals may be attached to a carbon atom to form a methylene (-CH2-) radical. Where used, either alone or within other terms such as "haloalkyl", "alkylsulfonyl", "alkoxyalkyl" and "hydroxyalkyl", "cyanoalkyl" and "mercaptoalkyl", the term "alkyl" embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. The term "alkenyl" embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms.
Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. The term "alkynyl" embraces linear or $ $~T(~~

branched radicals having at least one carbon-carbon triple bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals ' S having two to about six carbon atoms. Examples of alkynyl radicals include propargyl, 1-propynyl, 2-propynyl, 1-butyne, 2-butenyl and 1-pentynyl. The term "cycloalkyl" embraces saturated carbocyclic radicals having three to about twelve carbon atoms. The term "cycloalkyl" embraces saturated carbocyclic radicals having three to about twelve carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl"
radicals having three to about eight carbon atoms.
Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkylalkylene" embraces alkyl radicals substituted with a cycloalkyl radical. More preferred cycloalkylalkylene radicals are "lower cycloalkylalkylene" which embrace lower alkyl radicals substituted with a lower cycloalkyl radical as defined above. Examples of such radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. The term "cycloalkenyl" embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called "cycloalkyldienyl". More preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl. The term "halo" means halogens such as fluorine, chlorine, bromine or iodine. The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and ' polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals.
. "Lower haloalkyl" embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals.
Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms "alkoxy" and "alkyloxy" embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tent-butoxy.
The term "alkoxyalkyl" embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals. The term "aryl",' alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces BUB~t~~

aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. Aryl moieties may also be substituted at a substitutable position with one or more substituents selected independently from ' halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, vitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkylene, acyl, carboxy, and aralkoxycarbonyl. The term "heterocyclyl" embraces saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, which can also be called "heterocyclyl", "heterocycloalkenyl" and "heteroaryl" correspondingly, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e. g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e. g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e. g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.
Heterocyclyl radicals may include a pentavalent nitrogen, such as in tetrazolium and pyridinium radicals. The term "heteroaryl" embraces unsaturated heterocyclyl radicals. ' Examples of heteroaryl radicals include unsaturated 3 to membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, ' pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl, 1H
5 1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl . (e. g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.;
unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isocruinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e. g., tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (e. g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e. g. benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (e. g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e. g., benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term "heterocycle" also embraces radicals where heterocyclyl radicals are fused with aryl or cycloalkyl radicals.
Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said "heterocyclyl group" may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino, alkylthio and alkylamino. The term "heterocyclylalkylene" embraces su~~nTUrE sir (~ ~

heterocyclyl-substituted alkyl radicals. More preferred heterocyclylalkylene radicals are "lower heterocyclylalkylene" radicals having one to six carbon atoms and a heterocyclyl radicals. The term "alkylthio"
5 embraces radicals containing a linear or branched alkyl radical, of one to about ten carbon atoms attached to a .
divalent sulfur atom. More preferred alkylthio radicals are "lower alkylthio" radicals having alkyl radicals of one to six carbon atoms. Examples of such lower l0 alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio. The term "alkylthioalkylene"
embraces radicals containing an alkylthio radical attached through the divalent sulfur atom to an alkyl radical of one to about ten carbon atoms. More preferred 15 alkylthioalkylene radicals are "lower alkylthioalkylene"
radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylthioalkylene radicals include methylthiomethyl. The term "alkylsulfinyl"
embraces radicals containing a linear or branched alkyl 20 radical, of one to about ten carbon atoms, attached to a divalent -S(=0)- radical. More preferred alkylsulfinyl radicals are "lower alkylsulfinyl" radicals having alkyl radicals of one to six carbon atoms. Examples of such lower alkylsulfinyl radicals include methylsulfinyl, 25 ethylsulfinyl, butylsulfinyl and hexylsulfinyl. The term "sulfonyl", whether used alone or linked to other terms such as "alkylsulfonyl", "halosulfonyl" denotes a divalent radical, -S02-. "Alkylsulfonyl" embraces alkyl radicals attached to a sulfonyl radical, where alkyl is 30 defined as above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl and -propylsulfonyl. The "alkylsulfonyl" radicals may be 35 further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl 8U~~TIT~TEt~~~

radicals. The term "halosulfonyl" embraces halo radicals attached to a sulfonyl radical. Examples of such halosulfonyl radicals include chlorosulfonyl, and bromosulfonyl. The terms "sulfamyl", "aminosulfonyl" and "sulfonamidyl" denote NH202S-. The term "acyl" denotes a radical provided by the residue after removal of hydroxyl from an organic acid. Examples of such acyl radicals include alkanoyl and aroyl radicals. Examples of such alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and radicals formed from succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, malefic, fumaric, pyruvic, mandelic, pantothenic, /3-hydroxybutyric, galactaric and galacturonic acids. The term "carbonyl", whether used alone or with other terms, such as "alkoxycarbonyl", denotes -(C=0)-. The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -C02H. The term "carboxyalkyl"
embraces alkyl radicals substituted with a carboxy radical. More preferred are "lower carboxyalkyl" which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo.
Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term "alkoxycarbonyl" means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are "lower alkoxycarbonyl" radicals with alkyl portions having one to six carbons. Examples of such lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The term "alkoxycarbonylalkyl" embraces alkyl radicals substituted with a alkoxycarbonyl radical as defined above. More preferred are "lower alkoxycarbonylalkyl" radicals with alkyl portions having one to six carbons. Examples of such lower alkoxycarbonylalkyl radicals include substituted or unsubstituted methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonyl-ethyl and S ethoxycarbonylethyl. The term "alkylcarbonyl", includes radicals having alkyl, hydroxylalkyl, radicals, as defined herein, attached to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl. The term "aralkyl" embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in said aralkyl may be additionally substituted with one or more substituents selected independently from halo, alkyl, alkoxy, halkoalkyl, haloalkoxy, amino and nitro. The terms benzyl and phenylmethyl are interchangeable. The term "heterocyclylalkylene" embraces saturated and partially unsaturated heterocyclyl-substituted alkyl radicals (also can be called heterocycloalkylalkylene and heterocycloalkenylalkylene correspondingly), such as pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals (also can be called heteroarylalkylene), such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. The heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "aryloxy" embraces aryl radicals attached through an oxygen atom to other radicals. The term "aralkoxy" embraces aralkyl radicals attached through an oxygen atom to other radicals. The term "aminoalkyl" embraces alkyl radicals substituted with amino radicals. More preferred are "lower ' aminoalkyl" radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like. The term -"alkylamino" denotes amino groups which are substituted TtR~E?6~

with one or two alkyl radicals. Preferred are "lower alkylamino" radicals having alkyl portions having one to six carbon atoms. Suitable lower alkylamino may be ' monosubstituted N-alkylarnino or disubstituted N,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like. The term "arylamino" denotes amino groups which are substituted with one or two aryl radicals, such as N-phenylamino.
The "arylamino" radicals may be further substituted on the aryl ring portion of the radical. The term "aminocarbonyl" denotes an amide group of the formula -C(=o)NH2. The term "alkylaminocarbonyl" denotes an aminocarbonyl~group which has been substituted with one or two alkyl radicals on the amino nitrogen atom.
Preferred are "N-alkylaminocarbonyl" and "N,N-dialkylaminocarbonyl" radicals. More preferred are "lower N-alkylaminocarbonyl" and "lower N,N-dialkylaminocarbonyl" radicals with lower alkyl portions as defined above. The term "alkylcarbonylamino" embraces amino groups which are substituted with one alkylcarbonyl radicals. More preferred alkylcarbonylamino radicals are "lower alkylcarbonylamino" having lower alkylcarbonyl radicals as defined above attached to amino radicals.
The term "alkylaminoalkylene" embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical.
The "hydrocarbon" moieties described herein are organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Preferably, these moieties comprise 1 to 20 carbon atoms.
The heterosubstituted hydrocarbon moieties described herein are hydrocarbon moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, sulfur, or a ' halogen atom. These substituents include lower alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro -or fluoro; ethers; acetals; ketals; esters; heterocyclyl such as furyl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy; nitro; cyano; amino; and amido.
The additional terms used to describe the substituents of the pyrazole ring and not specifically defined herein are defined in a similar manner to that illustrated in the above definitions. As above, more preferred substituents are those containing "lower"
radicals. Unless otherwise defined to contrary, the term "lower" as used in this application means that each alkyl radical of a pyrazole ring substituent comprising one or more alkyl radicals has one to about six carbon atoms;
each alkenyl radical of a pyrazole ring substituent comprising one or more alkenyl radicals has two to about six carbon atoms; each alkynyl radical of a pyrazole ring substituent comprising one or more alkynyl radicals has two to about six carbon atoms; each cycloalkyl or cycloalkenyl radical of a pyrazole ring substituent comprising one or more cycloalkyl and/or cycloalkenyl radicals is a 3 to 8 membered ring cycloalkyl or cycloalkenyl radical, respectively; each aryl radical of a pyrazole ring substituent comprising one or more aryl radicals is a monocyclic aryl radical; and each heterocyclyl radical of a pyrazole ring substituent comprising one or more heterocyclyl radicals is a 4-8 membered ring heterocyclyl.
The present invention comprises the tautomeric forms of compounds of Formulas I and I~. As illustrated below, the pyrazoles of Formula I and I' are magnetically and structurally equivalent because of the prototropic tautomeric nature of the hydrogen:
R3 Rp R3 ~2 .
3 t 5 t~,N R,~ . ~ z/N~H
N N
H
C I ) C I ) The present invention also comprises compounds of Formula T_, IX,, X and XI having one or more asymmetric 5 carbons. It is known to those skilled in the art that those pyrazoles of the present invention having asymmetric carbon atoms may exist in diastereomeric, racemic, or optically active forms. All of these forms are contemplated within the scope of this invention.
10 More specifically, the present invention includes enantiomers, diastereomers, racemic mixtures, and other mixtures thereof.
The present invention comprises a pharmaceutical composition for the treatment of a TNF mediated disorder, 15 a P38 kinase mediated disorder, inflammation, and/or arthritis, comprising a therapeutically-effective amount of a compound of Formula I, or a therapeutically-acceptable salt or tautomer thereof, in association with at least one pharmaceutically-acceptable carrier, 20 adjuvant or diluent.
The present invention further encompasses substituted pyrazoles that specifically bind to the ATP
binding site of p38 kinase. Without being held to a particular theory, applicants hypothesize that these 25 substituted pyrazoles interact with p38 kinase as set forth below. As the substituent at the 3-position of the pyrazole ring approaches the ATP binding site of p38 8UE~~TE~T~R~E?6~

WO 98/52940 PC'TNS98/10436 kinase, a hydrophobic cavity in the p38 kinase forms around the 3-position substitutent at the binding site.
This hydrophobic cavity is believed to form as the 3-position substituent binds to a specific peptide sequence of the enzyme. In particular, it is believed to bind to the sidechains of Lys52, G1u69, Leu,3, IleB~, Leue" Leulol .
and the methyl group of the Thrlo, sidechain of p38 kinase at the ATP binding site (wherein the numbering scheme corresponds to the numbering scheme conventionally used l0 for ERK-2). Where the 3-position substituent is aryl or heteroaryl, such aryl or heteroaryl may be further substituted. It is hypothesized that such ring substituents may be beneficial in preventing hydroxylation or further metabolism of the ring.
The substituent at the 4-position of the pyrazole ring is one that is a partial mimic of the adenine ring of ATP, although it may be further elaborated.
Preferably, it is a planar substituent terminated by a suitable hydrogen bond acceptor functionality. It is hypothesized that this acceptor hydrogen bonds to the backbone N-H of the Metloe residue while one edge of this substituent is in contact with bulk solvent.
Substitution at the 5-position of the pyrazole ring is well tolerated and can provide increased potency and selectivity. It is hypothesized that such substituents extend out in the direction of the bulk solvent and that suitable polar functionality placed at its terminus can interact with the sidechain of Aspl°', leading to increased potency and selectivity.
Similarly, substitution on the nitrogen atom at the 1- or 2-position of the pyrazole ring is well tolerated and can provide increased potency. It is hypothesized that a hydrogen substituent attached to one of the ring ' nitrogen atoms is hydrogen bonded to Asplss~ Preferably, the nitrogen atom at the 2-position is double bonded to -the carbon atom at the 3-position of the pyrazole while the nitrogen atom at the 1-position of the pyrazole is available for substitution with hydrogen or other substituents.
' The 5-position substitutent and the 1- or 2-position substituent of the pyrazole can be selected so as to - improve the physical characteristics, especially aqueous solubility and drug delivery performance, of the substituted pyrazole. Preferably, however, these substituents each have a molecular weight less than about 360 atomic mass units. More preferably, these substituents each have a molecular weight less than about less than about 250 atomic mass units. Still more preferably, these substituents have a combined molecular weight less than about 360 atomic mass units.
. 15 A class of substituted pyrazoles of particular interest consists of those compounds having the formula:

s z N
Ra ,~
N
R (XII) wherein Rl is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units; and R~ is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical that binds with p38 kinase at said ATP binding site of p38 kinase; and R' is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality; and R' is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units;
provided R' is not 2-pyridinyl when R' is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido; further provided R2 is selected from aryl, .
heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R' is hydrido; and further provided R' is not methylsulfonylphenyl; or to a pharmaceutically-acceptable salt or tautomer thereof.
A class of substituted pyrazoles of particular interest consists of those compounds of Formula XI
wherein R1 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units; and R2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical wherein said radical binds with Lys52, G1u69, Leu,3, Ilee2, Leue" Leulol, and Thrlo3 sidechains at said ATP binding site of p38 kinase, said radical being substantially disposed within a hydrophobic cavity formed during said binding by p38 kinase at the ATP
binding site; and R' is a hydrocarbyl, heterosubstituted hydrocarbyl or _heterocyclyl radical having a hydrogen bond acceptor functionality that hydrogen bonds with the N-H backbone of Metros of p38 kinase; and R' is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units.
The present invention also comprises a therapeutic method of treating a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having or susceptible to such disorder or condition with a therapeutically-effective amount of a compound of Formula I

R, s ~ N
N
~I) wherein R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, WO 98/52940 PC1"IUS98/10436 alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or 5 R1 has the formula Rzs -C-(CH2~ ~- ~_N
H ~R2~
(II) wherein:
i is an integer from O to 9;
R25 is selected from hydrogen, alkyl, aralkyl, 10 heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and RZ6 is selected from hydrogen, alkyl, alkenyl, Z5 alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and R2' is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, 20 cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, 25 aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, 30 alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, ' alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, - cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or RZ' is -CHRs°R~' wherein R~8 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or R~6 and R" together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are ~Si~'(~'~~~~

optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy;
and R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, , alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl;
wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or Rz has the formula:
R3~ hi R32 -C-[ CH J - C -N/
q3~ 2 ~ p3 \R33 "' (III) wherein:
j is an integer from 0 to 8; and m is 0 or 1; and R'° and R'1 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, ' aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R'~ is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
R" is selected from hydrogen, alkyl , -C (O) R'S, -C (0) OR35, -SO2R'6, -C (O) NR"R'8, and -SOZNR'9R'°, wherein R~s, R36, R", R'8, R'9 and R'° are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R3' is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or Rz is -CR'1R'2 wherein R'1 is aryl, and R'2 is hydroxy;
and R' is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, o a nd 0 \R43 N 0 Ra3 (IV) (V) wherein R" is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;
and wherein the R' pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, ~E~~~~~~

carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, :alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl,~ hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR"R'S wherein R" is alkylcarbonyl or amino, and R'S is alkyl or aralkyl; and R' is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R' is optionally substituted with one or more radicals ' independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, __alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy;
provided R' is not 2-pyridinyl when R' is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido; further provided R~ is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R' is hydrido; and further provided R' is not methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof.

Also included in the family of compounds of Formula I are the pharmaceutically-acceptable salts thereof. The term "pharmaceutically-acceptable salts" embraces salts ' commonly used to form alkali metal salts and to form 5 addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formula I
may be prepared from an inorganic acid or from an organic 10 acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from~aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic and sulfonic 15 classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic., glucuronic, malefic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-20 hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic?, methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, ~i-hydroxybutyric, galactaric and galacturonic acid.
25 Suitable pharmaceutically-acceptable base addition salts of compounds of Formula I include metallic salts and organic salts. More preferred metallic salts include, but are not limited to appropriate alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts and 30 other physiological acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, including in part, tromethamine, diethylamine, 35 N,N~-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-t ss methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of Formulas I-III by reacting, for example, the appropriate acid or base with the compound of Formulas I-S III.
General Synthetic Procedures The compounds of the invention can be prepared according to the following procedures of Schemes I-XVIII
wherein R1, RZ, R', R', RS and Arl are as previously defined for the compounds of Formula I, IX, X and XI except where expressly noted.
SCHEME I

R
N i ~ p ~H base qa or basa/acic --~ /

RS
'I z q4 / R2 I

N
base/HZOa T~Nii~NHZ
/
R, R2 RS N
N ~ w RS
RZ
NHp~NH=
wat q ~ iN ~ac~a or R4 / R2 N base NNR~TS

Scheme I shows the synthesis of pyrazole 5 by two WO 98/52940 PC'T/US98/10436 routes. Condensation of the pyridylmethyl ketone 1 with aldehyde 2 in the presence of a base, such as piperidine, in a solvent, such as toluene or benzene, either in the ' absence or the presence of acetic acid at reflex, provides the a,~3-unsaturated ketone 3. In route 1, ketone 3 is first converted to epoxide 4, such as by treatment with hydrogen peroxide solution at room temperature, in the presence of base such as sodium hydroxide. Treatment of epoxide 4 with hydrazine in ethanol or other suitable solvent at a temperature ranging up to reflex, yields pyrazole 5. In route 2, ketone 3 is condensed directly with tosyl hydrazide in the presence of an acid such as acetic acid, at reflex, to provide pyrazole 5. Alternatively, the intermediate tosyl hydrazone 6 may be isolated, conversion of it to pyrazole 5 is effected by treatment with a base, such as potassium hydroxide, in a suitable solvent, such as ethylene glycol, at a temperature ranging from 25 °C up to 150 °C.
S~i SCHEME II
Ra X
/) halOQendtnOn RS N/ RS NJ

oase E
R~
N~NHNH

R

. R4 0 R
OEL NH
a N
N
R7,N-Rs Scheme II shows the synthesis of pyrazole 12 of the 5 present invention. The treatment of pyridine derivative 7 with ester 8 in the presence of a base, such as sodium bis(trimethylsilyl)amide, in a suitable solvent, such as tetrahydrofuran, gives ketone 9. Treatment of ketone 9 or a hydrohalide salt of ketone 9 with a halogenating l0 agent, such as bromine, N-bromosuccinimide or N-chlorosuccinimide, in suitable solvents, such as acetic acid, methylene chloride, methanol, or combinations thereof, forms the a-halogenated ketone 10 (wherein X is halo). Examples of suitable hydrohalide salts include the hydrochloride and hydrobromide salts. Reaction of haloketone IO with thiosemicarbazide 11 (where R6 and R' can be hyrido, lower alkyl, phenyl, heterocyclyl and the _ like or where R6 and R' form a heterocyclyl ring optionally containing an additional heteroatom) provides pyrazole 12. Examples of suitable solvents for this ~F~~~

reaction are ethanol and dimethylformamide. The reaction may be carried out in the presence or absence of base or acid at temperatures ranging from room temperature to ' 100 °C.
Thiosemicarbazides which are not commercially ' available may be conveniently prepared by one skilled in the art by first reacting an appropriate amine with carbon disulfide in the presence of a base, followed by treatment with an alkylating agent such as methyl iodide.
Treatment of the resultant alkyl dithiocarbamate with hydrazine results in the desired thiosemicarbazide. This chemistry is further described in E. Lieber and R.C.
Orlowski, J. O.ra. Chem., Vol. 22, p. 88 (1957). An alternative approach is to add hydrazine to appropriately substituted thiocyanates as described by Y. Nomoto et al., Chem. Pharm. Bull., Vol. 39, p.86 (1991). The Lieber and Nomoto publications are incorporated herein by reference.
SCHEME III

R~N~NH~ R~ N-H
R3 route 1 3 1 R

RZ~ x ~3 RZ N-NHZ ~ 0' C
R
i R 1' R, N N 0 route 2 Rz neat C180~_200~C]
R2 N-NHz R~ R~ R~
25'-200~C
N~ N
route 3 R' '9 PCT/[JS98I10436 Scheme III shows the synthesis of pyrazole 19 in more general form by three routes. In Route 1, ketone 13 is condensed with hydrazine 14 to give the substituted hydrazide 16, which is then reacted with acyl halide or 5 anhydride 17 at low temperature to provide acyl hydrazone 18. Upon heating at a temperature up to 200°C, acyl hydrazone 18 is converted to pyrazole 19. In Route 2, acyl hydrazone 18 is formed directly by reaction of ketone 13 with acyl hydrazide 15, formed by reaction of l0 hydrazine with a carboxylic acid ester, at room temperature. Heating acyl hydrazone 18 as above then provides pyrazole 19. In Route 3, ketone 13 is treated with acyl hydrazide 15 at a suitable temperature, ranging from room temperature to about 200 °C, to give pyrazole 15 19 directly. Alternatively, this condensation may be carried out in an acidic solvent, such as acetic acid, or in a solvent containing acetic acid.
SCHEME IV
0 Ra JI-~I R / R~
R ~ + --i Rz R<~H
2i route °asei HZOZ r°ute 2 TSNR~NHz p3 R~ R~
0 p7 p2 p3 23 p~
etno or / R~

NHR~NHZ q~ ~N oase NNFI'TS
heat 24 R~

Synthetic Scheme IV describes the preparation of pyrazole 19.
SCHEME V
x R1NHNH2 N'NHR' Solvent x NaHMDS/ THF
R4COOMe \ ~ ~R
Or I Ra R4C00Et X - ha I y I , a I ky I
R1 - wie, CH2CH20H
Rq - cyclopropyl, 4-pyridyi, 4-imida=Olyl Scheme V shows the two step synthesis of the 3-substituted 4-pyridyl-5-arylpyrazoles 33 of the present invention by cyclization of hydrazone dianions with carboxylates. In step 1, the reaction of substituted pyridylmethyl ketones 31 (prepared, for example, as later described in Scheme IX) with hydrazines in the presence of solvents such as ethanol gives ketohydrazones 32.
Examples of suitable hydrazines include, but are not limited to, phenylhydrazine and p-methoxyphenylhydrazine.
In step 2, the hydrazones 32 are treated with two equivalents of a base such as sodium bis(trimethylsilyl)amide in a suitable solvent such as tetrahydrofuran to generate dianions. This reaction may be carried out at temperatures of about 0 °C or lower.
8 S~T(RULE26~ .

WO 98/529~0 PC1'lUS98/10436 In the same step, the dianions then are condensed with esters such as methyl isonicotinate, methyl cyclopropanecarboxylate, to give the desired pyrazoles 33. It may be necessary to treat the product from this step with a dehydrating agent, such as a mineral acid, to produce the target pyrazole in some instances.

~, 'J ~y ' ~' v ~- E ~ a c C ~._ -i ~ L. ~ m m v a m m Q
n Q
c -r - C, f0 QJ .-~
u- E Q~ ~ m U N a r~ c O 'p (O °' a W
o -U C
U7 ., .
a --, c ' - >. z L N
a~ ~ v L
n L ~ ~ ~C O
f0 ~ ._ O ._ ~, c6 -L i,., C Z Z
+~ .Q
t0 m c !_ U1 C O _ C WS c t II
m v 2 ~ Q X
U
a Scheme VI shows an alternative method for synthesizing pyrazoles which are unsubstituted at the 5 position of the ring. In accordance with this method, a heteroarylmethyl ketone 34 is synthesized by first treating a heteroarylmethane with a strong base such as lithium hexamethyldisilazide or lithium diisopropylamide.
Examples of suitable heteroarylmethanes are 4-methylpyridine, 4-methylpyrimidine, 2,4-dimethylpyridine, 2-chloro-4-methylpyrimidine, 2-chloro-4-methylpyridine and 2-fluoro-4-methylpyridine. The resulting heteroarylmethyl lithium species is then reacted with a substituted benzoate ester to produce ketone 34.
Examples of suitable benzoate esters are methyl and ethyl p-fluorobenzoate and ethyl and methyl p-chlorobenzoate.
Ketone 34 is converted to the aminomethylene derivative 35 by reaction with an aminomethylenating agent such as dimethylformamide dimethyl acetal or tert-butoxybis(dimethylamino)methane. Ketone 35 is converted to pyrazole 36 by treatment with hydrazine.
A modification of this synthetic route serves to regioselectively synthesize pyrazole 38 which contains a substituted nitrogen at position 1 of the ring. Ketone 34 is first converted to hydrazone 37 by reaction with the appropriate substituted hydrazine. Examples of suitable hydrazines are N-methylhydrazine and N-(2-hydroxyethyl)hydrazine. Reaction of hydrazone 37 with an aminomethylenating agent produces pyrazole 38. Examples of suitable aminomethylenating agents include dimethylformamide dimethyl acetal and tert-butoxybis(dimethylamino)methane.
In cases where the R' substituent of pyrazoles 36 and 38 bears a leaving group such as a displaceable halogen, subsequent treatment with an amine produces an amino-substituted heteroaromatic derivative. Examples of such ' amines include benzylamine, cyclopropylamine and ammonia.

The leaving group may also be replaced with other nucleophiles such as mercaptides and alkoxides. Examples of substitutable R' groups include, but are not limited to, 2-chloropyridinyl and 2-bromopyridinyl groups.

a Z-2 N \ N

\ a N

O P

c \
a \
~
~

\ z ~
a z n Q

a a z O~ U~ i Z

i \ ~ z i \

N \ ~ -- r \

_ a Q v H

a a ~

~ ~

W

z z W

x a \
Z-= U
N ~ I I

v Q
\
z N
Z -_ a N
P
\ / a z Scheme VII describes the preparation of derivatives from pyrazole 5 (prepared in accordance with Scheme I) when RZ - CH,. Oxidation of pyrazole 5 gives carboxylic acid 39, which is then reduced to hydroxymethyl compoLnd 40, or coupled with amine NR1°R11 (wherein R1° and R11 are independently selected, for example, from hydrogen, alkyl and aryl, or together with the nitrogen atom to which they are attached form a 4-8 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur) to form amide 41 followed by reduction to generate amine derivative 42.
SCHEME VIII

Ra \ /NH

1. BdSt 2. R~-X

_ R3 ~~ N
Rn \N N~Ri N
Rq 4q 45 Scheme VIII illustrates the synthesis of pyrazoles 44 and 45 from pyrazole 43. The alkylation of the ring nitrogen atoms of pyrazole 43 can be accomplished using conventional techniques. Treatment of pyrazole 43 with an appropriate base (for example, sodium hydride) followed by treatment with an alkyl halide (for example, CH,I) yields a mixture of isomers 44 and 45.

SCHEME IX
COzEt CH

/ + ~ ~RS
N
R~2 a 7 46 lithium hexamethyldiSildZide tetrahydrofuran, RT
R~z R' "desoxybenzo~n dimethylformam~oe dimethyl aCetal (4 fold excess tetrahydrpfuran (~ volumes RT
\ Ri2 R~2 \
/ o hydrazine N
hydrate / ~N-H
\ \~ ethanol N / N I \ H
RS H3C~ ~CH3 N
RS

WO 98/52940 PCTIUS98110436 , Scheme IX illustrates the synthesis of 3-aryl-4-pyridyl-pyrazoles of the present invention. Benzoate 46 is reacted with pyridine 47 in the presence of a strong base, such as an alkali metal hexamethyldisilazide S (preferably sodium hexamethyldisilazide or lithium hexamethyldisilazide), in a suitable solvent, such as tetrahydrofuran, to give desoxyben~oin 48. Desoxybenzoin 48 is then converted to ketone 49 by treatment with an excess of dimethylformamide dimethyl acetal. Ketone 49 is then reacted with hydrazine hydrate in a suitable solvent such as ethanol to yield pyrazole 50. In Scheme _TX, R12 represents one or more radicals independently selected from the optional substituents previously defined for R'. Preferably, R1~ is hydrogen, alkyl, halo, trifluoromethyl, methoxy or cyano, or represents methylenedioxy.
The 3-aryl-4-pyrimidinyl-pyrazoles of the present invention can be synthesized in the manner of Scheme IX
by replacing pyridine 47 with the corresponding pyrimidine. In a similar manner, Schemes X through XVII
can be employed to synthesize 3-aryl-4-pyrimidinyl-pyrimidines corresponding to the 3-aryl-4-pyrimidinyl-pyrazoles shown in those schemes.

S CF~EME X
w Gt2 / O Gt2 N ~t NH.NH-C~~
\ H
N
RS R' dimetnyiformamide ~ ' dimetny aCetal Rt?
'\ \
/ N
~N-R~
\ H

Scheme X illustrates one variation of Scheme IX that S can be used to synthesize 3-aryl-4-pyridyl-pyrazoles that are further substituted on the nitrogen atom at position 1 of the pyrazole ring. If desoxybenzoin 48 (prepared in accordance with Scheme IX) instead is first converted to hydrazone 51 by treatment with hydrazine and hydrazone 51 is then treated with dimethylformamide dimethyl acetal, then the resulting product is pyrazole 52.
Schemes XI through XVIII illustrate further modifications that can be made to Scheme IX to synthesize other 3-aryl-4-pyridyl-pyrazoles having alternative substituents.

SCHEME XI
R' 2 / N
/ 0 ~ ~N-R, NHS- NHR ~
\ \ eLnanoi \
N
N /
N
/ H3C~N~CH R5 ma~o- D-,_.o;~-- ( \ R, / t;
~N
\ v H
N /
miner D~oouCL
R
5a SCHEME XII
R ~' 1 2 R
N
J-R1 / / WN-R, A t3NH- Rz0 ,n~ I \ \H
N /
R20iN~R13 In Scheme XII, X is chloro, fluoro or bromo; R1' is, for example, hydrogen, alkyl, phenyl, aralkyl, heteroarylalkyl, amino or alkylamino; and R2o is, for l0 example, hydrogen or alkyl.

WO 98/52940 PC?/US98/10436 SCHEME XIII
_,2 R,2 r:
\ \
/ N oromme / /rJ~fJ-R
/ \N ~1 DMF
acetic ac~o ' \ Br \ H f~ /
tJ
R
R
c ~
r -, J C

SCHEME XIV
R,z m~~PB~
~ wf~-R, i N-R
\ vH I \
1, N /
R 51~

5~
LrimeChyl5~ly1 cyanide I-R.

R

SCHEME XV
,z v ~I ~ N , ~~\
-~-~~ 0;1 ,- ~ N J ~ ~~ .. _ ~'.i''" .
r metnane suiron~i cniornoe \ -W
~.\ n H ~
\-N /
i ., S' 6C Rs i 6,:
R,2 I R,5 R , s I ~.,\
f,: - H
~ ~~,a R,a/
i H

RJ

Tn Scheme XV, n is 1, 2, 3, 4 or 5; and R1~ and Rls are independently selected from, for example, hydrogen, alkyl or aryl, or together with the nitrogen atom to which they are attached form a 4-7 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur.
SCHEME XVI
Ri2 R~2 ~\ ~ ~\
/ ~N\ N R, , Mg / N~
2 Gi5-CHO
\ Br I \
N / N / HO
Rs R5 S

In Scheme XVI, R'6 is selected, for example, from hydrogen, alkyl and phenyl.
SCHEME XVII
R~2 rt~2 \ \ , / 0 ~ / 0 N-ch~crOSUCCW micye CimeihylformamipE
\ I \ 'Ci N / N /
RS RS
ae N
\N-R~
\ yN-R~~
N /

In Scheme XVII, R1' is selected, for example, from 10 alkyl, phenylalkyl and heterocyclylalkyl.

SCHEME XVIII
X
X
NH
\ ~ LoJ JH H~~-\ / N 2 TIdSCN \N K,,C
I MezNCOCI
N J

X
NH /
\ OMB a~rcet~; i acetai NH
I \ / N M20H \
/ N
N / I
N / Rz COzMe p BR19NH

\ \
X
X /
/ NH
NH
\N I \ / N
\ / Y

N / R
COzH CONR~eR~9 Compounds wherein the 2-position of the pyridine ring is substituted by a carboxyl group or a carboxyl derivative may be synthesized according to the procedures outline in Scheme XVIII. The starting pyridyl pyrazole 67 is converted to the 2-cyano derivative 68 by first conversion to its pyridine N-oxide by reaction with an oxidizing agent such as m-chloroperoxybenzoic acid.
Treatment of the pyridine N-oxide with trimethylsilyl cyanide followed by dimethylcarbamoyl chloride produces the 2-cyano compound 68. Compound 68 is converted to its carboxamide 69 by reaction with hydrogen peroxide in t:~e presence of a suitable base. Examples of suitable bases include potassium carbonate and potassium bicarbonate.
Carboxamide 69 is converted to its methyl ester 70 by reaction with dimethylformamide dimethyl acetal in methanol. The ester 70 is converted to its carboxylic acid 71 by saponification. Typical saponification conditions include reaction with a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as ethanol or ethanol and water or methanol and water or the like. Ester 70 is also convertible to substituted amide 72 by treatment with a desired amine, such as methylamine at a suitable temperature.
Temperatures may range from room temperature to 180°C.
In Scheme XVIII, R18 and R19 are independently selected, for example, from hydrogen, alkyl and aryl, or together with the nitrogen atom to which they are attached form a 4-8 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur.
The following examples contain detailed descriptions of the methods of preparation of compounds of Formulas I, XI, X and XI. These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated. All compounds showed NMR
spectra consistent with their assigned structures. In some cases, the assigned structures were confirmed by nuclear Overhauser effect (NOE) experiments.
The following abbreviations are used:
HC1 - hydrochloric acid MgS04 - magnesium sulfate Na2S04 - sodium sulfate NaI04 - sodium periodate NaHS03 - sodium bisulfate NaOH - sodium hydroxide KOH - potassium hydroxide P205 - phosphorus pentoxide Me - methyl.
Et - ethyl MeOH - methanol EtOH - ethanol HOAc (or AcOH) - acetic acid EtOAc - ethyl acetate H20 - water H202 - hydrogen peroxide CH2C12 - methylene chloride KZCO, - potassium carbonate KMnO, - potassium permanganate NaHMDS - sodium hexamethyldisilazide DMF - dimethylformamide EDC - 1-(3-dimethylaminopropyl)3-ethylcarbodiiminde hydrochloride HOBT - 1-hydroxybenzotriazole mCPBA - 3-chloroperoxybenzoic acid Ts - tosyl TMSCN - trimethylsilyl cyanide Me2NCOC1 - N,N-dimethylcarbamoyl chloride SEM-C1 - 2-(trimethylsilyl)ethoxymethyl chloride h - hour hr - hour min - minutes THF - tetrahydrofuran TLC - thin layer chromatography DSC - differential scanning calorimetry b.p. - boiling point m.p. - melting point eq - equivalent RT - room temperature Example A-1 N~~

F I ~ ~N
\N~
0 h a-r 5-( 3-f I uoro-a-metnoxypt,eny I ]- 3-metlhy I- ~H-pyraZO I --,-y I ~pyr ~ d i n=
Step 1: Preparation of 4-(3-fluoro-4-methoxvlnhenvl)-3-pyridyl-3-butene-2-one A solution of 4-pyridylacetone (1.0 g, 7.4 mmol), 3-fluoro-p-anisaldehyde (1.25 g, 8.1 mmol), and piperidine (0.13 g, 1.5 mmol) in toluene (50 ml) was heated to reflux. After 18 hours, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The crude product (3.0 g) was purified by column chromatography (silica gel, 65:35 ethyl acetate/hexane) to give 4-(3-fluoro-4-methoxylphenyl)-3-pyridyl-3-butene-2-one as a pale yellow solid (1.60 g, 80%) .
Step 2: Preparation of 4-I5-(3-fluoro-4-methoxwhenvl)-3-methvl-1H-ovrazol-4-vllpvridine To a solution of 3-pyridyl-4-(3-fluoro-4-methoxylphenyl)-3-butene-2-one (step 1) (0.99 g, 3.65 mmol) in acetic acid (25 ml), p-toluenesulfonyl hydrazide (0.68 g, 3.65 mol) was added. The reaction solution was heated to reflux for 6 hours. Acetic acid was removed by distillation from the reaction solution. The resulting residue was diluted with CH2C12 (150 ml), washed with H20 WO 98/52940 PCT/US98/10436 , (2x100 ml), dried (Na2S04), filtered, and concentrated.
The crude product (1.5 g) was purified by chromatography (silica gel, ethyl acetate) to give 4-[5-(3-fluoro-4-' methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine as a pale yellow solid (213 mg, 20.7%): Anal. Calc'd for C16H14N30FØ1 H20: C, 67.41; H, 5.02; N, 14.74 . Found:
C, 67.37; H, 4.88; N, 14.35.
Example A-2 \ /CH3 H
4-[~-methyl-5-phenyl-1H-pyrazol-4-y1~
1~ pyridine Stem 1: Preparation of 4-pyridylacetone 4-Pyridylacetone was prepared according to the method of Ippolito et al, U.S. Patent 4,681,944.
Step 2: Dreparation of 4-nhenyl-3-(4-wridyl)-3-butene-2-one Using the procedure of Example A-1, step 1, 4-pyridylacetone (step 1) (1 g, 7.4 mmol) was condensed with benzaldehyde (790 mg, 7.4 mmol) in benzene (15 mL) containing piperidine (50 mg) at reflex. The desired 4-phenyl-3-(4-pyridyl)-3-butene-2-one (1.3 g, 78 %) was obtained as a crystalline solid: m. p. 101-103 °C. Anal.
Calc'd for C15H13N0 (223.28): C, 80.69; H, 5.87; N, 6.27. Found: C, 80.59; H, 5.79; N, 6.18.
Stets 3: Preparation of 4-phenyl-3-(4-pyridyl)-3 4-epoxy-2-butanone Using the procedure of Example A-1, step 2, a solution of 4-phenyl-3-(4-pyridyl)- 3-butene-2-one (step 2) (1.25 g, 5.6 mmol) in methanol (20 ml) was treated SH~ET'(R~~

with 30% aqueous hydrogen peroxide (1 ml) in the prese~ce of sodium hydroxide (230 mg, 5.7 mmol). The crude product was purified by chromatography (silica gel, 1:1 ethyl acetate/hexane) to give 4-phenyl-3-(4-pyridyl)-3,4-S epoxy-2-butanone (270 mg, 20%).
Step 4: Preparation of 4-(3-methyl-S-phenyl-1H-pyrazol-4 ~1 ) pyridine Using the procedure of Example A-1, step 3, a solution of 4-phenyl-3-(4-pyridyl)-3,4-epoxy-2-butanone (step 3) (250 mg, 1 mmol) in ethanol (15 ml) was treated with anhydrous hydrazine (50 mg, 1.5 mmol) and heated to reflux for 4 hours. The crude product was purified by chromatography (silica gel, 1:1 acetone/hexane). The product was recrystallized from ethyl acetate and hexane to give 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine (81 mg, 35%) as a crystalline solid: m. p. 212-214 °C.
Anal. Calc'd for C15H13N3 (235.29): C, 76.57; H, 5.57;
N, 17.86. Found: C, 76.49; H, 5.42; N, 17.39.
Example A-3 N
~H3 \ ~ n ~\N
\ ~ H
4-[5-methyl-3-(2-methylphenyl)-1H-pyraZOl-4-y1~pyridine Steo 1: Preparation of 4-(2-methvlphenyl)-3-(4-pyridvl)-3-butene-2-one A solution of 4-pyrridylacetone (Example A-S, step 1) (0.75 g, 5.56 mmol), o-tolualdehyde (0.73 g, 5.56 mmol) and piperidine (100 mg) in toluene (50 ml) was heated to reflux. Water generated during the reaction was removed by a Dean-Stark trap. After heating at ' PCT'/US98/I Oi36 reflux for 5 hours, the reaction mixture was stirred a~
room temperature for 15 hours. The mixture was concentrated to an orange color oily residue. The crude ketone was purified by chromatography to give 4-(2-methylphenyl)-3-(4-pyridyl)-3-butene-2-one: Anal. Calc'd for C16H15N0 (237.30): C, 80.98; H, 6.37; N, 5.9C. Found:
C, 80.78; H, 6.61; N, 5.85.
Step 2: Pre~aratior. of 4-(2-methylnhenyl)-3-(4-pyridvl)-3,4-epoxy-2-butanone To a solution of 4-(2-methylphenyl)-3-(4-py=idyl)-3-butene-2-one (step 1) (l.Og, 4.2 mmol) in methyl alcohol (18 ml), a solution of H202 (30s by wt.) (0.95 g, 8.4 mmol) and sodium hydroxide (0.18 g 4.6 mmol) in water (4 ml) was added. The reaction was stirred at room temperature for 70 hours. After methyl alcohol was removed, water (25 ml) and ethyl acetate (100 ml) were added and the two phase mixture was stirred for 30 minutes. The layers were separated, and the aqueous layer was washed with ethyl acetate (100 ml). The combined organic layer was dried with Na2S04, filtered and concentrated to give an oil. 4-(2-Methylphenyl)-3-(4-pyridyl)-3,4-epoxy-2-butanone was isolated from the oil residue by chromatography.
Step 3: Preparation of 4-f5-methyl-3-(2-methylphenvl)1H-pyrazol-4-vll wridine A solution of 4-(2-methylphenyl)-3-(4-pyridyl)-3,4-epoxy-2-butanone (step 2) (0.11 g, 0.434 mmol) and hydrazine hydrate (0.043 g, 0.868 mmol) in ethyl alcohol (50 ml) was heated at reflux far 20 hours. The solvent was removed and the resulting residue was purified by chromatography to give 4-[5-methyl-3-(2-methylphenyl)-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C16H15N3 (249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.66;
H, 5.91; N, 16.84.

Example A-4 \ ~ /C43 _ \ of / N
/ H
F
4-[S-methyl-3-~4-fluorOpnenyl)-1H-PYr3~ol-4-yl]PYrfdme By following the method of Example A-3 and substituting p-fluorobenzaldehyde for o-tolualdehyde, the titled compound was prepared: Anal. Calc'd for C15H12N3F
+ 0.1 H20: (249.32): C, 70.63; H, 4.82; N, 16.47. Found:
C, 70.63; H, 4.78; N, 16.40.
Example A-5 \ NON
/ H
4-(5-methyl-3-(4-methylphenyl)-1H-pyraZOl-4-y1)pyridine By following the method of Example A-3 (with one minor modification: in Step 2, the preparation of the intermediate epoxide was accomplished at 0-10 °C for 1 hour, and the reaction was quenched by being partitioned between water, containing 2 eq. sodium bisulfite, a::d ethyl acetate) and substituting p-tolualdehyde for o-tolualdehyde, the titled product was isolated: Anal.
Calc'd for C16H15N3 (249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.97; H, 6.09; N, 16.90.
Example A-6 \ /
\ / N
N
!, a_[ ~._m=Lhy i-3-[ ~-~maLY~y I thi _;JGti'='nY I~-1N-pyrdZ01-~ ;~1jpyry ne 3y following the method of Example A-5 and substituting ~-(methylthio)benzaldehyde for p-tolualdehyde, the titled product was prepared: Anal.
Calc'd for C16H15N3S (281.38): C, 68.30; H, 5.37; N, 14.93. Found: C, 68.34; H, 5.09; N, 14.78.

WO 98152940 PCTIUS98/10.t36 Example A-7 CHI
\ /
N
\ \
H
CI
a-[3-(a-chioropheny )-S-metny~-1H-pyrd~ol-4-y'']pyridine By following the method of Example A-5 and substituting p-chlorobenzaldehyde for p-tolualdehyde, the titled product was obtained. Anal. Calc'd for C15H12N3C1 (269.77): C, 66.79; H, 4.48; N, 15.58. Found: C, 66.43;
H, 4.44; N, 15.78.
Example A-8 \ /
N
\ \ /
H
4-[3-methyl-5-(3-methylphEny4)-1H-pyrazol-a-y1]pyridine By following the method of Example A-S and substituting m-tolualdehyde for p-tolualdehyde, the titled product was obtained: Anal. Calc'd for C16H15N3 +
0.2H20: C, 75.98; H, 6.14; N, 16.61. Found: C, 76.06; H, 6.05; N, 16.38.
Example A-9 \ /
\\rJ
\ \ tJ /
H
4-(5-(2,5-dim2thylphenyl]-3-cr,2thyl-1H-pyrazol-4-y1)pyridine By following the method of Example A-5 and substituting 2,5-dimethylbenzaldehyde for p-tolualdehyde, the titled product was obtained: Anal. Calc'd for C17H17N3 + O.1H20: C, 77.01; H, 6.54; N, 15.85. Found: C, 76.96; H, 6.81; N, 15.51.
Example A-10 \ ~ /CH3 \\.
~o ' ~ N/n Q ~ H
4-(5-(1,3-benzodioxot-5-y1]-3-methyi-1H-pyrazol-4-y1)pyridinB
4-Pyridylacetone (1.5 g, 12 mmol), piperonal (1.6 g, 10.6 mmol), acetic acid (110 mg, 1.8 mmol), and piperidine (110 mg, 1.3 mmol) were dissolved in toluene $~j$si~~~~~

(30 mL) and heated for 2 hours at reflux in a flask equipped with a Dean-Stark trap. The solution was cooled to room temperature, and ethyl acetate was added to precipitate a solid, which was collected on a filter plate (1.25 g). A sample (500 mg) of this solid was heated with p-toluensulfonyl hydrazide (348 mg, 1.81 , mmol) in acetic acid (5 mL) at 80 °C for 1 hour. The reaction was heated to reflux for 1 hour. The reaction was cooled to room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate, washed with 5% aqueous potassium carbonate, and water.
The organic layer was dried (MgS04), filtered and evaporated to obtain a yellow solid. This solid was triturated with methylene chloride, yielding 4-(5-(1,3-benzodioxol-5-yl)-3-methyl-1H-pyrazol-4-yl]pyridine which was collected on a filter plate (220 mg, 42% yield).
Anal. Calc'd for C16H13N302~ C. 68.81; H, 4.69; N, 15.04.
Found: C, 68.02; H, 4.54; N, 14.76. MS (M+H): 280 (base peak) .
Example A-11 \ I N /~N
Phi ~ / H
G
4-[3-methyl-5-~4-phenoxyphenyl) 1H-pyrBZ°I-4-y1)pyridine 4-Pyridylacetone (1.5 g, 12 mmol), 4-phenoxybenzoldehyde 92.1 g, 10.6 mmol), acetic acid (110 mg, 1.8 mmol), and piperidine (110 mg, 1.3 mmol) were dissolved in toluene (30 mL) and heated for 2 hours at reflux in a flask equipped with a Dean-Stark trap. The solution was cooled to room temperature and ethyl acetate was added to precipitate a solid, which was collected on ' a filter plate. A sample (223 mg) of this solid was heated with p-toluensulfonyl hydrazide (348 mg, 1.81 mmol) in ethylene glycol with potassium hydroxide (77 mg) at 110 °C for 0.5 hour. The work up procedure was the same as that in Example A-10. 4-[3-Methyl-5-(4-phenoxyphenyl)-1H-pyrazol-4-yl]pyridine was obtained (100 mg, 66~ yield): Anal. Calc'd for C21H17N30 + 0.1 H20:
C, 76.62; H, 5.27; N, 12.76. Found: C, 76.37; H, 5.19; N, 12.64 . MS (M+H) : 328 (base peak) .
Example A-12 \ I N /~N
H
Ph 4-[5-[[1,1 -bipnenyl~-4-y1~-3-methyl 1H-pyrazol-4-y1]pyridine The same procedure as for the preparation of Example A-10 was used, substituting 4-formylbiphenyl in place of piperonal, to give 4-[5-[(1,1'-biphenyl)-4-y1J-3-methyl-1H-pyrazol-4-yl]pyridine as a white solid: MS (M+H): 312 (base peak) .
Example A-13 o I
Phi ~ \ N/N
H
4-[3-methyl-S-[3-~phenoxyphenyl) 1H-pyrazol-4-y1]pyridine The same procedure for the preparation of Example A-was used, substituting 3-phenoxybenzaldehyde in place of piperonal, to give 4-[3-methyl-S-[3-(phenoxyphenyl)-1H-pyrazol-4-yl]pyridine as a white solid. ' Example A-14 _, Pn~O
\ N~ h / H
4-[3-metnyt-5-[3-[phenylmethoxy~phenyl;-' 1H-pyraZ01-4-y1)pyridine The same procedure for the preparation of Example A-10 was used, substituting 3-benzyloxybenzaldehyde in 10 place of piperonal, to give 4-[3-methyl-5-(3-(phenylmethoxy)phenyl]-1H-pyrazol-4-yl]pyridine as a white solid: MS (M+H): 342 (base peak).
Example A-15 N~i Ph CH3 \ ~ N/N
/ H
4-[3-methyl-5-[2-(phenylmethoxy)-Pnenyl)-1H-pyrazol-4-y1)pyridine The same procedure for the preparation of Example A-10 was used, substituting 2-benzyloxybenzaldehyde in place of piperonal, to give 4-[3-methyl-5-[2-WO 98/52940 PC?NS98/10436 (phenylmethyloxy)pheryl]-1H-pyrazol-4-yl)pyridine. MS
(M+H) : 34.2 (base peak) .
Example A-16 \ ~ 3 \ / N /~N
/ H
OH
2-[3-methyl-4-'4-pyrid~ny~]-1H-pyrdZOl-~:-y l~pnenol The same procedure for the preparation of Example A-~0 was used, substituting 2-hydroxybenzaldehyde in place of piperonal, to give 2-[3-methyl-4-(4-pyridinyl)-1H-pyrazol-4-yl)phenol: MS (M+H): 252 (base peak).
Example A-17 Ho \ Ni N
/ H
~-~ 3-methy I- 4-( 4-pyr i cy i ny I ]- 1H-pyraZol-4-y1jphenol The same procedure for the preparation of Example A-10 was used, substituting 3-hydroxybenzaldehyde in place of piperonal, to give 3-[3-methyl-4-(4-pyridinyl)-1H-pyrazol-4-yl]phenol: MS (M+H): 252 (base peak).

Example A-18 \ Ni N
\ ~ H
-hydroxy-4-(3-methyl-5-phenyl-1H-pyraZOl-4-y1)pyridinium To a solution of 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine (Example A-2) (2.06 g, 8.76 mmol) in a mixture of CH2C12 {10 mL) and MeOH {20 mL), was added 3-chloroperoxybenzoic acid (57--86%) (2.65 g, 8.76 mmol).
The reaction was stirred at room temperature for 2h, quenched with K2C03 solution (25%, 15 mL), and concentrated. The resulting residue was partitioned between EtOAc (2.0 L) and H20 (500 mL). The organic layer w~ separated, washed with H20 (500 mL), dried over MgSO4, filtered and concentrated to give 1-hydroxy-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl]pyridinium (1.12 g, 54.5%) : MS (M+H) : 252 (base peak) .
Example A-19 N
\ Ni N
H
F
5-(4-fluorophenyl]-N,N-dimethyl-4-(4-pyridinyl]-1H-pyrazol-3-amine Step 1: Preparation of 1-fluoro-4-(4'-Dvridvlacetvl)benzene To a solution of sodium bis(trimethylsilyi)amide (200 mL, 1.0 M in THF) at 0 °C was added a solution o~ 4-picoline (18.6 g, 0.20 mol) in dry THF (200 mL) over 30 minutes. The reaction mixture was stirred at 0-10 °C for another 30 minutes, then was added to a solution of e~hy' 4-fluorobenzoate (16.8 g, 0.10 mol) in dry THF (200 mL) at such a rate that the internal temperature didn't exceed 15 °C. After the addition, the resulting yellow suspension was stirred at room temperature for 3 hours.
Water (600 mL) was added and the aqueous phase was extracted with~ethyl acetate (3 X 200 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-fluoro-4-(4'-pyridylacetyl)benzene (19.9 g, 92 %) as an oil which solidified upon standing: m.p.. 90-91 °C; Anal. Calc'd ' for C13H10FN0: C, 72.55; H, 4.68; N, 6.51. Found: C, 72.07; H, 4.66; N, 6.62.
Step 2: Preparation of 1-fluoro-4-(4'-pyridvlbromoacetvl)benzene To a solution of 1-fluoro-4-(4'-pyridylacetyl)benzene (step 1) (10.0 g, 0.046 mol) in acetic acid (200 mL) was added a solution of bromine (8.2 g, 0.052 mol) in acetic acid (20 mL) dro~wise. The reaction mixture was stirred at room temperature overnight. After the solvent was removed, the residue was triturated with ethyl acetate. A yellow solid formed, which was filtered and air-dried to give 1-fluoro-4-(4'-pyridylbromoacetyl)benzene (14.5 g). The compound was used in next step without further purification.
8UBSt't~UTIES~ET ~

Steo 3: PreDara ion of 5-(4-fluorophenyl)-N, N-dimethvl-4- (4-nyridinvll -1H-wrazol-3-amine A mixture of 1-fluoro-4-(4'-pyridylbromoacetyl)-benzene (step 2) (3.8 g, 0.01 mol) and 4,4-dimethylamino-3-thiosemicarbazide (1.2 g, 0.01 mol) in ethanol (10 mL) was heated at reflux for 30 minutes. The dark gr=en solution was cooled and poured into water (100 mL). The aqueous phase was extracted with methylene chloride (100 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated.
The resulting residue was purified by chromatography (silica gel, ethyl acetate) to give 0.3 g 5-(4-fluorophenyl)-A1, N-dimethyl-4-(4-pyridinyl)-1H-pyrazoi-3-amine (0.3 g, 11 %) as a light yellow solid: m.p.. 245-247 °C. Anal. Calc'd for C16H,5FN4: C, 68.07; H, 5.36; N, 19.84. Found: C, 68.00; H, 5.37; N, 19.61.
Example A-20 H
N-Ph N~ N
H
F
'~-(4-fluorophenyl;-N-phenyl-4-(4-pyridmyl~-1H-pyrazol-3-amine 5-(4-Fluorophenyl)-N-phenyl-4-(4-pyridinyl)-1H-pyrazol-3-amine was prepared by the same procedure as described for Example A-19: m.p. 218-219 °C. Anal.
Calc'd for C2pH15FN4 + 0.1 H20: C, 72.33; H, 4.61; N, 16.87. Found: C, 72.16; H, 4.56; N, 16.77.

N~~
Example A-21 P r.
F
~ N
N
H
-( ;-~, 4-' I ;:or oGheny I )- ?-pneny I - 1H-pyrdzol-a-y~~pyridme Step 1: Preparation of 1-fluoro-a-(40- pvridvlacetvl) benzene N-benzoylhvdrazone To a solution of benzoic hydrazide (1.36 g, 0.01 mol) in THF (20 rnL) was added 1-fluoro-4- (4' -pyridylacetyl)benzene (2.15 g, 0.011 mol) in one portion followed by a drop of cone. HC1. The reaction mixture was stirred at room temperature overnight. There was white precipitate formed, which was filtered, washed with ether and air-dried to give 1-fluoro-4-(4'-pyridylacetyl)benzene N-benzoylhydrazone (2.90 g, 79 %) as a mixture of cis and traps (ratio, 1:9) isomers.
Step 2: Preparation of 4-f5-(4 -fluorophenyl)-3-~henyl-1H-pyrazol-4-yl~pyridine 1-Fluoro-4-(4'-pyridylacetyl)benzene N-benzoylhydrazone (step 1) (0.50 g, 1.5 mmol) was heated at 180 °C under N~ for 15 minutes, then cooled. The resulting solid was purified by chromatography (silica gel, 1:1 ethyl acetate/hexane) t~ give 4-[5-(4-fluorophenyl)-3-phenyl-1H-pyrazol-4-yl]pyridine (0.25 g, 53 %) as a pale yellow solid: m.p.. 265-267 °C. Anal.
Calc'd for C2pH14FN3 + 0.25 H20: C, 75.10; H, 4.57; N, 13.14. Found: C, 74.98; H, 4.49; N, 12.87.
~~~i~~~~j WO 98152940 PC'T/US98/10436 Example A-22 N~~
F F
F
~ ~~N
N
\ / H
-.-( 5-( 3-mEihy Ipheny I 1- 3-( it ~ f I uoromeihy I j-1H-pyra=ol-:1-y1]pyr i~yine Steo 1: Preparation of 3-(4'-Dyridvlacetvl)toluene 3-(4'-Pyridylacetyl)toluene was prepared by the same method as described for Example A-19, step 1 in 705 yield.
Step 2: Preparation of trifluoroa~etyl hydrazide A mixture of ethyl trifluoroacetate (14.2 g, 0.10 mol) and hydrazine hydrate (5.54 g, 0.11 mol) in ethanol (25 mL) was heated at reflux for 6 hours. Solvent was removed and the resulting residue was dried in vacuum to give trifluoroacetyl hydrazide (12.3 g, 96 %) as a clear oil which solidified upon standing.
Step 3: Preparation of 4-f5-(3-methylphenyl)-3-(trifluoromethyl)-1H-wrazol-4-yl]pyridine A mixture of 3-(4'-pyridylacetyl)toluene (2.11 g, 0.01 mol) and trifluoroacetyl hydrazide (step 2) (1.0 g, 0.01 mol) was heated at 200 °C under Nz for 15 minutes.
The crude residue was purified by chromatography (silica gel, 35:65 ethyl acetate/hexane) to give 4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine (0.56 g) as a white solid: m.p. 237-239 °C.
Anal. Calc'd for C16H12F3N3: C, 63.36; H, 3.99; N, 13.85.

WO 98!52940 PCT/US98/10a36 Found: C, 63.6; H, 4.00; N, 13.70.
Example A-23 J
4-(3-(4-fIuOrOphenyl)--7-~4-pyrldlnyl)-~H-pyraZOl-5-y~]pYr~d~ne A mixture of 1-fluoro-4-(4'-pyridylacetyl)benzene (1.0 g, 4.6 mmol) and isonicotinic hydrazide (0.63 g, 4.6 mmol) in THF (25 mL) was heated to dissolution and then evaporated to dryness. The resulting solid was heated first to 140 °C, which caused a phase change, and subsequently melted on further heating until 180 °C
whereupon a solid crystallized out. The reaction was immediately cooled, diluted with 10 % HC1 (SO mL) and washed with chloroform. The aqueous layer was neutralized with bicarbonate and a tan colored solid was precipitated out. The solid was purified by treatment with activated carbon (Darco°) in boiling MeOFi (100 mL), followed by filtration and concentration, to give 4-[3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-S-yl]pyridine (1.05 g, 69 %) as a shiny tan solid: m.p. 304 °C (DSC).
Mass (MH+) 137 (100%). Anal. Calc'd for C1gH13N4F.1/4H20:
C, 71.13; H, 4.24; N, 17.46. Found: C, 70.88; H, 3.87;
N, 17.38.
s~a~~~~j Example A-24 N~~

'\N
\ N~
H
4-~5-CyClOhexyl)-3-methyl-1H-pyrd=OI-4-y1)pyriW ne Ste~1: Dreparation of 4-cvclohexvl-3-wridvl-3-butene 2-one 4-Cyclohexyl-3-pyridyl-3-butene-2-one was prepared by the method of Example A-1, step 1 by replacing of 3-fluoro-p-anisaldehyde with cyclohexanecarboxaldehyde.
Step 2: Preparation of 4-(5-cvclohexvl)-3-methvl-1H-pyrazol-4-yl)pvridine 4-(5-Cyclohexyl)-3-methyl-1H-pyrazol-4-yl)pyridine was prepared by the method for Example A-1, step 2, by replacing 4-(3-fluoro-4-methoxylphenyl)-3-pyridyl-3-butene-2-one with 4-cyclohexyl-3-pyridyl-3-butene-2-one (step 1): Anal. Calc'd for C15H1gN3: C, 73.56; H, 7.98;
N, 17.16. Found: C, 73.72; H, 7.91; N, 19.98.
Example A-25 F ~ '1N
\ N~
H

/ 4-(5-(3-fluOro-5-methOxyphenyl]-3-2~ methyl-1H-pyra2ol-4-y~]pyridine 8118 SiTt'~U~ ' '' ~RL,~LF 2s) WO 98/52940 PCTlUS98lI0y36 4-{5-(3-Fluoro-5-me~hoxyt~henyl)-3-methyl-3-methyl-1H-pyrazol-4-yl}pyridine was prepared by the method of Example A-1, steps 1 and 2 by replacing 3-fluoro-p-~ anisaldehyde with 3-fluoro-m-anisaldehyde: Anal. Calc'd for C16H14N3~F: C, 67.83; H, 4.98; N, 14.83. Found: C, 67.68, H, 4.92; N, 14.92.
The following examples (No 26-55) listed in Table 1 were prepared by the procedures described above:

WO 98/52940 PC'T/US98/10436 Ri Rz R3 Ra m~P~ °r Anal.Calc'd ~ Anal. Calc'd (calcd/foundl DSC(°C Formula C H I N
H, 26 H 7~~C~H3 ~\' -f ~ ~ 185-186 Ct8H~9N3 77.95/ 6.90/ ( 15.15/
N 77.51 6.93 14.73 H.
271 H ~ y CHs ~ ~ ' .N ~ ,# ~ v ~ 142-144 CtsHtsN3 75.71/ 6.16/ ~ 16.55/
75.69 6.11 16.49 281 H ~ -f ~ ~ ~ f ~ ~ ~ -F ~ v ( 240-242 Cn 80.09/ 5.96/ ( 12.74/
~, N Ø25H,0 79.74 5.90 13.01 291 H . ( F~C \ I ~ ~ ~ I ~ 228.8 C 63.36/ 3.99/ 13.85/
~, N ~~ CH; 16 1 3 3 63.28 3.73 I 13.69 I
3 I H ( '~ CHs l f ~ ~. I ~ ~ \ ~ 189.6 CtsHtzN3C 6 4.55/ ~ 15.42/
vN CI .O.ISH.,O 65.98 4.31 15.74 311 Ii ~~ CHs ~ ~' ~N ( .~ ~ ~ ~ 171.6 Ct~HmN3 76.491 6.57/ ~ I5.74/I
0.2H,0 76.69 6.53 15.61 3~ .~.CHS ~ ~~ CHs ~ f V,N ~ ~ ~ ~ CI~ 88.6 CtsHtaN3C 67.35/ 5.29 ~ 15.02/
331 H ~ ~~ CHs ~ ~~ ~ -~ ~ v ~ 188.8 C16Hi4NsF 71.89/ 5.28/ 15.72/
~.~N F - 71.72 5.45 ~ 15.77 341 H ~ ~~ CHs ~ f~N ~ '~ i ~ ( 215.7 Ct~Ht~N3 77.54/ 6.51/ ~ 15.96/
77.24 6.80 15.71 35 H ~~ CHs ~' ~ ~ i v ~ 201.4 CoHmN3D 68.10/ 5.88/ ~ 14.01/
~.N n' I Ø25Hz0 67,92 5.65 13.65 'I n, 3~ H ~ ~~u~H3~ ~~~N ~ ~ ~ ~N0.~ 210.7 ~125~ 63.59/ 4.49/ I 19.31/
371 H ( ~~ CHs I ~. ~N ~ f ~ I N ~ 252.5 CoHtaN4 72.61/ 6.79 19.59/
73.63/ 5.45/ ~ 15.15/
H I .0 ~~ ~ f ~'N ~ ~~CH3 ~ 196.3 Ct~H15N3 73,43 5.46 15.19 39L H ( ~ 1 Br ~ fyN ~ ~~ CHs ~ 252.8 C15H~ 57.09/ 379/ ~ 13.06 I fi 40, H ~ ~ i fyN ~ .~ CHs ~ 198.5 CtSHtzNsF 71.13/ 4.78/ ~ 16.59/
71.23 5.01 16.76 411 H ~ -~ CHs ~ ~ ~'N ~ -f ~ v F ~ 225.6 CtsHt2N3F 7074/ 4.66/ I 16.44/ I
421 H , y CHs I f ~ ~N' -# ~ 'CF,) 219.5 CtsHtzF3N 63.19/ 4.07/ 13.38/
431 H 'y-CHzCHs I f ~'N I .~ ~ v I 227.7 CtsHtsNs 76.53/ 6.10/ ~ 16_73/
.O.1H.,0 76.53 6.20 16.49 No Ri Rz R3 Ra m.p. Anal.Calc'dAnal.
or Calc'd lcalcd/found) DSC(CFo~~a C H N

44 ~ 175.6C~sH1sN3071.70/5.75/ 15.68/
H 1CH~ ~,'N .f ~~
~

.O.15H,071.925.76 15.29 45 H ~~~CH ~ ~ - 77.54/6.51/ 15.96/
CH N ~ CmH~9N3 f ~' 77.136.28 15.69 66.42/4.091 15.49/
46 H ~CH3 ~'N ~ i 412.1CisHoN3Fz v F

66.123.86 15.25 47 H ~CHs ~~' ~.~ 168 CuHuN30 72.40/6.18/ 14.90/

N O'~ . Ø15H,072.395.87 I4.50 'r 48 H ~CH ~~ s ~ 211.2CisHizN3F362.62/4.07/ 13.69/

3 N CF3 Ø2H,0 62.644.06 13.35 49 H 1CH3 f ~'N x~ - C H N 64.71/4.59/ 17.41/
S

64.444.58 17.27 CI 59.23/3.651 13.81/
50 H fCH3 ~'N ~ 189.2C1sH11N3C1z ~ ~

~ 59.223.24 13.81 51 H ~CH3 f . f ~ 211.7CtsHIzN3C166.13/4.55/ 15.421 ~N ~
~' CI

_ .O.15H,066.334.62 15.05 CI 64.11/4.711 14.021 52 H vCH3 f ~ 'r: 219.8CISHIdN3C1 ~N ~

_ d 63.854.69 13.93 64.3214.83! 11.84/
53 H ~~ f ~' ~ ~ 4 CI-I,~N3ozC1 , 163 o N CI . 63.985.08 11.80 ~
54 .1.CH r~ f ~ - C,sHIzN3F70.15/4.86/ 16.351 ~ ~ H

F ~.N Ø2H,0 70.184.60 16.47 55 f' ~' ~ - C H N 70.2814.21/ 17.56/
H ~ H F
. to io s F ~ N 69.973.84 17.53 The following pyrazoles could be prepared by the procedures described above:
Example A-56 5-(5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
Example Ay57 5-(3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine;
Example A-58 5-[3-methyl-5-(2-methylphenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine;
Example A-59 5-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
Example A-60 5-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin'-2-amine;
Example A-61 5-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
Example A-62 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
Example A-63 4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
Example A-64 4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
Example A-65 4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
Example A-66 4-[5-(4-chlorophenyl)-3-methyl-IH-pyrazol-4-yl]pyridin-2-amine;
Example A-67 4-(5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
Example A-68 4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
Example A-69 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
Example A-70 2-methoxy-5-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
Example A-71 2-methoxy-5-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
Example A-72 4-(5-(3-chlorophenyl)-3-methyl-1H-pyrazol-St~~~lltf~~~f'~~

4-yl]-2-methoxypyridine;
Example A-73 2-methoxy-4-(3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
' Example A-74 2-methoxy-4-[3-methyl-5-(2-methylphenyl)-1H-pyrazol-4-yl]pyridine;
Example A-75 4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
Example A-76 4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
Example A-77 2-methoxy-4-[3-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]pyridine;
Example A-78 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
Example A-79 4-(5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
Example A-80 4-(5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
Example A-81 4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
Example A-B2 4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
Example A-83 4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
Example A-84 4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
Example A-85 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
Example A-86 4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
Example A-87 4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
Example A-88 4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
Example A-89 4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
Example A-90 4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-~E~t~~~

4-yl]pyridine-2-methanamine;
Example A-91 4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
Example A-92 5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
Example A-93 4-[5-(3-chlorophenyl)-3-methyl-IH-p~rrazol-4-yl]pyridine-2-carboxamide;
Example A-94 4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
Example A-95 4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
Example A-96 4-(5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
Example A-97 4-~[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
Example A-98 4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
Example A-99 4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
Example A-100 4-[5-(4-fluoro-3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
Example A-101 4-[5-(4-chloro-3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
Example A-102 4-(5-(2,3-dihydrobenzofuran-6-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
Example A-103 4-[5-(benzofuran-6-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
Example A-104 4-[5-(3-fluoro-5-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
Example A-105 4-[5-(3-chloro-5-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
Example A-106 4-[5-(1-cyclohexyen-1-yl)-3-methyl-1H-pyrazol-4-yl]pyridine; ' Example A-107 4-[5-(1,3-cyclohexadien-1-yl)-3-methyl-1H-pyrazol-4-yl]pyridine; -Example A-108 4-[5-(5,6-dihydro-2H-pyran-4-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
Example A-109 4-(5-cyciohexyl-3-methyl-1H-pyrazol-4-yl)pyridine;
' Example A-110 4-[5-(4-methoxy-3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
- Example A-111 4-[5-(3-methoxy-4-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
Example A-112 4-[5-(3-methoxy-5-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
Example A-113 4-[5-(3-furanyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
Example A-114 2-methyl-4-(3-methyl-5-phenyl-1H-pyrazol-4 -yl ) pyridine ;-Example A-115 2-methoxy-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
Example A-116 methyl 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxylate;
Example A-117 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxamide;
Example A-118 1-[4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridin-2-yl]ethanone;
Example A-119 N,N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazol-2-yl)pyridin-2-amine;
Example A-120 3-methyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
Example A-121 3-methoxy-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
Example A-122 methyl 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine-3-carboxylate;
Example A-123 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine-3-carboxamide;
Example A-124 1-[4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridin-3-yl]ethanone;
Example A-125 3-bromo-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
Example A-126 N,N-dimethyl-4-(3-methyl-5-phenyl-1H-WO 98/52940 PC'T/US98l10436 pyrazol-2-yl)pyridin-3-amine;
Example A-127 2-methyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidine;
Example A-128 4-(3-methyl-5-phenyl-IH-pyrazol-4-yl)pyrimidine;
Example A-129 2-methoxy-4-(3-methyl-5-phenyl-1H-pyrazol- _ 4-yl)pyrimidine;
Example A-130 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidin-2-amine;
Example A-131 N,N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidin-2-amine;
Example A-132 4-(5,6-dihydro-2H-pyran-4-yl)-3-methyl-5-phenyl-1H-pyrazole;
Example A-133 3-methyl-5-phenyl-4-(3-thienyl)-1H-pyrazole;
Example A-134 4-(3-furanyl)-3-methyl-5-phenyl-1H-pyrazole;
Example A-135 3-methyl-5-phenyl-4-(2-thienyl)-1H-pyrazole;
Example A-136 4-(2-furanyl)-3-methyl-5-phenyl-1H-pyrazole;
Example A-137 4-(3-isothiazolyl)-3-methyl-5-phenyl-1H-pyrazole;
Example A-138 4-(3-isoxazolyl)-3-methyl-5-phenyl-1H-pyrazole;
Example A-139 4-(5-isothiazolyl)-3-methyl-5-phenyl-1H-pyrazole;
Example A-I40 4-(5-isoxazolyl)-3-methyl-5-phenyl-1H-pyrazole;
Example A-141 3-methyl-5-phenyl-4-(5-thiazolyl)-1H-pyrazole;
Example A-142 3-methyl-4-(5-oxazolyl)-5-phenyl-1H-pyrazole;
Example A-143 2-methyl-4-[3-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
Example A-144 4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyridine;

WO 98/52940 PCT/US98/1043b Example A-145 4-(3-phenyl-1H-pyrazol-4-yl)pyridine;
Example A-146 2-methyl-4-(3-phenyl-1H-pyrazol-4-yl)pyridine;
Example A-147 4-[3-(3-chlorophenyl)-1-methyl-pyrazol-4-yl]pyridine;
Example A-148 4-[3-(4-chlorophenyl)-1-methyl-pyrazol-4-yl]pyridine;
Example A-149 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
Example A-150 4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
Example A-151 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-2-methylpyridine;
Example A-152 4-[3-(3-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
Example A-153 4-[3-(3-fluorophenyl)-1H-pyrazol-4-yl]pyridine; and Example A-154 4-[3-(3-chlorophenyl)-1-methyl-pyrazol-4-yl]-2-methylpyridine.
The compounds of Examples A-155 through A-172 were synthesized in accordance with the chemistry described above (particularly Scheme II) and illustrated by many of the previously disclosed Examples by selection of the corresponding starting reagents:
Example A-155 c~
H
/ N
I \N
~N
NW ~Ph 5-(4-chlorophenyl)-N-phenyl-4-(4-pyridinyl)-1H-WO 98152940 PC'T/US98110436 pyrazol-3-amine: DSC 261 °C. Anal. Calc'd for C~oHISCIN, + 0.25 Hz0 (MW 351.32): C, 68.38, H, 4.30, N, 15.95.
Found: C, 68.25, H, 4.41, N, 15.74.
Example A-156 c~
i I H
\ N
I \N
/
N \ I HN~
5-(4-chlorophenyl)-N-methyl-4-(4-pyridinyl)-1H-pyrazol-3-amine : DSC 260 °C. Anal . Calc' d for ClsHI,CIN, + 0 . 125 H20 (MW 287.00): C, 62.77, H, 4.57, N, 19.52. Found: C, 62.78, H, 4.33, N, 19.22.
Example A-157 ci H
N
I / N
a ~~ ~N-N
5-(4-chlorophenyla-N,N-dimethyl-4-(4-pyridinyl)-1H
pyrazol-3-amine dehydrate: DSC 230 °C. Anal. Calc'd for CisHisClN, + 2 Hz0 (MW 334.81) : C, 57.40, H, 4.52, N, 16.73.
Found: C, 57.72, H, 4.85, N, 16.54.

Example A-158 F
H
/ N
~N
\ N\
N
5-(3-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 227 °C. Anal. Calc'd for C,6H15FN9 +
S 0.125 Hz0 (NW 284.57): C, 67.53, H, 5.31, N, 19.69.
Found: C, 67.60, H, 5.20, N, 19.84.
Example A-159 H
N
N
I~~ /N\
N,N-dimethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 222 °C. Anal. Calc'd for C1,H18N, +
0.25 Hz0 (MW 282.86): C, 72.19, H, 6.41, N, 19.81. Found:
C, 71.99, H, 6.46, N, 19.90.

WO 98/52940 PC'TIUS98/10436 Example A-160 H

N

~

N

I ~

~ N

N

N-methyl-5-(3-~methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3 amine: DSC 226 °C. Anal . Calc' d for C16H1sN, + 0. 125 HZO
(MW 266.58): C., 72.09, H, 6.05, N, 21.02. Found: C, 72.12, H, 6.12, N, 20.83.
Example A-161 H

/ N

\

N

~

I~ NH

N Et /

N=ethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 227 ~C. Anal. Calc'd for C1,H18N4 + 0.125 Hz0 (MW 280.61): C, 72.77, H, 6.47, N, 19.97. Found: C, 72.63, H, 6.40, N, 19.73.

Example A-162 / N
I ~N
NI~ \N
Et~ \Et N,N-diethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine: DSC 234 °C. Anal. Calc'd for C19Hz2Nq (MW 306.41): C, 74.48, H, 7.24, N, 18.29. Found: C, 74.12, H, 7.18, N, 18.13.
Example A-163 c~
H
/ N
I ~N
N
N I
/ Et \Et l0 5-(4-chlorophenyl)- N,N-diethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine: m.p. 260-261°C. Anal. Calc'd for C18H19C1N, (MW 326.83) : C, 66.15, H, 5.86, N, 17.14.
- Found: C, 66.03, H, 5.72, N, 17.23 . [

WO 98I529d0 PC'TIUS98/10436 Example A-164 c~
i H
\ N
I \ N
N I N
W
~0 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]morpholine:~ DSC 279 °C. Anal. Calc'd for C18H1,C1N,0 +
0.25 Hz0 (MW 345.32): C, 62.61, H, 4.96, N, 16.23. Found:
C, 62.52, H, 4.77, N, 16.52.
Example A-165 c~
i H
\ N\
I \N
I N
Nw ~ ~n-Pr 5-(4-chlorophenyl)-N-propyl-4-(4-pyridinyl)-1H-pyrazol-3-amine : DSC 244 °C. Anal . Calc' d for C1,H1,C1N, + 0 . 125 HZO
(MW 315.06): C, 64.81, H, 5.44, N, 17.78. Found: C, 64.94, H, 5.43, N, 17.78.

Example A-166 m /
H
\ N
fJ
N - /J H N
Ph Isolated as 5-(4-chlorophenyl)-N-(phenylmethyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine hydrate (2:1): DSC 237 °C.
Anal . Calc' d for C21H1,C1Na + 0 . 5 Hz0 (MW 369. 86) : C, 68.20, H, 4.63, N, 15.15. Found: C, 68.09, H, 4.55, N, 15.15.
Example A-167 H
\ N
\N
i HN
N /
Cl l0 1 Isolated as 5-(4-chlorophenyl)-N-(2-methoxyethyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine monohydrate: DSC 223 °C.
Anal. Calc'd for C1,H1,C1N40 + HBO (MW 346.82) : C, 58.87, H, 4.94, N, 16.15. Found: C, 58.59, H, 4.79, N, 16.02.

Example A-168 c~
NH
N
NI /
c~

1,1-dimethylethyl 4-[S-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate: DSC 251 °C.
Anal . Calc' d for C23Hz6C1N50 (MW 439. 95) : C, 62 .79, H, 5.96, N, 15.92. Found: C, 62.40, H, 5.82, N, 15.82.
Example A-169 c~
/
;H
N
N ' /J
c~
N
H
Isolated as 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H- .
pyrazol-3-yl]piperazine trihydrochloride: DSC 99 °C.

WO 98/52940 PCT/CiS98/10.t36 Anal . Calc' d fcr C18H:8C1N, + 3 HC1 (MW 449 . 21 ) : C, 48 . 13 , H, 4.71, N, 15.59. Found: C, 47.76, H, 5.07, N, 15.51.
Example A-I70 ci NH
N
N~ N
N
1- [5- (4-chlorophenyl) -4- (4-pyrid:inyl) -1H-pyrazol-3-yl] -4-methylpiperazine: m.p. 247-249 °C. Anal. Calc'd for C,9HZOC1N5 + 0.75 H20 (MW 367.33) : C, 62.12, H, 5.49, N, 19.06. Found: C, 62.45, H, 5.86, N, 19.32.
Example A-171 F
NH
N
~ I~ N
N /
N
0/ _0~
1,1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate: m.p. 243-244 °C. Anal. Calc'd for C2,Hz6FNsOz + 0.5 CH3CH~COZCHzCH3 (MW
467.55): C, 64.22, H, 6.47, N, 14.98. Found: C, 63.90, H, 6.61, N, 14.88.
Example A-172 F
NH
I
N
I~ N

c~
N
H
1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine trihydrochloride: m.p. 204-206 °C. Anal.
Calc' d for C18H1BFn5 + 3 HC1 + 0.5 H~0 (MW 441 .77) : C, 48.94, H, 4.79, N, 15.85. Found: C, 48.66, H, 4.88, N, 15.50.
1-[5-(4-chlorophenyl)-4-(4-pyridinvl)-1H-pyrazol-3-yl]piperazine: m.p. 264-265 °C. Anal. Calc'd for CieHieClNS + 0.125 H20 (MW 342.08) : C, 63.20, H, 5.30, N, 20.47. Found: C, 63.04, H, 5.36, N, 20.33.
Additional compounds that were synthesized in accordance with the chemistry described in Scheme II by selection of the corresponding starting reagents further include the compounds disclosed in Table 2.

~ N h O ~ O (~ O ~ O
N ~ N N N N Z N N N

fl C 00 ~ ~ ~ ~ h h ~D M
7 ~O ~ N M ~O t''.V M 00 c.~_.er ~D O ~G V1 'V V' O~ V1 h N

U _ N

V ~ O M M 00 C M h M

~O O ~O ~ ~O C O w1 op N

'd C _ _ O O h O~OO 00 N ~ ~ r ' ~i vi eyp ~ ~n ~ ~D ~1 v~ Q

H

H x T
U O~ v0 v1.N-.V' 00 N oC v0 00 Y1 ~p R
U
l L x ~ ~ e ~ ~:

C 00 M m1h ~D ....V~ ~D 00 r h a ~ ~, M ~ ~, a ~, h ~ ~. a M

w ~ O~ 00~ ~ ~ ~ ~ 00 N ~!1 E~ U ~w o Wo ~ .o ~o ~ ~w o v M ~

V ' ~ ~ 1~ O v0 O Ov N O~ C
V O

~ ~ ~

U c :o v h ~ Q

N ~ U
x N '~ N M C
_ R O U c O Ova~ M
M .... N Z
O Z ~ N Z_ L:.O Z
~, ~oU ~. 0 U ~ U '~
U .N,~.~ Z O Gz N N ,_"., ~ U
h x N O~ ~ ~n N N N ~_a '~'~ _ N N N x er U U '\ ~ U N V ~ U
U U U U U U

a _ L
R ~ r:r.r~.~ r'rr.~ .~ ~~..rte..nor.
~~
C ~ .C .C s s .G .~ t .C .C Cn ~ fn !%~CnCn fn Cn C%~(n V7 Cn L

o, r, c ~n~ ~ oo a~ o - ei M
t~ ~ ~ ~ ~ ~ h o0 00 0~000 a a a a a a a a a a a w SUB~~Tl3~JTE~(~~~

WO 98!52940 PCT/US98/10436 Example A-173 F
NH
I
N
N / HN~NHZ
HN
3HCt N- [S- (4-chlorophenyl) -4- [2- (phenylmethyl) amino] -4-pyridinyl]-1H-pyrazol-3-yl]-1,3-propanediamine, trihydrochloride Example A-174 ct \
/
NH
\ / N
N _ /J
N
C~
N
Bn 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(phenylmethyl)piperazine ~E~~~~

WO 98/52940 PCT/US98/IO~i36 Example A-175 F
~ ~ ;H
\ / N
N /
N
c N
H
Isolated as 4-[3-(4-fluorophenyl)-5-(1-piperazinyl)-1H-pyrazol-4-yl]pyrimidine, dihydrochloride C
Example A-176 /
;H
/ N
N _ /J
NHBoC
1,1-dimethylethyl [3-[(5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]propyl]carbamate WO 98/52940 PCTlUS98/10436 c~
Example A-177 /
NH
/ N
NI~ H

Isolated as N-[5-[4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,3-propanediamine, trihydrochloride monohydrate Example A-178 F
NH
N
N _ /J H N
HN
0~ 0 1,1-dimethylethyl [2-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]ethyl]carbamate WO 98/529d0 PCT/US98/10436 Example A-179 c~
off I/
N
i N
N I
c~
N
Boc 1,1-dimethylethyl 4-[5-(4-chlorophenyl)-1-f2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl)-1-piperazinecarboxylate Example A-180 F
NH
I
N
N' N
Boc 1,1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4-pyrimidinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate Example A-181 c~
NH
I
N
NHBoc 1,1-dimethylethyl [3-[[5-(4-chlorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazol-3-yl]amino]propyl]carbamate Example A-182 CI
v NH
~~\N
I
N
c N~
I
Et 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-ethylpiperazine ~E.T ( R~JLE 26~

WO 98/52940 PCT/US98/10436 , Example A-183 c~
/
NN
/
I \
N~ HN
3H~~
HzN
N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2-ethanediamine The compounds of Examples A-184 through A-189 were synthesized in accordance with the chemistry described above (particularly in Schemes I and IV) and illustrated by the previously disclosed Examples by selection of the corresponding starting reagents:
Example A-184 F

N

\

NH

F

v I

N /

4-(3-(2,6-difluorophenyl)-5-methyl-1H-pyrazol-4-yl ] pyridine : Anal . Calc' d for C15H11F2N3 : C, 66 . 42 ; H, 4.09; N, 15.49. Found: C, 66.20; H, 3.94; N, 15.16; m.p.

236.67 °C.
Example A-185 4-(3-(3-ethylphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine:
Anal . Calc' d for CI,Hl,N3 : C, 77 . 54 ; H, 6 . 51; N, 15 . 96 .
Found; C, 77.16; H, 6.27; N, 15.69. m.p. (DSC): 189.25 °C.
Example A-186 c~
4-[3-(3-chlorophenyl)-5-ethyl-1H-pyrazol-4-yl]pyridine:
Anal Calc' d for C16H1,C1N3~0. 1 mole HzO: C, 67. 15; H, 4 . 91;
N, 14.33. Found: C, 66.95; H, 5.00; N, 14.36. DSC:
176.18 °C.

4-[3-ethyl-5-(3-ethylphenyl)-1H-pyrazol-4-yl]pyridine:
Anal . Cal c' d for ClgHi9N3~ 0 . 1 mole HBO: C, 77 . 44 ; H, 6 . 93 ;
N, 15.05. Found: C, 77.39; H, 6.94; N, 14.93. m.p.
(DSC): 192.66 °C.
Example A-188 c~
4-[3-(4-chlorophenyl)-5-(1-methylethyl)-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C1,H16C1N2~0.4M EtOAc: C, 67.08; H, 5.81; N, 12.62. Found: C, 67.40; H, 6.15; N, 12.34.
Example A-187 WO 98152940 PCT/US98/10~36 Example A-189 F
IH

N
4-(3-cyclopropyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl] pyridine : Anal . Calc' d for C1,H14FN3 : C, 73 . 1 ; H, 5 . 05 ;
N, 15.04. Found: C, 73.23; H, 4.89; N, 14.63; m.p.. 239-240 °C.
The compound of Example A-190 was synthesized in accordance with the chemistry described above (particularly in Scheme III) and illustrated by the previously disclosed Examples by selection of the corresponding starting reagents:
Example A-190 HN~N\ Cr3 _..
\ ~J
N
4- [3- (4-fluorophenyl) -5- (trifluoromethyl) -1H-pyrazol-4-yl]pyridine This compound was prepared by the same procedure as WO 981529d0 PCT/US98/I Oa36 described for Example A-22 by replacing 3-(4'-pyridylacetyl)toluene with 1-fluoro-4-(4'-pyridylacetyl) benzene (prepared as set forth in Example A-19).
Anal . Cal c' d for C15H9F,N, : C, 58 . 64 ; H, 2 . 95 ; N, 13.68. Found: C, 58.57; H, 3.07; N, 13.31. m.p. (DSC):
281.94 °C.
The compounds of Examples A-191 through A-198 were synthesized in accordance with the chemistry described above (particularly in Scheme V) by selection of the corresponding starting reagents:
Example A-191 F
N
N
4-[5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine Step 1: Preparation of 1-(4-fluoro~henvl)-2-(4-pyridinvl)ethanone methylhvdrazone F
NNHMe N
~-[a-tW oroonenyi)-2-(4-pyr~d~ny )ethanone methy by°razone suesmu~s~rt~~

To a solution of 4-fluorobenzoyl-4'-pyridinyl methane (8.60 g, 0.04 mol) and methyl hydrazine (2.14 g, 0.044 mol) in 50 mL of ethanol was added two drops of concentrated sulfuric acid. The reaction mixture was stirred at room temperature overnight. After the removal of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium carbonate solution, washed with brine, and dried over magnesium sulfate. The filtrate was concentrated and the crude product was recrystallized from diethyl ether and hexane to afford 7.5 g of a yellow solid product (77% yield), 1-(4-fluorophenyl)-2-(4-pyridinyl)ethanone methylhydrazone.
Step 2: Preparation of 4-f5-(cyclo"propyl-3-(4-(fluorophenyl)-1-methyl-1H-wrazol-4-yllpyridine To a solution of sodium hexamethyldisilazide (5.5 mL, 1.0 M in THF) at 0 °C was added a solution of the compound prepared in step 1 (0.67 g, 0.0028 mol) in l0 mL
of dry THF dropwise. The dark brown solution was stirred at this temperature for 30 minutes. Then a solution of methyl cyclopropanecarboxylate (0.34 g, 0.0034 mol) in 5 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 3 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was wished with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane/acetone, 10:9:1) to give 0.45 g of product, 4-[5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine, as a light yellow solid (55%
yield), mp: 129-130 °C; 1H NMR (CDCL3): b 8.53 (m, 2H), ' 7.32 (m, 2H), 7.14 (m, 2H), 6.97 (m, 2H), 4.00 (s, 3H), 1.83 (m, 1H), 0.95 (m, 2H), 0.36 (m, 2H); Anal. Calc'd For C18H1sFN,: C, 73.70; H, 5.50; N, 14.32. Found: C, WO 98152940 PCTlUS98/10436 73.63; H, 5.57; N, 14.08.
Example A-192 ~ F
N
N
~OH
5-cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-etranol Step 1: Preparation of 1-(4-fluorophenyl)-2-(4-ovridinyl)ethanone (2-hydroxyethyl)hydrazone F

N
1 0 ~-[4-fluorophenyl]-2-[4-pyridinyl]ethanone [2-hydroxyethyl]hydraZOne To a flask containing hydroxyethyl hydrazine (3.4 g, 0.04 mol) at 80 °C was added 4-fluorobenzoyl-4'-pyridinyl methane (8.6 g, 0.04 mol) portionwise. The yellow oil was stirred at this temperature overnight. The cooled reaction mixture was dissolved with hot ethyl acetate and then triturated with hexane to give 8.9 g of product, 1-(4-fluorophenyl) -2- (4-pyridinyl) ethanone (2-hydroxyethyl)hydrazone, as a yellow crystal (81%), mp:
122-123 °C.
mL, 1.0 M in THF) at 0 °C

WO 98/52940 PCTlUS98/10436 Step 2 ~ Pret~aration of 1- (a-fl uoro,-phenyl) -2- (4-p_yridinyl) ethanone (2- ( ( (1, 1-dimethylethyl)dimethylsilylloxylethyllhvdrazone F
/ NNHr_H~CHZ05~-t-Buuez N /
i-(a-riuorophenyi)-2-[4-pvrm ~nyi7etnanone [2-[[Ci,i-a~metny etnyy o~metny sm yi]oxy)etny ]nyorazone To a solution of the 1-(4-fluorophenyl)-2-(4-pyridinyl)ethanone (2-hydroxyethyl)hydrazone prepared in step 1 (2.73 g, 0.01 mol) and (1,1-dimethylethyl)dimethylsilyl chloride (1.5 g, 0.01 mol) in 25 mL of DMF was added imidazole portionwise. The reaction mixture was stirred at room temperature overnight. Water was added and extracted with ethyl acetate, the organic layer was washed with water, washed with brine, dried over magnesium sulfate and filtered.
The filtrate was concentrated to give 3.8 g of crude product , 1- ( 4 - f luorophenyl ) -2 - ( 4 -pyridinyl ) ethanone [ 2 -[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]hydrazone, as a yellow oil that was used in the next step without further purification. .

WO 98/52940 PCTIUS98110436 , Step 3: S-cyclonropvl-1-f2-[f(1,1-dimethvlethvl) dimethvl5ilylloxy)ethyl)-3,4-diphenyl-1H-pyrazole i ~N
/ \NCHZCH~OSi-t-8uMe2 5-cyciopropW -i-[2-[[Ci.~-°~metny etnyi~
o~metny sy i]oxy)etnyi]-3,a-dipnenyi-1H-pyrazoie To a solution of sodium hexamethyldisilazide (4.2 mL, 1.0 M in THF) at 0 °C was added a solution of the compound prepared in step 2 (0.78 g, 0.002 mol) in ZO mL
of dry THF dropwise. The dark brown solution was stirred at this temperature for 30 minutes. Then a solution of methyl cyclopropanecarboxylate (0.27 g, 0.0026 moI) in 5 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 3 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 0.30 g of product, 5-cyclopropyl-1-[2-[[(1,1-dimethylethyl) dimethylsilyl)oxy)ethyl)-3,4-diphenyl-1H-pyrazole, as a light yellow oil (35% yield), 1H NMR
(CDCL,) : b 8.53 (m, 2H) , 7.32 (m, 2H) , 7. 14 (d, J = 5.6 Hz, 2H) , 6. 97 (m, 2H) , 4 .47 (t, J = 4.8 Hz, 2H) , 4.14 (t, J = 4.8 Hz, 2H), 1.93 (m, 1H), 0.95 (m, 2H), 0.87 (s, 9H) , 0 . 41 (m, 2H) ; Anal . Calc' d For CZSH,zFN,OSi : C, 68 . 61 ;
H, 7.37; N, 9.60. Found: C, 68.39; H, 7.81; N, 9.23.
STiU1'E SHEET (RUi.E ~

WO 98/52940 PCT/US98/(O~t36 Step 4: Preparation of 5-cvclopropvl-3-(4-fluoro~henyl)-4-(4-pyri~dinyl)-1H-pvrazole-1-ethanol To a solution of the compound prepared in step 3 (0.27 g, 0.00062 mol) in S mL of THF was added tetrabutylammonium fluoride (1.9 mL of 1.0 M THF
solution) at room temperature. After 1 hour, water was , added and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 9:1) to give 0.16 g of product, 5-cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol, as a pale yellow solid, mp: 155-157 °C; 1H NMR (CDCL,): b 8.53 (br s, 2H), 7.32 (m, 2H), 7.14 (d, J = 5.6 Hz, 2H), 6.97 (m, 2H), 4.42 (t, J = 4.8 Hz, 2H), 4.14 (t, J = 4.8 Hz, 2H) , 1 . 83 (m, 1H) , 0. 93 (m, 2H) , 0.35 (m, 2H) ; Anal .
Calc' d For C19H18FN3~: C, 70.57; H, 5.61; N, 12. 99. Found:
C, 70.46; H, 5.87; N, 12.84.
Example A-193 F
N
N~OH
N / /
N OMe 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol To a solution of sodium hexamethyldisilazide (7.4 mL, 1.0 M in THF) at 0 °C was added a solution of the compound prepared in step 2 of Example A-192 (1.25 g, 0.0034 mol) in 15 mL of dry THF dropwise. The dark brown solution was stirred at this temperature for 30 minutes.
' Then a solution of methyl 4-(2-methoxy)pyridinecarboxylate (0Ø59 g, 0.0035 mol) in 5 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 3 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 0.28 g of product, 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol, as a yellow solid, mp: 168-169 °C; 'H NMR
(CDCL3): b 8.42 (m, 2H), 8.20 (dd, J = 0.7, 5.2 Hz, 1H), 7.37 (m, 2H), 7.02 (m, 2H), 6.95 (m, 2H), 6.71 (dd, J =
1.4, 5.2 Hz, 1H), 6.66 (t, J = 0.7 Hz, 1H), 4.20 (m, 2H), 4 . 14 (m, 2H) , 3 . 95 (s, 3H) ; Anal . Calc' d for C22H19FN40z : C, 67.86; H, 4.91; N, 14.35. Found: C, 67.46; H, 5.08; N, 14.03.
F
N
N
~OS i ( t-Bu)Me2 N ~!~
~N~OMe 4- [1- [2- [ [ (1, 1-dirnethylethyl) dimethylsilyl] -oxy]ethyl]-3-(4-fluorophenyl-4-(4-pyridinyl)-1H-pyrazol-5-yI]-2-methoxypyridine PCT/US98/10.t36 A second compound, 4-(1-(2-[[(1,1-dimethylethyl) dimethylsilyl]oxy]ethyl]-3-(4-fluorophenyl-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2-methoxypyridine also was isolated from the above reaction as a yellow oil by chromatography. 1H NMR (CDCL3): b 8.45 (m, 2H), 8.20 (m, 1H) , 7.40 (m, 2H) , 7.04 (m, 2H) , 6. 93 (m, 2H) , 6. 31 (m, 2H), 4.24 (m, 2H), 4.14 (m, 2H), 3.98 (s, 3H), 0.83 (s, 9H), 0.02 (s, 6H).
Example A-194 F

N

\ N

O

OH

N /

\

H

4- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl]-2(1H)-pyridinone To a solution of 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol (0.28 g, 0.0006 mol) in 5 mL of acetic acid was added 3 mL of 48%
hydrobromic acid. The reaction mixture was heated at reflux for 3 hour. The cooled mixture was then treated with water, basified with ammonium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and , filtered. The filtrate was concentrated and purified by chromatography on silica gel (MeOH/CH~Clz/NH40H, 5:94:1) to give 0.07 g of product, 4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl)-2(1H)-WO 98/52940 PCT/US98/1pa36 pyridinone, as a yellow solid mp: 250-251 (32% yield), C; 'H NMR (DMSO-d b) : b (d, J = 5.
11 . 74 0 (S, 1H) , 8.45 Hz, 2H), 7.35 (m, 3H), 7.16 (m, 2H), 7.03 d, J = 5.0 ( ' Hz, 2H), 6.37 (s, 1H), 6.05 (d, ~T = 5.2 1H), 5.0 (m, Hz, 1H), 4.13 (m, 2H), 3.81 (m, 2H); Anal. Calc'd for C~:H;,FNq020.2 HzO: C, 66.06; H, 4.65; N, 67. Found:
14. C, 66.31; H, 4.49; N, 14.27.

Example A-195 F
N
f \ N
~GH
N
N, w_0 1-acetyl-4-(3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2(IH)-pyridinone I-acetyl-4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-y1J-2(1H)-pyridinone was obtained as a byproduct of the reaction of Example A-194 in the form of a yellow-solid (38% yield), mp: 220-221 °C; 1H NMR (CDC13) : b 8.50 (m, 2H) , 7.39 (m, 3H) , 7.02 (m, 4H) , 6. 59 (m, 1H) 6. 08 (dd, J = 1.4, 5.2 Hz, 1H) , 4 .52 (t, J = 6.0 Hz, 2H), 4.43 (t, J = 6.0 Hz, 2H), 2.04 ' (s, 3H) ; Anal . Calc' d for Cz3H19FN'03~0.3 H20: C, 65.46; H, 4.63; N, 13.28. Found: C, 65.09; H, 4.64; N, 12.99.

Example A-196 F
~Ofi Ethyl 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]cyclopropanecarboxylate To a solution of sodium hexamethyldisilazide (17.0 mL, 1.0 M in THF) at 0 °C was added a solution of the compound prepared in step 1 of Example A-192 (1.37 g, 0.005 mol) in 20 mL of dry THF dropwise. The dark brown solution was stirred at this temperature for 30 minutes.
Then a solution of diethyl 1,2-cyclopropanedicarboxylate (1.12 g, 0.006 mol) in 10 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed, with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 8:2) to give 0.18 g of product, ethyl 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl) 1H-pyrazol-5-yl]cyclopropanecarboxylate, as a light yellow oil (35% yield) , 1H NMR (CDCL3) : b 8 .55 (m, 2H) , , 7.32 (m, 2H), 7.11 (m, 2H), 6.97 (m, 2H), 4.38 (m,2H), 4.16 (m, 4H), 2.47 (m, 1H), 1.53 (m, 2H), 1.26 (t, J=7.0 Hz, 3H), (m, 2H), 0.90 (m, 2H); Anal. Calc'd for C~~Hz2FN303~0.25 HBO: C, 66.07; H, 5.67; N, 10.51 Found: C, WO 98/52940 PCT,~LJS98/10436 65.89; H, 5.80; N, 9.95.
Example A-197 F
_ NH
N
N
COzH
2- [3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4- (4-pyridinyl) -1H-pyrazol-5-yl]cyclopropanecarboxylic acid To a solution of ethyl 2- [3- (4-fluorophenyl) -1- (2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]
cyclopropanecarboxylate prepared in accordance with Example A-196 (0.21 g, 0.00045 mol) in 10 mL of methanol was added a solution of sodium hydroxide (0.09 g, 0.0022 mol) in 2 mL of water. The reaction mixture was stirred at reflux for 6 hours. After the solvent was removed, the residue was dissolved with 10 mL of 1N HC1 and stirred for 30 minutes. The pH was then adjusted to 5-6 by addition of 1N sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium and filtered.
The filtrate was concentrated and the crude was purified ~ by recrystallization from ethanol and ether to give 0.1 g of product, 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl)cyclopropanecarboxylic acid, as a white solid (60% yield), mp: 253-255 °C; 1H NMR
(CD30D) : 8 8.46 (m, 2H) , 7.32 (m, 2H) , 7.25 (m, 2H) , 7. 04 (m, 2H), 4.39 (t, J = 5.0 Hz, 2H), 4.03 (m, 2H), 2.60 (m, 1H), 1.51 (m, 2H), 0.97 (m, 2H); Anal. Calc'd For C20H18~3~3 ~ C, 65 . 3 9 ; H, 4 . 94 ; N, 11 . 44 . Found : C, 64 . 92 ;
H, 4.77; N, 11.20.
Example A-198 F
.
fJ
fJ
OOH
N ~ /~NH
N=J
3-(4-fluorophenyl)-5-(4-imidazolyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol Steo 1: Preparation of methyl 1-(f2-(trimethylsilyl) ethoxv]methyl]-1H-,pyrrole-3-carboxvlate COZMe TMS~O~N~N
methyl 1-[[2-(trimethylsilyl)ethoxy]methyll-1H-pyrrole-3-carboxylate To a suspension of sodium hydride (1.0 g, 0.025 mol) in 50 mL of DMF was added methyl 4-imidazolecarboxylate (2.95 g, 0.023 mol) portionwise at room temperature. The mixture was stirred at room temperature for 0.5 hours.
Then SEM-C1 (4.17 g, 0.025 mol) was added dropwise over 5 minutes. The reaction mixture was stirred for 4 hours and quenched by adding water. The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude PC?/US98/10436 was purified by chromatography on silica gel (ethyl acetate/hexane, 8:2) to give 4.0 g of the major regioisomer as a clear oil.
Step 2: Preparation of 4-(1-(2-(((1 1 dimethvlethyl) - dimethylsilylloxylethvll-3-(4 fluoronhenvl 5 (1 (((2 trimethvsilyl)ethoxylmethyl-1H imidizol 4 yll 1H pvrazo~
4-yllpyridine F
N
\ ~ N
~05~[t-Bu~Me2 N /
~N
N --i TMS
4-[1-[2[[(1,1-dimethylethyl)dimethylsilyl]-oxy] ethyl] -3- (4-fluorophenyl) -5- [1- [ [2-trimethylsilyl)ethoxy]methyl]-1H-imidazol-4-yl]-1H-pyrazol-4-yl)pyridine To a solution of sodium hexamethyldisilazide (4.5 mL, 1.0 M in THF) at 0 °C under Ar was added a solution of the compound prepared in step 2 of Example A-192 (0. 8 g, 0.002 mol) in 10 mL of dry THF dropwise. The dark brown solution was stirred at this temperature for 30 minutes. Then a solution of the compound prepared in step 1 of the present Example (0.54 g, 0.0021 mol) in 5 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 1 hour. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 8:2) to give 0.98 g of product as a light yellow oil which solidified upon standing (91% yield), mp: 79-80 °C; 1H NMR
(CDCL3) : b 8.48 (d, J = 6.0 Hz, 2H) , 7.68 (d, J = 1.3 Hz, , 1H), 7.38 (d, J = 6.0 Hz, 2H), 7.10 (m, 2H), 7.00 (m, 2H), 6.93 (d, J = 1.3 Hz , 1H), 5.25 (s, 2H), 4.53 (t, J
- 6.0 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H), 3.84 (t, J = 8.0 Hz , 2H) , 0.92 (t, J = 8. 0 Hz, 2H) , 0.84 (s, 9H) , 0. 021 (s, 18H) ; Anal. Calc'd For C31H44~502S12: C, 62.70; H, 7.47; N, 11.79. Found: C, 62.98; H, 7.74; N, 11.88.
Step 3: Preparation of 3-(4-fluorophenyl) 5 (4 imidazolyl)-4-(4-pyridinyl)-1H-pvrazole 1 ethanol To a solution of the compound prepared in step 2 of the present Example (0.54 g, 0.001 mol) in 10 mL of THF
was added a solution of tetrabutylammonium fluoride (1.0 M in THF). After the mixture was heated at reflux for 3 hours, the solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified on silica gel (methylene chloride/methanol, 95:5) to give 0.22 g of the product, 3-(4-fluorophenyl)-5-(4-imidazolyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol, as a white solid (63% yield), mp:
227-228 °C; 1H NMR (DMSO-d6): b 8.45 (m, 2H), 7.83 (s, 1H), 7.35 (m, 2H), 7.15 (m, 4H), 7.09 (s, 1H), 5.20 (br s, 1H), 4.32 (s, 2H), 3.81 (m, 2H); Anal. Calc'd For C19H16~5~ ~ C. 65 . 32 ; H, 4 . 62 ; N, 20 . 05 . Found: C, 64 . 98 ;
H, 4.55; N, 19.79.
The compound of Example A-199 was synthesized in accordance with the chemistry described above (particularly in Scheme VI) by selection of the corresponding starting reagents:
Example A-199 N~~
~NH
N
CI
4-[3-(4-chloro-3-methylphenyl)-1H-pyrazol-4-yl]pyridine Anal. Calc'd for C15H1zN3C1 (269.74) : C, 66.79; H, 4.48; N, 15.58. Found: C, 66.57; H, 4.15; N, 15.54. m.p. (DSC):
198.17 °C.
The compounds of Examples A-200 through A-202 were synthesized in accordance with the chemistry described above (particularly in Scheme VII) by selection of the corresponding starting reagents:
ExampleA-200 w\ ~--~H

N
\ ~N' . . I H
F
5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid WO 98/52940 PCT/US98/10436 , A mixture of 4-[3-(4-fluorophenyl)-5-methyl-1H-pyrazol-4~-yl]pyridine prepared as set forth in Example A-4 (5.83 g, 24.0909 mmol) and potassium permanganate (7.6916 g, 48.1818 mmol) in water (7.5 ml) and tert-butanol (10 ml) was heated at reflux for 6 hours (or until all the potassium permanganate was consumed). The mixture was then stirred at room temperature overnight and then diluted with water (150 ml). Manganese dioxide was removed from the mixture by filtration. The filtrate l0 was extracted with ethyl acetate to remove unreacted starting material. The aqueous layer was acidified with 1~N HC1 to increase the pH to about 6. A white precipitate fbrmed, was collected by filtration, washed with water, and dried in a vacuum oven to give 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid (isolated as the monohydrate salt) (2.9777 g, 43.7 Anal. Calc~d for ClsHION,FO2.H20 (283 + 18) : C, 59.80;
H, 4.01; N, 13.95; Found: C, 59.48; H, 3.26; N, 13.65. MS
(MH') : 284 (base peak) .
Example A-201 N i \ OH
~N
\ ~N
H
F
5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-methanol To a suspension of 5-(4-fluorophenyl)-4-(4- , pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate prepared in accordance with Example A-200 (0.526 g, 2.0 mmol) in dry THF (15 ml) at reflux under nitrogen, a solution of 1N lithium aluminum hydride in THF (4.0 ml, 4.0 mmol) was added dropwise over 15 minutes. A
precipitate formed. The mixture was boiled for an additional hour. Excess lithium aluminum hydride was then decomposed by cautiously adding a solution of 4N
potassium hydroxide in water (0.5 ml). Upon hydrolysis, a white salt precipitated. After the addition was complete, the mixture was heated at reflux for 15 minutes. The hot solution was filtered by suction through a Buchner funnel, and remaining product was extracted from the precipitate by refluxing with THF (15 ml) for 1 hour, followed again by suction filtration. The combined filtrates were concentrated under reduced pressure. The 'resulting residue was taken into ethyl acetate, washed with water and brine, dried over MgS04 to give a crude product (0.45 g). Recrystallization of the crude product from methanol gave 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-methanol (0.2808 g, 56.5%). DSC:
260.26 °C; Anal. Calc'd for C15H1zN,F0 (269) : C, 66.91; H, 4.49; N, 15.60; Found: C, 66.07; H, 4.63; N, 15.20. MS
(MH') : 270 (base peak) .
Example A-202 N% o N NH
~N
\~ N
H
F
1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine SN~ET (RU~.E 26) Step 1: Preparation of 1 1-dimethylethyl 4-f~5 (4 fluorophenvl>-4-(4-pvridinyl)-IH-pyrazol-3-yllcarbonyll 1-piDerazinecarboxylate N% o N~NBoC
N
\~ ~ H ~
F
To a solution of 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid, monohydrate prepared in accordance with Example A-200 (0.9905 g, 3.5 mmol) and 1-hydroxybenzotriazole (0.4824 g, 3.57 mmol) in DMF (20 ml) at 0 °C under nitrogen, 1-(3-dimethylaminopropyl)3-ethylcarbodiiminde hydrochloride (0.6984 g, 3.57 mmol, Aldrich Chemical Co.) was added. The solution was ' stirred at 0 °C under nitrogen for 1 hour then 1-butoxycarbonylpiperazine (0.6585 g, 3.5 mmol) was added followed by N-methylmorpholine (0.40 ml, 3.6 mmol). The reaction was stirred from 0 °C to room temperature overnight. After 19 hours, the solvent was removed under reduced pressure, and resulting residue was diluted with ethyl acetate, washed with saturated NaHCO, solution, water and brine, and dried over MgSO,. After filtration, the solvent was removed under reduced pressure to give a crude product (1.7595 g). 1,1-Dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonylJ-1-piperazinecarboxylate (1.2372 g, 78.4%) was obtained by chromatography. Anal. Calc'd for C2,Hz6N503F. (451) : C, 63.85; H, 5.80; N, 15.51; Found: C, 63.75; H, 5.71; N, 15.16. MS (MH') : 452 (base peak) .

WO 98/52940 PC'T/US98/10436 Std 2: Preparation of 1-[(5-(4-f~uorophenyl) 4 (4 pvridinul)-1H-wrazol-3-yllcarbonyllpiperazine bis(trifluoroacetate) monoh~rdrate A solution of the compound prepared in step 1 (0.1804 g, 0.4 mmol) in methylene chloride (1.0 ml) and . TFA ( 0.3 ml) was stirred at room temperature under nitrogen for 2 hours. The solvent was removed under reduced pressure and TFA was chased by methylene chloride and methanol. The resulting colorless oily residue was dried in a vacuum oven overnight to give 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-y1]carbonyl]piperazine (isolated as the bis(trifluoroacetate), monohydrate salt) (0.24008, 100%) as a white solid. Anal. Calc'd for Cl9HieNsOF.2CF3COOH.H20(351 + 228 + 18) : C, 46.24; H, 3.71;
N, 11.72; Found: C, 45.87; H, 3.43; N, 11.45. MS (MH'):
352 (base peak) .
The compounds of Examples A-203 through A-206 were synthesized in accordance with the chemistry described above (particularly in Scheme VIII) by selection of the corresponding starting reagents:
Example A-203 N
\

N-N

4-(1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl)pyridine s s~rt~~s~

WO 98/52940 PCT/L'S98/10436 N i N
N
4-(1,3-dimethyl-5-phenyl-1H-pyrazol-4-yl]pyridine A 60~ dispersion of sodium hydride (41 mg, 0.00172 moles) (prewashed with hexane) in mineral oil (69 mg) was added with 5 ml of dioxane to a stirred solution of 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine (200 mg, 0.00086 moles) (prepared as set forth in Example A-2) in 50 ml of dioxane. After 3 hours a solution of CH3I (122 mg, 0.00086 mole) in 10 ml dioxane was added and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated to a solid. The products were partitioned between water (15 ml) and ethyl acetate (50 ml). The organic layer was dried over Na2S09, filtered and concentrated to a solid. The products were purified and separated by radial chromatography. NMR (NOE
experiments) showed that the first component off the column (the minor component) was 4-(1,3-dimethyl-5-phenyl-1H-pyrazol-4-yl]pyridine, and the second material off the column was 4-(1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl)pyridine.
Major isomer (4-(1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl)pyridine): m.p.: 94-99 °C. Anal. calc'd for ClsHlsN3'0 ~ 1MH20: C, 77.08; H, 6. 06; N, 16. 85. Found: C, 76.59; H, 5.70; N, 16.62 ' Example A-204 N'~
~ 'N
N
CI
4-[3-(4-chlorophenyl)-1,5-dimethyl-1H-pyrazol-4-yl]pyridine CI
\ ~ N
' /N
/ w N ~~
4-[5-(4-chlorophenyl)-1,3-dimethyl-1H-pyrazol-4-Yl]pyridine (the compound of Example A-32) 4-[3-(4-chlorophenyl)-1,5-dimethyl-1H-pyrazol-4-yl]pyridine and 4-[5-(4-chlorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl]pyridine were prepared by the same procedure as described for Example A-203 by replacing 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine with 4-(3-(4-chlorophenyl)-5-methyl-1H-pyrazol-4-yl)pyridine (prepared as set forth in Example A-7).
Major Isomer (4-[3-(4-chlorophenyl)-1,5-dimethyl-1H-pyrazol-4-yl] pyridine) : Anal . calc' d for C16H14N3~1 (283.76): C, 67.72; H, 4.97; N, 14.81; Found: C, 67.45;
H, 4.71; N, 14.63. m.p. (DSC): 190.67 °C.

WO 98/52940 PC'T/US98/10436 Minor Isomer (4-[5-(4-chlorophenyl)-1,3-dimethyl-1H- , pyrazol-4-yl]pyridine): m.p.. 82-88 °C. Anal. calc'd for Cl6HmN~C1 : C, 67 . 72 ; H, 4 . 97 ; N, 14 . 81 ; Found : C, 67.56; H, 4.96; N, 14.73.
Example A-205 4-[5-ethyl-1-methyl-3-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine \ ~ N
N
4-(3-ethyl-1-methyl-S-(3-methylphenyl)-1H-pyrazol-4-yl ] pyridine 4-[5-ethyl-1-methyl-3-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine and 4-(3-ethyl-1-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine were prepared by the same ' procedure as described for Example A-203 by replacing 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine with 4-(3-(4-methylphenyl)-5-ethyl-1H-pyrazol-4-yl)pyridine (prepared as set forth in Example A-45).
Major Isomer (4-[5-ethyl-1-methyl-3-(3-methylphenyl)-1H-v pyrazol-4-yl]pyridine) : Anal. Calc'd for C,BH,9N0,~0.45 MHO: C, 75.73; H, 7.03; N, 14.77. Found: C, 76.03; H, 6.87 N, 14.28.
Minor Isomer (4-[3-ethyl-1-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine): Anal. Calc'd for C18H19N~3~0.30MHz0: C, 76.46; H, 6. 99; N, 14 . 86. Found: C, 76.58; H, 6.,98; N, 14.63.
Example A-206 N i ~N-Ec _ /
N
CI
4-[3-(4-chlorophenyl)-1-ethyl-5-methyl-1H-pyrazol-4-yl] pyridine : Anal . Calc' d for C17H16N3C1 (297 . 79) : C, 68.57; H, 5.42; N, 14.11. Found: C, 68.33; H, 5.27; N, 14.08; m.p. (DSC) 164.36 °C.
Example A-207 N
\ \
/N
N
\ Et /
ci 4-[3-(4-chlorophenyl)-2-ethyl-5-methyl-1H-pyrazol-4-yl]pyridine: Anal. Calc'd for C"H16N3C1 (297.79) : C, 68.57; H, 5.42; N, 14.11. Found: C, 68.25; H, 5.36; N, 13.74; m.p. (DSC) 153.46 °C.
The compounds of Examples A-208 and A-209 were prepared in accordance with the chemistry described above (particularly in Scheme IX):
Example A-208 F
/ N
\N-H
N ~ /~ H
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl)pyridine Sten 1 : Preparation of 4-fluo~-obenzovl-4' -z~yri~l methane To a mixture of 4-picoline (32.6 g, 0.35 moles) and ethyl-4-fluorobenzoate (50.458, 0.3 moles), maintained at °C, was added lithium bis(trimethylsilylamide) (600 mL
(TM)) in a steady but rapid stream so as to maintain 20 aritbient temperature. The initial yellow solution turned into a suspension which was then stirred for an additional 2 hours. Toluene (250 mL) was added and the mixture cooled to 0 °C. The reaction mixture was quenched with concentrated HC1 at 0 °C to lower the pH to about 7. The organic layer was separated and the aqueous , layer re-extracted with of toluene (100 mL). The organic -layer was dried (sodium sulfate) and concentrated, to furnish a yellow solid which on trituration with hexanes .
(200 mL) provided the pure desoxybenzoin, 4-ET(RU~t.EE6~

fluorobenzoyl-4'-pyridyl methane, in 90% yield (58g). 1H
NMR was consistent with the proposed structure.
Steo 2:
To a suspension of the desoxybenzoin prepared in step 1 (30g, 0.14 moles) in tetrahydrofuran (50 mL) was added dimethylformamide dimethyl acetal (50 mL) and the mixture stirred at ambient temperature for two days. The solution was then concentrated to dryness and the solid paste obtained was triturated with hexanes (150 mL) to furnish a yellow solid which was of sufficient purity (as determined by NMR) and was used for the next step without additional purification. Yield: 33.9 g (90%). 1H NMR was consistent with the proposed structure.
Step 3:
The vinyl amine prepared in step 2 (33.9g, 0.1255 moles) was dissolved in 125 mL of ethanol and cooled to 0 °C. Hydrazine hydrate (B.Og of anhydrous or l6.Og. of hydrate, 0.25 moles) was they. added in one portion. The mixture was stirred well and allowed to warm up to ambient temperature for a total reaction time of 3 hours.
The mixture was concentrated and taken up in 200 mL of chloroform. After washing with water (100 mL), the organic layer was extracted with 150 mL of 10% HC1. The water layer was then treated with 0.5 g of activated charcoal at 70 °C for 10 minutes, filtered through celite and neutralized cautiously to pH 7 - 8 with vigorous stirring and cooling (20% sodium hydroxide was used). The fine off-white precipitate was filtered and dried to give 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine. Yield:
27.38. (91%). Mass spectrum: m/z = 240. 'H NMR was ' consistent with the proposed structure. Anal. calc'd for Cl,HIaFN3: C, 70.28; H, 4.21; N, 17.56. Found: C, 70.11; H, 4.33; N, 17.61.

WO 98/52940 PCT/US98/10436 , Example A-209 c~

i NH
~

N

N /

4-[3-(2-chlorophenyl)-1H-pyrazol-4-yl]pyridine This compound was prepared by the same procedure described for Example A-208 using the corresponding starting reagents.
Anal . Calc' d for Cl,HIOC1N3 : C, 65 . 76 ; H, 3 . 94 ; N, 16 . 43 .
Found: C, 65.22; H, 3.91; N, 16.50, m.p. (DSC): 208.46 °C.
The compounds of Examples A-X1.0 and A-211 illustrate were prepared in accordance with the chemistry described above (particularly in Scheme X):
Example A-210 F
/ N
~ ~ ~oH
N
\ \
N, / H
3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol SU~~TTTUTE SI~cT (F~k..E ~6~

PCT/US98/10436 , The desoxybenzoin prepared in step 1 of Example A-208, 4-fluorobenzoyl-4'-pyridyl methane, (12.7g, 0.059 moles) was mixed with 90% hydroxyethyl hydrazine (5.3g, 0.062 moles) in 30 mL of ethanol containing 0.5 mL of acetic acid in a 500 mL Erlenmeyer flask. After gentle boiling (1 hour), a small sample was evacuated at high vacuum and examined by 1H NMR to confirm completion of hydrazone formation. On cooling to ambient temperature, the reaction mass solidified to a yellow cake. DMF
dimethylacetal (36 mL, 0.27 moles) was then added and the mixture heated to 80C for lOmin, at which point all the solids dissolved and a clear yellow viscous solution was obtained. The'reaction mixture was immediately allowed to cool slowly to 25 °C, and water (20 mL) was added dropwise with stirring, at which point a cloudy yellow oily suspension was obtained. The solution was now warmed to approximatel~~ 50-60 °C, whereupon the solution turned clear yellow. Slow cooling to ambient temperature with stirring (a crystal seed if available speeds up the process) results in a copious formation of crystals.
Suction filtration followed by washing with 10% ethanol-water (50 mL), followed by drying, furnishes 3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol as a light yellow crystalline solid. Re-heating the filtrate to clarity as before, followed by cooling, yields additional product. The third and fourth recovery from the mother liquor on standing overnight furnishes the remaining 3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol. Total yield: {12.3 + 3.3 + 0.4 + 0.4~ -16.48. (97.6%). Mass spectrum, m/z = 284. 1H NMR was consistent with the proposed structure. Anal. calc'd for . C16H"FN30 + HzO: C, 63.78; H, 5.35; N, 13.95. Found: C, ' 63.55; H, 5.07; N, 13.69.
st~~r~ur~sc~rc~x.~~

WO 98/52940 PCT/US98/10436 , Example A-211 F
_ N
N~OH
N~ N
3-(4-fluorophenyl)-4-(4-pyrimidinyl)-1H-pyrazole-1-ethanol This compound was prepared by the same procedure as described for Example A-210 except that the 4-picoline used to synthesize the desoxybenzoin was replaced with 4-methyl-pyrimidine.
The compound of Example A-212 was prepared in accordance with the chemistry of Scheme XI:
F
Example A-212 N
~i 1 S N~~ ~H
4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)pyridine The vinyl amine prepared in Step 2 of Example A-208 20 (S.Og, 0.0185 moles) was taken up in ethanol (75mL) and cooled to 0 °C. Methyl hydrazine (1.7g, 0.037 moles) in ethanol (75mL) was added in one portion while maintaining the temperature at 0 to 10 °C. After 3 hours at ambient temperature the solvent was removed and the residue taken 25 up in methylene chloride (15o mL) and water (100 mL). The organic layer was separated, dried and concentrated to provide the crude regio-isomeric mixture as a light tan ' colored solid (80:20 by NMR in favor of the title compound). The crude isomeric mixture was taken up in , 30 10% HC1 (100 mL) and washed with methylene chloride (100 Si~T'(~E86) WO 98/52940 PCT/LS98/10.136 mL) and the water layer treated with activated charcoal (0.5g). After filtration through Celite, the solution was neutralized with sodium hydroxide (20%) to pH 8 witi:
good stirring and cooling. The cream colored precipitate was filtered, washed with water and dried. The solid (5 g) was dissolved in hot 10% heptane/toluene (70 mL) and allowed to cool slowly, first to ambient temperature and then to 15 °C. Scratching the sides of the flask starts the crystallization process. After 2 hours of standing, the solids formed were filtered, washed with cold 50%
toluene/heptane (25 mL) followed by hexane (25 mL) and dried to yield the pure title compound. 1H NMR confirmed the structure'(including regiochemistry using NOE
experiments). Yield: 2.1g. (45%). Mass spectrum, m/z =
254 (base peak) . Anal . calc' d for C15H1~FN3 + 0 . 2 Hz0 : C, 70.15; H, 4.86; N, 16.4. Found: C, 70.18; H, 4.6; N, 16.47.
The compound of Example A-213 was prepared in accordance with the chemistry of Scheme XII:
Example A-213 F
N- H
HN
~OH
2- [ [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl]amino]-1-butanol WO 98/529d0 PCTIUS98/10436 An intimate mixture of 2-fluoro-pyridinyl pyrazole (0.2g, (prepared by the same procedure as described for Example A-210 except that the 4-picoline used to synthesize the desoxybenzoin was replaced with 2-fluoro-4-methylpyridine) and (R, S)-2-amino-1-butanol (4 fold molar excess) was heated to 210-220 °C in a sealed vial for 1.5 hours. After cooling to 100 °C the vial was cautiously opened and 5 mL of toluene and 5 mL of water were added and stirred well for 1 hour. The solid obtained, 2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino)-1-butanol, was suction-filtered and washed with an additional 5 mL of water followed by toluene and dried. Yield: 190mg. (71%). Mass spectrum, m/z = 343. 1H NMR was consistent with the proposed structure.
The compound of Example A-214 was prepared in accordance with the chemistry of Schzme XIII:
Example A-214 F
/ N
i /~ Br 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine To a solution of 4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (2.7 g, 10.67 mmol) (prepared in accordance with Example A-212) in acetic acid (30 mL) and DMF (13 mL) was added bromine (19.5 g, 122.0 mmol). The solution was heated at 80 °C overnight. TLC indicated that the reaction was complete. The mixture was quenched slowly with KZCO, (25g). When pH was about S, a precipitate was formed. The precipitate was washed with water (SOmL x 5) to give 4-[5-bromo-3-(4-fluorophenyl?-1-methyl-1H-pyrazol-4-yl]pyridine (1.248, 35%): mp 174.38°C;
Mass spectrum m/z = 332, 334; 1H NMR was consistent with the proposed structure. Anal. Calc'd for C~SH11N,FBr~0.2 H20: C, 53.66; H, 3.42; N, 12.51. Found: C, 53.58; H, 3.12; N, 12.43.
The compound of Example A-215 was prepared in accordance with the chemistry of Scheme XIV:
Example A-215 F
\ N
\N- CH3 n \
N
cN
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarbonitrile Step 1:
To a solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-' yl]pyridine (4.3g, 17.97 mmol) (prepared in accordance with Example A-208) in methanol (100 mL) was added 3-chloroperoxybenzoic acid (5.44 g in 57 % purity, 17.97 mmol). The solution was stirred at 25 °C for overnight.
The mixture was concentrated. KZC03 (10%, 100 mL) was added to the residue. A precipitate was formed, filtered and washed with water (30 mL x 3) to give the corresponding N-oxide (3.7649, 81.66%).
Stets 2:
To a suspension of the N-oxide prepared in step 1 (0.40 g, 1.567 mmol) in DMF (5 mL) was added trimethysilyl cyanide (0.3 mL, 2.25 mmol). The mixture was stirred for 15 minutes at 25 °C. Dimethylcarbamyl chloride (O.B mL, 8.69 mmol) was added. The mixture was stirred at 25 °C for 2 hours. TLC indicated that the starting materials were gone. The mixture was partitioned into ethyl acetate:water (100 mL:20 mL). The organic layer was washed with KZC03 (10%, 20 mL), water (50 mL), brine (50 mL), dried over MgSO,, filtered and concentrated to give 4-[3-(4-fluorophenyl)-1H-pyrazol-4-ylJ-2-pyridinecarbonitrile (0.23 g, 56 % yield): mp 209.22 °C ; Mass spectrum (chemical ionization): m/z =
265; 'H NMR was consistent with the proposed structure.
Anal. Calc'd for C15H9N,F~0.2 HBO: C, 67.26; H, 3.54; N, 20.92. Found: C, 67.44; H, 3.40; N, 20.69.
The compound of Example A-216 was prepared in accordance with the chemistry of Scheme XV:
Example A-216 F
\ N
~N 0 N
I \
4-[2-[3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-1-yl ] ethyl ] morpholine ~U'..~T(RU~26'~

WO 98/52940 PC'TIUS98/10436 Step 1:
3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol (prepared in accordance with Example A-210) (10.0 g, 0.0353 moles) was suspended in pyridine (100 mL) and cooled to 0 °C. Methane sulfonyl chloride (4.4 g, 0.0388 moles) was added slowly while maintaining the temperature at 0 °C. After stirring overnight at 10 °C, chilled water (100 mL) and methylene chloride (150 mL) was added and the two layers separated. The water layer was re-extracted with 100 mL of methylene chloride and the organic layex dried and concentrated to a paste. After drying at high vacuum, a light tan colored cake was ob~ained which was triturated with ether (75 mL), filtered and dried to furnish a cream colored solid in 79% yield (l0.lg). 1H NMR was consistent with the proposed structure. The compound was used as such for step 2.
Step 2:
The mesylate prepared in step 1 (S.0 g, 0.0138 moles) was dissolved in an eight fold excess of morpholine (9.6 g, 0.11 moles) in methanol (SO mL) and heated at reflux for 3 to 4 hours. After an NMR sample confirmed completion, the mixture was concentrated and taken up in methylene chloride (150 mL) and washed with water (100 mL) and then with 75 mL of 5% HC1. The water layer was neutralized to pH 8 and extracted with methylene chloride (100 mL). On drying and concentration a light yellow pasty solid was obtained which was triturated With 25 mL of ether to furnish a solid. Re-' 30 crystallization from toluene/hexane provided 4-[2-[3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine as a solid. Yield: 4.Sg (B6%). Mass spectrum, m/z = 353. 1H NMR was consistent with the proposed structure. Anal. calc'd for C20H21~9~: C, 68.16;
H, 6.01; N, 15.90. Found: C, 68.20; H, 6.21; N, 15.80.

The compound of Example A-217 was prepared in accordance with the chemistry of Scheme XVI:
Example A-217 F
N
~ N\
N' /J
HO
3-(4-fluorophenyl)-1-methyl-a-phenyl-4-(4-pyridinyl)-1H-pyrazole-5-methanol To solid magnesium (60 mg, 5 mmol) under nitrogen was added a solution of 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine (450 mg, 1.35 mmol) (prepared in accordance with~Example A-214) in tetrahydrofuran (7 mL). The mixture was heated at 40 °C
for 2 hours. Benzaldehyde (1 mL) was added. The mixture was heated to 45 °C for 2 hours. It was quenched with HC1 (10 mL, 1N) and washed with ethyl acetate. The aqueous acid layer was basified and extracted with ethyl acetate.
The organic layer was washed with water, brine, dried over MgSO" filtered and concentrated to give a residue.
The residue was purified with a silica gel column to give the title compound (59 mg, 12% yield). MS: m/z = 360 (M+1); 1H NMR was consistent with the proposed structure.
Anal. Calc'd for CZ2H18N=OF~0.6EtOAC: C, 71.1; H, 5.6; N, 10.2; Found: C, 70.9; H, 5.47; N, 10.2.

The compound of Example A-218 was prepared in accordance with the chemistry described above (particularly Scheme XVII):
S Example A-218 F
/ N
i v N H
N I ~
N/ \0 N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-morpholineethanamine l0 The starting desoxybenzoin prepared in step 1 of Example A-208, 4-fluorobenzoyl-4'-pyridyl methane, (1.0 g, 0.0046 moles) was dissolved in 10 mL of DMF and cooled to -10 °C (dry ice-aqueous isopropanol). N-chlorosuccinimide (0.62 g, 0.0046 moles) was added in one 15 portion while maintaining the temperature at -10 °C.
After 5 minutes the thiosemicarbazide (0.0046 moles) was added in one portion at 0 °C and allowed to warm to ambient temperature slowly over 1 hour. After stirring overnight, the solvent was removed at high vacuum and 20 water and toluene (25 mL each) added and stirred well.
The toluene layer was separated and the water layer (starting pH of 5.5) treated with bicarbonate to pH 8.
. The fine precipitate formed was filtered and washed with water, toluene and ether. A final trituration with ether 25 (25 mL) furnished an off white solid, N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-morpholineethanamine, which was re-filtered and dried.

WO 981529d0 PCT/US98l10436 Yield: 0.95g. (56%). Mass Spec. m/z: 368 (base peak).
Anal. Calc'd for C~oH~~FN50. C, 65.38; H, 6.04; N, 19.06.
Found: C, 64.90; H, 5.92; N, 18.67.
Example A-219 N ~ / \
HzNHN
/ \ N
N~
I
H
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-2(1H)-pyridinone hydrazone Steo 1: Preparation of (E)-2-(2-bromo-4-pyridinyl)-N.N-dimethvlethenamine N 8r 4-Methyl-2-bromopyridine (1.0 g, 5.8 mmol) and t-butoxybis(dimethylamino)methane (5 ml) were heated to 150 °C for 16 hours. 4-Methyl-2-bromopyridine was prepared as set forth in B. Adger et al., J. Chem. Soc., Perkin Trans. 1, pp. 2791-2796 (1988), which is incorporated herein by reference. The contents were evaporated and the residue dissolved in ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and solvent removed in vacuo to give 1.0 g of (E)-2-(2-brorno-4-pyridinyl)-N,N-dimethylethenamine as an WO 98!52940 PCT/US98/10436 oil suitable for use in step 2.
Step 2: Preparation of (Z)-2-(2-bromo-4-pvridinvl)-1-f3-- chiorophenvl)-3-(dimethylamino)-2-proper.-1-one 0 NMe2 Ci /
N Br The product from step 1 (1.0 g, 4.4 mmol) was dissolved in methylene chloride (15 ml). Triethylamine (900 mg, 8.8 mmol) was added at 0 °C, followed by the addition of 3-chlorobenzoyl chloride (350 mg, 4.5 mmol).
The mixture was stirred under nitrogen for 16 hours.
Solvent was evaporated in vacuo and the residue was dissolved in ether (25 ml), stirred with magnesium sulfate (500 mg) and silica gel (500mg), and filtered.
Ether was evaporated and the residue was chromatographed on silica gel using mixtures of acetone and methylene chloride as eluents to give 670 mg of the product, (Z)-2-(2-bromo-4-pyridinyl)-1-(3-chlorophenyl)-3-(dimethylamino)-2-propen-1-one, as a glass which was used in step 3 without further purification.
Step 3: Preparation of 2-bromo-4-f3-(3-chlorophenyl)-1H-pyrazol-4-yllpyridine N~
Br N
N~
H

A solution of the product from step 2 (650 mg, 1.8 mmol) and hydrazine monohydrate (100 mg) in ethanol (10 ml) was refluxed for 24 hours. Solvent was evaporated and the residue was chromatographed on silica gel using mixtures of ethyl acetate and toluene as eluents to give 2-bromo-4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]pyridine (190 mg, 31%) as an oil: Anal. Calc'd for C1,H95rC1N3: C, 50.25; H, 2.71; N, 12.56. Found: C, 50.10; H, 2.60; N, 12.40.
Continued elution with mixtures of ethyl acetate and methanol gave 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-2(1H)-pyridindne hydrazone (190 mg, 36%) as a crystalline solid: rn.p. 163-164 °C.; MS (M+H) - 286. Anal. Calc'd for Cl,HIZN5C1: C, 58.85; H, 4.23; N, 24.51. Found: C, 58.53; H, 4.28; N, 24.87.
Example A-220 N ~ ~ ~ c~
PhHZCHN
N
N~
H
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyridinamine A solution of the bromopyridine compound prepared in step 3 of Example A-219 (150 mg, 0.5 mmol) in benzylamine (5 ml) was heated at 175 °C for six hours. After cooling, excess benzylamine was removed by high vacuum distillation and ethyl acetate added to the residue.
After washing the organic phase with water and drying -over magnesium sulfate, the solvent was removed in vacuo WO 98/52940 PCT/US98110436 , and the residue chromatographed on silica gel using mixtures of ethyl acetate and toluene to give 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyridinamine (110 mg, 61%) as a solid, m.p. 179-180 °C.
Anal. Calc'd For C21H1,C1N,: C, 69.90; H, 4.75; N, 15.53.
Found: C, 69.69; H, 4.81; N, 15.11.
Example A-221 N ~ ~ ~ c~
PhH2CHZCHN
\ N
N~
lO H
4-[3-(3-chlorophenyl)-1H-pyrazol-4-y1J-N-(phenylethyl)-2-pyridinamine A solution of the bromopyridine compound prepared in step 3 of Example A-219 (250 mg, 0.75 mmol) in phenethylamine (5 ml) was heated at 175 °C for six hours under a nitrogen atmosphere. The excess amine was distilled off under high vacuum and the residue was dissolved in ethyl acetate and washed with water. After drying over magnesium sulfate and removal of solvent, the residue was chromatographed on silica gel with mixtures . of ethyl acetate and toluene to give 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-(phenylethyl)-2-pyridinamine (230 mg, 81%) as a solid, m.p. 185-186 °C.
Anal . Calc' d For C22H19C1N, : C, 70 . 49 ; H, 5 . 11 ; N, 14.95. Found: C, 70.29; H, 5.15; N, 14.66.

Example A-222 N ~ ~ ~~~- C I
E t H N a N
N~
H
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-ethyl-2-pyridinamine A solution of the bromopyridine compound prepared in step 3 of Example A-219 (300 mg, 0.9 mmol) in ethylamine (3.5 ml) and ethanol (5 ml) as heated at 150 °C in a sealed tube for 9 hours. The solvent was removed in vacuo and the residue chromatographed on silica gel with 70 ethyl acetate/30 toluene to give 4-[3-(3-chlorophenyl)-1H-pyrazol-4-y1J-N-ethyl-2-pyridinamine (125 mg, 46%) as a solid, m.p. 186-187 °C.
Anal . Calc' d For C16H1sC1N, : C, 64 . 32 ; H, 7 . 06 ; N, 18 . 75 .
Found: C, 64.42; H, 7.01; N, 18.45.
The compounds of Examples A-223 through A-226 were synthesized in accordance with the chemistry described above (particularly in Scheme XVIII) by selection of the corresponding starting reagents:

WO 98!52940 PCT/US98II0436 Example A-223 F
NH
~ N
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxamide Step 1:
To a suspension of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine (prepared as set forth in Example A-208) (8.8 g, 0.037 mol) in methylene chloride was added m-chloroperoxybenzoic acid (mCPBA) in one portion at room temperature. After stirring for 16 hours, solvent was removed and the residue was treated with saturated sodium bicarbonate solution. The precipitate was filtered, air-dried to give 8.2 g of a product as a white solid (87%), mp: 207-209°C.
Sten 2: Preparation of 4-f3-(4-fluoronhenvl)-1H-wrazol-4-vll-2-pyridinecarbonitrile To a solution of the product of step 1 (5.1 g, 0.02 mol) in 20 mL of DMF was added trimethylsilyl cyanide (2.5 g, 0.025 mol), followed by a solution of N, N-dimethylcarbamoyl chloride (2.7 g, 0.025 mol) in 5 mL of DMF at room temperature. After stirring overnight, the su~n~ur~s~'c~~

reaction mixture was basified by 200 mL of 10~ potassium carbonate water solution. The aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was triturated with hexane and filtered to give 4.3 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl~-2-pyridinecarbonitrile (90%) as a pale yellow solid, mp:
238-239°C.
Step 3: Preparation of 4-f3-(4-fluorophenyl)-1H-pyrazol-4 yl ] - 2 -pyridinecarboxamide To a solution of 4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarbonitrile from step 2 (0.45 g, 0.0017 mol) in 10 mL of DMSO was added hydrogen peroxide (0.24 mL of 30% aqueous solution, 1.7 mmol) and potassium carbonate (0.04 g, 0.4 mmol) at 0°C. The mixture was stirred for 1 hour while allowing it to warm to room temperature. Water was added and the precipitate was collected by filtration and air-dried to give 0.32 g of 4-(3-(4-fluorophenyl)-1H-p~razol-4-yl]-2-pyridinecarboxamide as a white solid (67% yield), mp:
230-231 °C. Anal. Calc'd for C15H11FN,0: C, 63.83; H, 3.93; N, 19.85. Found C, 63.42; H, 3.66; N, 19.58.
Example A-224 F
;H
N
v N /
0~CH3 ~I'(R~~) Methyl 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinec.arboxylate To a suspension of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxamide prepared as set forth in Example A-223 (2.9 g, 0.01 mol) in 50 mL of methanol was added N,N-dimethylformamide dimethyl acetal (3.67 g, 0.03 mol) dropwise. The reaction mixture was stirred at room temperature overnight and heated at reflux for 4hours.
After cooling, the precipitate was collected by filtration and air-dried to give 2.0 g of methyl 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate as a white solid (69% yield), mp: 239-241°C. Anal. Calc'd for C16H1zFN30z: C,~ 64.64; H, 4.07; N, 14.13. Found: C, 64.36; H, 4.10; N, 14.27.
F
Example A-225 ;H
N
NI /
o~ N~
H
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyridinecarboxamide A mixture of methyl 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate prepared as set forth in Example A-224 (0.45 g, 1.5 mmol) and 20 mL of methylamine (40% aqueous solution) was heated at 120°C in . 25 a sealed tube for 16 hours. After cooling, water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to afford 0.4 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyridinecarboxamide as a white solid, mp: 8B-89°C. Anal. Calc'd for C16H13FN,0 + 0.4 H20:
C, 63.32; H, 4.58; N, 18.46. Found C, 63.10; H, 4.62; N, 18.35.
Example A-226 F
\H
~\~ N
NI /
0~ ~OH
4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxylic acid To a solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate prepared as set forth in Example A-224 (0.90 g, 0.003 mol) in 10 mL of ethanol was added a solution of sodium hydroxide (0.24 g, 0.006 mol) in 5 mL of water. The reaction mixture was heated at reflux for 10 hours. After the removal of solvent, the residue was dissolved in water and acidified with citric acid solution to pH 5. Then the aqueous phase was extracted with ethyl acetate and the organic phase was -dried over magnesium sulfate and concentrated. The crude was purified by treating with ether to give 0.62 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylic WO 98/52940 PC'fIUS98/10436 acid as a white solid (73~ yield), mp: 245°C(dec). Anai Calc'd for C15H1eFN~0 + 0.2 HzO: C, 62.80; H, 3.65; N, 14.65. Found: C, 62.77; H, 3.42; N, 14,58.
Additional compounds of the present invention which were prepared according to one or mcre of above reaction schemes (particularly Schemes IX through XVIII) are disclosed in Table 3. The specific synthesis scheme or schemes as well as the mass spectroscopy and elemental analysis results for each compound also are disclosed in Table 3.

WO 98/52940 PCTlUS98I10436 U 'n W of rl N N r-1H ~ 1fltI7lprl N

b ("., ~ CO~,,~N O N ~ ~ ~ N M ~iInr-1N t~U1N t0II1CO

41, tl1Q1M , . . ~ M 00M 01O M N O 00N lDQ~

w ~ ~ ~ ~DM lf1~ ~ ~ H ~ M l0cr~ l17M N tl1N a0U1 H H

ri riH r-1'"'~ri e-f H ,..~r1r-1ri r~r1H e--ir-1r-1r-i z e-I N N tJlM ~ CO~ ~' O ~'tIlll~M !IlO 01C~e--1~1r-i~ N

M ~'COtf1 cnM 00M M O ~ M M Q1O (~N

U ~ tf1~ tDM ll1'd'111II1~ ~'M lDtI1V' u'1M N Lf1~'N lD

M O ri~' rlH ('7r-1lD Ci'W -1C~lD~'M
lD L'1l ~ M ~ t~M N ~ r ~ 01LflO N O lDU1r~lItM l0 w ~ V'~ M d~d' ~' ~Dtf1M M M M M Q'M C'lDtf1C'M

o x U

W ~'aH ~.,~H O C'Q1CO ~ ~ l0Op01M v-1\D 01lf1H lDd'tf1CO
I

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i i ~ i ~ i ~ ~ i i i ~ ~ i ~ i i i i i ~ i ~
a a a a a a a a a a a a a a a a a a a a a a a WO 98/52940 PCT'/US98/10436 Example A-227 F
/ N
N-H
~H
N /
4-[3-(3-fluorophenyl)-1H-pyrazol-4-yl]pyridine S Example A-228 /- o / N
\ N- H
~H
4-[3-(1,3-benzodioxol-5-yl)-1H-pyrazol-4-yl]pyridine Example A-229 F
\ N
/ ~N-CH3 r N /
1~

4-[3-(3-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine Example A-230 c~
N
N-H ' N / N
4-(3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyridine Example A-231 o~o / \
N
/ ~N-CH3 N _ /J
4-[3-(1,3-benzodioxol-5-y)-1-methyl-1H-pyrazol-4-yl]pyrid ine Example A-232 ci ~i \ N
i N

WO 98/52940 PC'TIUS98110436 4-(3-(4-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine Example A-233 c~
i \ N

N / ~ isomer 4-[3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-methylp yridine and 4-[5-(3-chlorophenyl)-1-methyl-1H-pyrazol-4 -y1J-2-methylpyridine Example A-234 CI
\ N

NI- /J ~ isomer 4-[3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-ylJpyridine and 4-[S-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-ylJpyridine Example A-235 \ N
i N /

2-methyl-4-[1-methyl-3 (or 5)-(3-methylphenyl)-1H-pyrazol-4 -yl]pyridin~a S Example A-236 /
N
N-H
N /
4-(3-phenyl-1H-pyrazol-4-yl)pyridine Example A-237 \ N
i N-H
a N) 4-[3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine Example A-238 \ N

_ \
4-[1-methyl-3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine F
Example A-239 \ N
N- H
w, /J
4-[3-(3,4-difluorophenyl)-1H-pyrazol-4-yl]pyridine WO 98/52940 PCT/US98l10436 Example A-240 c~
N H
F
4-[3-(4-chlorophenyl)-2H-pyrazol-4-yl]-2-fluoropyridine Example A-241 Br \ N
N H
N, 4-[3-(4-bromophenyl)-1H-pyrazol-4y1]pyridine Example A-242 F
F
\ N

I \
4-[3-(3,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridi ne Br Example A-243 \ N

I \
N_ i S 4-[3-(4-bromophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine Example A-244 F
N- H
, (E) -4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2- (2-phenyleth enyl)pyridine Example A-245 c~
/
\ N
i N- H
I
N /

HN~CH3 S
(S) -4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -N- (2-methylbut yl)- 2-pyridinamine c~
Example A-246 i \ ~ N
N-H
\ ~/

HN \
4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxy-phenyl)methyl]- 2-pyridinamine ' WO 98/52940 PCT/US98/10i36 Exaatple A-247 c~
/
\ N
tJ- H
N /
H PJ
N
N-[4-[3-(4-ch~orophenyl?-1H-pyrazol-4-yl]-2-pyridinyi)-2-pyridinemethanamine Example A-248 F
/ ~~N
\ /
'NH
N/
\NH
N
N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-2-pyridinemethanamine Anal Calc'd: C, 41.12; H, 3.58; N, 9.22. Found: C' 41.74; H, 5.05; N, 11.11.

WO 98!52940 PCT/US98/1043b Example A-249 F
/ N
i NH
td / H
F
2-fluoro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine S Example A-250 i / N
NH
Ni /
4-[3-(4-iodophenyl)-1H-pyrazol-4-yl]pyridine Example A-251 i \ N
i \ ~/
N _ /J
1 ~~
4-[3-(4-iodophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine ~C~ ~~ ~~

Example A-252 \ N

, Nl 4-[1-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl ]pyridine Example A-253 F
/ N
NH
\ v I
N / F
HN \
R, S

N- [1- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -1H-pyra zol-4-yl~- 2-pyridinamine Example A-254 F
N
NH
\ a N / , HN \
F
N-((3-fluorophenyl)methylJ-4-[3-(4-fluorophenyl)-1H-pyraz ol-4-yl]- 2-pyridinamine S
F
Example A-255 \ N
i \~ ~/
NI /
N
H3C~ \NHz 4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-(1-methylhydrazino)pyridine '~ET (R~ Efe) WO 98/52940 PC'T/US98/10436 Example A-256 F
ni-CH3 F
2-fluoro-4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]p yridine Example A-257 F
F
NH
F
4-(3-(3,4-difluorophenyl)-1H-pyrazol-4-yl]-2-fluoro-pyridine ~~~Si~~~~

Example A-258 F
\ ~ N
\ fJ - H
N /
C r13 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-3-methylpyridine Example A-259 F
/
\ ~ N
~N-CH3 N
\CH3 4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-3-methylp yridine Example A-260 F
F

S~~T(R~.I~.E~B~

4-[3-(3,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-flu oropyridine Example A-261 F

\ ~ N ~ 'N
/ \N' V ~CH3 N_ 3-(4-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazo le-1-ethanamine Example A-262 F
\ N
/

\ v N / F

2-[2-(4-fluorophenyl)ethyl]-4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine Example A-263 F ., / N

NH

~/

r;
' /

HN
N \
4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N- [1-(phenylmethyl)-4-piperidinyl]-2-pyridinamine Example A-264 c !H
N
HN
N~
N' - [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -N,N-dimethyl-1,2-ethanediamine . ~d~'yl~LiTE~"~ t~1 WO 98!52940 PCT/US98/10436 Example A-265 F
/ N
N
v N / F
/ \/
N-NH
2,4-bis(3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine Example A-266 F
IH

N
HN' V 'N
~0 N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-4-morpholineethanamine WO 98!52940 PCT/US98/10436 r Example A-267 / N ~OH
/ ~ \~//
PJ
\ v N /
F
3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazole-1-ethanol Example A-268 F
NH
N
N /
HN~N~N
4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N- [2- (1H-imidazol-1-yl)ethyl]-2-pyridinamine WO 981529d0 PC'TIUS98/1Od36 Example A-269 ~G
F
S 4-(2-(3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-_~-pyrazol-1-yl]ethyl]morpholine Example A-270 F
t ~ ~oH
n (E) -3- (4-fluorophenyl) -4- (2- (2- (4-fluorophenyl) ethenyl] -4-pyridinyl]-1H-pyrazole-1-ethanol WO 98/52940 PCTIUS98/1Od36 F
Example A-271 / N I
/ ~ ~N
N ~CH3 N
F
3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-N,N-dimethyl-1H-pyrazole-1-ethanamine Example A-272 F
N
N~OH
3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethyl]-4-pyridinyl]-1H-pyrazole-1-ethanol CVO 98152940 PCT/US98/10.i36 Example A-273 F
_ N
N~ N
I
N /
/N~
4- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -1H-pyrazol-4-yl]~-N,N-dimethyl-2-pyridinamine S
Example A-274 F
/
_ N
~_ N fNi I
N
HN
F
4- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -1H-pyrazol-4-yl]-N-[(4-fluorophenyl)methyl]-2-pyridinamine Example A-275 F
N
Nf Ni I
3- (4-fluorophenyl) -4- [2- (2- (4-fluorophenyl) ethyl ] -4-pyridinyl]-N,N-dimethyl-1H-pyrazole-1-ethanamine Example A-276 F
_ N
\ ~ Nf N
NI / ~0 HN
F
N- [ (4-fluorophenyl) methyl] -4- [3 (or 5) - (4-fluorophenyl) -1-[[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl]-2-pyridinamine Example A-277 F
NH
HN
N hi 4-[3-(~-fluorophenyl)-1H-pyrazol-4-yl]-N-4-p~peradinyl-2-p~.~riciinamine Example A-278 i N
N~. J
N
i J
N
N,N-diethyl-3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazole-1-ethanamine Example A-279 F
N
\ w N f N ~\
N
HN
F
4- [1- j2- (diethyl amino) ethyl] -3- (4-fluorophenyl) -1H-pyrazol-4-yl]-N-[(4-fluorophenyl)methyl]-2-pyridinamine WO 98!52940 PCT/US98/10436 , Example A-280 F
- / N
' ~ \
NH
' N
HN
OOH
2-[[4-[3-(4-(~luorophenyl)-1H-pyrazol-4-yl)-2-pyridinyl]amino]ethanol F
Example A-281 N
N-1:H3 N, /
HN
OH
2-[[4-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-- l0 pyridinyl] amino] ethanol Example A-282 C
NH
HN~OH
3-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-1-propanol F
Example A-283 / N
\ ~ 'OH
/ ~N
\~
N / F
HN \
3 (or S) - (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl)methyl]amino]-4-pyridinyl]-1H-pyrazole-1-ethanol B~I~Ct~~

Example A-284 F
\ ~CH3 / N
\N~ NBC I
a N\/
N,N-diethyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanamine Example A-285 . / N
N
N
I
N / F
HN \
N- [ (4-fluorophenyl) methyl] -4- [3- (4-fluorophenyl) -1- [2- (4-morpholinyl)ethyl]-1H-pyrazol-4-yl]-2-pyridinamine Example A-286 F
/ N
i N
HN
N ~ ~' ~//
N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-morpholinepropanamine WO 98/529d0 PCT/US98/10.i36 Example A-287 F
/ N

\ -_ N
HN
N \CFi3 N'-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-dimethyl-1,3-propanediamine Example A-288 F
/ N
N- H
N HN
5-(4-fluorophenyl)-N-2-propynyl-4-(4-pyridinyl)-1H-pyrazol-3-amine Example A-289 F
/ N OOH
N
_ , N / F
HN \

3-(4-fluorophenyl)-4-(2-[[(4-fiuorophenyl)methyl]aminoj-4-pyridinyl]-1H-pyrazole-1-ethanol ~ Example A-290 F
N~O H
N
r! / F
HN
S- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl) methyl] amino] -4-pyridinyl)-1H-pyrazole-1-ethanol Example A-291 / N
\ N- H
\ v NI. /
4-(3-[(4-fluorophenyl)-1H-pyrazol-4-yl]quinoline Example A-292 F
N ' N- H
NI V H
COzMe N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]glycine methyl ester Example A-293 F
/ N
NH
N,J
I.OzH
N-[5-(4-fluorophenyl}-4-(4-pyridinyl)-1H-pyrazol-3-l0 yl] glycine Example A-294 F
/ N
\ ~ N
sir (R~x.E~s?

WO 98/52940 PC'f/U S98J10436 4- [3- (4-fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4-yl]pyridine Example A-295 F
/ N
N
I~ v N
4-[5-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazol-4-yl]pyridine Example A-296 N' \

I / N

i NH

l N

4,4'-(1H-pyrazole-3,4-diyl)bis[pyridine]
Example A-297 c~
c~
' NH

4-[3-(3,4-dichlorophenyl)-1H-pyrazol-4-yl]pyridine Example A-298 cl \ N
i NH
\ .
N~ HN NH
N-(5-(4-Chlorophenyl)-4-(q-pyridinyl~-1H-pyraZOl-3-yl]
-4-piperidinamine The pyrimidine-substituted compounds of Examples A-299 through A-312 were synthesized in accordance with the chemistry described in Schemes I-XVIII by selection of the corresponding starting reagents:
Example A-299 G
i w N~N
~IC%I
N
I
NH
2-Chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine Step 1:

WO 98!52940 PC'T/US98/I0436 ~NMez N_ i_N
NMe2 A mixture of 2,6-dichloro-4-methylpyrimidine (5.0 g, 0.031 mol), triethylamine (6.23 g, 0.062 mol) and catalytic amount of 5% Pd/C in 100 mL of THF was hydrogenated on a Parr apparatus under 40 psi at room temperature. After 0.5 hour, the catalyst was filtered and the filtrate was concentrated. The crude was purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 2.36 g of product as a pale yellow crystal (50% yield); mp: 47-49 °C.
Step 2: Preparation of 2-(2-chloro-4-gvrimidinvl)-1-(4-fluorophenvl)ethanone F

N_ ,_N
~CI
2-(2-ch~oro-4-pyr~m~oW yy -t-(4-tlUOropneny ]etnEnOne To a solution of lithium diisopropylamide (generated from BuLi (0.045 mol) and diisopropylamine (0.048 mol) in THF) at -78 °C was added a solution of the compound prepared in step 1 (5.5 g, 0.037 mol) in THF slowly over 30 minutes. After 1 hour, a solution of ethyl 4-fluorobenzoate (7.62 g, 0,045 mol) in THF was added and the reaction mixture was stirred overnight and allowed to warm up to room temperature. Water was added and the aqueous phase was extracted with ethyl acetate. Organic layer was washed with brine, dried over magnesium sulfate ;
S and filtered. The filtrate was concentrated and the crude product purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 4.78 g of a yellow solid (51g yield), mp: 112-113 °C.
l0 Ste~3: Preparation of (E)-2-(2-chloro 4 pvrimidinyl) 3 ~dimethylamino)-1-(4-fluorophenyl)-2-Dropen 1 one F
.

\ \
N' /_N NM2z IvCI
[ E]- 2-[ 2-C h I or o-4-pyr i m i d i ny I ]- 3-[ d t met by I am i no]- 1-C4-~ ~ ~orophwy 1 ~_ 2-croaen- i-one A mixture of the compound prepared in step 2 (4.7 g, 0.017 mol) in 100 mL of dimethylformamide dimethyl acetal 15 was stirred at room temperature overnight. Excess dimethylformamide dimethyl acetal was removed under vacuum to give 4.5 g of crude product as a thick brown oil, which was used without further purification.
20 Step 4: Preparation of 2-chloro-4- 3-(4-fluorophenyl) 1H-pvrazol-4-vllpvrimidine A solution of the compound prepared in step 3 (4.4 g) and hydrazine hydrate (0.82 g, 0.014 mol) was stirred at room temperature for 6 hours. The yellow precipitate 25 was collected by filtration and air-dried to give 1.85 g of 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-~IJ~~J~E ~'~ET (F~J~..E 2~

yl]pyrimidine as a yellow solid, mp: 204-205 °C; Anal, Calc'd for Cl,HeCIFN,: C, 56.84; H, 2.94; N, 20.40; C1, 12.91. Found: C, 56.43; H, 2.76; N, 20.02; C1, 12.97.
Example A-300 NH
I
N
N' /'N

4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2 (1H) -pyrimidinone hydrazone A solution of the compound prepared in step 3 of Example A-299 (1.5 g) and hydrazine hydrate (5mL) in ethanol was heated at reflux overnight. After the reaction mixture was cooled, the solvent was removed.
The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by recrystallization from ethyl acetate and hexane to give 0.5 g of product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2(1H)-pyrimidinone hydrazone, as a pale yellow solid (38%
yield) , mp: 149-150 °C; Anal. Calc'd for C13H1zFN6: C, . 57.77; H, 4.10; N, 31.10. Found: C, 57.70; H, 4.31; N, 30.73.

Example A-301 F
NH
I
N
N_ i_N
~I%N
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N,N-dimethyl-2-pyrimidinamine Step 1: Preparation of NMEz N_ i_N
~NMez A solution of the compound prepared in step 2 of Example A-299 (3.0 g, 0.02 mol) and tert-butylbis(dimethylamino)methane (10.45 g, 0.06 mol) in 40 mL of DMF was stirred at 110 °C overnight. After the solvent was removed under vacuum, water was added and extracted With ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by recrystallization from ethyl acetate and hexane to give ' 1.23 g of a yellow solid product (32~ yield), mp: 76-77 °C; Anal. Calc~d for C1oH16N,: C, 62.47; H, 8.39; N, 29.14. Found: C, 62.19; H, 8.58; N, 29.02.

Step 2: Preparation of 4-f3-(4-fluorophenvl)-1H-pyra~o~-4-yll-N,N-dimethyl-2-pyrimidinamine To a solution of the compound prepared in step 1 oy the present Example (1.2 g, 0.0064 mol) and triethylamine S (0.65 g, 0.0064 mol) in 10 mL of toluene was added 4-fluorobenzoyl chloride dropwise. The mixture was heated at reflux for 10 hours and the solvent was removed. The residue was partitioned between ethyl acetate and water.
The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude (1.6 g) was then dissolved in SO mL of ethanol. The solution was treated with hydrazine hydrate (0.36 g, 0.006 mol) and the mixture was heated at reflux for 2 hours. After ethanol was removed, the residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 0.6 g of product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N,N-dimethyl-2-pyrimidinamine, as a yellow solid (33% yield), mp: 155-156 °C; Anal. Calc'd for C15H1,FN5: C, 63.59; H, 4.98; N, 24.72. Found: C, 63.32; H, 4.92; N, 24.31.
Example A-302 F
-N
i w _NH
N~ N
HIYN
~CH3 4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyrimidinamine A suspension of 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 (0.3 g, 0.0011 mol) in 10 mL of methylamine (40% water solution) was heated in a sealed tube at 100 °C overnight. The mixture was then cooled to room temperature and the precipitate was filtered, air-dried to give 0.2 g of product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyrimidinamine, as a white solid (68% yield) , mp: 217-218 °C; Anal Calc'd for C,qH12FN5: C, 62.45; H, 4.4'9; N, 26.01. Found: C, 62.58; H, 4.36; N, 25.90.
Example A-303 w N

NH
N / N
HN \
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyrimidinamine This compound was synthesize by refluxiny 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 in benzylamine overnight. The product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyrimidinamine, was obtained as a white solid in 95% yield; mp: 216-217 °C;

Anal. Calc'd for C~QHISFNs: C, 69.55; H, 4.67; N, 20.28.
Found: C, 69.73; H, 4.69; N, 19.90.
Example A-304 C
NH
N
N' /_N
HIvN
N-cyclopropyl-4-[3-(4-fluorophenyl>-1H-pyrazol-4-yl)-2-pyrimidinamine This compound was synthesized by stirring 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 with excess cyclopropylamine in methanol at 50 °C for 12 hours. The product, N-cyclopropyl-4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl)-2-pyrimidinamine, was obtained as a white solid in 26% yield, mp: 203-204 °C; Anal. Calc'd for C16H1,FNs: C, 65.07; H, 4.78; N, 23.71. Found: C, 64.42; H, 4.82; N, 23.58.

WO 98/529d0 PCTIUS98/10436 Example A-305 F
NH
I
N
N_ ,_N
HN
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyrimidinamine This compound was synthesized by refluxing 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 in 4-methoxybenzylamine overnight. The product, 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyrimidinamine, was obtained as a off-white solid in 80%
yield, mp: 183-185 °C; Anal . Calc' d for C21H1eFNs0: C, 67.19; H, 4.83, N, 18.66. Found: C, 67.01; H, 5.11; N, 18.93.
Example A-306 F
NH
I
N
N_ i_N
~NHz 4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine A solution of 4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyrimidinamine prepared in accordance with Example A-305 (0.35 g, 0.00093 mol) in mL of trifluoroacetic acid was heated at reflux for to hours. Solvent was removed and the residue was partitioned between ethyl acetate and 1 N ammonia hydroxide. Organic layer was washed with brine, dried 10 over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate) to give 0.14 g of product, 4-[3-(4-fluorophenyl)~-1H-pyrazol-4-yl]-2-pyrimidinamine, as a pale yellow solid (59~ yield), mp: 273-274 °C; Anal.
15 Calc'd for C13H1oFNs~0.25 H20: C, 60.11; H, 4.07; N, 26.96.
Found: C, 60.15; H, 3.82; N, 26.38.
Example A-307 F
NH
N
N' /_N ' 0\ 'N /
N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-N-(phenylmethyl)acetamide To a mixture of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyrimidinamine prepared in accordance with Example A-303 (0.15 g, 0.00043 mol), DMAP

(0.027 g, 0.00022 mol) and acetic anhydride (0.066 g, 0.00066 mol) in 10 mL of THF was added triethylamine (0.053 g, 0.00052 mol). The solution was stirred at room temperature overnight. After the removal of solvent, the ;
residue was partitioned between ethyl acetate and water.
The organic layer was washed with saturated NaHCO" washed with brine, dried over magnesium sulfate and filtered.
The filtrate was concentrated and the crude product was triturated with ether to give 0.1 g of product, N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-y1J-2-pyrimidinyl]-N-(phenylmethyl)acetamide, as a white solid (60~ yield), mp : 176-178 °C; Anal . Calc' d for CzzH18FN5: C, 68 . 21; H, 4.68; N, 18.08. Found: C, 67.67; H, 4.85; N, 17.79.
Example A-308 F
NH
. N
N_ ,_N
HN~p ~I,,I~O
Ethyl (4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]carbamate To a suspension of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine prepared in accordance with Example A-306 (0.26 g, 0.001 mol) in 5 mL of pyridine was added ethyl chloroformate dropwise. After the addition, the clear solution was stirred at room temperature for 6 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was trituated with ether to give 0.15 g of product, ethyl (4-(3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]carbamate, as a white solid (46~ yield), mp:
163-165 °C; Anal. Calc'd for C16H1,FNSOZ: C, 58.71; H, 4.31;
N, 21.04. Found: C, 59.22; H, 4.51; N, 21.66.
Example A-309 i 1h N
N~ N
4-(3-(3-methylphenyl)-1H-pyrazol-4-yl]pyrimidine This compound was prepared by the same procedure as described for Example A-208 except that 1-methyl-3-(4'-pyrimidinylacetyl) benzene (prepared as set forth in Step 1 of Example A-19 from 4-methyl-pyrimidine and methyl 3-methylbenzoate) was used in place of 4-fluorobenzoyl-4-pyridinyl methane.
Anal. Calc'd for Cl,HlzN, (236.27) : C, 71.17; H, 5.12; N, 23.71. Found C, 70.67; H, 5.26; N, 23.53. m.p. (DSC):
151.67 °C.
S~IIE~~T~i~TESh~T tR~ILE 2s) Example A-310 N \
i ~N / NH
N
CI
4-[3-(4-chlorophenyl)-1H-pyrazol-4-yI]pyrimidine This compound was prepared according to the chemistry described in Schemes VI and IX by selection of the corresponding pyrimidine starting material in place of the pyridine starting material.
Anal. Calc'd for C1,H9N,C1~0.25MH20: C, 59.78; H, 3.67; N, 21.45. Found: C, 59.89; H, 3.32; N, 21.56. m.p. (DSC):
218.17 °C.
Example A-311 N~~
~N ~ N
NH
4-[3-(3-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine This compound was prepared according to the chemistry described in Schemes VI and IX by selection of WO 98!52940 PCT/US98I10436 the corresponding pyrimidine starting material in place of the pyridine starting material.
Anal . Calc' d for Cl,HgIV,F (240 . 24 ) : C, 64 . 99 ; H, 3 . 78 ; N, 23.22. Found: C, 64.78; H, 3.75; N, 23.31. m.p. (DSC):
168.58 °C.
Example A-312 N
~N ~ N
!
NH
.
F
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine This compound was prepared according to the chemistry described in Schemes VI and IX by selection of the corresponding pyrimidine starting material in place of the pyridine starting material.
Anal. Calc'd for C1,H9N,F (240.24) : C, 64.99; H, 3.78; N, 23.32. Found: C, 64.94; H, 3.56; N, 23.44. m.p. (DSC):
191.47 °C.
Additional compounds of the present invention which could be prepared using one or more of the reaction schemes set forth in this application include, but are not limited to, the following:
s~rc~~

ci Br Y/
\ N
i \
NH
\ , \ , N~N N
'-- N
H
a-(3-(4-chlorophenyl]-5-(1-piperaZinyl)-1H-pyraZOl-4-yl]pyrimidine \ N
NH
~N
N /
~N
H
1-~5-(4-bromophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]pipera2ine WO 98/529d0 PCT/US98/10i36 F 3 ~_ \ N
NH
\
iJ / N /
'- N
H
1-[4-(~-PYridinyl)-5_ [q-(trifluorometny )phenyy -1H-pyrazol-3-yl~piperazine NC
\ N
i \
NH
N J N
~N
H
a-[5-(1-pipera~inyl-4-(9-pyridinyl) -1H-pyrazol-3-yl]benzonitrile ~.

WO 98152940 PC'T/US98I10436 HCC
\ N
/ \
NH
I \
N / N
~N
H
1-~5-(4-eLhynylphenyl)-4-(4-pyridm yl) -1H-pyrazol-3-yl]piperazine F
\ N
i \
NH
t.J I /J
\% ~H
5-(4-fluorophenyl)-4-f 4- py r i d i n y I 1 - N- 3- p y r r p I i d i n y I -1H-pyraZOi-3-amine CI
\ N
NH
NI- /J
'_-NH
5-(4-Chlorophenyl)-4-(9-pyridinyl)-N-3-pyrrolidinyl-1H-pyrazoi-3-amine F
\ N
i \
NH
' n / NH
N-( 5-( 4-f I uoropheny I ]--i-~4-pyridW yl)-1H-pyrdZ01-3-yl) -4-piperidinamine F
~/
N' ~0H
N
\
N
/,/
N
H
3-(4-fluorophenyt)-5-~1-~iperazinyl]-4-(4-pyridinyl)-1H-pyraZOle-1-ethanol WO 98/52940 PC'T/US98110436 CI
/ _ \ N ~OH
/ \N
, N _ /J
~N ' H
3-(4-ChlorOphenyl)-5-C 1-~p ~ peraZ i ny I )-4-(4-pyridinyl)-1H-pyrazole-1-ethanol F
~/
\ N
N
\ OH
I N
~NH

4-[2-aminoethyl)-2-(4-fluoro phe-nyI]-4.5,6,7-tetrahydro-3-(4-pyridinyl)pyrdZOlo [1,5-a]pyrimidin-6-of ES1~T(RI~EEB~

WO 98152940 PCT/US98/10436 , cl /
\ N
\N
\ OH
N
N /
~NH

4-[2-aminOethyl)-2-[4-~hloro pne-nyl)-4,5,6,7-tetrahydro-3-[4-pyridinyl)pyrdZ010 [1,5-3)pyrimidin-6-OI
CI
\ N
~OH
vN
N~N
3-[4-ChlOrOphenyl)-9-[-i-pyrimidinyl~-1H-pyrazolE-1-ethanol F
NHz F
S-(4-fluorophenyl]-4-(q-pyrimiW nyl]-1H-pyraZOle-3-ethanamine CI
/

\ N

NH

N~
N

\ N

/

NH

N
N

~

NHz 5-(4-chlorophenyl]-4-(4-pyrimidinyl]-1H-pyraZOle-3-ethanamine \ ~ N
~NH
N~N
NH
S-[3-(4-fluorophenyl)-5-(4-piperidinyl]_ 'IH-pyraZOl-4-y~~pyrimidine WO 98/529d0 PCTlUS98/10436 cl \ N

NH

N
N

~

F
CI
'-NH
4-[3-[4-ChlOrOphenyl)-5_[4_piperidinyl)-1H-pyra~ol-4-yt]pyrimidine N
,\
NH
N~ N
~IIN/HCOMe N-(4-(3-[4-fluorophenyl)-1H-pyraZOl-4-yl]-2-pyrimidinyl]acetamide \ N
NH
N' /' N
IYNHCOMe N-(4-[3-~4-chlorophenyl)-1H-pyraZOl-4-yl]-2-pyrimidinyl]acetamide su~~st~r~~~

F
\ N
r \
NH
\ , N_ ,_N
IvNHCOEL
N-[4-[3-[4-fluoropheny )-1H-pyrazo~-4-yl~-2-pyrimidinylproGanamide CI
\ N
NH
N ~ CJ
NHCOEL
N-[4-[3-[4-fluorophenyl)-1H-pyraZ01-4-yl~-2-pyrimidinyl]propanamide F
\ N
\NH
N ~
N /
N
NHJ
6-[3-[4-fluorophenyl)-1H-pyrazol-4-yl]-1H-purine ~~~st~~

cl i N
NH
', ~ r, w N /
CI
~N
NH~
6-[3-(4-ChlOrOphenyl]-1H-pyr3Zol-4-yl~-'IH-purm a \ N
NH
N_ i_N
\IN%COM2 Bn~
w-[~-[3-[a-chlorophenyl]-~H-pyrdZOl-4-yl)-2-pyrimidinyl)-N-(phenylmethyl]dcatamide F
\ N
~NH
w N' /' N
IYNCOEt Bn~
N-[4-[3-[4-fluorophenyl~-1H-pyrazol-4-yl)-2-pyrimidinyl)-N-(phenylmethyl)propanamide c~
NH
N_ i_N
~NCOEt Bni N-~4-~3-(4-GhlOrOphenyl)-1H-pyrdZ01-4-yl~-2-pyr~mipinyl~-N-(phenylmethyl)prOpanamiCle BIOLOGICAL EVALUATION
p38 Kinase Assay Cloning of human D38a:
The coding region of the human p38a cDNA was obtained by PCR-amplification from RNA isolated from the human monocyte cell line THP.1. First strand cDNA was synthesized from total RNA as follows: 2 ~g of RNA was annealed to 100 ng of random hexamer primers in a 10 ~cl reaction by heating to 70 °C for 10 minutes followed by 2 minutes on ice. cDNA was then synthesized by adding 1 ~.1 o~f RNAsin (Promega, Madison WI), 2 ~C1 of 50 mM dNTP's, 4 ~C1 of 5X buffer, 2 ~.1 of 100 mM DTT and 1 ~C1 (200 U) of Superscript II TM AMV reverse transcriptase. Random primer, dNTP's and Superscript TM reagents were all purchased from Life-Technologies, Gaithersburg, MA. The -reaction was incubated at 42 °C for 1 hour.
Amplification of p38 cDNA was performed by aliquoting 5 .
~cl of the reverse transcriptase reaction into a 100 ul PCR reaction containing the following: 80 ul dH20, 2 ul 50 mM dNTP's, 1 ~C1 each of forward and reverse primers _ t~~~

WO 98152940 PC'TIUS98/10436 ( 50 pmol /ul ) , 10 ~cl of l OX buffer and 1 ~cl Expand TM
polymerase (Boehringer Mannheim). The PCR primers incorporated Bam HI sites onto the 5' and 3' end of the amplified fragment, and were purchased from Genosys. Tre sequences of the forward and reverse primers were 5'-GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3' and 5'GATCGAGGATTCTCAGGACTCCATCTCTTC-3' respectively. The PCR amplification was carried out in a DNA Thermal Cycler (Perkin Elmer) by repeating 30 cycles of 94 °C for 1 minute, 60 °C for 1 minute and 68 °C for 2 minutes.
After amplification, excess primers and unincorporated dNTP's were removed from the amplified fragment with a Wizard TM PCR'prep (Promega) and digested with Bam HI
(New England Biolabs). The Bam HI digested fragment was ligated into BamHI digested pGEX 2T plasmid DNA
(PharmaciaBiotech) using T-4 DNA ligase (New England Biolabs) as described by T. Maniatis, Molecular Cloning:
A Laboratory Manual, 2nd ed. (1989). The ligation reaction was transformed into chemically competent E.
coli DH10B cells purchased from Life-Technologies following the manufacturer's instructions. Plasmid DNA
was isolated from the resulting bacterial colonies using a Promega WizardTM miniprep kit. Plasmids containing the appropriate Bam HI fragment were sequenced in a DNA
Thermal Cycler (Perkin Elmer) with PrismTM (Applied Biosystems Inc.), cDNA clones were identified that coded for both human p38a isoforms (Lee et al. Nature 372, 739). One of the clones which contained the cDNA for p38a-2 (CSBP-2) inserted in the cloning site of pGEX 2T, 3' of the GST coding region was designated pMON 35802.
The sequence obtained for this clone is an exact match of the cDNA clone reported by Lee et al. This expression plasmid allows for the production of a GST-p38a fusion protein.
s~rc~~

Expression of human p38a:
GST/p38a fusion protein was expressed from the plasmid pMON 35802 in E. coli, stain DH10B (Life Technologies, Gibco-BRL). Overnight cultures were grow:
in Luria Hroth (LB) containing I00 mg/ml ampicillin. The next day, 500 ml of fresh LB was inoculated with l0 ml o~
overnight culture, and grown in a 2 liter flask at 37 °C
with constant shaking until the culture reached an absorbance of 0.8 at 600 nm. Expression of the fusion protein was induced by addition of isopropyl b-D-thiogalactosidse (IPTG) to a final concentration of 0.05 mM. The cultures were shaken for three hours at room temperature, and the cells were harvested by centrifugation. The cell pellets were stored frozen until protein purification.
Purification of p38 Kinase-a~
All chemicals were from Sigma Chemical Co. unless noted. Twenty grams of E. coli cell pellet collected from five 1 L shake flask fermentations was resuspended in a volume of PBS (140 mM NaCl, 2.7 mM KC1, 10 mM
Na2HP04, 1.8 mM KH2p04~ pH 7.3) up to 200 ml. The cell suspension was adjusted to 5 mM DTT with 2 M DTT and then split equally into five 50 ml Falcon conical tubes. The cells were sonnicated (Ultrasonics model W375) with a 1 cm probe for 3 X 1 minutes (pulsed) on ice. Lysed cell material was removed by centrifugation (12,000 x g, 15 minutes) and the clarified supernatant applied to glutathione-sepharose resin (Pharmacia).
Glutathione-Sepharose Affinity Chromatoaraphy Twelve ml of a 50% glutathione sepharose-PBS
suspension was added to 200 ml clarified supernatant and -incubated batchwise for 30 minutes at room temperature.
The resin was collected by centrifugation (600 x g, 5 min) and washed with 2 x 150 ml PBS/1% Triton X-100, WO 98/52940 PCT/US98/10~36 followed by 4 x 40 ml PBS. To cleave the p38 kinase fro;n the GST-p38 fusion protein, the glutathione-sepharose resin was resuspended in 6 ml PBS containing 250 units '. thrombin protease (Pharmacia, specific activity > 7500 units/mg) and mixed gently for 4 hours at room temperature. The glutathione-sepharose resin was removed by centrifugation (600 x g, 5 min) and washed 2 x 6 ml with PBS. The PBS wash fractions and digest supernatant containing p38 kinase protein were pooled and adjusted to 0.3 mM PMSF.
Mono O Anion Exchange Chromatography:
The thrombin=cleaved p38 kinase was further purified by FPLC-anion exchange chromatography. Thrombin-cleaved sample was diluted 2-fold with Buffer A (25 mM HEPES, pH
7.5, 25 mM beta-glycerophosphate, 2 mM DTT, 5$ glycerol) and injected onto a Mono Q HR 10/10 (Pharmacia) anion exchange column equilibrated with Buffer A. The column was eluted with a 160 ml 0.1 M-0.6 M NaCl/Buffer A
gradient (2 ml/minute flowrate). The p38 kinase peak eluting at 200 mM NaCl was collected and concentrated to 3-4 ml with a Filtron 10 concentrator (Filtron Corp.).
Sephacryl 5100 GelFiltration ChromatoQra~h The concentrated Mono Q- p38 kinase purified sample was purified by gel filtration chromatography (Pharmacia HiPrep 26/60 Sephacryl S100 column equilibrated with Buffer B (50 mM HEPES, pH 7.5, 50 mM NaCl, 2 mM DTT, 5°s glycerol)). Protein was eluted from the column with Buffer B at a 0.5 ml/minute flowrate and protein was detected by absorbance at 280 nm. Fractions containing p38 kinase (detected by SDS-polyacrylamide gel electrophoresis) were pooled and frozen at -80 °C.
Typical purified protein yields from 5 L E. coli shake flasks fermentations were 35 mg p38 kinase.
SIJE~T~UTE~~ ~~

In Vitro Assay The ability of compounds to inhibit human p38 kinase alpha was evaluated using two in vitro assay methods. In the first method, activated human p38 kinase alpha phosphorylates a biotinylated substrate, PHAS-I
(phosphorylated heat and acid stable protein-insulin inducible) , in the presence of gamma 'zP-ATP ('ZP-ATP) .
PHAS-I was biotinylated prior to the assay and provides a means of capturing the substrate which is phosphorylated l0 during the assay. p38 Kinase was activated by MKK6.
Compounds were tested in 10 fold serial dilutions over the range of 100 ~.M to 0.001 ACM using 1% DMSO. Each concentration'of inhibitor was tested in triplicate.
All reactions were carried out in 96 well polypropylene plates. Each reaction well contained 25 mM
HEPES pH 7.5, 10 mM magnesium acetate and 50 uM unlabeled ATP. Activation of p38 was required to achieve sufficient signal in the assay. Biotinylated PHAS-I was used at 1-2 ~cg per 50 ~cl reaction volume, with a final concentration of 1.5 ACM. Activated human p38 kinase alpha was used at 1 ~.g per 50 ~cl reaction volume representing a final concentration of 0.3 ~cM. Gamma 32p_ ATP was used to follow the phosphorylation of PHAS-I.
32p_ATP has a specific activity of 3000 Ci/mmol and was used at 1.2 ~CCi per 50 ~1 reaction volume. The reaction proceeded either for one hour or overnight at 30 °C.
Following incubation, 20 ~cl of reaction mixture was transferred to a high capacity streptavidin coated filter plate (SAM-streptavidin-matrix, Promega) prewetted with phosphate buffered saline. The transferred reaction mix was allowed to contact the streptavidin membrane of the Promega plate for 1-2 minutes. Following capture of biotinylated PHAS-I with 32P incorporated, each well was washed to remove unincorporated 32P-ATP three times with 2M NaCl, three washes of 2M NaCl with 1% phosphoric, three washes of distilled water and finally a single wash St~'(RULE86j of 95% ethanol. Filter plates were air dried and 20 ~cl of scintillant was added. The plates were sealed and counted. Results are shown in Table 4.
A second assay format was also employed that is based on p38 kinase alpha induced phosphorylation of EGFRP (epidermal growth factor receptor peptide, a 21 mer) in the presence of "P-ATP. Compounds were tested in l0 fold serial dilutions over the range of 100uM to O.OOI~eM in 1% DMSO. Each concentration of inhibitor was l0 tested in triplicate. Compounds were evaluated in 50~c1 reaction volumes in the presence of 25 mM Hepes pH 7.5, mM magnesium acetate, 4% glycerol, 0.4% bovine serum albumin, 0.4mM DTT, 50~CM unlabeled ATP, 25 ~g EGFRP
(200~.M), and 0.05 uCi gamma "P-ATP. Reactions were initiated by addition of 0.09 ~cg of activated, purified human GST-p38 kinase alpha. Activation was carried out using GST-MKK6 (5:1,p38:MKK6) for one hour at 30 °C in the presence of 50~cM ATP. Following incubation for 60 minutes at room temperature, the reaction was stopped by addition of 150u1 of AG 1X8 resin in 900 mM sodium formate buffer, pH 3.0 (1 volume resin to 2 volumes buffer). The mixture was mixed three times with pipetting and the resin was allowed to settle. A total of 50.1 of clarified solution head volume was transferred from the reaction wells to Microlite-2 plates. 150~c1 of Microscint 40 was then added to each well of the Microlite plate, and the plate was sealed, mixed, and counted.

WO 98/52940 PCT/US98/10436 , Example p38 kinase IC50 (uM) 1 4.6 2 1.5 8 <0.1 16 3.8 23 1.5 25 2.6 26 0,7 28 0.3 33 2.5 34 8.0 36 12.1 38 0,8 39 ~ 1.1 40 1.3 42 . 0.3 43 <0.1 44 <0.1 45 <0.1 46 <0.1 47 3.2 48 1.8 50 2.3 51 <0.1 52 0.1 53 0.9 54 0.7 55 6.4 143 <0.1 TNF Cell Assays Method of Isolation of Human Peripheral Blood Mononuclear Cells:
Human whole blood was collected in Vacutainer tubes containing EDTA as an anticoagulant. A blood sample (7 ml) was carefully layered over 5 ml PMN Cell Isolation Medium (Robbins Scientific) in a 15 ml round bottom centrifuge tube. The sample was centrifuged at 450-500 x g for 30-35 minutes in a swing out rotor at room temperature. After centrifugation, the top band of cells were removed and washed 3 times with PBS w/o calcium or magnesium. The cells were centrifuged at 400 x g for 10 minutes at room temperature. The cells were resuspended s~s~c~~~

in Macrophage Serum Free Medium (Gibco BRL) at a concentration of 2 million cells/ml.
LPS Stimulation of Human PBMs:
PBM cells (0.1 ml, 2 million/ ml) were co-incubated with 0.1 ml compound (10-0.41 uM, final concentration) for 1 hour in flat bottom 96 well microtiter plates.
Compounds were dissolved in DMSO initially and diluted in TCM for a final concentration of 0.1% DMSO. LPS
(Calbiochem, 20 ng/ml, final concentration) was then added at a volume of 0.010 ml. Cultures were incubated overnight at 37 °C. Supernatants were then removed and tested by ELISA for TNF-a and IL1-b. Viability was analyzed using MTS. After 0.1 ml supernatant was collected, 0.020 ml MTS was added to remaining 0.1 ml cells. The cells were incubated at 37 °C for 2-4 hours, then the O.D. was measured at 490-650 nM.
Maintenance and Differentiation of the U937 Human Histiocytic Lymphoma Cell Line:
U937 cells (ATCC) were propagated in RPMI 1640 containing 10% fetal bovine serum, 100 IU/ml penicillin, 100 ug/ml streptomycin, and 2 mM glutamine (Gibco).
Fifty million cells in 100 ml media were induced to terminal monocytic differentiation by 24 hour incubation with 20 ng/ml phorbol 12-myristate 13-acetate (Sigma).
The cells were washed by centrifugation (200--x g for 5 min) and resuspended in 100 ml fresh medium. After 24-48 hours, the cells were harvested, centrifuged, and resuspended in culture medium at 2 million cells/ml.
LPS Stimulation of TNF production by U937 Cells:
U937 cells (0.1 ml, 2 million/ml) were incubated with 0.1 ml compound (0.004-50 uM, final concentration) for 1 hour in 96 well microtiter plates. Compounds were prepared as 10 mM stock solutions in DMSO and diluted in culture medium to yield a final DMSO concentration of 0.1% in the cell assay. LPS (E coli, 100 ng/ml final concentration) was then added at a volume of 0.02 ml.
After 4 hour incubation at 37°C, the amount of TNF-a released in the culture medium was quantitated by ELISA.
Inhibitory potency is expressed as ICSO (~M).
Results of these TNF Cell Assays are shown in Table S. ' Example Human PBM Assay U937 Cell Assay IC50 (uM) IC50 ( (~eM) . 1 0.5 2 1.6 0.578 4 0.1 0.222 5 0.274 7 0.2 0.201 ' 8 <0.1 9 0.4 10 0.7 1.687 12 8.5 13 4.8 14 1.2 17 1.1 19 0.3 0.484 1.089 21 , 0.077 22 3.2 20 24 8.2 26 <0.1 0.029 27 2.7 28 0.1 29 2.2 30 2.6 31 0.8 1.053 32 2.696 33 0.4 34 0.5 35 0.7 36 1.4 37 1.5 0.099 38 0.2 0.208 39 0.7 0.244 40 0.4 41 1.0 42 0.7 43 <0.1 0.243 44 0.4 0.477 45 <0.1 0.04 46 0.329 47 2.359 48 2.2 0.522 49 6.8 50 0,g 51 0.074 54 0.2 0.13 <0.1 0.228 143 0.301 Rat Assay The efficacy of the novel compounds in blocking the production of TNF also was evaluated using a model based on rats challenged with LPS. Male Harlen Lewis rats [Sprague Dawley Co.] were used in this model. Each rat weighed approximately 300 g and was fasted overnight prior to testing. Compound administration was typically ' by oral gavage (although intraperitoneal, subcutaneous and intravenous administration were also used in a few instances) 1 to 24 hours prior to the LPS challenge.
Rats were administered 30 ~.g/kg LPS [salmonella typhosa, Sigma Co.] intravenously via the tail vein. Blood was collected via' heart puncture 1 hour after the LPS
challenge. Serum samples were stored at -20 °C until quantitative analysis of TNF-a by Enzyme Linked-Immuno-Sorbent Assay ("ELISA") [Biosource]. Additional details of the assay are set forth in Perretti, M., et al., Br.
J. Pharmacol. (1993), 110, 868-874, which is incorporated ' by reference in this application.
Mouse Assay Mouse Model Of LPS-Induced TNF Alpha production TNF alpha was induced in 10-12 week old BALB/c female mice by tail vein injection with 100 ng lipopolysaccharide (from S. Typhosa) in 0.2 ml saline.
One hour later mice were bled from the retroorbital sinus and TNF concentrations in serum from clotted blood were quantified by ELISA. Typically, peak levels of serum TNF
ranged from 2-6 ng/ml one hour after LPS injection.
The compounds tested were administered to fasted mice by oral gavage as a suspension in 0.2 ml of 0.5%
methylcellulose and 0.025% Tween 20 in water at 1 hour or 6 hours prior to LPS injection. The 1 hour protocol allowed evaluation of compound potency at Cmax plasma levels whereas the 6 hour protocol allowed estimation of compound duration of action. Efficacy was determined at each time point as percent inhibition of serum TNF levels relative to LPS injected mice that received vehicle only.
Additional results obtained using the above-described assays are set forth in Table 6 below. p38 assay and U937 cell assay results are expressed as ICS
(gym). Mouse-LPS assay results are expressed as percent inhibition.

WO 98/52940 2 ~ 0 PCT/US98/10436 Example j p38~U937 j mLPS mLPS mLPS
~ p38' I
~

T
8h 6h lh, 30mpk dose j _ i ! A-212 10.49 0.74 0.096720 10 A-208 X0.1040.049 6.189698 _ 30 ; 97 A-227 0.06 I j g6 A-228 0.76 0.339 0.417332~ 30 i 92 A-229 j 1.4 0.462276 ~ j 91 A-230 0.42 0.178 ' ~ g6 A-231 0.174 0.322586 30 94 A-232 0.048 ~ 96 A-233 0.044 j 53 A-234 0.103 A-235 0.104 ~ 56 A-236 0.237 I 94 A-237 0.093 0.087 ; 60 A-238 0.177 0.4016 I

A-239 0.034 51 30 87 A-240 0.961] 78 30 85 A-24I 0.338 79 30 87 A-242 0.047 95 30 8?

A-243 0.729 ' 82 A-244 0.099 A-245 <.001 0.0337 65 A-246 0.403 0.592 0.4952 j A-247 <0.01 0.166 j I

A-249 0.432 73 30 j 86 A-250 2.873 A-251 0.637 32 87 A-252 0.774 1.197 48 30 75 A-253 <.001 0.0044 61 A-254 0.081 0.1411 A-215 2.34 0.297638 30 80 A-256 0.813 0.4562 A-257 1.081 <.O1 0.5167 A-213 0.22 j 57 A-258 0.48 1.2083 6g I

A-259 0.17 0.7574 62 A-210 0.16 0.198385 30 93 A-260 0.23 1.282147 30 79 A-214 0.06 1.4006 70 A-261 0.008 0.254248 30 92 A-216 0.018 1.828727 30 91 A-262 <0.1 0.3267 45 A-263 <0.01 <0.1 0.5434 4g ~5{~~

Example I p381 i P38' ' I

I
mLPS

mLPS mLPS

8h 6h dose lh, 30mak A-264 0.2594 A-265 ~<0.1 0.6016 A-266 i 0.5393 I Q

- ~ 0.43 A-267 2.6681 . 80 <0.01~0.0074 I

A-217 0.697 0.3486 A-269 >10 uM

A-270 ~ 0.015 0.3466 A-271 0.216 ;
4.2144 A-272 0.073 0.583 68 A-273 6.98 >10 A-274 <0.1 0 ~ 2 I

. 1 30 , 10.14 ' A-275 2 >10 A-276 0.176 0.45 -24 30 A-277 0.026 33 30 I

A-278 0.285 2.3 62 30 ' A-279 0.005 0.7 64 30 A-280 0.134 15 30 A-281 0.053 ~ 22 30 A-218 0.044 18 30 A-282 0.045 0.097330 30 A-283 <0.1 0.7998-20 30 A-284 0.98 0.5088-1 A-285 <0.1 0.179511 30 ~

A-286 0.057 0.09 29 30 A-287 0.041 0.27 -24 30 A-288 0.017 0.3 40 30 A-289 <0.1 0.14 44 30 i A-290 6.01914 30 A-291 0.388 1.130936 3p A-292 1.15 >10 A-293 0.73 A-294 0.015 0.5 61 30 A-295 7.66 >10 94 30 A-297 0.52 0.17 89 30 ' p38a in vitro assay results based on PHAS-I assay procedure z p38a in vitro assay results based on EGFRP assay procedure WO 98/52940 PC'T/US98110a36 Induction And Assessment Of Collacten-Induced Arthritis In Mice:
Arthritis was induced in mice according to the procedure set forth in J.M. Stuart, Collagen Autoimmune Arthritis, Annual Rev. Immunol. 2:199 (1984), which is incorporated herein by reference. Specifically, arthritis was induced in 8-12 week old DBA/1 male mice by injection of 50 ~g of chick type II collagen (CII) (provided by Dr. Marie Griffiths, Univ. of Utah, Salt Lake City, UT) in complete Freund's adjuvant (Sigma) on day 0 at the base of the tail. Injection volume was 100 ~,1. Animals were boosted on day 21 with 50 ~cg of CII in incomplete Freund's adjuvant (100 ~C1 volume). Animals were evaluated several times each week for signs of arthritis. Any animal with paw redness or swelling was counted as arthritic. Scoring of arthritic paws was conducted in accordance with the procedure set forth in Wooley et al., Genetic Control of Type II Collagen Induced Arthritis in Mice: Factors Influencing Disease Suspectibility and Evidence for Multiple MHC Associated Gene Control., Trans. Proc., 15:180 (1983). Scoring of severity was carried out using~a score of 1-3 for each paw (maximal score of 12/mouse). Animals displaying any redness or swelling of digits or the paw were scored as 1. Gross swelling of the whole paw or deformity was scored as 2. Ankylosis of joints was scored as 3.
Animals were evaluated for 8 weeks. 8-10 animals per group were used.
Preparation And Administration Of Compounds:
The compounds tested on mice having collagen-induced arthritis were prepared as a suspension in 0.5%
methylcelluose (Sigma, St. Louis, MO), 0.025% Tween 20 -(Sigma). The compound suspensions were administered by oral gavage in a volume of 0.1 ml b.i.d. Administration began on day 20 post collagen injection and continued ' WO 98/52940 PC'TIUS98/10436 daily until final evaluation on day 56. Scoring of arthritic paws was conducted as set forth above. Assay results are set forth in Table 7.

. Compound % Inhibition of Arthritis A-210 58.5 Q 15 mpk A-172 49.3 Q 100 mpk A-189 51.6 Q 30 mpk A-208 97.5 Q 60 mpk A-208 75.0 Q 60 mpk Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of this invention in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as ~~carrier~~ materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition may, for example, be administered orally, intravascularly (IV), intraperitoneally, subcutaneously, intramuscularly (IM) or topically. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, hard or soft capsule, lozenges, dispensable powders, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection (IV, IM, subcutaneous or jet) as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier. The pH of ~5i~~~~

the composition may be adjusted, if necessary, with suitable acid, base, or buffer. Suitable bulking, dispersing, wetting or suspending agents, including mannitol and PEG 400, may also be included in the S composition. A suitable parenteral composition can also include a compound formulated as a sterile solid substance, including lyophilized powder, in injection ' vials. Aqueous solution can be added to dissolve the compound prior to injection. The amount of therapeutically active compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a 'variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the inflammation or inflammation related disorder, the route and frequency of administration, and the particular compound employed, and thus may vary widely. The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 1000 mg, preferably in the range of about 7.0 to 350 mg. A daily dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50 mg/kg body weight and most preferably between about 0.5 to 30 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. In the case of skin :conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day. For disorders of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical gel, , spray, ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base.
S~IE~~f~tllTE~t~~~

Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30~ w/w of a polyhydric alcohol such. as propylene glycol, butane-1,3-diol, mannitol, sorbitol, . glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. The transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an . oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifiers) with or without stabilizers) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glycery~
monostearate, and sodium lauryl sulfate, among others.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. Formulations suitable for .topical administration to the eye also include eye drops :wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The anti-inflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to .
10% and particularly about 1.5% w/w. For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and - sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.
Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
All patent documents listed herein are incorporated by reference.
Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.
su~~rrru~s~'t~zs) Description of parallel array synthesis methodology utilized to prepare compounds of Examples B-i, B-ii, and B-iii.
Scheme B-1 describes the parallel array reaction blocks that were utilized to prepare compounds of Examples B-0001 through B-1574, and by analogy could also be used to prepare compounds of Examples B-1575 through B-2269.
Parallel reactions were performed in multi-chamber reaction blocks. A typical reaction block is capable of performing 48 parallel reactions, wherein a unique compound is optionally prepared in each reaction vessel BZ. Each reaction vessel Bl is made of either t5 polypropylene or pyrex glass and contains a frit B2 toward the base of the vessel. Each reaction vessel is connected to the reaction block valve assembly plate B3 via leur-lock attachment or through a threaded connection. Each vessel valve 84 is either opened or closed by controlling the leur-lock position or by the opening or closing of levers HS within a valve assembly plate row. Optionally, solutions can be either. drained or maintained above the vessel frits by leaving the valves in the opened position and controlling the back pressure beneath the valve assembly plate by control of inert gas flow through the inert gas inlet valve H6. The parallel reactions that are performed in these reaction blocks are allowed to progress by incubation in a ' jacketed, temperature controlled shaking station.
Temperature control of the reaction chambers is effected -by passing a heat-transfer liquid through jacketed aluminum plates that make contact with the reaction block mantle B7. Mixing is effected at the shaking staticr. by either vertical orbital shaking of the up-right reaction block or by lateral shaking of the reaction block ~ilte~
on its side.
Functionalized resins are optionally added to eac:-~
reaction vessel H1 during the course of reaction or at the conclusion of the reaction. These functio:.ali~ed resins enable the rapid purification of each reactio-:
vessel product. Vacuum filtration of the reaction block apparatus by opening of the vacuum valve BB allows purified products to be separated from resin-sequestereG
non-product species. Valve 88 is located on the bottom reaction block chamber 810 which houses the quadrant collection vial racks BI1. The desired products are obtained as filtrates in unique collection vials H9.
Removal of solvent from these collection vials affords desired products.

WO 981529d0 PCT/US98I10436 Scheme B-2 illustrates the various utilizations of functionalized resins to purify reaction vessel products B22 prior to filtration from the fritted vessels B1 into collection vials B9. Said functionalized resins perform as 1) resin-bound reagents B12, which give rise to resin-bound reagent byproducts B13; 2) sequestrants B14 or B15 of excess solution-phase reactants BI6 or B17, respectively. Solution-phase reactants B16 and E17 contain inherent reactive functionality -rfl and -rf~

which enable their chemoselective sequestration by the complementary reactive functionality -Cr~~ and -C~f-attached to resins B14 and 815; 3) sequestrants HI8 of solution-phase byproducts 819. Byproduct B19 contains molecular recognition functionality -mr2 which enables ~~s chemoselective sequestration by the comp;ementar_~
functionality -Cmr2 attached to resin 818; 4) reactic~-quenching resins 820 which give rise to quenched resins B21. Resin B20 contains functionality -Q which mediates IO reaction quenching (for instance, proton. transfer) of product B22 to form a desired isolable form of produc~
B22. Upon performing reaction quench, the resin B20 is converted to resin B21 wherein -q represents the s~_er.t functionality on resin 821 ; 5) sequestrants B23 of chemically-tagged reagents B24 and their corresponding reagent byproducts 825. The soluble reagent B24 contains a bifunctional chemical group, -tag, which is inert to the reaction conditions but is used to enable the post-reaction sea_uestration of B24 by the complementary functionality -Ctag attached to resin 823. Additionally, the soluble reagent byproduct 825, formed during the course of reaction, contains the same chemical function -tag that also enables its sequestration by resin B23.
Additionally, some reactants 816, particularly ~5 sterically-hindered reactants and/or electron deficient nucleophiles, contain poorly sequestrable functionality (rfl in this case is a poorly sequestable functionality).
These poorly seguestable reactants 816 can be transformed in situ to more robustly sequestrable species B27 through their reaction with sequestration-enabling-reagents 826.
826 contain highly reactive, complementary functionality Crfl which reacts with B16 to form B27 in situ. The bifunctional molecular recognition functionality, mr, contained within B26 is also present on the ir. si~L
derivatized 827. Both B26 and B27 are sequestered by the complementary molecular recognition functional_tv attached to resin B28: By analogy, some reac:.~ons contain poorly sequestable byproducts B19, wherein the molecular recognition functionality mr2 in this case is not able to mediate the direct sequestration of B19 by the complementary functionality attached to resin B18.
t0 Similar use of the bifunctional sequestration-enabling-reagent 829 transforms B19 into the more readily sequestrable 'species 830. The imparted molecular recognition functionality, mr, present in B30 is readily sequestered by the complementary functionality, Cmr, attached to resin B31. In some reactions, multiple sequestration resins are utilized simultaneously to perform reaction purifications. Even resins contain=ng incompatible (mutually reactive) functional groups can be used simultaneously because these resins scavenge 2o complementary functionalized solution phase reactants, reagents, or byproducts from solution phase faster than resin cross-neutralization. Similarly, resins containing mutually reactive or neutralizing reaction-quenching functionality are able to quench solution phase reactants, products, or byproducts faster than resin cross-neutralization.

WO 98/SZ940 PCT/US98IIOd36 Scheme B-2 A-Ser-mr i Cmr-0 Cmr-~~- BP
Ser-mr Crf~-~r-mr ~ Cmr2 Ser-mr R ~ Rb 9 B' B26 p _ B12 ~ B13 A-rf~ + B-rlz P + PB-mr2 B16 B17 g~, B19 R-tag Rbp-tag -0 -0 ~

Crf2 g~ B~ Cmr2-0 Crf~

B14 B15 C-0 Q~

B20 B=1 . Cta9"

~ Denotes insoluble B'-3 resin Scheme B3 describes the modular robotics laboratory environment that was utilized to prepare compounds of Examples B0001 through Bxacxx. Chemicals that are utilized in the robotics laboratory are weighed and then dissolved or suspended into solvents at Station #1 (Automated Chemistry Prep Station). Thus, solutions or suspensions of known molarity are prepared for use at the other robotics workstations. Station #1 also optionally bar-code labels each chemical solution so that its identity can be read by bar-code scanning at this and other robotics workstations.
l5 Reactions are initiated at the modular Stations #2 and #2 DUP. Station #2DUP is defined as a duplicate of Station #2 and is used to increase capacity within the robotics _ laboratory. A reaction block is mounted at Station #2 or #2 DUP. Also, racks containing reactants, reagents, solvents, and resin slurries are also mounted at Station #2 or #2 DUP. Under the control of a chemical WO 98152940 pCTIUS98~t0436 inrormatics mapping file, reactions are initiated by the transfer of reactant solutions, reagent soluticns, solvents, and/or resin slurries into each mou.~.te~
reaction block vessel. The transfer of known volumes e=
solutions, suspensions, or solvents is mediated by syringes which control a one-up septum pierc_ng/a~c~n purging cannula, a wide-bore resin slurry-desper.sing cannula, or by a six-up .cannula which can simultaneous'_y deliver volumes to a row of six reaction vessels. '.'he reaction block and/or chemical solution racks may be optionally cooled below room temperature during ~he chemical solution transfer operations. After the transfer of chemical solutions and solvents has been performed by Station#2 or #2DUP, incubation of the ~5 reaction block may occur while the reaction block is mounted at the robot station. Preferably, however, the reaction block is removed after all volume transfers are complete and the reaction block is brought to ambient temperature. The reaction block is transferred off-line to either a vertical- or lateral shaking Incubator Station #5.
The Automated weighing/archival Station #3 performs the functions of weighing empty collection vials (to obtain tare weights of collection vials) and also performs the functions of weighing collection vials containing filtered, purified products (to obtain gross weights of collection vials). After product-containing collection vials have been weighed (gross weight determinations) at workstation #3, the collection vial products are 3o optionally redissolved into an organic solvent at workstation #3. Transfer of solvents is accomplished ;
with syringes which control a mounted one-up septum-piercing/argon purging cannula. Each product-containing collection vial is prepared as a solution of K;,o~
molarity as directed and recorded by the chemical informatics sys-tem. These product solutions may be subsequently mounted at Station #2 or #2DUP for subsequent reaction steps or taken to Station #7 or #iDUP
. for analytical processing.
Rapid solvent evaporation of product-containing collection vials is accomplished by mounting the o collection racks at Savant Automated Solvent Evaporation Stations #4, #4 DUP, or #4 TRIP, wherein #4DUP and #4TRTP
are defined as.a duplicate and a triplicate of Station #4 to increase the capacity for solvent removal within the robotics laboratory. Commercially available solvent removal stations were purchased from the Savant Company (model # SC210A speedvac unit equipped with model #
RVT4104 vapor trap and model # VN100 vapornet cryopump).
Stations #7 and #7DUP perform analytical processing functions. Station #7DUP is defined as a duplicate of Station #7 to increase capacity within the robotics laboratory. Product-containing collection racks are mounted ~t either of these stations. Each product-containing collection vial is then prepared as a solution of known molarity as directed and recorded by the chemical informatics mapping file. Optionally, this dissolution function is performed by prior processing of the collection vial rack at Station #3 as described above. Station#7 or #7DUP, under the control of the chemical informatics mapping file, transfers aliquots of each product vial into unique and identifable microtiter plate wells that are utilized to perform analytical determinations.

One such microtiter plate is prepared at.Station #7 0 #7DUP for subsequent utilization at the Automated HPLC/Mass Spectrometer Station #8 or #BDUP. Station #8DU?
is a duplicate of Station #8 to increase the analyt~ca_ capacity of the robotics laboratory. Stations #8 and #BDUP are commercially available benchtop LC/Mass spec units purchased from Hewlett Packard (model HP1100 HPLC
connected to HP1100 MSD (G1946A) mass spectrometer; this unit is also equipped with a model# GI322A solver.;.
degasser, model # G1312A binary pump, a model # G1316A
column heater, and a model # G1315A diode array detector.
The HP unit has been interfaced with a commercially available autosampler rack (Gilson Company # 215 autosampler). Station #8 or #BDUP is utilized for the determination of product purity and identity by performing high performance liquid chromatography (HPLC) and companion atmospheric pressure chemi-ionization (APCI) or electrospray mass spectrometry for molecular weight determination.
Another microtiter plate is prepared at Station #7 or #7DUP for subsequent utilization at a commercially available flow-probe Varian NMR spectrometer Station #10 (Varian Instruments flow probe NMR, 300 MHz, interfaced with a commercially available Gilson 215 autosampler).
~5 Proton, 13-Carbon, and/or 19-Fluorine NMFt spectra are determined at this Station #10.
Other microtiter plates are optionally mounted at Station #7 or #7DUP for the purpose of preparing product-containing plates for biological assays. Aliquots of 3o product-containing collection vials are transferred to these biological assay microtiter plates under the control of the chemical informatics mapping file.
Identity and amount of each transferred product is recorded by the chemical informatics system for retrieval by biologists who perform the biological assaying o=
products.
S The Fourier Transfrom InfraRed (FT-IR) Spectrome~er Station #11 is utilized to analyze resins for the identity of organic functional groups chemically attachec to these resins. The resins, as mentioned above, contair.
chemical functionality utilized as reagents, 1o chemoselective sequestrants, or reaction quenching media for the workup and purification of the crude product mixtures contained within reaction block vessels. The robotics laboratory utilizes a commercially available FT-IR spectrometer purchased from Nicolet Instruments (model 15 # MagnaIR 560 interfaced with an InspectIR microscope for resin mounting and positioning).
Scheme B-3 The lines interconnecting the modular Stations denote the '0 transfer of chemical racks, reaction blocks, and/or collection vial racks from one modular Station to another.

Automated Automated Chemistn~ Prep Reaction Building Station #I Station #2 Automated Automated Oliline Reaction weighinglarchival Reaction building Incubator Station #3 Station #2 DUP Station #5 Automated Automated Automated Solvent Evap. Solvent Evap. Solvent Evap.
Station #4 Station #4 DUP Station #4 TRIP
Automated Automated Automated HPLC/
Analytical Prep. Analytical Prep. Mass Spec Station #7 Station #7 DUP Station #8 FT-IR Flow Probe Automated HPLC/
Station #1I NMR Mass Spec Station #IO Station #8 DUP
The ChemLib IT system is a composite of software running on the client's desktop and software running on a remote server.
The ChemLib IT system is a client/server software application developed to support and document the data handling flow in the robotics laboratory described above.
This IT system integrates the chemist with the robotics synthesis laboratory and manages the data generated by this processes.
The software running on the server warehouses all the IS electronic data for the robotics chemistry unit. This WO 98/52940 PCT/US98It0436 server, a Silken Graphics IRIX station v6.2, r;~ns database software, Oracle 7 v7.3.3.5.0, that warehouses the data: Connection from the client's desktop to she server is provided by Oracle's TCP/IP Adapter v2.2.2.1.C
and SQL*Net v2.2.2.1.0A. SQL*Net is Oracle's network interface that allows applications running on the ' clier_t's desktop to access data in Oracles' database.
The client's desktop is Microsoft Windows 95. Tne ChemLib IT system client software is composed of Om~is v3 .5 and Microsoft Visual C++ v5Ø This compositio : on the client side is what is herein referred to as ChemL'_b.
ChemLib commur_icates with the server for its data v-la Oracle's PL/SQL v2.3.3.4Ø These PL/SQL calls within ChemLib creates a network socket connection to Oracle's ~5 SQL*Net driver and the TCP/IP Adapter thereby allowing access to the data on the server.
A "library" is defined as a composite number of wells, where each well defines a single compound. ChemLib deffines a library in a module called the Electrcric Spreadsheet. The Electronic Spreadsheet is then a composite of n-number of wells containing the components that are required to synthesize the compound that exist in each these well(s).
'_'S
The chemist begins by populating the ~lec~ronic Spreadsheet with those components required for the compound synthesis. The identity and the availability of these components are defined in the Building Block Catalog module of ChemLib. The Building Block Catalog is a catalog of a listing of all reagents, solvents, peripherals available in the robotics laboratory. Upon selecting the components for each compound we also declare the quantity of each component to be utilite~_.
The quantity of each component can be identified by its molarity and volumetric amounts (ul) or by i~'s solid state form (mg) . Therefore a well in the Elec~~e:.ic Spreadsheet defines a compound that is identified by its components and the quantity of each of these components.
The assembly or the synthesis of these components fo=
each compound in the Electronic Spreadsheet is defined __.
the wS Sequence module of ChemLib. The Define G.~S
Sequence module identifies the synthesis steps to be performed at the robotics workstations and any acti~'_~ies to be performed manually or off-line from the robotics workstation. With this module we identify which !5 cctnponents from the Electronic Spreadsheet and the activity that should. be performed with this component in the robotics laboratory. In the Define WS Sequence module the chemist chooses from a list of activities to be per~ermed in the robotics laboratory and assembles 20 them in the order in which they are to occur. The ChemLib system takes these set of activities identified, and with the component data in the Electronic Spreadsheet assembles and reformats these instructions into terminology for the robotics workstation use. This ~5 robotics terminology is stored i.n a 'sequence' file on a common server that is accessible by the robotics workstation.
The robotics workstation performs the synthesis in a 30 reaction block apparatus as described. Each well in the Electronic Spreadsheet is tracked and mapped to a unique ;
location in the reaction block apparatus on the robotics workstation. The compound or product synthesized at the robotics workstation in the reaction block is her.
captured into collection vials.
The collection vials are first tarred then grossed or_ the robotics workstation after collecting their products from the reaction block. These weights (tare and gross) are recorded into the ChemLib system with the TarelGr ess Session module. The TarelGross Session module then calculates the product or compound yields and its final mass.
Preparation of the compou_~d for analytical analysis anc screening is defined by the Analytical WS Setup module in ChemLib. The Analytical WS Se~up module identifies the dilution factor for each well in the Electronic Spreadsheet, based on the compound's product yield and the desired molar concentration. This identifies the qua_~tity, in uL, to be transferred at the robotics workstation, to a specific location on the MTP
(microtiter plate> to be sent for analysis and/or biological assaying. The mass spectrometric and HPLC
results for each well are recorded and scored into the ChemLib system.
The DilutelArchive WS module further identifies each compound by mapping the compound's well from the Electronic Spreadsheet to a specific MX block location for long term storage and archival as part of the registration process.
All communications between ChemLib and the robotics workstations are by ASCII files. These files are placed on a server by the ChemLib system that is accessible by WO 98/52940 PC'T/US98/10436 the robotics workstations. Reports generated by robotics workstations are also placed on the server whe=a the ChemLib system can read these files to record the data generated. Each robotics workstation consists c robotics hardware by Bohdan Automation, Inc. Mundelein, Illinois, and a PC currently running Microsoft Windows for Workgroup v3.11 and Ethernet software. The robotics workstation PC is logged into the network for one-way communication that allows the workstation to access the server for file access only.
General Scheme~B4 Scaffold C-i with a primary amine =unctiona_ity contained within the R4 substituent is reacted ir.
spatially addressed, parallel array reaction block vessels with excess of electrophiles RJ-Q wherein Q is chloro, bromo, or an acid activating group including but not limited to N-hydroxysuccinimide. RJ-Q includes acid 2o chlorides, alkyl chloroformates, sulfonyl chlorides, activated esters of carboxylic acids, activated carbamates, and isocyanates. Reaction of scaffold C-i with RJ-Q'is effected in the presence of a tertiary amir_e base at room temperature in a mixture of a polar aprotic solvent and/or a halogenated solvent. As illustrated in Scheme B-4 the products of the general formulae B-i are isolated in purified form by addition of a carbonyl-functionalized resin B32 which covalently sequesters any unreacted primary amine scaffold C-i as resin-bound adduct B35, and also by the addition of a primary amine-functionalized resin B33 which covalently sequesters any remaining electrophile RJ-Q from each reaction mixture as resin-bound adduct B34. Resin B33 also seguesters the F:, byproduct from the reaction mixture by proton transFer . from solution-phase Base-HQ. Incubation at room temperature, filtration, rinsing of the resin cake, 'and concentration of the filtrates affords purified products B-i filtered away from resin-bound adducts B32, B33, 834, B35, and H36.
Scheme 8-4 N--NH
N- NH
RZ ~ ~ Ra + R~-Q R2 ~ ~ Ra R
Base Base-HQ
C-i B-i R' contains a prirnarv R' contains a derivatized amine function -NH: .NH-R~ function CHO ~--NHZ ~--NH2 N--NH
Ny~ ~ ~ Rz ~NH-R~ ~NH2 . HQ
B35 ~ B34 B~
. Scheme B-5 specifically illustrates the derivatization of the primary amine-containing scaffold C1 to afford the desired products B-i in a parallel ~ 15 array synthesis format. In a parallel array synthesis reaction block, individual reaction products are prepared in each of multiple reaction block vessels in a spatially WO 98/52940 PCTlUS98/10436 addressed format. A solution of the desired pri:~ar~,~
amine-containing scaffold C1 (limiting a.~nou_nt,) in dimethylformamide (DMF) is added to the reaction vesse_s followed by a 4.0 fold stoichiometric excess solution of N-methylmorpholine in DMF. To each reaction vessel is then added the electrophiles: either a 2.0 fold stoichiometric excess when R'-Q is an acid chloride or alkyl chloroformate, or a 1.5 fold stoichiometric excess when R''-Q is a sulfonyl chloride, or a 1.25 ~ol~
stoichiometric excess when RJ-Q is an isocyanate. Excess electrophiles and N-methylmorpholine were used to effect more rapid and/or more complete conversion of sca~fold C1 to products B-0001-B-0048 compared to reactions that do not utilize stoichiometric excesses of electrophiles and N-methylmorpholine. The reaction mixtures are incubated at ambient temperature for 2-3 h. Each reaction vessel is then charged with a large excess (15-20 fold stoichiometric excess) of the amine-functionalized resin 833 and the aldehyde-functionalized resin 832. The resin-charged reaction block is shaken vertically for 14-20 h on an orbital shaker at ambient temperature to allow optimum agitation of the resin-containing vessel mixtures. The excess electrophiles RJ-Q and any unreacted scaffold amine C1 are removed from the reaction medium as insoluble adducts 834 and 837 respectively. Ir.
addition the N-methylmorpholine hydrochloride salt formed during the course of the reaction is also neutralized to its free base form by proton transfer reaction to the ' amine-functionalized resin H33. Simple filtration of the insoluble resin- adducts 832, 833, B34, B36, and B37, -rinsing of the resin cake with dichloroethane, and evaporation of the filtrates affords the desired products e-i in purified form. -WO 98/52940 PCTIUS98/10~36 s~~m~ B-s N--NH N-NH
' ~ ~ NHZ + R~-Q _ ~ ~ NH, R,:
F I / / ~ F I / ~.

N
CN~ ~ ~ ~ N
I N~HO B'~
C-1 ~H~ CHI
~NHZ
--pHO B33 -NHS
~NH-R'~ B33 ~N
(~~rj-:~// F ~ NHp . Hp B3' ~c~mme rs-o illustrates a general synthetic method involving the parallel array reaction of a scaffold C-ii containing a secondary amine functionality within the definition of the Ra substituent. Each reaction vessel is ' charged with the secondary amine-containing scaffold C
ii, followed by the introduction of a stoichiometric t0 excess of an optionally unique electrophile RL-Q into each vessel, wherein Q is chloro, bromo, or an acid activating group including but not limited to N-hydroxysuccinimide.
RL-Q includes acid chlorides, alkyl chloroformates, WO 98/52940 PCT/LIS98/10436 , sulfonyl chlorides, activated esters of carboxylic acids, activated carbamates, and isocyanates. Reaction. of scaffold C-ii with RL-Q is effected in the presence of tertiary amine base at room temperature or elevated .
temperature in a mixture of a polar aprotics solvent and/or a halogenated solvent. After solution-phase reactions have progressed to afford crude product mixtures in each vessel, the products B-ii are isolated in purified form by the addition of the isocyanate-functionalized resin B38 which covalently sequesters remaining secondary amine scaffold C-ii as resin-bound adduct H39, and also by the addition of the primary amine-functionalized resin B33 which ~ovalently sequesters remaining electrophile R"-Q from each reaction vessel as resin-bound adducts 840. Resin B33 also sequesters the HQ byproduct in each vessel as 836, formed by proton transfer from solution-phase Base-HQ.
Incubation with these resins, either simultaneously or sequentially, followed by filtration, rinsing, and concentration of the filtrates affords purified products B-ii filtered away from resin-adducts B33, B36, B38, 839, and 840.

WO 98/52940 PC'?/US98/10436 Scheme B-6 N-" NH N--NH
R2 ~ / Ra + R~-Q R2 ~ / Ra Base Base-HQ
C-ii B-ii R' contains a secondary R' contains a derivatized amine function -NH. -N-R~ amine function O--N_C=O ~--NH2 NHZ

N-NH
o R°. ~ / R2 N.Ra~ R3 ~-NH-Rt ~"_NHp . HO
-N VH
B39 B40 B~
Scheme B-7 illustrates the conversion of the secondary-s amine containing scaffold C-2 to the desired products B-ii. In a parallel array synthesis reaction block, individual reaction products are prepared in each of 48 multiple reaction block vessels. A solution of the scaffold C-2 (limiting amount) in dimethylformamide (DMF) is added to the reaction vessels followed by a 4.0-fold stoichiometric excess solution of N-methylmorpholine in DMF. To each reaction vessel is then added an electrophile RL-Q as a dichloroethane (DCE) solution:
either a 2.0 fold stoichiometric excess is used when RL-Q
is an acid chloride or alkyl chloroformate, or a 1.5 fold stoichiometric excess when R''-Q is a sulfonyl chloride, or a 1.25 fold stoichiometric excess when RL-Q is an isocyanate. The reaction mixtures are incubated at ambient temperature for 2-6 h. Each reaction vessel is then charged with a large excess (15-20 fold stoichiometric excess) of the amine-functionalized resin B33 and the isocyanate-functionalized resin B32. The resin-charged reaction block is shaken vert~~cally for 14-20 h on an orbital shaker at ambient temperature to allow optimum agitation of the resin-containing vessel mixtures. The excess electrophiles R''-Q and unreacted scaffold amine C-2 are removed from the reaction medium as insoluble adducts B40 and B39, respectively. Resin.
B33 also sequesters the HQ byproduct in each vessel as 836, formed by'proton transfer from solution-phase Base-HQ. Incubation with these resins, followed by filtration and rinsing with solvent miaaures of DMF and/or DCE, affords purified product solutions in collection vials filtered away from resin-adducts B33, B36, H38, B39, and 840. Concentration of Filtrates affords purified products H-ii.

Scheme B-7 N~ NH
+ R~-Q \
F ~H ~ F ~ N. R~
°
C ~ ° ,N
N CN B-ii C-' CH C 3 H°
NHp ~--CAD ' B33 N' ~-NHp F
NH-Ft~ B33 .
° ~ B40 N
HN~ N
NH ~---NHp . HQ

Scheme B-8 illustrates another general synthetic method involving the parallel array reaction of a scaffold C-ii containing a secondary amine functionality within the definition of the R4 substituent. Each reaction vessel is charged with the secondary amine-containing scaffold C-Iu ii, followed by the introduction of a stoichiometric excess of an optionally unique electrophile RL-Q into each - vessel. Reaction of scaffold C-ii with RL-Q is effected in the presence of tertiary amine base at room temperature or elevated temperature in a mixture of a polar aprotic 15 solvent and/or a halogenated solvent.
st~rt~~l ~xcess electrophiles and N-methylmorpholine are used to effect more rapid and/or more complete conversion of scaffold C-ii to products B-ii compared to reactions that do not utilize stoichiometric excesses of electrophiles S and N-methylmorpholine. The reaction mixtures are incubated at ambient temperature for 2-8 h. Each reaction vessel is then charged with the sequestration-enabling reagent phenylsulfonylisocyanate B41. This reagent B41 reacts with remaining secondary amine to scaffold C-ii, converting C-ii to the in situ-derivatized compound B42. Subsequent incubation of these vessel mixtures with a'large excess (15-20 fold stoichiometric excess) of the amine-functionalized resin B33 sequesters the solution-phase species R''-Q, HQ, 841, and B42 as the IS resin-bound adducts B40, H36, B44, and B43, respectively.
The resin-charged reaction block is shaken vertically for 14-20 h on an orbital shaker at ambient temperature to allow optimum agitation of the resin-containing vessel mixtures. Filtration of the insoluble resin- adducts 20 B33, H36, 840, B43 and B44 and subsequent rinsing of the-vessel resin-bed with DMF and/or DCE affords filtrates containing the purified products B-ii. Concentration of the filtrates affords the purified products 8-ii.
B~~~T~ITf E~ET (~ ~

DEMANDES OU BREVE"TS VOLUMINEUX

COMPREND PLUS D'UN TOME.
C~CI EST LE TOME ~ DE -NOTE: Pour les tomes additionels, veuiilez corttacter le Bureau canadien des brevets -t JUMBO APPL1CATIONSIPATEiVTS
THIS SECTION OF THE APPLICATION/PATEM CONTAINS MORE
THIS 1S VOLUME ~ OF
PtOTE: For additionai voiumes~piease contact'the Canadian Patent Offfice

Claims (139)

WHAT WE CLAIM IS:
1. A compound of Formula I
wherein R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or R1 has the formula wherein:
i is an integer from 0 to 9;
R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R16 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or R27 is -CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy;
and R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl;
wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, arylsulfonyl, and aralkylsulfonyl; or R2 has the formula:

wherein:
j is an integer from 0 to 8; and m is 0 or 1; and R30 and R31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
R13 is selected from hydrogen, alkyl, -C(O)R35, -C(O)OR35, -SO2R36, -C(O)NR37R38 and -SC2NR39R40, wherein R35, R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or R2 is -CR41R42 wherein R41 is aryl, and R42 is hydroxy; and R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;
and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR44R45 wherein R44 is alkylcarbonyl or amino, and R45 is alkyl or aralkyl; and R4 is selected from hydrido, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbcnyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy;
provided R3 is not 2-pyridinyl when R4 is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido;
and further provided R2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; or a pharmaceutically-acceptable salt or tautomer thereof.
2. A compound of Claim 1 wherein R1 is selected from hydrido, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower aralkyl, lower alkoxyalkyl, lower mercaptoalkyl, lower alkylthioalkylene, amino, lower alkylamino, lower arylamino, lower alkylaminoalkylene, and lower heterocyclylalkylene; or R1 has the formula wherein:
i is 0, 1 or 2; and R25 is selected from hydrogen, lower al kyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, lower phenoxyalkylene, lower aminoalkyl, lower alkylaminoalkyl, lower phenoxyaminoalkyl, lower alkylcarbonylalkylene, lower phenoxycarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene; and R26 is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkoxycarbonylalkylene, and lower alkylaminoalkyl; and R27 is selected from lower alkyl, lower cycloalkyl, lower alkynyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower cycloalkylalkylene, lower cycloalkenylalkylene, lower cycloalkylarylene, lower cycloalkylcycloalkyl, lower heterocyclylalkylene, lower alkylphenylene, lower alkylphenylalkyl, lower phenylalkylphenylene, lower alkylheterocyclyl, lower alkylheterocyclylalkylene, lower alkylheterocyclylphenylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl, lower alkoxyheterocyclyl, lower alkoxyalkoxyphenylene, lower phenoxyphenylene, lower phenylalkoxyphenylene, lower alkoxyheterocyclylalkylene, lower phenoxyalkoxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonylalkylene, lower aminoalkyl, lower alkylaminoalkylene, lower phenylaminocarbonylalkylene, lower alkoxyphenylaminocarbonylalkylene, lower aminocarbonylalkylene, arylaminocarbonylalkylene, lower alkylaminocarbonylalkylene, lower phenylcarbonylalkylene, lower alkoxycarbonylphenylene, lower phenoxycarbonylphenylene, lower alkylphenoxycarbonylphenylene, lower phenylcarbonylphenylene, lower alkylphenylcarbonylphenylene, lower alkoxycarbonylheterocyclylphenylene, lower alkoxycarbonylalkoxylphenylene, lower heterocyclylcarbonylalkylphenylene, lower alkylthioalkylene, cycloalkylthioalkylene, lower alkylthiophenylene, lower phenylalkylthiophenylene, lower heterocyclylthiophenylene, lower phenylthioalklylphenylene, lower phenylsulfonylaminoalkylene, lower alkylsulfonylphenylene, lower alkylaminosulfonylphenylene; wherein said lower alkyl, lower cycloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower heterocyclylalkylene, lower alkylheterocyclylphenylene, lower alkoxyphenylene, lower phenoxyphenylene, lower phenylaminocarbonylalkylene, lower phenoxycarbonylphenylene, lower phenylcarbonylphenylene, lower alkylthiophenylene, lower heterocyclylthiophenylene, lower phenylthioalklylphenylene, and lower alkylsulfonylphenylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, and cyano; or R27 is -CHR46R47 wherein R46 is lower alkoxycarbonyl, and R47 is selected from lower phenylalkyl, lower phenylalkoxyalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower alkoxycarbonylalkylene, lower alkylthioalkylene, and lower phenylalkylthioalkylene; wherein said phenylalkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from lower alkyl and nitro; or R26 and R27 together with the nitrogen atom to which they are attached form a 4-8 membered ring heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenoxyalkylene, lower alkoxyphenylene, lower alkylphenoxyalkylene, lower alkylcarbonyl, lower alkoxycarbonyl, lower phenylalkoxycarbonyl, lower alkylamino and lower alkoxycarbonylamino; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclylalkylene and lower phenoxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, lower alkyl and lower alkoxy; and R2 is selected from hydrido, halogen, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, lower haloalkyl, lower hydroxyalkyl, 5- or 6-membered heterocyclyl, lower alkylheterocyclyl, lower heterocyclylalkyl, lower alkylamino, lower alkynylamino, phenylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkylaminoalkylamino, lower cycloalkyl, lower alkenyl, lower alkoxycarbonylalkyl, lower cycloalkenyl, lower carboxyalkylamino, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonyl, alkoxycarbonylalkyl, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylsulfonyl, lower heterocyclyloxy, and lower heterocyclylthio; wherein the aryl, heterocylyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, lower alkyl, lower alkynyl, phenyl, 5- or 6-membered heterocyclyl, lower phenylalkyl, lower heterocyclylalkyl, lower epoxyalkyl, carboxy, lower alkoxy, lower aryloxy, lower phenylalkoxy, lower haloalkyl, lower alkylamino, lower alkylaminoalkylamino, lower alkynylamino, lower amino(hydroxyalkyl), lower heterocyclylalkylamino, lower alkylcarbonyl, lower alkoxycarbonyl, lower phenylalkylsulfonyl, and phenylsulfonyl; or R2 has the formula:

wherein:
j is 0, 1 or 2; and m is 0;
R30 and R31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R33 is selected from hydrogen, alkyl, -C(O)R35, -C(O)OR35, -SO2R36, -C(O)NR37R38, and -SO2NR39R40;
wherein R35 is selected from alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl, cycloalkenylalkylene, heterocyclylalkylene, alkylarylene, alkylheterocyclyl, arylarylene, arylheterocyclyl, alkoxy, alkenoxy, alkoxyalkylene, alkoxyaralkyl, alkoxyarylene, aryloxyalkylene, aralkoxyalkylene, cycloalkyloxyalkylene, alkoxycarbonyl, heterocyclylcarbonyl, alkylcarbonyloxyalkylene, alkylcarbonyloxyarylene, alkoxycarbonylalkylene, alkoxycarbonylarylene, aralkoxycarbonylheterocyclyl, alkylcarbonylheterocyclyl, arylcarbonyloxyalkylarylene, and alkylthioalkylene;
wherein said aryl, heterocyclyl, aralkyl, alkylarylene, arylheterocyclyl, alkoxyarylene, aryloxyalkylene, cycloalkoxyalkylene, alkoxycarbonylalkylene, and alkylcarbonylheterocyclyl groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; or R35 is CHR48R49 wherein R48 is arylsulfonylamino or alkylarylsulfonylamino, and R49 is selected from aralkyl, amino, alkylamino, and aralkylamino; or R35 is -NR35R51 wherein R50 is alkyl, and R51 is aryl;
and wherein R36 is selected from alkyl, haloalkyl, aryl, heterocyclyl, cycloalkylalkylene, alkylarylene, alkenylarylene, arylarylene, aralkyl, aralkenyl, heterocyclylheterocyclyl, carboxyarylene, alkoxyarylene, alkoxycarbonylarylene, alkylcarbonylaminoarylene, alkylcarbonylaminoheterocyclyl, arylcarbonylaminoalkylheterocyclyl, alkylaminoarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, alkylsulfonylaralkyl, and arylsulfonylheterocyclyl;
wherein said aryl, heterocyclyl, cycloalkylalkylene, aralkyl, alkylcarbonylaminoheterocyclyl, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and wherein R37 is selected from hydrogen and alkyl; and wherein R38 is selected from hydrogen, alkyl, alkenyl, aryl, heterocyclyl, aralkyl, alkylarylene, arylcycloalkyl, arylarylene, cycloalkylalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, aryloxyarylene, arylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylene, alkoxycarbonylarylene, alkylcarbonylcarbonylalkylene, alkylaminoalkylene, alkylaminoaralkyl, alkylcarbonylaminoalkylene, alkylthioarylene, alkylsulfonylaralkyl, and aminosulfonylaralkyl; wherein said aryl, heterocyclyl, aralkyl, and heterocyclylalkylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; or R38 is -CR52R53 wherein R52 is alkoxycarbonyl, and R53 is alkylthioalkylene; or R37 and R38 together with the nitrogen atom to which they are attached form a heterocycle; and R39 and R40 have the same definition as R26 and R27 in claim 1; or R2 is -CR41R42 wherein R41 is phenyl and R42 is hydroxy;
or R2 is selected from the group consisting of wherein k is an integer from 0 to 3; and R56 is hydrogen or lower alkyl; and R57 is hydrogen or lower alkyl; or R56 and R57 form a lower alkylene bridge; and R5a is selected from hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, -C(O)R59 -SO2R60, and -C(O)NHR61;
wherein R59 is selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl; wherein said aryl, heterocyclyl, and aralkyl groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and wherein R60 is selected from alkyl, aryl, heterocyclyl, alkylarylene, alkylheterocyclyl, aralkyl, heterocyclylheterocyclyl, alkoxyarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, and arylsulfonylheterocyclyl; wherein said aryl, heterocyclyl, and aralkyl groups are optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and wherein R61 is selected from alkyl, aryl, alkylarylene, and alkoxyarylene; wherein said aryl group is optionally substituted with one or more radicals independently selected from alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, and wherein R43 is selected from hydrogen, lower alkyl, lower aminoalkyl, lower alkoxyalkyl, lower alkenoxyalkyl and lower aryloxyalkyl; and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from lower alkylthio, halo, lower alkyl, lower aralkyl, lower phenylalkenyl, lower phenylheterocyclyl, carboxy, cyano, lower alkoxycarbonyl, aminocarbonyl, lower alkylcarbonylamino, lower haloalkyl, hydroxy, lower alkoxy, amino, lower cycloalkylamino, lower alkylamino, lower alkenylamino, lower alkynylamino, lower aminoalkyl, arylamino, lower aralkylamino, nitro, halosulfonyl, lower alkylcarbonyl, lower alkoxycarbonylamino, lower alkoxyphenylalkylamino, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyphenylalkylamino, hydrazinyl, lower alkylhydrazinyl, or -NR44R45 wherein R44 is lower alkylcarbonyl or amino, and R45 is lower alkyl or lower phenylalkyl; and R4 is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, aryl selected from phenyl, biphenyl, and naphthyl, and 5- or 6- membered heterocyclyl; wherein the lower cycloalkyl, lower cycloalkenyl, aryl and 5-10 membered heterocyclyl groups of R4 are optionally substituted with one or more radicals independently selected from lower alkylthio, halo, lower alkyl, lower alkynyl, lower alkoxy, lower aryloxy, lower aralkoxy, lower heterocyclyl, lower haloalkyl, amino, cyano, nitro, lower alkylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof.
3. A compound of Claim 2 wherein R1 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methylthiomethyl; and R2 is selected from hydrido, chloro, fluoro, bromo, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, phenyl, biphenyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxymethyl, hydroxyethyl, pyridinyl, isothiazolyl, isoxazolyl, thienyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, N-methylpiperazinyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-n-propylamino, N,N-dimethylamino, N-methyl-N-phenylamino, N-phenylamino, piperadinylamino, N-benzylamino, N-propargylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, N,N-dimethylaminoethylamino, N,N-dimethylaminopropylamino, morpholinylethylamino, morpholinylpropylamino, carboxymethylamino, methoxyethylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1,1-dimethylethoxycarbonyl, 1,1-dimethylethoxycarbonylaminoethylamino, 1,1-dimethylethoxycarbonylaminopropylamino, piperazinylcarbonyl, and 1,1-dimethylethoxycarbonylpiperazinylcarbonyl; wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, isopropyl, tert-butyl, isobutyl, benzyl, carboxy, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, dimethylamino, methoxycarbonyl, ethoxycarbonyl, and 1,1-dimethylethylcarbonyl; or R2 is -CR41R42 wherein R41 is phenyl and R42 is hydroxy;
and R3 is selected from pyridinyl, pyrimidinyl, and purinyl; wherein R3 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methyl-hydrazinyl , or -NR44R45 wherein R44 is methyl carbonyl or amino, and R45 is methyl, ethyl or phenylmethyl; and R4 is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R4 are optimally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof.
4. A compound of Claim 3 wherein R1 is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl;
R2 is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, methoxycarbonylethyl, N,N-dimethylamino, N-phenylamino, piperidinyl, piperazinyl, pyridinyl, N-methylpiperazinyl, and piperazinylamino;
wherein the phenyl, piperidinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, methyl, ethyl, and trifluoromethyl;
R3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R3 is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl;
R4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R4 are optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof.
5. A compound of Claim 4 wherein R1 is hydrido or methyl;
R2 is selected from hydrido, methyl or ethyl;
R' is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R' is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl;
R~ is selected from phenyl which is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-accepta:~le salt or tautomer thereof.
6. A compound of Claim 2 wherein R1 is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorcmethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methylthiomethyl; and R2 has the formula:
wherein:
j is 0, 1 or 2; and m is 0; and R30 and R31 are independently selected from hydrogen and lower alkyl;
R32 is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, aryloxyalkylene, aminoalkyl, lower alkylaminoalkyl, lower phenylaminoalkyl, lower alkylcarbonylalkylene, lower phenylcarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene;
R33 is selected from hydrogen, lower alkyl, -C(O)R35, -C(O)OR35, -SO2R36, -C(O)NR37R38, and -SO2NR39R40;
wherein R35 is selected from lower alkyl, lower cycloalkyl, lower haloalkyl, lower alkenyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower phenylcycloalkyl, lower cycloalkenylalkylene, lower heterocyclylalkylene, lower alkylphenylene, lower alkylheterocyclyl, phenylphenylene, lower phenylheterocyclyl, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower alkoxyphenylalkyl, lower alkoxyphenylene, lower phenoxyalkylene, lower phenylalkoxyalkylene, lower cycloalkyloxyalkylene, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkylcarbonyloxyalkylene, lower alkylcarbonyloxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower phenylalkoxycarbonylheterocyclyl, lower alkylcarbonylheterocyclyl, lower phenylcarbonyloxyalkylphenylene, and lower alkylthioalkylene; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylheterocyclyl, lower alkoxyphenylene, lower phenoxyalkylene, lower cycloalkoxyalkylene, lower alkoxycarbonylalkylene, and lower alkylcarbonylheterocyclyl groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano;
or R35 is CHR48R49 wherein R48 is phenylsulfonylamino or lower alkylphenylsulfonylamino, and R49 is selected from lower phenylalkyl, amino, lower alkylamino, and lower phenylalkylamino; or R35 is -NR50R51 wherein R50 is lower alkyl, and R51 is aryl selected from phenyl, biphenyl and naphthyl; and wherein R36 is selected from lower alkyl, lower haloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower alkylphenylene, lower alkenylphenylene, phenylphenylene, lower phenylalkyl, lower phenylalkenyl, lower heterocyclylheterocyclyl, carboxyphenylene, lower alkoxyphenylene, lower alkoxycarbonylphenylene, lower alkylcarbonylaminophenylene, lower alkylcarbonylaminoheterocyclyl, lower phenylcarbonylaminoalkylheterocyclyl, lower alkylaminophenylene, lower alkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene, lower alkylsulfonylphenylalkyl, and lower phenylsulfonylheterocyclyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkylcarbonylaminoheterocyclyl, and lower alkylsulfonylphenylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano;
and wherein R37 is selected from hydrogen and lower alkyl; and wherein R38 is selected from hydrogen, lower alkyl, lower alkenyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylcycloalkyl, phenylphenylene, lower cycloalkylalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower phenoxyphenylene, phenylcarbonyl, lower alkoxycarbonyl, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower alkylcarbonylcarbonylalkylene, lower alkylaminoalkylene, lower alkylaminophenylalkyl, lower alkylcarbonylaminoalkylene, lower alkylthiophenylene, lower alkylsulfonylphenylalkyl, and lower aminosulfonylphenylalkyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, and lower heterocyclylalkylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; or R38 is -CR52R53 wherein R52 is lower alkoxycarbonyl, and R53 is lower alkylthioalkylene; or R37 and R38 together with the nitrogen atom to which they are attached form a 4-8 membered ring heterocycle;
R39 and R40 have the same definition as R26 and R27 in claim 2; or R2 is selected from the group consisting of wherein k is an integer from 0 to 2; and R56 is hydrogen or lower alkyl; and R57 is hydrogen or lower alkyl; and R58 is selected from hydrogen, lower alkyl, lower phenylalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower heterocyclylalkyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, lower phenylsulfonyl, -C(O)R59, -SO2R60, and -C(O)NHR61;
wherein R59 is selected from lower alkyl, lower haloalkyl, lower cycloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower alkylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower alkoxy, lower alkenoxy, lower phenylalkoxy, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, and lower phenylalkyl groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and wherein R60 is selected from lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower alkylphenylene, lower alkylheterocyclyl, lower phenylalkyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene, lower alkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene, and lower phenylsulfonylheterocyclyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, and lower phenylalkyl groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano;
and wherein R61 is selected from lower alkyl, aryl selected from phenyl, biphenyl and napthyl, lower alkylphenylene, and lower alkoxyphenylene; wherein said aryl group is optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and R3 is selected from pyridinyl, pyrimidinyl, and purinyl; wherein R3 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, oropyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methyl-hydrazinyl, or -NR44R45 wherein R45 is methyl carbonyl or amino, and R45 is methyl, ethyl or phenylmethyl; and R4 is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R4 are optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof.
7. A compound of Claim 6 wherein R1 is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl;
R2 has the formula:

wherein:
j is 0, 1 or 2; and m is 0; and R30 is hydrogen; and R31 is selected from hydrogen and lower alkyl; and R32 is selected from hydrogen and lower alkyl; and R33 is selected from lower alkyl, -C(O)R35, -C(O)OR35, -SO2R36, -C(O)NR37R38, and -SO2NR39R40;
wherein R35 is selected from lower alkyl, lower cycloalkyl, phenyl, lower heterocyclyl, lower alkylphenylene, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower phenoxyalkylene, and lower phenylalkoxyalkylene; wherein said phenyl and lower phenoxyalkylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, and lower haloalkyl; and wherein R36 is selected from lower alkyl, phenyl, lower heterocyclyl, lower alkylphenylene, phenylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene, and lower alkylamino; wherein said phenyl and lower heterocyclyl groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and wherein R37 is hydrogen; and wherein R38 is selected from lower alkyl, phenyl, and lower alkylphenylene;
wherein R39 and R40 have the same definition as R26 and R27 in claim 2; or R2 is selected from the group consisting of wherein k is an integer from 0 or 1; and R56 is hydrogen; and R57 i s hydrogen; and R58 is selected from -C(O)R59 and -SO2R60;
wherein R59 is selected from lower alkyl, lower cycloalkyl, phenyl, lower alkylphenylene, and lower alkoxyalkylene; wherein said phenyl group is optionally substituted with one or more radicals independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and wherein R60 is selected from lower alkyl; and R3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R3 is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and R4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R4 are optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, ar_d hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof.
8. A compound of Claim 7 wherein R1 is hydrido or methyl; and R3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R3 is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and R4 is selected from phenyl which is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof.
9. A compound of Claim 1 wherein R1 is hydrido.
10. A compound of Claim 2 wherein R1 is hydrido.
11. A compound of Claim 3 wherein R1 is hydrido.
12. A compound of Claim 6 wherein R1 is hydrido.
13. A compound of Claim 3 wherein R1 is methyl or ethyl.
14. A compound of Claim 6 wherein R1 is methyl or ethyl.
15. A compound of Claim 2 wherein R2 is hydrido.
16. A compound of Claim 3 wherein R2 is hydrido.
17. A compound of Claim 2 wherein R4 is optionally substituted phenyl.
18. A compound of Claim 3 wherein R4 is optionally substituted phenyl.
19. A compound of Claim 6 wherein R4 is optionally substituted phenyl.
20. A compound of Claim 2 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl.
21. A compound of Claim 3 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl
22. A compound of Claim 2 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl;
and R4 is optionally substituted phenyl.
23. A compound of Claim 3 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl;
and R4 is optionally substituted phenyl.
24. A compound or Claim 1 having Formula IX

wherein Z represents a carbon atom or a nitrogen atom; and R1 is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aralkyl, lower aminoalkyl and lower alkylaminoalkyl; and R2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or R2 is -CR41R42 wherein R41 is phenyl and R42 is hydroxy;
and R4 is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl, 5- or 6-membered heterocyclyl, and aryl selected from phenyl, biphenyl, naphthyl; wherein R4 is optionally substituted at a substitutable position with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and R5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR44R45 wherein R44 is lower alkylcarbonyl or amino, and R45 is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof.
25. A compound of Claim 24 wherein R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and R2 is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein tile phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinirl, and pyridinyl groups are optionally substituted wir_h one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl; and R~ is selected from cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and RS is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, and 1-methylhydrazinyl, or -NR44R45 wherein R44 is methylcarbonyl or amino, and R45 is methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof.
26. A compound of Claim 24 wherein R1 is hydrido.
27. A compound of Claim 25 wherein R1 is hydrido.
28. A compound of Claim 24 wherein R1 is lower alkyl.
29. A compound of Claim 25 wherein R1 is lower alkyl.
30. A compound of Claim 24 wherein R2 is hydrido.
31. A compound of Claim 25 wherein R2 is hydrido.
32. A compound of Claim 24 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl.
33. A compound of Claim 25 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl.
34. A compound of Claim 25 wherein Z represents a carbon atom.
35. A compound of Claim 1 having Formula X

wherein Z represents a carbon atom or a nitrogen atom; and R1 is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and R2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, S- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or R2 is -CR41R42 wherein R41 is phenyl and R42 is hydroxy;
and R4 is selected from 5- or 6-membered heteroaryl, and aryl selected from phenyl, biphenyl, and naphthyl;
wherein R4 is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and R5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR44R45 wherein R44 is lower alkylcarbonyl or amino, and R45 is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof.
36. A compound of Claim 35 wherein R1 is selected from methyl, ethyl, hydroxyethyl and propargyl; and R2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, piperadinylamino, dimethylaminoethylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, N-methylpiperazinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, and 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl; and R4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and R5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, propargylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, and 1-methylhydrazinyl, or -NR44R45 wherein R44 is methylcarbonyl or amino, and R45 is methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof.
37. A compound of Claim 35 wherein R1 is lower alkyl.
38. A compound of Claim 36 wherein R1 is lower alkyl.
39. A compound of Claim 35 wherein R2 is hydrido.
40. A compound of Claim 36 wherein R2 is hydrido.
41. A compound of Claim 35 wherein R1 is methyl or ethyl, and R2 is selected from hydrido, methyl and ethyl.
42. A compound of Claim 36 wherein R1 is methyl or ethyl, and R2 is selected from hydrido, methyl and ethyl.
43. A compound of Claim 35 wherein Z represents a carbon atom.
44. A compound of Claim 1 having Formula XI

wherein Z represents a carbon atom or a nitrogen atom; and R1 is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and R2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or R2 is -CR41R42 wherein R41 is phenyl and R42 is hydroxy;
and R4 is selected from 5- or 6-membered heteroaryl, and aryl selected from phenyl, biphenyl, and naphthyl;
wherein R4 is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and R5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR44R45 wherein R44 is lower alkylcarbonyl or amino, and R45 is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof.
45. A compound of Claim 44 wherein R1 is selected from methyl, ethyl, hydroxyethyl and propargyl; and R2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl;
R4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and R5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, and 1-methylhydrazinyl, or -NR44R45 wherein R44 is methylcarbonyl or amino, and R45 is methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof.
46. A compound of Claim 44 wherein R1 is lower alkyl.
47. A compound of Claim 45 wherein R1 is lower alkyl.
48. A compound of Claim 44 wherein R2 is hydrido.
49. A compound of Claim 45 wherein R2 is hydrido.
50. A compound of Claim 44 wherein R1 is methyl or ethyl, and R2 is selected from hydrido, methyl and ethyl.
51. A compound of Claim 45 wherein R1 is methyl or ethyl, and R2 is selected from hydrido, methyl and ethyl.
52. A compound of Claim 44 wherein Z represents a carbon atom.
53. A compound of Claim 1 having Formula IX

wherein Z represents a carbon atom or a nitrogen atom; and R1 is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and R2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6-membered heterocyclyl selected from piperidinyl, piperazinyl, imidazolyl, pyridinyl and morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or R2 is -CR41R42 wherein R41 is phenyl and R42 is hydroxy;
and R4 is phenyl that is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and R5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR444R45 wherein R44 is lower alkylcarbonyl or amino, and R45 is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof.
54. A compound of Claim 53 wherein R1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl;
R2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl-ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1-dimethyl)ethoxycarbonyl;
R4 is phenyl that is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and R5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, and 1-methylhydrazinyl, or -NR44R45 wherein R44 is methylcarbonyl or amino, and R45 is methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof.
55. A compound of Claim 53 wherein R1 is hydrido or lower alkyl.
56. A compound of Claim 54 wherein R1 is hydrido or lower alkyl.
57. A compound oz Claim 53 wherein R1 is hydrido.
58. A compound of Claim 54 wherein R1 is hydrido.
59. A compound of Claim 53 wherein R2 is hydrido.
60. A compound of Claim 54 wherein R2 is hydrido.
61. A compound of Claim 53 wherein R4 is phenyl substituted with one or more fluoro, chloro or bromo.
62. A compound of Claim 54 wherein R4 is phenyl substituted with one or more fluoro, chloro or bromo.
63. A compound of Claim 53 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl.
64. A compound of Claim 54 wherein R1 and R2 are selected independently from hydrido, methyl and ethyl.
65. A compound of Claim 53 wherein Z represents a carbon atom.
66. A compound of Claim 1 having Formula IX

wherein Z represents a carbon atom or a nitrogen atom; and R1 is selected from hydrido, lower alkyl, lower hydroxyalkyl and lower alkynyl; and R2 is selected from hydrido and lower alkyl; and R4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more halo radicals; and R5 is selected from hydrido, halo and alkylhydrazinyl; or a pharmaceutically-acceptable salt or tautomer thereof.
67. A compound of Claim 66 wherein Z represents a carbon atom; and R1 is selected from hydrido, methyl, hydroxyethyl, propargyl; and R2 is hydrido; and R4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more radicals independently selected from chloro, fluoro and bromo; and R5 is selected from hydrido, fluoro, and 1-methylhydrazinyl; or a pharmaceutically-acceptable salt or tautomer thereof.
68. A compound of Claim 67 wherein 2 represents a carbon atom; and R1 is selected from hydrido and methyl; and R2 is hydrido; and R4 is selected from phenyl that is optionally substituted with one or more radicals independently selected from chloro, fluoro and bromo; and R5 is selected from hydrido and fluoro; or a pharmaceutically-acceptable salt or tautomer thereof.
69. A compound of Claim 1 selected from compounds, their tautomers and their pharmaceutically acceptable salts, of the group consisting of 4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
4-[5-methyl-3-(2-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-methyl-3-(4-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[5-methyl-3-[4-(methylthio)phenyl]-1H-pyrazol-4-yl]pyridine;
4-[3-(4-chlorohpenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[5-(2,5-dimethylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(1,3-benzodioxol-5-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-(4-phenoxyphenyl)-1H-pyrazol-4-yl]pyridine;
4-[5-[(1,1'-biphenyl)-4-yl]-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-[3-(phenoxyphenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-[3-(phenylmethoxy)phenyl]-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-[2-(phenylmethoxy)phenyl]-1H-pyrazol-4-yl]pyridine;
2-[3-methyl-4-(4-pyridinyl)-1H-pyrazol-4-yl]phenol;
3-[3-methyl-4-(4-pyridinyl)-1H-pyrazol-4-yl]phenol;
1-hydroxy-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl]pyridinium;
5-(4-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
5-(4-fluorophenyl)-N-phenyl-4-(4-pyridinyl)-1H-pyrazol-3-amine; 4-[5-(4-fluorophenyl)-3-phenyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine;4-[3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]pyridine;
4-(5-cyclohexyl)-3-methyl-1H-pyrazol-4-yl)pyridine;
4-[5-(3-fluoro-5-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-methylphenyl)-3-propyl-1H-pyrazol-4-yl]pyridine;
4-[(3-methyl-5-phenyl-1H-pyrazol-4-yl)methyl]pyridine;
4-[3,5-bis(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[4-methyl-2-(2-trifluorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(2-chlorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-methyl-3-(2,4-dimethylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[5-(4-chlorophenyl)-1,3-dimethyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3-fluoro-2-methylphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3,5-dimethylphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;

4-[3-(3,5-dimethoxyphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-methyl-3-(3-nitrophenyl)-1H-pyrazol-4-yl]pyridine;
N,N-dimethyl-4-[5-methyl-4-(4-pyridinyl)-1H-pyrazol-3 yl]benzenamine;
4-[3-(2,3-dihydrobenzofuran-5-yl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(4-bromophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(2-fluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3-fluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-[3-(trifluoromethyl)phenyl)-1H-pyrazol-4 yl]pyridine;
4-(3-ethyl-4-phenyl-1H-pyrazol-4-yl)pyridine;
4-[5-(3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl}pyridine;
4-[3-ethyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[5-(3,4-difluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-ethoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl]pyridine;
4-[3-methyl-5-(3-thienyl)-1H-pyrazol-4-yl]pyridine;
4-[5-(2,4-dichlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-chloro-4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
ethyl 3-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazole-5-propanoate;
4-[3-(4-fluorophenyl)-1-methyl-pyrazol-4-yl]pyridine;
5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
5-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine;
5-[3-methyl-5-(2-methylphenyl)-1H-pyrazol-4-yl]pyrimidin-2-amine;
5-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
5-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
5-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyrimidin-2-amine;
5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-y1]pyridin-2-amine;
4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-y1]pyridin-2-amine;
4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-amine;
5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
2-methoxy-5-[3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
2-methoxy-5-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
2-methoxy-4-(3-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
2-methoxy-4-[3-methyl-5-(2-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2-methoxypyridine;
2-methoxy-4-[3-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]pyridine;
5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-y1]pyridin-2-ol;
4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2-ol;
5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-methanamine;
5-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
4-[5-(3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
4-[5-(2-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
4-[5-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
4-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine-2-carboxamide;
4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(4-fluoro-3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(4-chloro-3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(2,3-dihydrobenzofuran-6-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(benzofuran-6-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-fluoro-5-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-chloro-5-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(1-cyclohexyen-1-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(1,3-cyclohexadien-1-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(5,6-dihydro-2H-pyran-4-yl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-(5-cyclohexyl-3-methyl-1H-pyrazol-4-yl)pyridine;
4-[5-(4-methoxy-3-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-methoxy-4-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-methoxy-5-methylphenyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-furyl)-3-methyl-1H-pyrazol-4-yl]pyridine;
2-methyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
2-methoxy-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;

methyl 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyri-dine-2-carboxylate;
4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxamide;
1-[4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridin-2-yl]ethanone;
N,N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazol-2-yl)pyridin-2-amine;
3-methyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;
3-methoxy-4-(3-methyl-5-phenyl-1H-pyrazol-4-y1)pyridine;
methyl 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine-3-carboxylate;
4-(3-methyl-5-phenyl-1H-pyrazol-4-y1)pyridine-3-carboxamide;
1-[4-(3-methyl-S-phenyl-1H-pyrazol-4-yl)pyridin-3-yl]ethanone;
3-bromo-4-(3-methyl-S-phenyl-1H-pyrazol-4-yl)pyridine;
N,N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazol-2-yl)pyridin-3-amine;
2-methyl-a-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidine;
4-(3-methyl-5-phenyl-1H-pyrazol-4-y1)pyrimidine;
2-methoxy-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidine;
4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidin-2-amine;
N,N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidin-2-amine;
4-(5,6-dihydro-2H-pyran-4-yl)-3-methyl-5-phenyl-1H-pyrazole;
3-methyl-5-phenyl-4-(3-thienyl)-1H-pyrazole;
4-(3-furyl)-3-methyl-5-phenyl-1H-pyrazole;
3-methyl-5-phenyl-4-(2-thienyl)-1H-pyrazole;
4-(2-furyl)-3-methyl-5-phenyl-1H-pyrazole;
4-(3-isothiazolyl)-3-methyl-5-phenyl-1H-pyrazole 4-(3-isoxazolyl)-3-methyl-5-phenyl-1H-pyrazole;
4-(5-isothiazolyl)-3-methyl-5-phenyl-1H-pyrazole;
4-(5-isoxazolyl)-3-methyl-5-phenyl-1H-pyrazole;

3-methyl-5-phenyl-4-(5-thiazolyl)-1H-pyrazole;
3-methyl-4-(5-oxazolyl)-5-phenyl-1H-pyrazole;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
2-methyl-4-[3-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-(1-methyl-3-phenyl-1H-pyrazol-4-yl)pyridine;
4-(3-phenyl-1H-pyrazol-4-yl)pyridine;
2-methyl-4-(3-phenyl-1H-pyrazol-4-yl)pyridine;
4-[3-(3-chlorophenyl)-1-methyl-pyrazol-4-yl]pyridine;
4-[3-(4-chlorophenyl)-1-methyl-pyrazol-4-yl]pyridine;
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-2-methyl pyridine;
4-[3-(3-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3-fluorophenyl)-1H-pyrazol-4-y1] pyridine;
4-[3-(3-chlorophenyl)-1-methyl-pyrazol-4-yl]-2-methylpyridine;
5-(4-chlorophenyl)-N-phenyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
5-(4-chlorophenyl)-N-methyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
5-(4-chlorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine dehydrate;
5-(3-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
N,N-dimethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine;
N-methyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine;
N-ethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine;
N,N-diethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine;
5-(4-chlorophenyl)-N,N-diethyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]morpholine;

5-(4-chlorophenyl)-N-propyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
5-(4-chlorophenyl)-N-(phenylmethyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine hydrate (2:1);
5-(4-chlorophenyl)-N-(2-methoxyethyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine monohydrate;
1,1-dimethylethyl-4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate;
1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine trihydrochloride;
1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine;
1,1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate;
1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine trihydrochloride;
1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]piperazine;
N-[5-(4-chlorophenyl)-4-[2-(phenylmethyl)amino]-4-pyridinyl]-1H-pyrazol-3-yl]-1,3-propanediamine, trihydrochloride;
1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-(phenylmethyl)piperazine;
4-[3-(4-fluorophenyl)-5-(1-piperazinyl)-1H-pyrazol-4-yl]pyrimidine, dihydrochloride;
1,1-dimethylethyl [3-[(5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]propyl]carbamate;
N-[5-[4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,3-propanediamine, trihydrochloride monohydrate;
1,1-dimethylethyl [2-[[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]amino]ethyl]carbamate;
1,1-dimethylethyl 4-[5-(4-chlorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate;
1,1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4-pyrimidinyl)-1H-pyrazol-3-yl]-1-piperazinecarboxylate;

1,1-dimethylethyl[3-[[5-(4-chlorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazol-3-yl]amino]propyl]carbamate;
1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-ethylpiperazine;
N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-1,2-ethanediamine;
4-[3-(2,6-difluorophenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3-ethylphenyl)-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3-chlorophenyl)-5-ethyl-1H-pyrazol-4-yl]pyridine;
4-[3-ethyl-5-(3-ethylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-chlorophenyl)-5-(1-methylethyl)-1H-pyrazol-4-yl]pyridine;
4-[3-cyclopropyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]pyridine;
4-[5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
5-cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol;
3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol;
4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2(1H)-pyridinone;
1-acetyl-4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2(1H)-pyridinone;
Ethyl 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]cyclopropanecarboxylate;
2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]cyclopropanecarboxylic acid;
3-(4-fluorophenyl)-5-(4-imidazolyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol;
4-[3-(4-chloro-3-methylphenyl)-1H-pyrazol-4-yl]pyridine 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-carboxylic acid;

5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-methanol;
1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]piperazine;
1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate;
4-(1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl)pyridine;
4-(1,3-dimethyl-S-phenyl-1H-pyrazol-4-yl]pyridine;
4-[3-(4-chlorophenyl)-1,5-dimethyl-1H-pyrazol-4-yl ] pyridine ;
4-[5-(4-chlorophenyl)-1,3-dimethyl-1H-pyrazol-4-y1]pyridine;
4-[5-ethyl-1-methyl-3-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-ethyl-1-methyl-5-(3-methylphenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-chlorophenyl)-1-ethyl-5-methyl-1H-pyrazol-a-yl]pyridine;
4-[3-(4-chlorophenyl)-2-ethyl-5-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(2-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol;
3-(4-fluorophenyl)-4-(4-pyrimidinyl)-1H-pyrazole-1-ethanol;
4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-y1]-2-pyridinyl]amino]-1-butanol;
4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarbonitrile;
4-[2-[3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine;
3-(4-fluorophenyl)-1-methyl-a-phenyl-4-(4-pyridinyl)-1H-pyrazole-5-methanol;

N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-morpholineethanamine;
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-2 (1H)-pyridinone hydrazone;
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-(phenylmethyl)-2-pyridinamine;
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-(phenylethyl)-2-pyridinamine;
4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-ethyl-2-pyridinamine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxamide;
Methyl 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-methyl-2-pyridinecarboxamide;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylic acid;
4-[3-(3-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(1,3-benzodioxol-5-yl)-1H-pyrazol-4-yl]pyridine;
4-[3-(3-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(1,3-benzodioxol-5-y)-1-methyl-1H-pyrazol-4-yl]pyrid ine;
4-[3-(4-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-methylp yridine; 4-[5-(3-chlorophenyl)-1-methyl-1H-pyrazol-a -yl]-2-methylpyridine;
4-[3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
4-[5-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
2-methyl-4-[1-methyl-3-(3-methylphenyl)-1H-pyrazol-4 -yl]pyridine;
2-methyl-4-[1-methyl-5-(3-methylphenyl)-1H-pyrazol-4 -yl] pyridine;
4-(3-phenyl-1H-pyrazol-4-yl)pyridine;
4-[3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl] pyridine 4-[1-methyl-3-[3-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl ]pyridine;
4-[3-(3,4-difluorophenyl)-1H-pyrazol-4-y1]pyridine;
4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-fluoropyridine;
4-[3-(4-bromophenyl)-1H-pyrazol-4y1]pyridine;
4-[3-(3,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridi ne;
4-[3-(4-bromophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
(E)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-(2-phenyleth enyl)pyridine;
(S)-4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-(2-methylbut yl)-2-pyridinamine;
4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxy-phenyl)methyl]-2-pyridinamine;
N-[4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-2-pyridinemethanamine;
N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-2-pyridinemethanamine;
2-fluoro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-iodophenyl)-1H-pyrazol-4-yl]pyridine;
4-[3-(4-iodophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
4-[1-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-y1 ]pyridine;
N- [1- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -1H-pyra zol-4-yl]-2-pyridinamine;
N- [ (3-fluorophenyl)methyl] -4- [3- (4-fluorophenyl) -1H-pyraz ol-4-yl]-2-pyridinamine;
4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-(1-methylhydrazino)pyridine;
2-fluoro-4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]p yridine;
4-[3-(3,4-difluorophenyl)-1H-pyrazol-4-yl]-2-fluoro-pyridine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-3-methylpyridine;
4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-3-methyl pyridine;
4-[3-(3,4'-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-flu oropyridine;
3-(4-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl)-1H-pyrazo le-1-ethanamine;
2-[2-(4-fluorophenyl)ethyl]-4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[1-(phenylmethyl)-4-piperidinyl]-2-pyridinamine;
N'-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-N,N-dimethyl-1,2-ethanediamine;
2,4-bis[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine;
N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]-4-morpholineethanamine;
3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazole-1-ethanol;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[2-(1H-imidazol-1-yl)ethyl]-2-pyridinamine;
4-[2-[3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazol-1-yl]ethyl]morpholine;
(E)-3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethenyl]-4-pyridinyl]-1H-pyrazole-1-ethanol;
3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-N,N-dimethyl-1H-pyrazole-1-ethanamine;
3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethyl]-4-pyridinyl]-1H-pyrazole-1-ethanol;
4-[1-[2-(dimethylamino)ethyl]-3-(4-fluorophenyl) -1H-pyrazol-4-yl]-N,N-dimethyl-2-pyridinamine;
4-[1-[2-(dimethylamino) ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-fluorophenyl)methyl]-2-pyridinamine;
3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethyl]-4-pyridinyl]-N,N-dimethyl-1H-pyrazole-1-ethanamine;
N-[(4-fluorophenyl) methyl]-4-[3(or 5)-(4-fluorophenyl)-1-[[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl]-2-pyridinamine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-4-piperadinyl-2-pyridinamine;
N,N-diethyl-3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-1H-pyrazole-1-ethanamine;
4-[1-[2-(diethyl amino) ethyl]-3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-fluorophenyl)methyl]-2-pyridinamine;
2-[[4-[3-(4-(fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]ethanol;
2-[[4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-pyridinyl] amino] ethanol;
3-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinyl]amino]-1-propanol;
3-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino]-4-pyridinyl]-1H-pyrazole-1-ethanol;
5-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino]-4-pyridinyl]-1H-pyrazole-1-ethanol;
N,N-diethyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanamine;
N-[(4-fluorophenyl)methyl]-4-[3-(4-fluorophenyl)-1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl]-2-pyridinamine;
N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-morpholinepropanamine;
N'-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-N,N-dimethyl-1,3-propanediamine;
5-(4-fluorophenyl)-N-2-propynyl-4-(4-pyridinyl)-1H-pyrazol-3-amine;
3-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino]-4-pyridinyl]-1H-pyrazole-1-ethanol;
5-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl)methyl]amino]-4-pyridinyl]-1H-pyrazole-1-ethanol;
4-[3-[(4-fluorophenyl)-1H-pyrazol-4-yl]quinoline;
N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]glycine methyl ester;
N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]glycine;
4-[3-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazol-4-yl]pyridine;

4-[5-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazol-4-yl]pyridine;
4,4'-(1H-pyrazole-3,4-diyl)bis[pyridine];
4-[3-(3,4-dichlorophenyl)-1H-pyrazol-4-yl]pyridine;
N-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-piperidinamine;
2-Chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2(1H)-pyrimidinone hydrazone;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N,N-dimethyl-2-pyrimidinamine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-y1]-N-methyl-2-pyrimidinamine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-y1]-N-(phenylmethyl)-2-pyrimidinamine;
N-cyclopropyl-4-[3-(4-fluorophenyl)-1H-pyrazol-4-y1]-2-pyrimidinamine;
4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl]-2-pyrimidinamine;
4-[3-(4-fluorophenyl)-1H-pyrazole-4-y1]-2-pyrimidinamine;
N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-N-(phenylmethyl)acetamide;
Ethyl [4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]carbamate;
4-[3-(3-methylphenyl)-1H-pyrazol-4-y1]pyrimidine;
4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyrimidine;
4-[3-(3-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine; and 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine.
70. A compound of Claim 1 selected from compounds, their tautomers and their pharmaceutically acceptable salts, of the group consisting of
71. A compound of claim 1 that is 4-[5-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazol-4-yl]pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
72. A compound of claim 1 that is 4-[3-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazol-4-yl]pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
73. A compound of claim 1 that is 3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol or a pharmaceutically-acceptable salt or a tautomer thereof.
74. A compound of claim 1 that is 4-[3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-(1-methylhydrazino)pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
75. A compound of claim 1 that is 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-y1]piperazine or a pharmaceutically-acceptable salt or a tautomer thereof.
76. A compound of claim 1 that is 4-[3-cyclopropyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
77. A compound of claim 1 that is 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
78. A compound of claim 1 that is 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-y1]-4-methylpiperazine or a pharmaceutically-acceptable salt or a tautomer thereof.
79. A compound of claim 1 that is 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine or a pharmaceutically-acceptable salt or a tautomer thereof.
80. A compound of claim 1 that is 2-fluoro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
81. A compound of claim 1 that is 4- [3- (3, 4-diflurophenyl) -1-methyl -1H-pyrazol-4 -yl]pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
82. A compound of claim 1 that is 4-[3-(4-bromophenyl)-1H-pyrazol-4y1]pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
83. A compound of claim 1 that is 4-[3-(4-chlorophenyl)1H-pyrazol-4-yl]-2-fluoropyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
84. A compound of claim 1 that is 4-[3-(1,3-benzodioxol 5-y)-1-methyl-1H-pyrazol-4-yl]pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
85. A compound of claim 1 that is 4-[3-(3-fluorophenyl)1-methyl-1H-pyrazol-4-y1]pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
86. A compound of claim 1 that is 4-[3-(3-fluorophenyl)-1-methyl-pyrazol-4-yl]pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
87. A compound of claim 1 that is 5-(4-fluorophenyl)-N-2-propynyl-4-(4-pyridinyl)-1H-pyrazol-3-amine or a pharmaceutically-acceptable salt or a tautomer thereof.
88. A substituted pyrazole that specifically binds to an ATP binding site of p38 kinase.
89. A compound of claim 88 having the formula:
wherein R1 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units; and R2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical that binds with p38 kinase at said ATP binding site of p38 kinase; and R3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality; and R4 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units;
provided R3 is not 2-pyridinyl when R4 is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido; further provided R2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and further provided R4 is not methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof.
90. A compound of claim 89 wherein R2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical that binds with Lys52, Glu69, Leu73, Ile82, Leu84, Leu101, and Thr103 sidechains at said ATP
binding site of p38 kinase, said radical being substantially disposed within a hydrophobic cavity formed during said binding by p38 kinase at the ATP binding site.
91. A compound of claim 89 wherein R3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality that hydrogen bonds with the N-H backbone of Met106 of p38 kinase.
92. A compound of claim 89 wherein R1 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 250 atomic mass units.
93. A compound of claim 89 wherein R4 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 250 atomic mass units.
94. A compound of claim 89 wherein R1 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units; and R2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical wherein said radical binds with Lys52, Glu69, Leu73, Ile82, Leu94, Leu101, and Thr103 sidechains at said ATP binding site of p38 kinase, said radical being substantially disposed within a hydrophobic cavity formed during said binding by p38 kinase at the ATP
binding site; and R3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality that hydrogen bonds with the N-H backbone of Met106 of p38 kinase; and R4 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units.
95. A compound of claim 94 wherein R1 and R4 are independently selected from hydrocarbyl, heterosubstituted hydrocarbyl and heterocyclyl radicals and have a combined molecular weight less than about 360 atomic mass units.
96. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the compounds of Claims 1; or a pharmaceutically acceptable salt thereof.
97. A pharmaceutical composition of Claim 96 wherein said compound is selected from the compounds of Claim 3;
or a pharmaceutically acceptable salt thereof.
98. A pharmaceutical composition of Claim 96 wherein said compound is selected from the compounds of Claim 4;
or a pharmaceutically acceptable salt thereof.
99. A pharmaceutical composition of Claim 96 wherein said compound is selected from the compounds of Claim 5;
or a pharmaceutically acceptable salt thereof.
100. A pharmaceutical composition of Claim 96 wherein said compound is selected from the compounds of Claim 6; or a pharmaceutically acceptable salt thereof.
101. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the compounds of Claim 24; or a pharmaceutically acceptable salt thereof.
102. A pharmaceutical composition of Claim 101 wherein said compound is selected from the compounds of Claim 25; or a pharmaceutically acceptable salt thereof.
103. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the compounds of Claim 25; or a pharmaceutically acceptable salt thereof.
104. A pharmaceutical composition of Claim 103 wherein said compound is selected from the compounds of Claim 36; or a pharmaceutically acceptable salt thereof.
105. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the compounds of Claim 44; or a pharmaceutically acceptable salt thereof.
106. A pharmaceutical composition of Claim 105 wherein said compound is selected from the compounds of Claim 45; or a pharmaceutically acceptable salt thereof.
107. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the compounds of Claim 53; or a pharmaceutically acceptable salt thereof.
108. A pharmaceutical composition of Claim 107 wherein said compound is selected from the compounds of Claim 54; or a pharmaceutically acceptable salt thereof.
109. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the of compounds of Claim 66; or a pharmaceutically acceptable salt thereof.
110. A pharmaceutical composition comprising a therapeutically-effective amount of a compound, said compound selected from the compounds of Claims 69; or a pharmaceutically salt thereof.
111. A pharmaceutical composition of Claim 110 wherein said compound is 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
112. A method of treating a TNF mediated disorder, said method comprising treating the subject having or susceptible to such disorder with a therapeutically-effective amount of a compound of Formula I
wherein R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, zeterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or R1 has the formula wherein:
i is an integer from 0 to 9;
R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyelylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or R27 is -CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy;
and R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkulamino, and heterocyclylsulfonyl;
wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or R2 has the formula:
wherein:
j is an integer from 0 to 8; and m i s 0 or 1 ; and R10 and R11 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
R33 is selected from hydrogen, alkyl, -C(O) R35, -C (O) OR35, -SO2R36, -C(O)NR37R38, and -SO2NR39R40, wherein R35 R36, R37, R38 R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or R2 is -CR41R42 wherein R41 is aryl, and R42 is hydroxy; and R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, (IV) (V) wherein R3 is selected from hydrogen, alkyl, amincalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;
and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyaikyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkcxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR44R45 wherein R44 is alkylcarbonyl or amino, and R45 is alkyl or aralkyl; and R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy;
provided R3 is not 2-pyridinyl when R4 is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido;
further provided R2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and further provided R4 is not methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof.
113. A method of treating a p38 kinase mediated disorder, said method comprising treating the subject having or susceptible to such disorder with a therapeutically-effective amount of a compound of Formula I
wherein R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or R1 has the formula wherein:
is an integer from 0 to 9;
R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, vitro, and cyano; or R27 is -CHR28R29 wherein R26 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and vitro; or R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy;
and R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylaminc, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl;
wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylamincalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or R2 has the formula:
wherein:
j is an integer from 0 to 8; and m i s 0 or 1 ; and R10 and R11 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
R33 is selected from hydrogen, alkyl, -C(O) R35, -C(O)OR35, -SO2R36, -C(O)NR37R38, and -SO2NR39R40, wherein R35, R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or R2 is -CR41R42 wherein R41 is aryl, and R42 is hydroxy; and R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;
and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR44R45 wherein R44 is alkylcarbonyl or amino, and R45 is alkyl or aralkyl; and R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, vitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy;
provided R3 is not 2-pyridinyl when R4 is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido;
further provided R2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and further provided R4 is not methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof.
114. A method of treating inflammation; said method comprising treating the subject having or susceptible to inflammation with a therapeutically-effective amount of a compound of Formula I
wherein R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or R1 has the formula wherein:

i is an integer from 0 to 9;
R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or R27 is -CHR28R29 wherein R28 is alkoxycarbonyl , and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy;
and R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylamincalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylaminc, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl;
wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or R2 has the formula:
wherein:
j is an integer from 0 to 8; and m is 0 or 1; and R30 and R31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
R33 is selected from hydrogen, alkyl, -C (O) R35, -C(O)OR25, -SO2R36, -C(O)NR37R38, and -SO2NR39R40, wherein R35, R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or R2 is -CR41R42 wherein R41 is aryl, and R42 is hydroxy; and R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;
and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR44R45 wherein R44 is alkylcarbonyl or amino, and R45 is alkyl or aralkyl; and R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, vitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy;
provided R3 is not 2-pyridinyl when R4 is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido;
further provided R2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and further provided R4 is not methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof.
115. A method of treating arthritis, said method comprising treating the subject having or susceptible to arthritis with a therapeutically-effective amount of a compound of Formula I

wherein R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cyclcalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or R1 has the formula wherein:
i is an integer from 0 to 9;

R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or R27 is -CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy;
and R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl;
wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or R2 has the formula:
wherein:
j is an integer from 0 to 8; and m is 0 or 1; and R30 and R31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
R33 is selected from hydrogen, alkyl, -C (O) R35, -C(O)OR35, -SO2R36, -C(O) NR37R38, and -SO2NR39R40, wherein R35, R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or R2 is -CR41R42 wherein R41 is aryl, and R42 is hydroxy; and R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;
and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR44R45 wherein R44 is alkyl carbonyl or amino, and R45 is alkyl or aralkyl; and R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy;
provided R3 is not 2-pyridinyl when R4 is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido;
further provided R2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R4 is hydrido; and further provided R4 is not methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof.
116. A method of treating a p38 kinase mediated disorder, said method comprising treating the subject having or susceptible to such disorder with a therapeutically-effective amount of a compound of Formula I

wherein Z represents a carbon atom or a nitrogen atom; and R1 is selected from hydrido, lower alkyl, lower hydroxyalkyl and lower alkynyl; and R2 is selected from hydrido and lower alkyl; and R4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more halo radicals; and R5 is selected from hydrido, halo and alkylhydrazinyl; or a pharmaceutically-acceptable salt or tautomer thereof.
117. The method of Claim 112 wherein the TNF
mediated disorder is selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and cachexia.
118. The method of Claim 112 wherein the TNF
mediated disorder is inflammation.
119. The method of Claim 112 wherein the TNF
mediated disease is arthritis.
120. The method of Claim 112 wherein the TNF
mediated disorder is asthma.
121. The method of claim 112 wherein the compound is 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.
122. The method of claim 112 wherein the compound is 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4-methylpiperazine or a pharmaceutically-acceptable salt or a tautomer thereof.
123. The method of Claim 113 wherein the disorder is a p38.alpha. kinase mediated disorder.
124. The method of Claim 113 wherein the p38 kinase mediated disorder is selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and cachexia.
125. The method of Claim 113 wherein the p38 kinase mediated disorder is inflammation.
126. The method of Claim 113 wherein the p38 kinase mediated disorder is arthritis.
127. The method of Claim 113 wherein the p38 kinase mediated disorder is asthma.
128. The method of Claim 116 wherein the disorder is a p38a kinase mediated disorder.
129. The method of Claim 116 wherein the p38 kinase mediated disorder is selected from the group of disorders consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease and cachexia.
130. The method of Claim 116 wherein the p38 kinase mediated disorder is inflammation.
131. The method of Claim 116 wherein the p38 kinase mediated disorder is arthritis.
132. The method of Claim 116 wherein the p38 kinase mediated disorder is asthma.
133. A method of preparing pyrazoles of Formula I

wherein R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or R1 has the formula wherein:
i is an integer from 0 to 9;

R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or R27 is -CHR28BR29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy;
and R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl;
wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or R2 has the formula:

wherein:
j is an integer from 0 to 8; and m is 0 or 1; and R10 and R11 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
R33 is selected from hydrogen, alkyl, -C(O)R35, -C(O)OR35, -SO2R36, -C(O)NR37R38, and -SO2NR39R40, wherein R35, R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or R2 is -CR41R42 wherein R41 is aryl, and R42 is hydroxy; and R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;
and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR44R45 wherein R44 is alkylcarbonyl or amino, and R45 is alkyl or aralkyl; and R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof, said method comprising the steps of forming an acyl hydrazone and condensing to form the substituted pyrazole.
134. The process of Claim 133 wherein the acyl hydrazone is formed by reaction of a ketone with an acyl hydrazide.
135. The process of Claim 133 wherein the condensation is performed at a temperature from about 25 °C to about 200 °C.
136. A method of preparing pyrazoles of Formula I

wherein R1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or R1 has the formula wherein:
i is an integer from 0 to 9;
R25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and R27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or R27 is -CHR28R29 wherein R28 is alkoxycarbonyl, and R29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or R26 and R27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy;
and 818~

R2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl;
wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or R2 has the formula:

wherein:
j is an integer from 0 to 8; and m is 0 or 1; and R30 and R31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;
R33 is selected from hydrogen, alkyl, -C(O)R35, -C(O)OR35, -SO2R36, -C(O)NR37R38, and -SO2NR39R40, wherein R35, R36, R37, R38, R39 and R40 are independently selected from hydrocarbon, heterosubstituted hyrdrocarbon and heterocyclyl; and R34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or R2 is -CR41R42 wherein R41 is aryl, and R42 is hydroxy; and R3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, wherein R43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;
and wherein the R3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR44R45 wherein R44 is alkylcarbonyl or amino, and R45 is alkyl or aralkyl; and R4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof, said method comprising the steps of treating a substituted ketone with an acyl hydrazide to give the pyrazole.
137. The process of Claim 136 wherein it is carried out in an acidic solvent.
138. The process of Claim 137 wherein the acidic solvent is acetic acid.
139. The process of Claim 137 wherein the acidic solvent is an organic solvent containing an acid.
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