AU7588398A - Substituted pyrazoles as p38 kinase inhibitors - Google Patents

Description

WO 98/52940 PCTIUS98/10436 SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS 5 Cross-Reference to Related Application This application claims priority from U.S. Provisional Application Serial No. 60/047,570 filed May 22, 1997. 10 Field of the Invention This invention relates to a novel group of pyrazole compounds, compositions and methods for treating p38 kinase mediated disorders. 15 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 20 nutritional and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines. The p38 MAP kinase group is a MAP family of various isoforms, including p38u, p380 and p387, and is responsible for phosphorylating and activating transcription factors 25 (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-u) and interleukin-1 30 (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 35 production has been implicated in mediating a number of diseases. Recent studies indicate that TNF has a causative role in the pathogenesis of rheumatoid SUSSlTUTE8HEE (RUL 26) WO98/52940 PCTIUS98/10436 2 arthritis. Additional studies demonstrate that inhibition of TNF has broad application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma. 5 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 10 (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 15 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 20 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 25 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 30 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 35 Renault, describes derivatives of pyrazole-5-acetic acid as having anti-inflammatory activity. Specifically, [l suesmnESHEE(FUE6 WO 98/52940 PCT/US98/10436 3 isobutyl-3,4-diphenyl-lH-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 5 process for the preparation of diphenyl-3,4-methyl-5 pyrazole derivatives. WO 95/06036, published March 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 10 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 15 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 20 viral drugs. EP 115640, published Dec 30, 1983, describes 4-imidazolyl-pyrazole derivatives as inhibitors of thromboxane synthesis. 3-(4-Isopropyl-l methylcyclohex-l-yl)-4-(imidazol-l-yl)-lH-pyrazole is specifically described. WO 97/01551, published Jan 16, 25 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. 30 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)-5H-pyrazole is 35 described. WO 96/03385, published February 8, 1996, describes 3,4-substituted pyrazoles, as having anti SUBWUESBHEET (RULE 26 WO98/52940 PCT/US98/10436 4 inflammatory activity. Specifically, 4-[l-ethyl-4-(4 pyridyl)-5-trifluoromethyl-lH-pyrazol-3 yl]benzenesulfonamide is described. The invention's pyrazolyl compounds are found to 5 show usefulness as p38 kinase inhibitors. Description of the Invention A class of substituted pyrazolyl compounds useful in 10 treating p38 mediated disorders is defined by Formula I: R 12 4 3 5 2 N I (I) wherein R' is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, 15 cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, 20 alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, 25 alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, asmCUISEET (U.E2) WO98/52940 PCT/US98/10436 5 alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, 5 alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, 10 arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or

R

I has the formula R25 O | p 26 I /I

-C-(CH

2 ) -C-N I \ 27 H (II) wherein: 15 i is an integer from 0 to 9;

R

25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and 20 heterocyclylcarbonylaminoalkylene; and

R

26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and

R

27 is selected from alkyl, cycloalkyl, alkynyl, 25 aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, 30 aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, usTrI ESHEEr (RI LE ) WO98/52940 PCT/US98/10436 6 alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, 5 alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, 10 alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, 15 arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, 20 aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, 25 alkoxy, keto, amino, nitro, and cyano; or

R

27 is -CHR 2 8

R

29 wherein R 2 1 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and 30 aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or

R

26 and R 27 together with the nitrogen atom to which 35 they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more mTUTEF(RULE2 WO98/52940 PCTIUS98/10436 7 radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, 5 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; 10 and

R

2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, 15 heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, 20 arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, 25 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, 30 aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, 35 arylsulfonyl, and aralkylsulfonyl; or

R

2 has the formula: p Tffs1HEET (RUL E26) WO 98/52940 PCT/US98/10436 8

R

3 0 HR32 -C--( CH 2 - C -N 31 1H ) '1 R 3 L (III) wherein: j is an integer from 0 to 8; and m is 0 or 1; and 5 R 3 and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and

R

3 is selected from hydrogen, alkyl, aralkyl, 10 heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;

R

33 is selected from hydrogen, alkyl, -C(O)R", 15 -C(O)OR 5 , -S0 2

R

6 , -C(O)NR R 8 , and -S0 2

NR

39

R

4 0 , wherein R 35 ,

R

36 , R 37 , R 38 , R 39 and R 4° are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and

R

34 is selected from hydrogen, alkyl, aminocarbonyl, 20 alkylaminocarbonyl, and arylaminocarbonyl; or

R

2 is -CR 41

R

42 wherein R 4 is aryl, and R 42 is hydroxy; and

R

* is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, and 0 R N 0 143 25 (IV) (V) ammUTSHEET(RULE26) WO98/52940 PCT/US98/10436 9 wherein R 43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and wherein the R' pyridinyl, pyrimidinyl, quinolinyl and 5 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, 10 aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, 15 alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, 20 alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR 44

R

45 wherein R 44 is alkylcarbonyl or amino, and R 45 is alkyl or aralkyl; and

R

4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein 25 R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, 30 alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, 35 arylaminoalkylene, aminoalkylamino, and hydroxy; provided R 3 is not 2-pyridinyl when R 4 is a phenyl SUBMTUMESWE(RULE2) WO98/52940 PCT/US98/10436 10 ring containing a 2-hydroxy substituent and when R1 is hydrido; further provided R 2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R 4 is hydrido; and further provided R 4 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 15 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, 20 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 25 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 30 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 35 immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), pneumonia, and herpesvirus. The S ESHEET(RULE 2) WO98/52940 PCT/US98/10436 11 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 5 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 10 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 15 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, 20 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 25 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 30 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 35 be useful for preventing the production of cyclooxygenase-2. SUBSTMUTE swEET (RU 26) WO98/52940 PCT/US98/10436 12 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 5 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, 10 immunosuppressive agents, NSAIDs, 5-lipoxygenase inhibitors, LTB 4 antagonists and LTA 4 hydrolase inhibitors. As used herein, the term "TNF mediated disorder" refers to any and all disorders and disease states in 15 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 20 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, 25 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 30 mediated by p38. As TNF-0 has close structural homology with TNF-u (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-0 are 35 inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF" unless WTIT UTESHEET(RULE26) WO98/52940 PCTIUS98/10436 13 specifically delineated otherwise. A preferred class of compounds consists of those compounds of Formula I wherein

R

I is selected from hydrido, lower alkyl, lower 5 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 10 alkylaminoalkylene, and lower heterocyclylalkylene; or RI has the formula R25 0 -C-CCH2 i-C-N I kn27 H (II) wherein: i is 0, 1 or 2; and 15 R 25 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 20 lower heterocyclylcarbonylaminoalkylene; and

R

2 1 is selected from hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkoxycarbonylalkylene, and lower alkylaminoalkyl; and 25 R 27 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 30 heterocyclylalkylene, lower alkylphenylene, lower alkylphenylalkyl, lower phenylalkylphenylene, lower alkylheterocyclyl, lower alkylheterocyclylalkylene, lower 8USTfUE SHEET (RULE 26) WO98/52940 PCT/US98/10436 14 alkylheterocyclylphenylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl, lower alkoxyheterocyclyl, lower alkoxyalkoxyphenylene, lower 5 phenoxyphenylene, lower phenylalkoxyphenylene, lower alkoxyheterocyclylalkylene, lower phenoxyalkoxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonylalkylene, lower 10 aminoalkyl, lower alkylaminoalkylene, lower phenylaminocarbonylalkylene, lower alkoxyphenylaminocarbonylalkylene, lower aminocarbonylalkylene, arylaminocarbonylalkylene, lower alkylaminocarbonylalkylene, lower phenylcarbonylalkylene, 15 lower alkoxycarbonylphenylene, lower phenoxycarbonylphenylene, lower alkylphenoxycarbonylphenylene, lower phenylcarbonylphenylene, lower alkylphenylcarbonylphenylene, lower 20 alkoxycarbonylheterocyclylphenylene, lower alkoxycarbonylalkoxylphenylene, lower heterocyclylcarbonylalkylphenylene, lower alkylthioalkylene, cycloalkylthioalkylene, lower alkylthiophenylene, lower phenylalkylthiophenylene, lower 25 heterocyclylthiophenylene, lower phenylthioalklylphenylene, lower phenylsulfonylaminoalkylene, lower alkylsulfonylphenylene, lower alkylaminosulfonylphenylene; wherein said lower alkyl, 30 lower cycloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower heterocyclylalkylene, lower alkylheterocyclylphenylene, lower alkoxyphenylene, lower phenoxyphenylene, lower phenylaminocarbonylalkylene, lower 35 phenoxycarbonylphenylene, lower phenylcarbonylphenylene, lower alkylthiophenylene, lower MTITUSHEET(RULE 26) WO98/52940 PCT/US98/10436 15 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

R

27 is -CHR 46

R

47 wherein R 46 is lower alkoxycarbonyl, and R 47 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

26 and R 27 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 20 alkyl, aryl selected from phenyl, biphenyl and naphthyl, heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenoxyalkylene, lower alkoxyphenylene, lower alkylphenoxyalkylene, lower alkylcarbonyl, lower alkoxycarbonyl, lower 25 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 30 selected from halogen, lower alkyl and lower alkoxy; and

R

2 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 35 heterocyclylalkyl, lower alkylamino, lower alkynylamino, phenylamino, lower heterocyclylamino, lower SUBSTTUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 16 heterocyclylalkylamino, lower phenylalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkylaminoalkylamino, lower cycloalkyl, lower alkenyl, lower alkoxycarbonylalkyl, lower cycloalkenyl, lower 5 carboxyalkylamino, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonyl, alkoxycarbonylalkyl, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower 10 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, 15 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 20 amino(hydroxyalkyl), lower heterocyclylalkylamino, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, and phenylsulfonyl; or

R

2 has the formula:

R

3 0 H R 3 2 II / -C-(CH. C -N 31 2] - 3 'q P L m (III) 25 wherein: j is 0, 1 or 2; and m is 0;

R

30 and R 3 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, 30 aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and

R

2 is selected from hydrogen, alkyl, aralkyl, SUBSmTUTEmsHEET (RULE26) WO98/52940 PCT/US98/10436 17 heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and 5 R" is selected from hydrogen, alkyl, -C(O)R 5 ,

-C(O)OR

5 , -S0 2 R 36 , -C(O)NR 37

R

38 , and -S0 2

NR

3 9

R

40 ; wherein R 3 1 is selected from alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl, cycloalkenylalkylene, 10 heterocyclylalkylene, alkylarylene, alkylheterocyclyl, arylarylene, arylheterocyclyl, alkoxy, alkenoxy, alkoxyalkylene, alkoxyaralkyl, alkoxyarylene, aryloxyalkylene, aralkoxyalkylene, cycloalkyloxyalkylene, alkoxycarbonyl, heterocyclylcarbonyl, 15 alkylcarbonyloxyalkylene, alkylcarbonyloxyarylene, alkoxycarbonylalkylene, alkoxycarbonylarylene, aralkoxycarbonylheterocyclyl, alkylcarbonylheterocyclyl, arylcarbonyloxyalkylarylene, and alkylthioalkylene; wherein said aryl, heterocyclyl, aralkyl, alkylarylene, 20 arylheterocyclyl, alkoxyarylene, aryloxyalkylene, cycloalkoxyalkylene, alkoxycarbonylalkylene, and alkylcarbonylheterocyclyl groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, 25 keto, amino, nitro, and cyano; or

R

35 is CHR 4

"R

49 wherein R 48 is arylsulfonylamino or alkylarylsulfonylamino, and R 49 is selected from aralkyl, amino, alkylamino, and aralkylamino; or

R

35 is -NR 5

"R

51 wherein R 5 " is alkyl, and R" is aryl; 30 and wherein R 3 is selected from alkyl, haloalkyl, aryl, heterocyclyl, cycloalkylalkylene, alkylarylene, alkenylarylene, arylarylene, aralkyl, aralkenyl, heterocyclylheterocyclyl, carboxyarylene, alkoxyarylene, 35 alkoxycarbonylarylene, alkylcarbonylaminoarylene, alkylcarbonylaminoheterocyclyl,

SJMUTESHEET(RULEM)

WO98/52940 PCT/US98/1 0436 18 arylcarbonylaminoalkylheterocyclyl, alkylaminoarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, alkylsulfonylaralkyl, and arylsulfonylheterocyclyl; wherein said aryl, heterocyclyl, cycloalkylalkylene, 5 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 10 wherein R 37 is selected from hydrogen and alkyl; and wherein R 3 " is selected from hydrogen, alkyl, alkenyl, aryl, heterocyclyl, aralkyl, alkylarylene, arylcycloalkyl, arylarylene, cycloalkylalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, 15 aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, aryloxyarylene, arylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylene, alkoxycarbonylarylene, alkylcarbonylcarbonylalkylene, alkylaminoalkylene, alkylaminoaralkyl, alkylcarbonylaminoalkylene, 20 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, 25 haloalkoxy, keto, amino, nitro, and cyano; or

R

38 is -CRs 2

R

53 wherein R 52 is alkoxycarbonyl, and R1 3 is alkylthioalkylene; or R 37 and R 3 1 together with the nitrogen atom to which they are attached form a heterocycle; and 30 R 39 and R 4 " have the same definition as R 26 and R 27 in claim 1; or

R

2 is -CR 54

R

55 wherein R 54 is phenyl and R 5 is hydroxy; or

R

2 is selected from the group consisting of SIESTITUTSHEET(RULE26) WO98/52940 PCT/US98/10436 19 R 558 R58 57 1 561 N P 5 5 N N -a Nand

CCH

2 )k N 0 CCH 2 Dk (CH2)k (VI) (VII) (VIII) wherein k is an integer from 0 to 3; and 5 R 56 is hydrogen or lower alkyl; and

R

57 is hydrogen or lower alkyl; or R" and R1 7 form a lower alkylene bridge; and

R"

8 is selected from hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl, 10 alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, -C(O)R 9 , -S0 2

R

6 0 , and -C(O)NHR 61 ; wherein R' 9 is selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy, 15 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 20 cyano; and wherein R 6 1 is selected from alkyl, aryl, heterocyclyl, alkylarylene, alkylheterocyclyl, aralkyl, heterocyclylheterocyclyl, alkoxyarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, and 25 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 SUSmnmTESHEETU 2 6) WO 98/52940 PCT/US98/10436 20 wherein R 6 " 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

3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, and 0 N 0 R (IV) 10 wherein R 4 is selected from hydrogen, lower alkyl, lower aminoalkyl, lower alkoxyalkyl, lower alkenoxyalkyl and lower aryloxyalkyl; and wherein the R 3 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 25 alkoxyphenylalkylamino, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyphenylalkylamino, hydrazinyl, lower 30 alkylhydrazinyl, or -NR 62

R

63 wherein R 62 is lower alkylcarbonyl or amino, and R 6 " is lower alkyl or lower SUBmUTE T(RULE ) WO98/52940 PCT/US98/1 0436 21 phenylalkyl; and

R

4 is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, aryl selected from phenyl, biphenyl, and naphthyl, and 5- or 6- membered heterocyclyl; wherein the 5 lower cycloalkyl, lower cycloalkenyl, aryl and 5-10 membered heterocyclyl groups of R 4 are optionally substituted with one or more radicals independently selected from lower alkylthio, lower alkylsulfonyl, lower alkylsulfinyl, halo, lower alkyl, lower alkynyl, lower 10 alkoxy, lower aryloxy, lower aralkoxy, lower heterocyclyl, lower haloalkyl, amino, cyano, nitro, lower alkylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof. 15 A class of compounds of particular interest consists of these compounds of Formula I wherein R' is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, 20 difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, 25 ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, 30 methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and 35 methylthiomethyl; and

R

2 is selected from hydrido, chloro, fluoro, bromo, U~MTUTESHE (RULE

)

WO98/52940 PCT/US98/10436 22 methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, phenyl, biphenyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, 5 difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxymethyl, hydroxyethyl, pyridinyl, isothiazolyl, isoxazolyl, thienyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, 10 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, 15 N-phenylamino, piperadinylamino, N-benzylamino, N propargylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, N,N 20 dimethylaminoethylamino, N,N-dimethylaminopropylamino, morpholinylethylamino, morpholinylpropylamino, carboxymethylamino, methoxyethylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1,1 dimethylethoxycarbonyl, 1,1 25 dimethylethoxycarbonylaminoethylamino, 1,1 dimethylethoxycarbonylaminopropylamino, piperazinylcarbonyl, and 1,1 dimethylethoxycarbonylpiperazinylcarbonyl; wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl groups are 30 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, 35 dimethylamino, methoxycarbonyl, ethoxycarbonyl, and 1,1 dimethylethylcarbonyl; or WO98/52940 PCT/US98/10436 23

R

2 is -CR 54

R

55 wherein R 4 is phenyl and R" is hydroxy; and

R

3 is selected from pyridinyl, pyrimidinyl, and purinyl; wherein R 3 is optionally substituted with one or 5 more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, 10 difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, 15 fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2 methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, 20 diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N dimethylaminoethylamino, hydroxypropylamino, 25 hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, 30 methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methyl hydrazinyl, or -NR 62

R

63 wherein R 62 is methylcarbonyl or amino, and R 63 is methyl, ethyl or phenylmethyl; and

R

4 is selected from hydrido, cyclopropyl, cyclobutyl, 35 cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, suesTm sEHEET(RULE) WO98/52940 PCT/US98/10436 24 biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, 5 pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R 4 are optionally substituted with one or more 10 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, 15 dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof. Another class of compounds of particular interest 20 consists of these compounds of Formula I wherein

R

I is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl;

R

2 is selected from hydrido, methyl, ethyl, propyl, 25 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 30 independently selected from fluoro, chloro, bromo, methyl, ethyl, and trifluoromethyl;

R

3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R 3 is optionally substituted with one or more radicals independently selected from fluoro, 35 bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, BHSmut (RU WO98/52940 PCTIUS98/10436 25 dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl;

R

4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, 5 dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of RI are optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, 10 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 R' is hydrido or methyl;

R

2 is selected from hydrido, methyl or ethyl;

R

3 is selected from pyridinyl, pyrimidinyl or 20 quinolinyl; wherein R 3 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

4 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, 30 trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof. Still another class of compounds of particular 35 interest consists of those compounds of Formula I wherein R' is selected from hydrido, methyl, ethyl, propyl, SUBMTUTESHEE(RULE 26) WO98/52940 PCTIUS98/100436 26 isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, 5 dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, 10 piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, 15 cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methylthiomethyl; and

R

2 has the formula: R 30 H R 3 I I / -- C--CH 2 - C -N 1 1 3 4 3 3 P m (III) 20 wherein: j is 0, 1 or 2; and m is 0; and

R

30 and R 3 are independently selected from hydrogen and lower alkyl; 25 R 32 is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, aryloxyalkylene, aminoalkyl, lower alkylaminoalkyl, lower phenylaminoalkyl, lower alkylcarbonylalkylene, lower phenylcarbonylalkylene, and 30 lower heterocyclylcarbonylaminoalkylene; R" is selected from hydrogen, lower alkyl, -C(O)R",

-C(O)OR

s 3 5 , -S0 2 R 36 , -C(O)NR 37

R

3 8 , and -S0 2 NR 39 R 40 SMTITUTMSEET(FU.E28) WO98/52940 PCT/US98/1 0436 27 wherein R 3 " 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 5 cycloalkenylalkylene, lower heterocyclylalkylene, lower alkylphenylene, lower alkylheterocyclyl, phenylphenylene, lower phenylheterocyclyl, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower alkoxyphenylalkyl, lower alkoxyphenylene, lower phenoxyalkylene, lower 10 phenylalkoxyalkylene, lower cycloalkyloxyalkylene, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkylcarbonyloxyalkylene, lower alkylcarbonyloxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower 15 phenylalkoxycarbonylheterocyclyl, lower alkylcarbonylheterocyclyl, lower phenylcarbonyloxyalkylphenylene, and lower alkylthioalkylene; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower 20 phenylalkyl, lower alkylphenylene, lower phenylheterocyclyl, lower alkoxyphenylene, lower phenoxyalkylene, lower cycloalkoxyalkylene, lower alkoxycarbonylalkylene, and lower alkylcarbonylheterocyclyl groups are optionally 25 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

35 is CHR 48

R

49 wherein R 48 is phenylsulfonylamino or 30 lower alkylphenylsulfonylamino, and R 49 is selected from lower phenylalkyl, amino, lower alkylamino, and lower phenylalkylamino; or

R

35 is -NR 5

°R

5 ' wherein R 5 1 is lower alkyl, and R" is aryl selected from phenyl, biphenyl and naphthyl; and 35 wherein R" is selected from lower alkyl, lower haloalkyl, aryl selected from phenyl, biphenyl and SUsTrUTESHEET(LE2) WO98/52940 PCT/US98/10436 28 naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower alkylphenylene, lower alkenylphenylene, phenylphenylene, lower phenylalkyl, lower phenylalkenyl, lower heterocyclylheterocyclyl, carboxyphenylene, lower 5 alkoxyphenylene, lower alkoxycarbonylphenylene, lower alkylcarbonylaminophenylene, lower alkylcarbonylaminoheterocyclyl, lower phenylcarbonylaminoalkylheterocyclyl, lower alkylaminophenylene, lower alkylamino, lower 10 alkylaminophenylene, lower alkylsulfonylphenylene, lower alkylsulfonylphenylalkyl, and lower phenylsulfonylheterocyclyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower phenylalkyl, lower 15 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; 20 and wherein R 37 is selected from hydrogen and lower alkyl; and wherein R 38 is selected from hydrogen, lower alkyl, lower alkenyl, aryl selected from phenyl, biphenyl and 25 naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylcycloalkyl, phenylphenylene, lower cycloalkylalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower 30 alkoxyphenylene, lower phenoxyphenylene, phenylcarbonyl, lower alkoxycarbonyl, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower alkylcarbonylcarbonylalkylene, lower alkylaminoalkylene, lower alkylaminophenylalkyl, lower 35 alkylcarbonylaminoalkylene, lower alkylthiophenylene, lower alkylsulfonylphenylalkyl, and lower SST UTESEE(RULEM) WO98/52940 PCT/US98/10436 29 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 5 independently selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; or

R

38 is -CR 52

R

53 wherein R 52 is lower alkoxycarbonyl, and R.

3 is lower alkylthioalkylene; or 10 R 37 and R 38 together with the nitrogen atom to which they are attached form a 4-8 membered ring heterocycle;

R

39 and R 4° have the same definition as R 2 6 and R 27 in claim 2; or

R

2 is selected from the group consisting of

P

5 8 p 5 8 R58 57 1 561 PN R 56 N N and CCH 2 _D N O CCH 2 )k 15

CCH

2 ]k (VI) (VII) (VIII) wherein k is an integer from 0 to 2; and

R"

6 is hydrogen or lower alkyl; and 20 R 57 is hydrogen or lower alkyl; and

R"

8 is selected from hydrogen, lower alkyl, lower phenylalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower heterocyclylalkyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower 25 phenylalkylsulfonyl, lower phenylsulfonyl, -C(0)R", -S0 2

R

60 , and -C(O)NHR 6 1 ; wherein R' 9 is selected from lower alkyl, lower haloalkyl, lower cycloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower sussmTMSTE EE(RU LE) WO98/52940 PCT/US98/10436 30 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 R" 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 R" 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 3 is optionally substituted with one or more radicals independently selected from methylthio, 35 methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, SESmfuTESHEE(RULE6 WO98/52940 PCT/US98/10436 31 isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, 5 fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, 10 ethylamino, dimethylamino, diethylamino, 2 methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, 15 methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, 20 piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methyl 25 hydrazinyl, or -NR" 2

R

63 wherein R" 2 is methylcarbonyl or amino, and R1 3 is methyl, ethyl or phenylmethyl; and

R

4 is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, 30 biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, 35 dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein mmTESHEE (RULE 26) WO98/52940 PCT/US98/10436 32 the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R 4 are optionally substituted with one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, 5 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 10 thereof. Still another class of compounds of particular interest consists of those compounds of Formula I wherein R1 is hydrido, methyl, ethyl, propargyl, 15 hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl;

R

2 has the formula:

R

3 0 H R I I /

-C--CCH

2 DJ- C -N 31 1a 3 R 3 L - m wherein: 20 j is 0, 1 or 2; and m is 0; and R" is hydrogen; and

R

3 is selected from hydrogen and lower alkyl; and R1 2 is selected from hydrogen and lower alkyl; and 25 R 33 is selected from lower alkyl, -C(O)R, -C(O)OR", -S0 2

R

6 , -C(O)NR 37

R

38 , and -S0 2

NR

39

R

4 0 ; wherein R 35 is selected from lower alkyl, lower cycloalkyl, phenyl, lower heterocyclyl, lower alkylphenylene, lower alkoxy, lower alkenoxy, lower 30 alkoxyalkylene, lower phenoxyalkylene, and lower phenylalkoxyalkylene; wherein said phenyl and lower phenoxyalkylene groups are optionally substituted with 8uMTUESHEE(RULE2) WO98/52940 PCT/US98/10436 33 one or more radicals independently selected from lower alkyl, halo, and lower haloalkyl; and wherein R 36 is selected from lower alkyl, phenyl, lower heterocyclyl, lower alkylphenylene, 5 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 10 selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and wherein R 37 is hydrogen; and wherein R 8 is selected from lower alkyl, phenyl, and 15 lower alkylphenylene; wherein R 39 and R 4 " have the same definition as R 26 and

R

27 in claim 2; or

R

2 is selected from the group consisting of

R

5 8 R58 R58 6 N N C ) 'and CH 2 Dk N 0 CCH 2

D

k 2CH 2 )k 20 (VI) (VII) (VIII) wherein k is an integer from 0 or 1; and

R

56 is hydrogen; and

R"

7 is hydrogen; and 25 R" 8 is selected from -C(O)R 9 and -S0 2

R

6 ; wherein R 9 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 SUTESHEET(UL

)

WO98/52940 PCTIUS98/10436 34 selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and wherein R 6 " is selected from lower alkyl; and 5 R' is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R 3 is optionally substituted with one or more radicals independently selected from fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, 10 dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and

R

4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the 15 cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of

R

4 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 20 hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof. Still another class of compounds of specific 25 interest consists of those compounds of Formula I wherein R' is hydrido or methyl; and

R

3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R 3 is optionally substituted with one or more radicals independently selected from fluoro, 30 bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; and

R

4 is selected from phenyl which is optionally 35 substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, SWSTIUESHET(RULE 28) WO98/52940 PCT/US98/10436 35 ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof. 5 In one embodiment of the present invention, the compounds of Formula I satisfy one or more of the following conditions: R' is hydrido or lower alkyl; more preferably, R I is 10 hydrido or methyl; and still more preferably, R' is hydrido;

R

2 is hydrido or lower alkyl; more preferably, R 2 is hydrido or methyl; and still more preferably, R 2 is hydrido; 15 R 3 is substituted or unsubstituted pyridinyl; and preferably, the pyridinyl is a 4-pyridinyl; or

R

4 is substituted or unsubstituted phenyl; and preferably, R 4 is phenyl substituted with halo. In addition, where R 3 is substituted pyrimidinyl, 20 preferably at least one R 3 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-lH-pyrazol-4 yl]pyridine; 30 4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine; 4-[5-methyl-3-(2-methylphenyl)-1H-pyrazol-4-yl]pyridine; 4-[3-(4-fluorophenyl)-5-methyl-lH-pyrazol-4-yl]pyridine; 4-[5-methyl-3-(4-methylphenyl)-lH-pyrazol-4-yl]pyridine; 4-[5-methyl-3-[4-(methylthio)phenyl]-lH-pyrazol-4 35 yl]pyridine; 4-[3-(4-chlorohpenyl)-5-methyl-lH-pyrazol-4-yl]pyridine; SBssmUTESHEET(RULE2) WO 98/52940 PCT/US98/1 0436 36 4- [3-methyl-5- (3-methyiphenyl) -1H-pyrazol-4-yllpyridine; 4-15- (2,5-dimethyiphenyl) -3-methyl-lH-pyrazol-4 yl] pyridine; 4- [5-(1,3-benzodioxol-5-yl)-3-methyl-lH-pyrazol-4 5 yllpyridine; 4- [3-methyl-5- (4-phenoxyphenyl) -1H-pyrazol-4-yllpyridine; 4- [5- [(1,1' -biphenyl) -4-yl] -3-methyl-lH-pyrazol-4 yl] pyridine; 4- [3-methyl-5- [3- (phenoxyphenyl) -lH-pyrazol-4 10 yllpyridine; 4- [3-methyl-5- [3- (phenylmethoxy)phenyl] -1H-pyrazol-4 yl Ipyridine; 4- [3-methyl-5- [2- (phenylmethoxy) phenyll -lH-pyrazol-4 yl] pyridine; 15 2- [3-methyl-4- (4-pyridinyl) -lH-pyrazol-4-yllphenol; 3- [3-methyl-4- (4-pyridinyl) -1H-pyrazol-4-yllphenol; 1-hydroxy-4- (3-methyl-5-phenyl-lH-pyrazol-4 yl] pyridinium; 5- (4-f luorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -lH 20 pyrazol-3-amine; 5- (4-f luorophenyl) -N-phenyl-4- (4-pyridinyl) -lH-pyrazol-3 amine; 4- [5- (4-f luorophenyl) -3-phenyl-1H-pyrazol-4 yl] pyridine; 4- [5- (3-methyiphenyl) -3- (trifluoromethyl) -1H-pyrazol-4 25 yllpyridine;4-[3-(4-fluorophenyl)-4-(4-pyridinyl)-1H pyrazol-5-ylI pyridine; 4- (5-cyclohexyl) -3-methyl-1H-pyrazol-4-yl)pyridine; 4- [5- (3-f luoro-5-methoxyphenyl) -3-methyl-lH-pyrazol-4 yl Ipyridine; 30 4- [5- (3-methyiphenyl) -3-propyl-lH-pyrazol-4-yllpyridine; 4- [(3-methyl-5-phenyl-lH-pyrazol-4-yl)methyllpyridile; 4- [3,5-bis (3-methyiphenyl) -1H-pyrazol-4-yllpyridine; 4- [4-methyl-2- (2-trifluorophenyl) -lH-pyrazol-4 yll pyridine; 35 4- [3- (2-chiorophenyl) -5-methyl-1H-pyrazol-4-yllpyridine; 4- [5-methyl-3- (2,4-dimethylphenyl) -1H-pyrazol-4 SLWMHEiET (MLE26) WO 98/52940 PCTIUS98/1 0436 37 yl] pyridine; 4- [5-(4-chlorophenyl)-1,3-dimethyl-1H-pyrazol-4 yll pyridine; 4- [3- (3-f luoro-2-methylphenyl) -5-rethyl-1H-pyrazol-4 5 yllpyridine; 4- [3- (3,5-dimethyiphenyl) -5-methyl-1H-pyrazol-4 yl] pyridine; 4- [3- (3,5-dimethoxyphenyl) -5-methyl-1H-pyrazol-4 yl] pyridine; 10 4- [5-methyl-3- (3-nitrophenyl) -1H-pyrazol-4-yllpyridine; 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 yll pyridine; 15 4- [3- (4-bromophenyl) -5-methyl-lH-pyrazol-4-yllpyridine; 4- [3- (2-f luorophenyl) -5-methyl-lH-pyrazol-4-yllpyridine; 4- [3- (3-f luorophenyl) -5-methyl-lH-pyrazol-4-yllpyridine; 4- [3-methyl-5- [3- (trifluoromethyl)phenyl] -1H-pyrazol-4 yl] pyridine; 20 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-rethylphenyl) -lH-pyrazol-4-yllpyridine; 4-[5-(3,4-difluorophenyl)-3-rnethyl-lH-pyrazol-4 yl] pyridine; 25 4- [5- (3-ethoxyphenyl) -3-methylL-lH-pyrazol-4-yllpyridine; 4- [3-methyl-5- [4- (trifluoromethyl)phenyl] -lH-pyrazol-4 yl] pyridine; 4- [3-methyl-5- (3-thienyl) -1H-pyrazol-4-y1]pyridine; 4- [5- (2,4-dichiorophenyl) -3-rethyl-1H-pyrazol-4 30 yllpyridine; 4-Es- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine; 4- [5- (3-chloro-4-methoxyphenyl) -3-methyl-11{-pyrazol-4 yl] pyridine; ethyl 3- (4-chiorophenyl) -4- (4-pyridinyl) -1H-pyrazole-5 35 propanoate; 4- [3- (4-f luorophenyl) -1-methyl-pyrazol-4-yllpyridine; BU8STMTSHEE(MULE26) WO 98/52940 PCT/US98/10436 38 5- [5- (3-chiorophenyl) -3-methyl-lH-pyrazol-4-yllpyrimidil 2-amine; 5- [3-methyl-5- (3-methyiphenyl) -lH-pyrazol-4-yllpyrimidil 2-amine; 5 5- [3-methyl-5- (2-methyiphenyl) -lH-pyrazol-4-yllpyrimidin 2-amine; 5- [5- (4-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyrimidil 2-amine; 5- [5- (4-f luorophenyl) -3-methyl-lH-pyrazol-4-yllpyrimidil 10 2-amine; 5-Es- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4 yll pyrimidin-2 -amine; 5-Es- (3-chiorophenyl) -3-methyl-lH-pyrazol-4-yllpyridin-2 amine; 15 4-ES- (3-chiorophenyl) -3-methyl-lH-pyrazol-4-yllpyridin-2 amine; 4-Es- (3-methylphenyl) -3-methyl-lH-pyrazol-4-yllpyridin-2 amine; 4-Es- (2-methylphenyl) -3-methyl-lH-pyrazol-4-yllpyridin-2 20 amine; 4-Es- (4-chiorophenyl) -3-methyl-lH-pyrazol-4-yllpyridin-2 amine; 4-ES- (4-f luorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2 amine; 25 4-ES- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yllpyridil 2-amine; 5- [5- (3-chiorophenyl) -3-methyl-lH-pyrazol-4-yl] -2 methoxypyridine; 2-methoxy-5- [3-methyl-5- (3-methyiphenyl) -lH-pyrazol-4 30 yl]pyridine; 2-methoxy-5- [5- (4-methoxyphenyl) -3-methyl-lH-pyrazol-4 yl] pyridine; 4- [5- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yl] -2 methoxypyridine; 35 2-methoxy-4- [3-methyl-5- (3-methyiphenyl) -lH-pyrazol-4 yll pyridine; WO 98/52940 PCT/US98/10436 39 2-methcxy-4- [3-methyl-5- (2-methylpheiyl) -1H-pyrazol-4 yl] pyridine; 4- [5- (4-chlcrophenyl) -3-methyl-1H-pyrazol-4-yl] -2 methoxypyridine; 5 4-[5-(4-flucrcphenyl)-3-mfethyl-lH-pyrazcl-4-yll-2 methoxypyridine; 2-methcxy-4- E3-methyl-5- (4-methylphenyl) -lH-pyrazol-4 yll pyridine; 5-Es- (3-chlcrophenyl) -3-methyl-lH-pyrazol-4-yllpyridil-2 10 oi; 4- [5- (3-chicrophenyl) -3-rethyl-lH-pyrazcl-4-yllpyridin-2 ci; 4- [5- (3-methyiphenyl) -3-methyl-1H-pyrazcl-4-yllpyridil-2 oi; 15 4- [5- (2-methylphenyl) -3-methyl-lH-pyrazcl-4-yllpyridil-2 ci; 4-Es- (4-chicrophenyl) -3-methyl-lH-pyrazol-4-ylpyridil-2 ci; 4-Es- (4-f lucrophenyl) -3-methyl-lH-pyrazcl-4-yllpyridil-2 20 ci; 4-ES- (4-methoxyphenyl) -3-methyl-1H-pyrazl-4-y-]pyridil 2-cl; 5-ES- (3-chicrophenyl) -3-rethyl-1H-pyrazcl-4-yllpyridile 2 -rethanamine; 25 4-ES- (3-chlcrophenyl) -3-methyl-lH-pyrazci-4-yllpyridile 2 -methanamine; 4-ES- (3-methyiphenyl) -3-methyl-lH-pyrazci-4-y]pyridile 2 -methanamine; 4- [5-(2-methyiphenyl) -3-methyl-lH-pyrazcl-4-yllpyridile 30 2-methanamine; 4-ES- (4-chicrophenyl) -3-rethyl-lH-pyrazcl-4-yllpyridile 2-me thanamine; 4-[S- (4-f lucrophenyl) -3-methyl-lH-pyrazcl-4-yilpyridine 2 -me thanamine; 35 4-Es- (4-methcxyphenyi) -3-methyi-lH-pyrazci-4-ylpyridile 2 -methanamine; BUSS~nTE 8HE~ (R 90 26 WO 98/52940 PCT/US98/1 0436 40 5- [5- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine 2- carboxamide; 4- [5- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine 2 -carboxamide; 5 4-Es- (3-methyiphenyl) -3-methyl-1H-pyrazol-4-yljpyridine 2- carboxamide; 4-15- (2-methyiphenyl) -3-methyl-1H-pyrazol-4-yllpyridine 2 -carboxamide; 4- [5- (4-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine 10 2-carboxamide; 4- [5- (4-f luorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine 2 -carboxamide; 4- [5- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yllpyridine 2 -carboxamide; 15 4- [5- (3-f luoro-4-methoxyphenyl) -3-rethyl-1H-pyrazol-4 yll pyridine; 4- [5- (4-f luoro-3-methoxyphenyl) -3-methyl-1H-pyrazol-4 yll pyridine; 4-Es- (4-chloro-3-methoxyphenyl) -3-methyl-lH-pyrazol-4 20 yllpyridine; 4-Es- (2,3-dihydrobenzofuran-6-yl) -3-methyl-lH-pyrazol-4 yl] pyridine; 4-Es- (benzofuran-6-yl) -3-methyl-1H-pyrazol-4-yllpyridile; 4-Es- (3-f luoro-5-methoxyphenyl) -3-methyl-lH-pyrazol-4 25 yllpyridine; 4-ES- (3-chloro-5-methoxyphenyl) -3-rnethyl-1I--pyrazol-4 yl] pyridine; 4-Es- (i-cyclohexyen-1-yl) -3-methyl-1H-pyrazol-4 yl]I pyridine; 30 4-[5-(1,3-cyclohexadien-1-y)-3-methy-lI--pyrazol-4 yl] pyridine; 4-Es- (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-ES- (4-methoxy-3-methylphenyl) -3-rethyl-1H-pyrazol-4 yl]pyridine; su~m7SmEUT(RLE~ WO98/52940 PCTIUS98/1Q436 41 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; 5 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; 10 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine-2 carboxamide; 1-[4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridin-2 yl]ethanone; N,N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazol-2 15 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-lIH-pyrazol-4yl)pyridine-3 carboxylate; 20 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine-3 carboxamide; 1-[4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridin-3 yl]ethanone; 3-bromo-4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine; 25 N,N-dimethyl-4-(3-methyl-5-phenyl-lH-pyrazol-2 yl)pyridin-3-amine; 2-methyl-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidine; 4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyrimidine; 2-methoxy-4-(3-methyl-5-phenyl-lH-pyrazol-4 30 yl)pyrimidine; 4-(3-methyl-5-phenyl-lH-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-iH 35 pyrazole; 3-methyl-5-phenyl-4-(3-thienyl)-lH-pyrazole; SITIUTE8HEET(RULE 26) WO 98/52940 PCT/US98/10Q436 42 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-lH-pyrazole; 4- (3-isothiazolyl) -3-methyl-5-phenyl-1H-pyrazole 5 4- (3-isoxazolyl) -3-methyl-5-phenyl-lH-pyrazole; 4- (5-isothiazolyl) -3-methyl-5-phenyl-1H-pyrazole; 4- (5-isoxazolyl) -3-methyl-5-phenyl-1H-pyrazole; 3-rethyl-5-phenyl-4- (5-thiazolyl) -lH-pyrazole; 3-methyl-4- (5-oxazolyl) -5-phenyl-lH-pyrazole; 10 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yllpyridine; 2-methyl-4-[13- (3-rethylphenyl) -lH-pyrazol-4-yllpyridine; 4- (1-methyl-3-phenyl-1H-pyrazol-4-yl)pyridine; 4- (3-phenyl-1H-pyrazol-4-yl)pyridine; 2-methyl-4- (3-phenyl-lH-pyrazol-4-yl)pyridine; 15 4-113- (3-chiorophenyl) -l-methyl-pyrazol-4-yllpyridine; 4-13- (4-chiorophenyl) -1-methyl-pyrazol-4-yllpyridine; 4-113- (3-chiorophenyl) -lH-pyrazol-4-yllpyridine; 4-13- (4-chiorophenyl) -1H-pyrazol-4-yllpyridine; 4- [3- (3-chiorophenyl) -1H-pyrazol-4-yl] -2-methylpyridine; 20 4-113- (3-f luorophenyl) -1-methyl-1H-pyrazol-4-yllpyridine; 4-113- (3-f luorophenyl) -1H-pyrazol-4-yllpyridine; 4-13- (3-chiorophenyl) -l-methyl-pyrazol-4-yl] -2 rethylpyridine; 5- (4-chiorophenyl) -N-phenyl-4- (4-pyridinyl) -lH-pyrazol-3 25 amine; 5- (4-chiorophenyl) -N-methyl-4- (4-pyridinyl) -lH-pyrazol-3 amine; 5- (4-chiorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -lpyrazol -3-amine dihydrate; 30 5- (3-f luorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -1H pyrazol-3-amine; N,N-dimethyl-5- (3-methyiphenyl) -4- (4-pyridinyl) -lH pyrazol-3-amine; N-methyl-5- (3-methyiphenyl) -4- (4-pyridinyl) -1H-pyrazol-3 35 amine; N-ethyl-5- (3-methyiphenyl) -4- (4-pyridinyl) -lH-pyrazol-3- WO 98/52940 PCT/US98/1 Q436 43 amine; N,N-diethyl-5- (3-methyiphenyl) -4- (4-pyridinyl) -1H pyrazol -3-amine; 5- (4-chiorophenyl) - N,N-diethyl-4- (4-pyridinyl) -1H 5 pyrazol-3-amine; 4- [5- (4-chiorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3 yl] morpholine; 5- (4-chiorophenyl) -N-propyl-4- (4-pyridinyl) -1H-pyrazol-3 amine; 10 5- (4-chiorophenyl) -N- (phenylmethyl) -4- (4-pyridinyl) -1H pyrazol-3-amine hydrate (2:1); 5- (4-chiorophenyl) -N- (2-methoxyethyl) -4- (4-pyridinyl) -1H pyrazol -3-amine monohydrate; 1, 1-dimethylethyl 4- [5- (4-chiorophenyl) -4- (4-pyridinyl) 15 1H-pyrazol-3-yl] -1-piperazinecarboxylate; 1- [5- (4-chiorophenyl) -4- (4-pyridinyl) -1I--pyrazol-3 yl] piperazine trihydrochioride; 1- [5- (4-chiorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4 methylpiperazine; 20 1,1-dimethylethyl 4- [5- (4-fluorophenyl) -4- (4-pyridinyl) 1H-pyrazol-3-yl] -1-piperazinecarboxylate; 1- [5- (4-f luorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3 y11 piperazine trihydrochioride; 1- [5- (4-chiorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3 25 yllpiperazine; N- [5- (4-chiorophenyl) -4- [2- (phenylmethyl) aminol -4 pyridinyll -11-pyrazol-3-yl] -1, 3-propanediamine, trihydrochioride; 1- [5- (4-chiorophenyl) -4- (4-pyridinyl) -1I-pyrazol-3-yl] -4 30 (phenylmethyl) piperazine; 4- [3- (4-f luorophenyl) -5- (1-piperazinyl) -1H-pyrazol-4 yl] pyrimidine, dihydrochioride; 1,1-dimethylethyl [3- [[5-(4-chlorophenyl)-4-(4 pyridinyl) -1H-pyrazol-3-yl] amino] propyll carbamate; 35 N- [5- [4-chiorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] 1,3 -propanediamine, trihydrochioride monohydrate; St~rrrUTEsE9(RLL 2 6) WO 98/52940 PCTIUS98/1 0436 44 1,1-dimethylethyl [2- [[5-(4-chlorophenyl)-4-(4 pyridinyl) -1H-pyrazol-3-yl] amino] ethyl] carbamate; 1,1-dimethylethyl 4-[5-(4-chlorophenyl)-l-(2 hydroxyethyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -1 5 piperazinecarboxylate; 1 1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4 pyrimidinyl) -lH-pyrazol-3-yl] -1-piperazinecarboxylate; 1,1-dimethylethyl [3- [[5-(4-chlorophenyl)-4-(2-fluoro-4 pyridinyl) -lH-pyrazol-3-yll amino] propyl] carbamate; 10 l-[5-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4 ethylpiperazine; N- [5- (4-chiorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] 1, 2-ethanediamine; 4- [3- (2,6-difluorophenyl) -5-methyl-lH-pyrazol-4 15 yllpyridine; 4- [3- (3-ethyiphenyl) -5-methyl-lH-pyrazol-4-yl]pyridine; 4- [3- (3-chiorophenyl) -5-ethyl-lH-pyrazol-4-yllpyridine; 4- [3-ethyl-5- (3-ethyiphenyl) -1H-pyrazol-4-yl]pyridine; 4- [3- (4-chiorophenyl) -5- (1-methylethyl) -lH-pyrazol-4 20 yllpyridine; 4- [3-cyclopropyl-5- (4-f luorophenyl) -lH-pyrazol-4 yl] pyridine; 4- [3- (4-f luorophenyl) -5- (trifluoromethyl) -lH-pyrazol-4 yl] pyridine; 25 4-[5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl-lH pyrazol-4-yl] pyridine; 5-cyclopropyl-3- (4-f luorophenyl) -4- (4-pyridinyl) -1H pyrazole-1- ethanol; 3- (4-fluorophenyl) -5- (2-methoxy-4-pyridinyl) -4- (4 30 pyridinyl) -1H-pyrazole-1-ethanol; 4- [3- (4-f luorophenyl) -1-(2-hydroxyethyl) -4- (4-pyridinyl) iH-pyrazol-5-yl] -2 (lH) -pyridinone; l-acetyl-4- [3- (4-fluorophenyl) -1-(2-hydroxyethyl) -4- (4 pyridinyl) -lH-pyrazol-5-yll -2 (lH)-pyridinone; 35 Ethyl 2- [3-(4-fluorophenyl)-l-(2-hydroxyethyl)-4-(4 pyridinyl) -1H-pyrazol-5-yl] cyclopropanecarboxylate; SBSTffUTESHEEF(RLLE O) WO 98/52940 PCTIUS98/1 Q436 45 2- [3- (4-f luorophenyl) -1-(2-hydroxyethyl) -4- (4-pyridinyl) 1H-pyrazol-5-yl] cyclopropanecarboxylic acid; 3- (4-f luorophenyl) -5- (4-imidazolyl) -4- (4-pyridinyl) -lH pyrazole- 1-ethanol; 5 4- [3- (4-chloro-3-methylphenyl) -1H-pyrazol-4-yllpyridine 5- (4-f luorophenyl) -4- (4-pyridinyl) -lH-pyrazole-3 carboxylic acid; 5- (4-f luorophenyl) -4- (4-pyridinyl) -lH-pyrazole-3 methanol; 10 l-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-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; 15 4- (l,3-dimethyl-5-phenyl-lH-pyrazol-4-yllpyridine; 4-[3-(4-chlorophenyl)-1,5-dimethyl-lH-pyrazol-4 yl] pyridine; 4-[5-(4-chlorophenyl)-1,3-dimethyl-lH-pyrazol-4 yl] pyridine; 20 4- [5-ethyl-l-methyl-3- (3-methylphenyl) -lH-pyrazol-4 yl] pyridine; 4- [3-ethyl-l-methyl-5- (3-methylphenyl) -lH-pyrazol-4 yl] pyridine; 4- [3- (4-chlorophenyl) -l-ethyl-5-methyl-lH-pyrazol-4 25 yllpyridine; 4- [3- (4-chlorophenyl) -2-ethyl-5-methyl-1H-pyrazol-4 yl] pyridine; 4- [3- (4-f luorophenyl) -1H-pyrazol-4-yllpyridine; 4- [3- (2-chlorophenyl) -lH-pyrazol-4-yllpyridine; 30 3- (4-f luorophenyl) -4- (4-pyridinyl) -lH-pyrazole-l-ethanol; 3- (4-f luorophenyl) -4- (4-pyrimidinyl) -1H-pyrazole-l ethanol; 4- [3- (4-f luorophenyl) -l-methyl-1H-pyrazol-4-yllpyridine; 2- [[4-[13- (4-fluorophenyl) -11--pyrazol-4-yl] -2 35 pyridinyl] amino] -1-butanol; 4- [5-bromo-3- (4-f luorophenyl) -1-methyl-1H-pyrazol-4 Us~LaTmEu~(RULE 26) WO 98/52940 PCT/US98/10436 46 yl]pyridine; 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2 pyridinecarbonitrile; 4-[2-[3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-1 5 yl]ethyl]morpholine; 3-(4-fluorophenyl)-l-methyl-a-phenyl-4-(4-pyridinyl)-1H pyrazole-5-methanol; N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4 morpholineethanamine; 10 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-2(1H)-pyridinone hydrazone; 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]-N-(phenylmethyl) 2-pyridinamine; 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]-N-(phenylethyl)-2 15 pyridinamine; 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-N-ethyl-2 pyridinamine; 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2 pyridinecarboxamide; 20 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 25 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; 30 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 35 -yll]-2-methylpyridine; 4-[3-(3-chlorophenyl)-1-methyl-1H-pyrazol-4-yl]pyridine; SUBSTITUTESEET (RULE 26) WO 98/52940 PCT/UJS98/1 0436 47 4- [5-(3-chiorophenyl) -1-methyl-1H-pyrazol-4-yllpyridine; 2-methyl-4- [l-methyl-3- (3-methyiphenyl) -lH-pyrazol-4 -yl] pyridine; 2-methyl-4- [l-methyl-5- (3-methyiphenyl) -1H-pyrazol-4 5 -yllpyridine; 4- (3-phenyl-lH-pyrazol-4-yl)pyridine; 4- [3- [3- (trifluoromethyl)phenyl] -lH-pyrazol-4-yllpyridine 4- [1-methyl-3- [3- (trifluoromethyl)phenyll -1H-pyrazol-4-yl 10 ]pyridine; 4- [3- (3,4-difluorophenyl) -lH-pyrazol-4-yllpyridine; 4- [3- (4-chiorophenyl) -1H-pyrazol-4-yl] -2-f luoropyridine; 4- [3- (4-bromophenyl) -1H-pyrazol-4yllpyridine; 4- [3- (3,4-difluorophenyl) -l-methyl-lH-pyrazol-4-yllpyridi 15 ne; 4- [3- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yllpyridine; (E) -4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2- (2-phenyleth enyl) pyridine; (S) -4- [3- (4-chiorophenyl) -1H-pyrazol-4-yl] -N- (2-methylbut 20 yl)- 2-pyridinamine; 4- [3- (4-chiorophenyl) -1H-pyrazol-4-yl] -N- [(4-methoxy phenyl)methyll - 2-pyridinamine; N- [4- [3- (4-chiorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] 2 -pyridinemethanamine; 25 N- [4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] 2 -pyridinemethaiamine; 2-fluoro-4- [3- (4-f luorophenyl) -1H-pyrazol-4-yllpyridine; 4- [3- (4-iodophenyl) -1H-pyrazol-4-yllpyridine; 4- [3- (4-iodophenyl) -1-methyl-1H-pyrazol-4-yllpyridine; 30 4- [l-methyl-3- [4- (trifluoromethyl)phenyl] -1H-pyrazol-4-yl ] pyridine; N- [1-(4-f luorophenyl) ethyl] -4- [3- (4-f luorophenyl) -lH-pyra zol -4 -yl] -2 -pyridinanine; N- [(3-f luorophenyl)methyl] -4- [3- (4-f luorophenyl) -1H-pyraz 35 ol-4-yl] -2-pyridinamine; 4- [3- (4-fluorophenyl) -1-methyl-lH-pyrazol-4-yl] -2- (1 SUaBn1UESHEE(RLLE26) WO 98/52940 PCT/US98/1 0436 48 methyihydrazino) pyridine; 2-f luoro-4- [3- (4-f luorophenyl) -l-methyl-lH-pyrazol-4-yllp yridine; 4- [3- (3,4-difluorophenyl) -lH-pyrazol-4-yl] -2-f luoro 5 pyridine; 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -3-methylpyridine; 4- [3- (4-f luorophenyl) -1-methyl-lH-pyrazol-4-yl] -3-methyl pyridine; 4- [3- (3,4-difluorophenyl) -l-methyl-lH-pyrazol-4-yl] -2-flu 10 oropyridine; 3- (4-f luorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -iN-pyrazo le-l-ethanamine; 2- [2- (4-fluorophenyl) ethyl] -4- [3- (4-fluorophenyl) -1 methyl-lH-pyrazol-4-yl] pyridine; 15 4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N-[l (phenylmethyl) -4 -piperidinyl 1-2 -pyridinamine; N' -[4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2-pyridinyll N, N-dimethyl -1, 2-ethanediamine; 2,4-bis [3- (4-f luorophenyl) -lH-pyrazol-4-yllpyridine; 20 N- [4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] -4 morphol ineethariamine; 3- (4-f luorophenyl) -4- (2-f luoro-4-pyridinyl) -lH-pyrazole 1-ethanol; 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -N- [2- (lH-imidazol 25 l-yl)ethyl] -2-pyridinamine; 4- [2- [3- (4-fluorophenyl) -4- (2-fluoro-4-pyridinyl) -lH pyrazol - -yl Iethyl] morpholine; (E) -3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethenyl] 4-pyridinyl] -lH-pyrazole-l-ethanol; 30 3- (4-f luorophenyl) -4- (2-f luoro-4-pyridinyl) -N,N-dimethyl lH-pyrazole-l-ethananine; 3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4 pyridinyl] -lH-pyrazole-l-ethanol; 4- [1-[2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -1K 35 pyrazol-4-yl] -N,N-dimethyl-2-pyridinamine; 4- [1-[2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -lH SUBTMSHEER RULE 26) WO 98/52940 PCTIUS98/1 0436 49 pyrazol-4-yl] -N- [(4-fluorophenyl)methyl] -2-pyridinamine; 3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4 pyridinyl] -N,N-dimethyl-lH-pyrazole-l-ethanamile; N-[(4-fluorophenyl)methyl]-4- [3(or 5)-(4-fluorophenyl)-l 5 [[2- (4-morpholinyl)ethyl] -lH-pyrazol-4-yl] -2 pyridinamine; 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -N-4-piperadinyl-2 pyridinamine; N,N-diethyl-3- (4-f luorophenyl) -4- (2-f luoro-4-pyridinyl) 10 lH-pyrazole-l-ethanamine; 4- [1-[2- (diethylamino) ethyl] -3- (4-fluorophenyl) -lH pyrazol-4-yl] -N- [(4-f luorophenyl) methyl] -2-pyridinamine; 2- [[4- [3- (4- (fluorophenyl) -lH-pyrazol-4-yl] -2 pyridinyl] amino] ethanol; 15 2-[[4-[3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]-2 pyridinyl] amino] ethanol; 3- [[4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2 pyridinyl] amino] -1-propanol; 3- (4-f luorophenyl) -4- [2- [[(4-f luorophenyl) methyl] amino] 20 4-pyridinyl] -lH-pyrazole-l-ethanol; 5- (4-f luorophenyl) -4- [2- [[(4-f luorophenyl)methyl] amino] 4-pyridinyl] -lH-pyrazole-l-ethanol; N,N-diethyl-3- (4-fluorophenyl) -4- (4-pyridinyl) -1H pyrazole- 1-ethanamine; 25 N-[(4-fluorophenyl)methyl]-4-[3-(4-fluorophenyl)-l- [2-(4 morpholinyl) ethyl] -lH-pyrazol-4-yl] -2-pyridinamine; N- [5- (4-f luorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4 morphol inepropanamine; N - [5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] 30 N,N-dimethyl-l, 3-propanediamine; 5- (4-f luorophenyl) -N-2-propynyl-4- (4-pyridinyl) -lii pyrazol -3-amine; 3- (4-f luorophenyl) -4- [2- [[(4-f luorophenyl)methyl] amino] 4-pyridinyl] -lH-pyrazole-1-ethanol; 35 5- (4-f luorophenyl) -4- [2- [[(4-f luorophenyl)methyl] amino] 4-pyridinyl] -lH-pyrazole-l-ethanol; VUBBTfIUTEET(RULE=) WO 98/52940 PCTIUS98/1 0436 50 4- [3- [(4-f luorophenyl) -lH-pyrazol-4-yl] quinoline; N- [5- (4-f luorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3 yllglycine methyl ester; N- [5- (4-f luoropheiyl) -4- (4-pyridinyl) -lH-pyrazol-3 5 yllglycine; 4- [3- (4-fluorophenyl) -1-(2-propynyl) -lH-pyrazol-4 yl] pyridine; 4- [5- (4-fluorophenyl) -1-(2-propynyl) -lH-pyrazol-4 yll pyridine; 10 4,4'-(lH-pyrazole-3,4-diyl)bis[pyridine]; 4- [3- (3,4-dichiorophenyl) -lH-pyrazol-4-yllpyridine; N- [5- (4-chiorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4 piperidinamine; 2-Chloro-4- [3- (4-f luorophenyl) -lH-pyrazol-4 15 yllpyrimidine; 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yll -2 (lH) -pyrimidinone hydra zone; 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yll -N,N-dimethyl-2 pyrimidinamine; 20 4- [3- (4-f luorophenyl) -1H-pyrazol-4-yl] -N-methyl-2 pyrimidinamine; 4- [3- (4-f luorophenyl) -1H-pyrazol-4-yl] -N- (phenylmethyl) 2 -pyrimidinamiie; N-cyclopropyl-4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2 25 pyrimidinamine; 4- [3- (4-f luorophenyl) -1H-pyrazol-4-yll -N- [(4 methoxyphenyl) methyl] -2 -pyrimidinamine; 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2-pyrimidinamine; N- [4- [3- (4-f luorophenyl) -lI--pyrazol-4-yl] -2-pyrimidinyl] 30 N- (phenylmethyl) acetamide; Ethyl [4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2 pyrimidinyl Icarbamate; 4- [3- (3-methyiphenyl) -lH-pyrazol-4-yllpyrimidine; 4- [3- (4-chiorophenyl) -1H-pyrazol-4-yl]pyrimidine; 35 4- [3- (3-f luorophenyl) -lI-pyrazol-4-yl]pyrimidine; and 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yllpyrimidine. SATEK7RaB WO98/52940 PCT/US98/10436 51 Within Formula I there is another subclass of compounds of high interest represented by Formula IX: R 5 N2 z R2 4 ZR 5 2 N N (IX) wherein 5 Z represents a carbon atom or a nitrogen atom; and

R

I is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower heterocycyl, lower aralkyl, lower aminoalkyl and lower alkylaminoalkyl; and

R

2 is selected from hydrido, lower alkyl, aryl 10 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, 15 lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower 20 carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and SUBS1U TESHEET (RULE 2) WO98/52940 PCT/US98/100436 52 heteroaryl groups are optionally substituted with one or more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower 5 heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or

R

2 is -CR 54 R 5 5 wherein R 54 is phenyl and R 55 is hydroxy; and

R

4 is selected from hydrido, lower cycloalkyl, lower 10 cycloalkenyl, lower cycloalkyldienyl, 5- or 6-membered heterocyclyl, and aryl selected from phenyl, biphenyl, naphthyl; wherein R 4 is optionally substituted at a substitutable position with one or more radicals independently selected from halo, lower alkyl, lower 15 alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and

R

s is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower 20 aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower 25 heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR 62

R

63 wherein R1 2 is lower alkylcarbonyl or amino, and R 63 is lower alkyl or lower 30 phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof. A preferred class of compounds consists of those 35 compounds of Formula IX R1 is selected from hydrido, methyl, ethyl, SUESM MSHEE (RULE26) WO98/52940 PCT/US98/10436 53 hydroxyethyl and propargyl; and

R

2 is selected from hydrido, methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, 5 N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, 10 piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1 dimethyl)ethylcarbonyl, (1,1 dimethyl)ethylcarbonylaminopropylamino, (1,1 dimethyl)ethylcarbonylaminoethylamino, 15 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, 20 bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1 dimethyl)ethoxycarbonyl; and

R

4 is selected from cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl,. biphenyl, pyridinyl, 25 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, 30 benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and RI is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, 35 aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, &eBTTTE8HEET(RULE26) WO98/52940 PCT/US98/1 0436 54 ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, 5 phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, 10 methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or NR 62

R

63 wherein R1 2 is methylcarbonyl or amino, and R 63 is methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof. 15 Within Formula I there is another subclass of compounds of high interest represented by Formula X: z 5 2N 2

R

s N RI (X) wherein 20 Z represents a carbon atom or a nitrogen atom; and R' is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and

R

2 is selected from hydrido, lower alkyl, aryl BSMUMSHEE(RULE26) WO98/52940 PCT/US98/10436 55 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 aminoalkyl, 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

R

2 is -CR 54

R

55 wherein R" 4 is phenyl and R 55 is hydroxy; and

R

4 is selected from 5- or 6-membered heteroaryl, and 25 aryl selected from phenyl, biphenyl, and naphthyl; wherein R 4 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 30 R 5 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 sUBSTUTE EHEET(RULE 2) WO98/52940 PCT/US98/10436 56 alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower 5 alkylhydrazinyl, or -NR 6 2

R

6 " wherein R 62 is lower alkylcarbonyl or amino, and R 6 1 is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof. 10 A preferred class of compounds consists of those compounds of Formula X R' is selected from methyl, ethyl, hydroxyethyl and propargyl; and 15 R 2 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, 20 aminopropylamino, propargylamino, benzylamino, piperadinylamino, dimethylaminoethylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, N-methylpiperazinyl, 25 carboxymethylamino, methoxyethylamino, (1,1 dimethyl)ethylcarbonyl, (1,1 dimethyl)ethylcarbonylaminopropylamino, (1,1 dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, and 1,1-dimethyl 30 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, 35 methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1 dimethyl)ethoxycarbonyl; and SsmUMTiEET (RULE ) WO98/52940 PCT/US98/10436 57

R

4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R 4 is optionally substituted with one or more radicals 5 independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and R' is selected from fluoro, chloro, bromo, methyl, 10 fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, 15 hydroxyethylamino, propargylamino, imidazolylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, 20 ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and l-methylhydrazinyl, or NR 62

R

R

" wherein R 62 is methylcarbonyl or amino, and R 63 is 25 methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof. Within Formula I there is another subclass of 30 compounds of high interest represented by Formula XI: SamUTESHEET(ULE26) WO98/52940 PCT/US98/10436 58 R 5 NY z R' N (XI) wherein Z represents a carbon atom or a nitrogen atom; and

R

I is selected from lower alkyl, lower hydroxyalkyl, 5 lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and

R

2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6 membered heterocyclyl selected from piperidinyl, 10 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 15 aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, 20 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 agOTEMSHEET(RULE26) WO98/52940 PCTIUS98/10436 59 alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or 5 R 2 is -CR 54

R

55 wherein R1 4 is phenyl and R 55 is hydroxy; and

R

4 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 10 radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and

R

5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower 15 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 20 alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR 62 R1 3 wherein R 62 is lower 25 alkylcarbonyl or amino, and R 63 is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof. 30 A preferred class of compounds consists of those compounds of Formula XI

R

I is selected from methyl, ethyl, hydroxyethyl and propargyl; and

R

2 is selected from methyl, ethyl, propyl, phenyl, 35 trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N SSmUTE HEET(RULE 2) WO98/52940 PCTIUS98/10436 60 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

4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, 20 dihydrobenzofuryl, and benzodioxolyl; wherein R 4 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

R

5 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, (l-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, 35 phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, BIMUTESEET (RULE26) WO98/52940 PCT/US98/10436 61 ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or 5 NR 6

'

2

R

3 wherein R 62 is methylcarbonyl or amino, and R 6 is methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof. 10 A preferred class of compounds consists of those compounds of Formula IX wherein Z represents a carbon atom or a nitrogen atom; and R' is selected from hydrido, lower alkyl, lower 15 hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and

R

2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6 membered heterocyclyl selected from piperidinyl, 20 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 25 aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, 30 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 35 alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower SUSS1TUTESHEET(RULEM) WO98/52940 PCTIUS98/10436 62 heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or

R

2 is -CR 54

R

5 5 wherein R 54 is phenyl and R 5 1 is hydroxy; and 5 R 4 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 10 R s 5 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 15 arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower 20 alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR 62 3 R" wherein R 62 is lower alkylcarbonyl or amino, and R 6 " is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer 25 thereof. A class of compounds of specific interest consists of those compounds of Formula IX wherein

R

1 is selected from hydrido, methyl, ethyl, 30 hydroxyethyl and propargyl;

R

2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N ethylamino, N,N-diethylamino, N-propylamino, N 35 phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, SIMUTUTESEETREA2Wm WO98/52940 PCT/US98/10436 63 dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1 5 dimethyl)ethylcarbonylaminopropylamino, (1,1 dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and 10 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; 15 R 4 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 20 R 5 is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, 25 ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, 30 cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or 35 NR 62 R 63 wherein R 62 is methylcarbonyl or amino, and R 63 is methyl or benzyl; or USTITESHEE(RULE26) WO98/52940 PCT/US98/10436 64 a pharmaceutically-acceptable salt or tautomer thereof. Another class of compounds of specific interest 5 consists of those compounds of Formula IX wherein Z represents a carbon atom or a nitrogen atom; and R' is selected from hydrido, lower alkyl, lower hydroxyalkyl and lower alkynyl; and 10 R 2 is selected from hydrido and lower alkyl; and

R

4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more halo radicals; and R' is selected from hydrido, halo and 15 alkylhydrazinyl; or a pharmaceutically-acceptable salt or tautomer thereof. Still another class of compounds of specific 20 interest consists of those compounds of Formula IX wherein Z represents a carbon atom; and R' is selected from hydrido, methyl, hydroxyethyl, propargyl; and 25 R 2 is hydrido; and

R

4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more radicals independently selected from chloro, fluoro and bromo; and 30 R s is selected from hydrido, fluoro, and 1 methylhydrazinyl; or a pharmaceutically-acceptable salt or tautomer thereof. 35 A preferred class of compounds of specific interest consists of those compounds of Formula IX wherein Um11SHET (RULE 2) WO98/52940 PCTIUS98/10436 65 Z represents a carbon atom; and

R

I is selected from hydrido and methyl; and

R

2 is hydrido; and

R

4 is selected from phenyl that is optionally 5 substituted with one or more radicals independently selected from chloro, fluoro and bromo; and R'is selected from hydrido and fluoro; or a pharmaceutically-acceptable salt or tautomer thereof. 10 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 15 a methylene (-CH 2 -) 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 20 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, 25 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 30 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 35 "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. The term "alkynyl" embraces linear or SUBSUOTESHEE (RULE 6) WO98/52940 PCTIUS98/10436 66 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 5 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 10 "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, 15 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 20 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 25 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 30 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 35 the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, mBTUTSHEEU(RULE&) WO98/52940 PCT/US98/10436 67 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 5 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, 10 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 15 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, 20 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 25 having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-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 30 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 35 wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces SUe8HTUTESHEE(RuLE2) WO98/52940 PCT/US98/10436 68 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 5 halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, 10 aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, 15 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 20 "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, 25 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., 30 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 35 "heteroaryl" embraces unsaturated heterocyclyl radicals. Examples of heteroaryl radicals include unsaturated 3 to

SUSETTEHEET(UE

WO98/52940 PCT/US98/1 0436 69 6 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-l,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, isoquinolyl, 10 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 15 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 20 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, 25 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 30 "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 35 alkyl, hydroxyl, halo, alkoxy, oxo, amino, alkylthio and alkylamino. The term "heterocyclylalkylene" embraces suesmUTEMSHEET(RULE 26) WO98/52940 PCT/US98/10436 70 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 10 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(=O)- 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, -SO 2 -. "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 SWTESEET (RU. 26) WO98/52940 PCT/US98/10436 71 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 5 "sulfonamidyl" denote NH 2 0 2 S-. 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, 10 butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and radicals formed from succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, mandelic, pantothenic, 0-hydroxybutyric, galactaric and 15 galacturonic acids. The term "carbonyl", whether used alone or with other terms, such as "alkoxycarbonyl", denotes -(C=O)-. The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -CO2H. The term "carboxyalkyl" 20 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 25 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 30 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 35 with a alkoxycarbonyl radical as defined above. More preferred are "lower alkoxycarbonylalkyl" radicals with SWITUTESHEET(RULE26) WO98/52940 PCTIUS98/10436 72 alkyl portions having one to six carbons. Examples of such lower alkoxycarbonylalkyl radicals include substituted or unsubstituted methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonyl-ethyl and 5 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, 10 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 15 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 20 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 25 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 30 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 35 aminomethyl, aminoethyl, and the like. The term "alkylamino" denotes amino groups which are substituted US9 TUTESHEET(RULE26) WO98/52940 PCT/US98/10436 73 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-alkylamino or disubstituted N,N 5 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 10 the aryl ring portion of the radical. The term "aminocarbonyl" denotes an amide group of the formula C(=O)NH 2 . The term "alkylaminocarbonyl" denotes an aminocarbonyl group which has been substituted with one or two alkyl radicals on the amino nitrogen atom. 15 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 20 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 25 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 30 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 35 carbon atoms. The heterosubstituted hydrocarbon moieties described SUBSITRJTE SHEEf(RULE 26) WO98/52940 PCT/US98/10436 74 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 5 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. 10 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" 15 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 20 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 25 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 30 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 IX. As illustrated below, 35 the pyrazoles of Formula I and I' are magnetically and structurally equivalent because of the prototropic UESHEEf

(RULE)

WO 98/52940 PCTIUS98/10436 75 tautomeric nature of the hydrogen: R 3 R 2 R 3 2 R 4 ~2 "

'

_ 1H R '. N N N H CID C I ') The present invention also comprises compounds of Formula I, 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 DMJTITUTESHEET(RULE2 P) WO98/52940 PCT/US98/10436 76 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 5 of the enzyme. In particular, it is believed to bind to the sidechains of Lys 52 , Glu 69 , Leu 73 , Ile 82 , Leu 84 , Leu101 and the methyl group of the Thr 103 sidechain of p38 kinase at the ATP binding site (wherein the numbering scheme corresponds to the numbering scheme conventionally used 10 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. 15 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 20 hypothesized that this acceptor hydrogen bonds to the backbone N-H of the Met 06 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 25 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 Asp' 09 , leading to increased potency and selectivity. 30 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 Asp 65 s. Preferably, 35 the nitrogen atom at the 2-position is double bonded to the carbon atom at the 3-position of the pyrazole while TTUTSHEET (RULE26) WO98/52940 PCT/US98/10436 77 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 5 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 10 360 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: R l 3 \ . 5 2N ,I , N R (XII) wherein

R

I is a hydrocarbyl, heterosubstituted hydrocarbyl or 20 heterocyclyl radical having a molecular weight less than about 360 atomic mass units; and

R

2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical that binds with p38 kinase at said ATP binding site of p38 kinase; and 25 R 3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality; and 8uWSmUTESEE (RULE 26) WO98/52940 PCTIUS98/10436 78

R

4 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units; provided R 3 is not 2-pyridinyl when R 4 is a phenyl 5 ring containing a 2-hydroxy substituent and when R' is hydrido; further provided R 2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R 4 is hydrido; and further provided R 4 is not methylsulfonylphenyl; or 10 a pharmaceutically-acceptable salt or tautomer thereof. A class of substituted pyrazoles of particular interest consists of those compounds of Formula XI wherein 15 R1 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units; and

R

2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical wherein said radical binds with 20 Lys 52 , Glu69, Leu73, Ile82, Leu84, Leu 01 , and Thr 103 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 25 R 3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality that hydrogen bonds with the N-H backbone of Met 106 of p38 kinase; and R' is a hydrocarbyl, heterosubstituted hydrocarbyl or 30 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 35 mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having SUSHEE(RULE2) WO98/52940 PCT/US98/10436 79 or susceptible to such disorder or condition with a therapeutically-effective amount of a compound of Formula I R R 2 4R3 5 2 N N (I) 5 wherein R' is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, 10 haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, 15 alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, 20 alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, 25 aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, SUBSTITUTE SHEEf (RU.E 26) WO98/52940 PCT/US98/10436 80 alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or 5 R' has the formula

R

2 5 0 2 -C-(CH2 - C-N I \R27 H H (II) wherein: i is an integer from 0 to 9;

R

25 is selected from hydrogen, alkyl, aralkyl, 10 heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and

R

26 is selected from hydrogen, alkyl, alkenyl, 15 alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and

R

27 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, %WEE (RLE rWA WO98/52940 PCTIUS98/1 0436 81 aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, 5 heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein 10 said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, 15 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

R

27 is -CHR 28

R

29 wherein R 28 is alkoxycarbonyl, and R 29 20 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one 25 or more radicals independently selected from alkyl and nitro; or

R

26 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more 30 radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and 35 alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are SUBBTf SHEET (RULEr28) WO 98/52940 PCTIUS98/10436 82 optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and

R

2 is selected from hydrido, halogen, alkyl, alkenyl, 5 alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, 10 arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, 15 carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, 20 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, 25 aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or

R

2 has the formula: p 3 0 H R 3 2 I I N/ -C-( CH 2 )J 31Q ~JI 3 'q P 30 R m (III) wherein: j is an integer from 0 to 8; and su TrME8M EE(RULEM) WO98/52940 PCT/US98/10436 83 m is 0 or 1; and

R

3 ' and R 3 ' are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, 5 alkoxyalkyl, and alkylcarbonyloxyalkyl; and R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and 10 heterocyclylcarbonylaminoalkylene;

R

33 is selected from hydrogen, alkyl, -C(O)R", -C (0) OR 3 5 , -S0 2

R

36 , -C (0) NR 37

R

38 , and -S0 2

NR

39

R

40 , wherein

R

35 , R 3 6 , R 3 7 , R 38 , R 39 and R 4 " are independently selected from hydrocarbon, heterosubstituted 15 hydrocarbon and heterocyclyl; and

R

34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or

R

2 is -CR 41

R

42 wherein R 41 is aryl, and R 42 is hydroxy; and 20 R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, N and O 0 3N 0 S43 (IV) (V) wherein R 43 is selected from hydrogen, alkyl, 25 aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and wherein the R 3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, 30 aralkyl, aralkenyl, arylheterocyclyl, carboxy, jBS MUTESHEE(RULE6) WO98/52940 PCT/US98/10436 84 carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, 5 cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, 10 aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR 44

R

45 wherein R 44 is alkylcarbonyl or 15 amino, and R 45 is alkyl or aralkyl; and

R

4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein

R

4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, 20 alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, 25 aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; provided R' is not 2-pyridinyl when R 4 is a phenyl 30 ring containing a 2-hydroxy substituent and when R I is hydrido; further provided R 2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R 4 is hydrido; and further provided R 4 is not methylsulfonylphenyl; or 35 a pharmaceutically-acceptable salt or tautomer thereof. susTM SHEET (RULE2 WO98/52940 PCT/US98/10436 85 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, maleic, 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, 0 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 ssmTESHEE (RULE 26) WO 98/52940 PCT/US98/10436 86 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 5 III. General Synthetic Procedures The compounds of the invention can be prepared according to the following procedures of Schemes I-XVIII 10 wherein R1, R 2 , R 3 , R 4 , R 5 and Ar' are as previously defined for the compounds of Formula I, IX, X and XI except where expressly noted. SCHEME I 0 R 5 base 4 H or base/acld R P R 2 R 2 2 ~ P 2 N b s e / H202 TSNRINH , 3 0 N \ R base/ H 2 0 2 1H 0j 0 N 5 N A 2 NHR 1

NH

2 \ acid or 4 P 2 heat 4 /N base N NNR Ts R 5 6 15 Scheme I shows the synthesis of pyrazole 5 by two SsHEs (mJLE WO98/52940 PCT/US98/10436 87 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 reflux, 5 provides the u,g-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 10 ethanol or other suitable solvent at a temperature ranging up to reflux, 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 reflux, to provide pyrazole 5. Alternatively, the intermediate 15 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 oC up to 150 oC. SUSMUTESHE (RULEM26) WO98/52940 PCT/US98/10436 88 SCHEME II R 0 4 O R 0 X halogenation R N 10 9 S base R N 7/ N NHNH 2 CH 11 R 0 + 5 R NN N-R 12 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 10 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 15 the hydrochloride and hydrobromide salts. Reaction of haloketone 10 with thiosemicarbazide 11 (where R' and R 7 can be hyrido, lower alkyl, phenyl, heterocyclyl and the like or where R 6 and R 7 form a heterocyclyl ring optionally containing an additional heteroatom) provides 20 pyrazole 12. Examples of suitable solvents for this WO 98/52940 PCT/US98/10436 89 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. 5 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. 10 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. Org. Chem., Vol. 22, p. 88 (1957). An alternative approach is to add hydrazine to appropriately 15 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 4 ROI NNH N--N 14 0 H H 3 ro ute 1 R1 17 16 R 2 X 13

-NH

2 O 0 C 15AP

N

route 2 \ 2 A R3 18 0 heat C180 0 -200*C)

A

2

N-NH

2 15 25o-2000C N NI route 3 I 20 19 0MMMS8 (WLEx) WO98/52940 PCT/US98/10436 90 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 0 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 10 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 oC, 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 R 3 0 IR P2 P 2+ R 4 ) HINy 21 20 22 O route I route 2 base/

H

2 0 2 { TsNRINH2 4 2 3 R N NN

R

3

R

2

R

3 heat N 24 T 20 19 8tWMUM (FU.EM) WO98/52940 PCT/US98/100436 91 Synthetic Scheme IV describes the preparation of pyrazole 19. SCHEME V X X 7 0 / N R NHNH 2

NHR

1 So I vent N/N 31 32 x N NaHMDS/THF I R COOMe R 1 or R COOEt 33 X = halyl, alkyl R = Me, CH 2

CH

2 0H R = cyclopropyl, 4-pyridyl, 4- imidazoly I 5 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 10 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. 15 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 oC or lower. SU MUTEMSHEET (RUE 26) WO98/52940 PCT/US98/10436 92 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 5 step with a dehydrating agent, such as a mineral acid, to produce the target pyrazole in some instances. 84ASTUTEEET(RULE26O) WO 98/52940 PCT[US98/10436 93

~

4 -1 4-J (D a) z LL r mm EFr crr EFr 04 r 0~ 0 4 -J xcJ 4-J -0 v =5 m I0 Ery 6UBSfl1UM8HEE1(RULE 26) WO98/52940 PCT/US98/10436 94 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 5 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, 10 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 15 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 20 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 25 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 30 dimethylformamide dimethyl acetal and tert butoxybis(dimethylamino)methane. In cases where the R 3 substituent of pyrazoles 36 and 38 bears a leaving group such as a displaceable halogen, subsequent treatment with an amine produces an amino 35 substituted heteroaromatic derivative. Examples of such amines include benzylamine, cyclopropylamine and ammonia. SUSTUTE8EET (RULE26) WO98/52940 PCT/US98/10436 95 The leaving group may also be replaced with other nucleophiles such as mercaptides and alkoxides. Examples of substitutable R 3 groups include, but are not limited to, 2-chloropyridinyl and 2-bromopyridinyl groups. 5 8=1fUM ESHEE (RULE Z26) WO 98/52940 PCT/US98/1 0436 96 T z CC z-ICT z c2 H, a Cc m aY zz z -Im If)l aoMTUTEFM(RULE 26) WO 98/52940 PCT/US98/10436 97 Scheme VII describes the preparation of derivatives from pyrazole 5 (prepared in accordance with Scheme I) when R 2 = CH 3 . Oxidation of pyrazole 5 gives carboxylic acid 39, which is then reduced to hydroxymethyl compound 5 40, or coupled with amine NRi 0

R

1 " (wherein R i o and R" 1 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 10 oxygen, nitrogen or sulfur) to form amide 41 followed by reduction to generate amine derivative 42. SCHEME VIII R3 R 2 4 N 43 P N 1 .Base RR 2

RR

3 R 2 \ /

R

4 N, R N N 15 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 20 conventional techniques. Treatment of pyrazole 43 with an appropriate base (for example, sodium hydride) followed by treatment with an alkyl halide (for example,

CH

3 I) yields a mixture of isomers 44 and 45. SMI11UMESHEET(RULE26) WO 98/52940 PCT/US98/10436 98 SCHEME IX

CO

2 Et CH 3 + 5 N 12 47 46 lithium hexamethyldisilazide tetrahydrofuran, RT N

R

5 48 "desoxybenzoin' dimethylformamide dimethyl acetal C(4 fold excess) tetrahydrofuran C(1 volume) RT R 1 2 70 hydrazine N hydrate z N-H \ ethanol N / N H

H

3 C5CH 3 N/

R

5 49 50 suesmUMH(M2) WO98/52940 PCTIUS98/10436 99 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 5 (preferably sodium hexamethyldisilazide or lithium hexamethyldisilazide), in a suitable solvent, such as tetrahydrofuran, to give desoxybenzoin 48. Desoxybenzoin 48 is then converted to ketone 49 by treatment with an excess of dimethylformamide dimethyl acetal. Ketone 49 10 is then reacted with hydrazine hydrate in a suitable solvent such as ethanol to yield pyrazole 50. In Scheme IX, R 12 represents one or more radicals independently selected from the optional substituents previously defined for R 4 . Preferably, R 2 is hydrogen, alkyl, halo, 15 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 20 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. SUBSTRUTESHEET (RULE6) WO98/52940 PCTIUS98/1Q436 100 SCHEME X P12 12 N12

NH

2

NH-R

1 N N

R

5

R

5 48 dimethy Iformam[de 51 dimethyl acetal

R

1 2 N-R H N ,

R

5 52 Scheme X illustrates one variation of Scheme IX that 5 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 10 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 15 substituents. StaiTUTESHEET(RUJLEM0) WO 98/52940 PCT/US98/10436 101 SCHEME XI 1 1 2 NH2-NHR 1 C- 0 A N - P ethanol H N N /- N 5 major product 5

H

3 C

CH

3 53 49 R12 / N N H N/ 54 5 SCHEME XII 12 p 1 2 /- N N / N-P N-P R 13 NH-

R

2 0 210C H 1hr H N / N X N R20 N 'R 13 55 56 In Scheme XII, X is chloro, fluoro or bromo; R1 3 is, for example, hydrogen, alkyl, phenyl, aralkyl, heteroarylalkyl, amino or alkylamino; and R 20 is, for 10 example, hydrogen or alkyl. 8USMMTUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 102 SCHEME XIII 12

P

1 2 N bromine N -\ 1 / _-N--R DMF acetic acid Br N N 55 5 5 SCHEME XIV 12 R2 __N__ N mCPBA N 1 SN-R H1 H H N / ,KN / P 5 58 52 R12 trimethylsilyl N cyanide 7N- P N H CN 59 SHEET(RULE £6) WO 98/52940 PCT/US98/10436 103 SCHEME XV R12 R12 7 N N N OH N NOMs methane sulfonyl chloride H H 60 n5 61 R12 R15 615 N N H NN "7N N * 14 614 ' H N 62 63 5 In Scheme XV, n is 1, 2, 3, 4 or 5; and R 14 and R1 5 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 10 contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur. SCHEME XVI R12 R12 N N 7 N-R z 7 N-6 - 2 R 1 5 -CHO N N HO R5 5 57 64

&

8 %TffU SHEERME0 WO 98/52940 PCT/US98/10436 104 In Scheme XVI, R 16 is selected, for example, from hydrogen, alkyl and phenyl. 5 SCHEME XVII R12

P

1 2 0 0 N-chlorosuccinimide dimethyIformamide CI N N/ 5 5 H N N

H

2 N N NN____ / N-R <

HN-R

1 7

N

5 P 55 66 In Scheme XVII, R 17 is selected, for example, from 10 alkyl, phenylalkyl and heterocyclylalkyl. UBSnUTmS.SHET(RULE28) WO 98/52940 PCT/US98/10436 105 SCHEME XVIII x x N H S 1. [0] NH H 2 0 2 / N 2. TMSCN N 2CO Me2NCOC I R N P 2 67 CN 68 x x NH / \ DMF dimethyl acetal NH MeOH N N 2 . P 2

CONH

2

C

2 Me 569 70 sapon ify p18 R 19

NH

2 x x NHNH N N N 2 N / p2 CONR 1R19

CO

2 H 72 71 Compounds wherein the 2-position of the pyridine 5 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 SeSM1UTESHEE(RULE26) WO98/52940 PCT/US98/1 0436 106 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 5 the 2-cyano compound 68. Compound 68 is converted to its carboxamide 69 by reaction with hydrogen peroxide in the 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 10 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 15 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 1800C. 20 In Scheme XVIII, R 18 and R" 9 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. 25 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 30 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 35 spectra consistent with their assigned structures. In some cases, the assigned structures were confirmed by UBMUMSHEET(RULE26) WO98/52940 PCT/US98/10Q436 107 nuclear Overhauser effect (NOE) experiments. The following abbreviations are used: HCl - hydrochloric acid MgSO4 - magnesium sulfate 5 Na2SO4 - sodium sulfate NaIO4 - sodium periodate NaHSO3 - sodium bisulfite NaOH - sodium hydroxide KOH - potassium hydroxide 10 P 2 05 - phosphorus pentoxide Me - methyl Et - ethyl MeOH - methanol EtOH - ethanol 15 HOAc (or AcOH) - acetic acid EtOAc - ethyl acetate H20 - water H202 - hydrogen peroxide

CH

2 Cl 2 - methylene chloride 20 K 2

CO

3 - potassium carbonate KMnO 4 - potassium permanganate NaHMDS - sodium hexamethyldisilazide DMF - dimethylformamide EDC - 1-(3-dimethylaminopropyl)3-ethylcarbodiiminde 25 hydrochloride HOBT - l-hydroxybenzotriazole mCPBA - 3-chloroperoxybenzoic acid Ts - tosyl TMSCN - trimethylsilyl cyanide 30 Me 2 NCOCl - N,N-dimethylcarbamoyl chloride SEM-Cl - 2-(trimethylsilyl)ethoxymethyl chloride h - hour hr - hour min - minutes 35 THF - tetrahydrofuran TLC - thin layer chromatography SmEET (RULEM ) WO98/52940 PCT/US98/10436 108 DSC - differential scanning calorimetry b.p. - boiling point m.p. - melting point eq - equivalent 5 RT - room temperature Example A-1 N S CH 3 F N N, 0H 4-[5-C3-fluoro-4-methoxyphenyl)-3 methy l- IH-pyrazol-4-y I]pyridine 10 Step 1: Preparation of 4-(3-fluoro-4-methoxylphenyl)-3 pyridvl-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 15 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 20 pyridyl-3-butene-2-one as a pale yellow solid (1.60 g, 80%). Step 2: Preparation of 4-[5-(3-fluoro-4-methoxvphenyl)-3 methyl-lH-pvrazol-4-yllpyridine 25 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 30 distillation from the reaction solution. The resulting residue was diluted with CH2C12 (150 ml), washed with H20 SUBSfrESHEET (RULE 26) WO98/52940 PCT/US98/10436 109 (2x100 ml), dried (Na2SO4), 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-lH-pyrazol-4-yl]pyridine as a 5 pale yellow solid (213 mg, 20.7%): Anal. Calc'd for

C

16

H

14

N

3 0F.0.1 H20: C, 67.41; H, 5.02; N, 14.74. Found: C, 67.37; H, 4.88; N, 14.35. Example A-2 N

CH

3 N N' H 4-C3-methyl-5-phenyl-1H-pyrazol-4-y1) 10 pyr idine Step 1: Preparation of 4-pyridylacetone 4-Pyridylacetone was prepared according to the method of Ippolito et al, U.S. Patent 4,681,944. 15 Step 2: Preparation of 4-phenyl-3-(4-pyridyl)-3-butene 2-one Using the procedure of Example A-1, step 1, 4 pyridylacetone (step 1) (1 g, 7.4 mmol) was condensed 20 with benzaldehyde (790 mg, 7.4 mmol) in benzene (15 mL) containing piperidine (50 mg) at reflux. 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 oC. Anal. Calc'd for C 15

H

13 NO (223.28): C, 80.69; H, 5.87; N, 25 6.27. Found: C, 80.59; H, 5.79; N, 6.18. Step 3: Preparation of 4-phenvl-3-(4-pyridyl)-3,4 epoxy-2-butanone Using the procedure of Example A-1, step 2, a 30 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

SUSMUTESHEE(RULE)

WO98/52940 PCT/US98/10436 110 with 30% aqueous hydrogen peroxide (1 ml) in the presence 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 5 epoxy-2-butanone (270 mg, 20%). Step 4: Preparation of 4-(3-methyl-5-phenyvl-lH-pyrazol 4-yl)pyridine Using the procedure of Example A-1, step 3, a 10 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 15 product was recrystallized from ethyl acetate and hexane to give 4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine (81 mg, 35%) as a crystalline solid: m. p. 212-214 oC. Anal. Calc'd for C 15

H

13

N

3 (235.29): C, 76.57; H, 5.57; N, 17.86. Found: C, 76.49; H, 5.42; N, 17.39. 20 Example A-3

CH

3 N N_ H 4-[5-methyl-3-C2-methylphenyl)-1H pyrazol-4-yl]pyridine Step 1: Preparation of 4-(2-methylphenyl)-3-(4-pyvridyl) 25 3-butene-2-one A solution of 4-pyrridylacetone (Example A-5, 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 30 was removed by a Dean-Stark trap. After heating at SMBMTMEEET (RULE " WO98/52940 PCT/US98/10436 111 reflux for 5 hours, the reaction mixture was stirred at 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 5 methylphenyl)-3-(4-pyridyl)-3-butene-2-one: Anal. Calc'd for C 16

H

15 NO (237.30): C, 80.98; H, 6.37; N, 5.90. Found: C, 80.78; H, 6.61; N, 5.85. Step 2: Preparation of 4-(2-methylphenyvl)-3-(4-pyridyl) 10 3,4-epoxy-2-butanone To a solution of 4-(2-methylphenyl)-3-(4-pyridyl)-3 butene-2-one (step 1) (1.0g, 4.2 mmol) in methyl alcohol (18 ml), a solution of H 2 0 2 (30% by wt.) (0.95 g, 8.4 mmol) and sodium hydroxide (0.18 g 4.6 mmol) in water (4 15 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 20 layer was washed with ethyl acetate (100 ml). The combined organic layer was dried with Na2SO4, 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. 25 Step 3: Preparation of 4-[5-methyl-3-(2-methylphenyl)1H pyrazol-4-yll]pyridine A solution of 4-(2-methylphenyl)-3-(4-pyridyl)-3,4 epoxy-2-butanone (step 2) (0.11 g, 0.434 mmol) and 30 hydrazine hydrate (0.043 g, 0.868 mmol) in ethyl alcohol (50 ml) was heated at reflux for 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 C 16

H

15

N

3 35 (249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.66; H, 5.91; N, 16.84. SUB8TF sE~~EU(RILE 26) WO 98/52940 PCT/US98/10436 112 Example A-4 N CH N H 4-[5-methyl-3-C4-fluorophenylD-I H pyrazoI-4-y I]pyridine By following the method of Example A-3 and 5 substituting p-fluorobenzaldehyde for o-tolualdehyde, the titled compound was prepared: Anal. Calc'd for C 15

H

12

N

3 F + 0.1 H20: (249.32): C, 70.63; H, 4.82; N, 16.47. Found: C, 70.63; H, 4.78; N, 16.40. 10 Example A-5

CH

3

N

/ N H 4-[5-methyl-3-(4-methylphenyl]-1H pyrazo I-4-yl]pyr d ine By following the method of Example A-3 (with one minor modification: in Step 2, the preparation of the 15 intermediate epoxide was accomplished at 0-10 oC for 1 hour, and the reaction was quenched by being partitioned BsusmTUTESEEt (RULE2) WO 98/52940 PCT/US98/10436 113 between water, containing 2 eq. sodium bisulfite, and ethyl acetate) and substituting p-tolualdehyde for o tolualdehyde, the titled product was isolated: Anal. Calc'd for C 16

H

15

N

3 (249.32): C, 77.08; H, 6.06; N, 5 16.85. Found: C, 76.97; H, 6.09; N, 16.90. Example A-6 N

CH

3 N N H S 4-[5-methyl-3-[4-CmethylIthio)phenylI] 1H-pyrazol-4-yl]pyridine 10 By following the method of Example A-5 and substituting 4-(methylthio)benzaldehyde for p tolualdehyde, the titled product was prepared: Anal. Calc'd for C 16

H

15

N

3 S (281.38): C, 68.30; H, 5.37; N, 14.93. Found: C, 68.34; H, 5.09; N, 14.78. SUBSMIUTESHEE (RULE26) WO 98/52940 PCT/US98/10436 114 Example A-7

CH

3 N N CI H H 4-[3-C4-chlo I ropheny D)-5-methy - 1H pyrazol-4-yl]pyridine 5 By following the method of Example A-5 and substituting p-chlorobenzaldehyde for p-tolualdehyde, the titled product was obtained. Anal. Calc'd for C 15

H

12

N

3 C1 (269.77): C, 66.79; H, 4.48; N, 15.58. Found: C, 66.43; H, 4.44; N, 15.78. 10 Example A-8 N

CH

3 / N H 4-[3-methy l-5-C3-methy lpheny I - IH pyrazo Il-4-y 1]pyridine By following the method of Example A-5 and 15 substituting m-tolualdehyde for p-tolualdehyde, the titled product was obtained: Anal. Calc'd for C 16

H

15 N3 + 0.2H20: C, 75.98; H, 6.14; N, 16.61. Found: C, 76.06; H, WO98/52940 PCT/US98/10436 115 6.05; N, 16.38. Example A-9

CH

3 N N' 4-[5-C2,5-dimethylpheny ID-3-methylI 5 1H-pyrazol-4-yl]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 10 C1 7 H17N3 + 0.1H20: C, 77.01; H, 6.54; N, 15.85. Found: C, 76.96; H, 6.81; N, 15.51. Example A-10

CH

3 0 N N H 4-[5-[1,3-benzodioxol-5-ylD-3-methyl IH-pyrazol-4-yl]pyridine 15 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 MMSEET(RULE26) WO98/52940 PCT/US98/10436 116 (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 5 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 oC for 1 hour. The reaction was heated to reflux for 1 hour. The reaction was cooled to room temperature and the solvent was 10 evaporated. The residue was dissolved in ethyl acetate, washed with 5% aqueous potassium carbonate, and water. The organic layer was dried (MgSO4), filtered and evaporated to obtain a yellow solid. This solid was triturated with methylene chloride, yielding 4-[5-(1,3 15 benzodioxol-5-yl)-3-methyl-lH-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). 20 Example A-11 N

CH

3 N N Ph O H 4-[3-methyl-5-C4-phenoxyphenyl) IH-pyrazol-4-yl]pyridine 4-Pyridylacetone (1.5 g, 12 mmol), 4 phenoxybenzoldehyde 92.1 g, 10.6 mmol), acetic acid (110 25 mg, 1.8 mmol), and piperidine (110 mg, 1.3 mmol) were dissolved in toluene (30 mL) and heated for 2 hours at anTUTEsHEE (RU 26) WO 98/52940 PCT/US98/10436 117 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 5 heated with p-toluensulfonyl hydrazide (348 mg, 1.81 mmol) in ethylene glycol with potassium hydroxide (77 mg) at 110 oC 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]lpyridine was obtained (100 10 mg, 66% yield): Anal. Calc'd for C 2 1

H

17

N

3 0 + 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

CH

3 N I N Ph H 4-[5-[ 1,1 -bipheny l]-4-yl]-3-methyl 15 1H-pyrazo l-4-yl]pyr idine 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,l'-biphenyl)-4-yl]-3-methyl 20 1H-pyrazol-4-yl]pyridine as a white solid: MS (M+H): 312 (base peak). Example A-13

CH

3 N Ph N H 4-[3-methyl-5-[3-(phenoxyphenyDl) 1H-pyrazol-4-yl]pyridine susmUTEHEET(RULE WO98/52940 PCT/US98/10436 118 The same procedure for the preparation of Example A 10 was used, substituting 3-phenoxybenzaldehyde in place of piperonal, to give 4-[3-methyl-5-[3-(phenoxyphenyl) 1H-pyrazol-4-yl]pyridine as a white solid. 5 Example A-14

CH

3 Ph ,_,/ N N H 4-[3-methyl-5-[3-Cphenylmethoxy)pheny l] 1H-pyrazol-4-yl]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 Ph

CH

3 N N H 4-[3-methyl-5-[2-(phenylmethoxy) 15 pheny l]-1H-pyrazolI-4-yl]pyr idine 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 PCT/US98/10436 119 (phenylmethyloxy)phenyl] -1H-pyrazol-4-yl]pyridine. MS (M+H): 342 (base peak). 5 Example A-16 N

CH

3 N N H OH 2-[3-methy I -4-(4-pyridiny l)-1H pyrazol-4-yl]phenol The same procedure for the preparation of Example A 10 was used, substituting 2-hydroxybenzaldehyde in place of piperonal, to give 2-[3-methyl-4-(4-pyridinyl)-1H 10 pyrazol-4-yl]phenol: MS (M+H): 252 (base peak). Example A-17

NCH

3 HO N N I I H 3-[3-methyl-4-C4-pyridiny I- 1H pyrazol-4-yl]phenol The same procedure for the preparation of Example A 15 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). s sTESEE

(ULE)

WO 98/52940 PCT/US98/10436 120 Example A-18 CH3

N

/ H 1-hydroxy-4-[3-methyl-5-phenyl-I1H pyrazo I -4-y 1] pyr idin i um To a solution of 4-(3-methyl-5-phenyl-lH-pyrazol-4 yl)pyridine (Example A-2) (2.06 g, 8.76 mmol) in a 5 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 K2CO3 solution (25%, 15 mL), and concentrated. The resulting residue was partitioned 10 between EtOAc (2.0 L) and H20 (500 mL). The organic layer was separated, washed with H20 (500 mL), dried over MgSO4, filtered and concentrated to give l-hydroxy-4-[3 methyl-5-phenyl-lH-pyrazol-4-yl]pyridinium (1.12 g, 54.5%): MS (M+H): 252 (base peak). 15 Example A-19 N N H 5-(4-fluorophenylD-NN-dimethyl-4-C4 pyridinyl)-1H-pyrazoI-3-amine WO98/52940 PCT/US98/10436 121 Step 1: Preparation of l-fluoro-4-(4' pyridylacetyl)benzene To a solution of sodium bis(trimethylsilyl)amide (200 mL, 1.0 M in THF) at 0 oC was added a solution of 4 5 picoline (18.6 g, 0.20 mol) in dry THF (200 mL) over 30 minutes. The reaction mixture was stirred at 0-10 oC for another 30 minutes, then was added to a solution of ethyl 4-fluorobenzoate (16.8 g, 0.10 mol) in dry THF (200 mL) at such a rate that the internal temperature didn't 10 exceed 15 oC. 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 15 magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give l-fluoro-4-(4' pyridylacetyl)benzene (19.9 g, 92 %) as an oil which solidified upon standing: m.p.: 90-91 oC; Anal. Calc'd for C 13 Ho 10 FNO: C, 72.55; H, 4.68; N, 6.51. Found: C, 20 72.07; H, 4.66; N, 6.62. Step 2: Preparation of l-fluoro-4-(4' pyridylbromoacetvl)benzene To a solution of l-fluoro-4-(4' 25 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) dropwise. The reaction mixture was stirred at room temperature overnight. After the solvent was removed, the residue 30 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. sue~fh~iTEHEET( no%~ WO 98/52940 PCTIUS98/10436 122 Step 3: Preparation of 5-(4-fluorophenyl)-N, N-dimethyl 4-(4-pyridinyl)-lH-pyrazol-3-amine A mixture of 1-fluoro-4-(4'-pyridylbromoacetyl) benzene (step 2) (3.8 g, 0.01 mol) and 4,4-dimethylamino 5 3-thiosemicarbazide (1.2 g, 0.01 mol) in ethanol (10 mL) was heated at reflux for 30 minutes. The dark green 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, 10 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)-N, N-dimethyl-4-(4-pyridinyl)-lH-pyrazol-3 amine (0.3 g, 11 %) as a light yellow solid: m.p.: 245 15 247 OC. Anal. Calc'd for C 16

H

15

FN

4 : C, 68.07; H, 5.36; N, 19.84. Found: C, 68.00; H, 5.37; N, 19.61. Example A-20 N H N-Ph N N FH 5-C4-fI uorophenylD-N-phenyl-4 C(4-pyridinyID)-1H-pyrazol-3-amine 20 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 oC. Anal. Calc'd for C 2 0H15FN4 + 0.1 H20: C, 72.33; H, 4.61; N, 16.87. Found: C, 72.16; H, 4.56; N, 16.77. SUBS UTESHEET(RULEM) WO 98/52940 PCT/US98/10436 123 Example A-21 N Ph N N H F 4-[5-C(4-f I uoropheny l)- 3-pheny I - 1H pyrazol-4-yl]pyridine Step 1: Preparation of 1-fluoro-4-(40- pyridylacetyl) benzene N-benzoylhydrazone 5 To a solution of benzoic hydrazide (1.36 g, 0.01 mol) in THF (20 mL) was added 1-fluoro-4-(4' pyridylacetyl)benzene (2.15 g, 0.011 mol) in one portion followed by a drop of conc. HC1. The reaction mixture was stirred at room temperature overnight. There was 10 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 trans (ratio, 1:9) isomers. 15 Step 2: Preparation of 4-[5-(4-fluorophenvyl)-3-phenvyl 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 oC under N 2 for 15 minutes, then cooled. The 20 resulting solid was purified by chromatography (silica gel, 1:1 ethyl acetate/hexane) to 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 oC. Anal. Calc'd for C 20 H14FN3 + 0.25 H20: C, 75.10; H, 4.57; N, 25 13.14. Found: C, 74.98; H, 4.49; N, 12.87. SUBSMlTUTEHEE(RULE2 ) WO 98/52940 PCT/US98/10436 124 Example A-22 N F F FF F N I N H 4-[5-C3-methylphenylD-3-(trifluoromethyl 1H-pyrazol-4-yl]pyridine Step 1: Preparation of 3-(4'-pyridylacetyl)toluene 3-(4'-Pyridylacetyl)toluene was prepared by the same 5 method as described for Example A-19, step 1 in 70% yield. Step 2: Preparation of trifluoroacetyl hydrazide A mixture of ethyl trifluoroacetate (14.2 g, 0.10 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. 15 Step 3: Preparation of 4-[5-(3-methylphenyl)-3 (trifluoromethyl)-1H-pyrazol-4-yllpyridine A mixture of 3-(4'-pyridylacetyl)toluene (2.11 g, 0.01 mol) and trifluoroacetyl hydrazide (step 2) (1.0 g, 20 0.01 mol) was heated at 200 oC under N 2 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 oC. 25 Anal. Calc'd for C 16

H

12 F3N3: C, 63.36; H, 3.99; N, 13.85. WWM- =%IMr (RLLE 20 WO 98/52940 PCT/US98/10436 125 Found: C, 63.6; H, 4.00; N, 13.70. Example A-23 N, N N I \ N N H F 4-[3-(4-f I uoropheny I ]-4-(4-pyridiny l) 5 I1H-pyrazol-5-yl]pyridine 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 10 first to 140 oC, which caused a phase change, and subsequently melted on further heating until 180 oC whereupon a solid crystallized out. The reaction was immediately cooled, diluted with 10 % HC1 (50 mL) and washed with chloroform. The aqueous layer was 15 neutralized with bicarbonate and a tan colored solid was precipitated out. The solid was purified by treatment with activated carbon (Darco®) in boiling MeOH (100 mL), followed by filtration and concentration, to give 4-[3 (4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl]pyridine 20 (1.05 g, 69 %) as a shiny tan solid: m.p. 304 oC (DSC). Mass (MH ) 137 (100%). Anal. Calc'd for C1 9 H1 3

N

4 F.1/4H20: C, 71.13; H, 4.24; N, 17.46. Found: C, 70.88; H, 3.87; N, 17.38. 3 mTE HEE (RULE6) WO 98/52940 PCT/US98/10436 126 Example A-24 N / C H 3 N N H 4-C5-cyclIohexyI)-3-methyl-1H-pyrazoI-4-ylDpyridine Step 1: Preparation of 4-cyclohexyl-3-pyridv1-3-butene 2-one 5 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-cyclohexyl)-3-methyl-1H 10 pyrazol-4-yl)pyridine 4-(5-Cyclohexyl)-3-methyl-lH-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 15 (step 1): Anal. Calc'd for C15H19N3: C, 73.56; H, 7.98; N, 17.16. Found: C, 73.72; H, 7.91; N, 19.98. Example A-25 N

CH

3 F N 'N H 0 0 4-[5-(3-f I uoro-5-methoxypheny I)-3 20 methyl-1H-pyrazol-4-yl]pyrldine WO98/52940 PCT/US98/10436 127 4-{5-(3-Fluoro-5-methoxyphenyl)-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 5 for C 16

H

14

N

3 0F: 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: susmUsTESHEET(RUE2) WO 98/52940 PCT/US98/10436 128 No R 2 R 4 m.p. or Anal.Calc'd iAnal. Calc'd (calcd/found) A- _ R2_ R R DSC(OC Formula C H N H2 26 H Cs ,H 3 -re -I0 185-186 C 18

H

19

N

3 77.95/ 6.90/ 15.15/ C N 77.51 6.93 14.73 271 H 1 C H 3

NC

1 6 _14244CH 15

N

3 75.71/ 6.16/ 16.55/ CH . 142-144 CHi 75.69 6.11 16.49 28 H N - -N 240-242 22 3 80.09/ 5.96/ 12.74/ ____ N .0.25H 2 0 79.74 5.90 13.01 22 .8CH28F 63.36/ 3.99/ 13.85/ 29 H N CH 3 228.8 16

H

12

N

3

F

3 63.28 373 13.69 30 H CH3 189.6 C 15

H

12

N

3 C 66.13/ 4.55/ 15.42/ C l .0.15H,O0 65.98 4.31 15.74 31 H \CH 3 1 . - 171.6 C 17

H

17

N

3 76.49/ 6.57/ 15.74/ 311 / 1 - .0.2HO 76.69 6.53 15.61 32 . CH 3

ICH

3 T1 88.6 C 16

H

14

N

3 C 67.72/ 4.97/ 14.81/ c1 67.35 5.29 15.02 33 H CH 188.8 C 16

H

4

N

3 F 71.89/ 5.28/ 15.72/ 33 N F_ _H71.72 5.45 15.77 341 H CH 3 T N 215.7 C 17

H

17

N

3 77.54/ 6.51/ 15.96/ ___________ _____ ____ ______77.24 6.80 15.71 35 H - CH 3 . 201.4 C 17

H

17

N

3 0 68.10/ 5.88/ 14.01/ HN 0 .0.25H 2 0 67.92 5.65 13.65 36 H ,CH3 1 210.7 C 15

H

12

N

4 0, 63.26/ 4.42/ 19.67/ - N NO 2 .0.25H 2 0 63.59 4.39 19.31 37 H *CH 3 " N N 252.5 C 17

H

1 8

N

4 7335/ 652/ 20.13/ N 72.61 6.79 19.59 38 H 1 C 73.63/ 5.45/ 1 15.151 3 H N CH 3 196.3 C 1 7

H

15

N

3 73.43 5.46 15.19 ___ __I ' N__ _ 3___ _ __ _ _ _ _ _ _3.43 5 15.19/ 39 H Ea3L 10 CH 3 252.8 C 5

H

12 N 3 Bi 57.34/ 3.85/ 13.37/ 0Br N 57.09 3.79 13.06 140 H K C- N .CH 3 198.5 C 15

H

12

N

3 F 71.13/4.78/ 16.59 ______ ______ ___________ _______ 71.23 5.01 16.76 41 15 H N F, 71.13/ 4.78/ 16.59/ 41 H CH3 Ne' A 225.6 C s 1 , 2 12 3 70.74 4.66 16.44 42 219.5 CH 12 F N 63.36/ 3.99/ 13.85/ H "H CH 3 " 21 I - C 63.19 4.07 13.38 43 H -i-CHCH3 227.7 C 16

H

15

N

3 76.53/ 6.10/ 16.73/ N .0.1HO 76.53 6.20 16.49 SLOMMM8EUr(BULE26) WO 98/52940 PCT/US98/10436 129 No R1 R 2 R R4 m.p. or Anal.Cale'd Anal. Cale'd (calcd/found) L _ DSC(oC Formula C H N 44 H '0tCHz ,O 175.6 C16H15N30 71.70/ 5.75/ 15.68/ H 4- 1 C .0.15H 2 0 71.92 5.76 15.29 45 H CH 2 CHi N C 17

H

9

N

3 77.54/ 6.51/ 15.96/ 4 H 2 N 77.13 6.28 15.69 i'oo, F 66.42/ 4.09/ 15.49/ 46 H '4CH 3 F 412.1 C15H NF2 66.12 3.86 15.25 47 H CH 3 168.5 C 17

H-I

17

N

3 0 72.40/ 6.18/ 14.90/ S.0 .15H 2 0 72.39 5.87 14.50 48 H 'CH 3 " -, 211.2 C 16

H

12

N

3

F

3 62.62/ 4.07/ 13.69/ 48 __ H ____N CF 3 .0.2HO 62.64 4.06 13.35 49 H 4CH 3 ' - 13 11

N

3 S 64.71/ 4.59/ 17.41/ _ CH_ _ s13HlN3 64.44 4.58 17.27 50 H *'CH 3 . 189.2 C 15

H

11 N Cl 59.23/ 3.65/ 13.81/ 50 _H____ -_NC___-'IN 3C2 59.22 3.24 13.81 51 H t,CH 3 "'N r,'- Cl 211.7 C 15

H

12

N

3 C1 66.13/ 4.55/ 15.42/ .. !z.- N .0.15H 2 0 66.33 4.62 15.05 52 H **CH 3 N l 219.8 C 16

H

14

N

3 C1 64.11/ 4.71/ 14.02/ 52 H IC N 219.8 C 3 63.85 4.69 13.93 S N 163.4 C 19 H17N 3 0 2 C16432/ 4.83/ 11.84/ O' kZN 634 jqI730CI63.98 5.08 11.80 54 4

*CH

3 H - C 15

H

12

N

3 F 70.15/ 4.86/ 16.35/ S F -N .0.2H 2 0 70.18 4.60 16.47 55 H- C14HONF 70.28/ 4.21/ 17.56/ H F N H F69.97 3.84 17.53 St wflf=EMs (RULE0) WO98/52940 PCTIUS98/10436 130 The following pyrazoles could be prepared by the procedures described above: Example A-56 5-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol 5 4-yl]pyrimidin-2-amine; Example A-57 5-[3-methyl-5-(3-methylphenyl)-1H-pyrazol 4-yl]pyrimidin-2-amine; Example A-58 5-[3-methyl-5-(2-methylphenyl)-lH-pyrazol 4-yl]pyrimidin-2-amine; 10 Example A-59 5-[5-(4-chlorophenyl)-3-methyl-lH-pyrazol 4-yl]pyrimidin-2-amine; Example A-60 5-[5-(4-fluorophenyl)-3-methyl-lH-pyrazol 4-yl]pyrimidin-2-amine; Example A-61 5-[5-(4-methoxyphenyl)-3-methyl-lH-pyrazol 15 4-yl]pyrimidin-2-amine; Example A-62 5-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol 4-yl]pyridin-2-amine; Example A-63 4-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol 4-yl]pyridin-2-amine; 20 Example A-64 4-[5-(3-methylphenyl)-3-methyl-lH-pyrazol 4-yl]pyridin-2-amine; Example A-65 4-[5-(2-methylphenyl)-3-methyl-lH-pyrazol 4-yl]pyridin-2-amine; Example A-66 4-[5-(4-chlorophenyl)-3-methyl-lH-pyrazol 25 4-yl]pyridin-2-amine; Example A-67 4-[5-(4-fluorophenyl)-3-methyl-lH-pyrazol-4 yl]pyridin-2-amine; Example A-68 4-[5-(4-methoxyphenyl)-3-methyl-IH-pyrazol 4-yl]pyridin-2-amine; 30 Example A-69 5-[5-(3-chlorophenyl)-3-methyl-lH-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 35 1H-pyrazol-4-yl]pyridine; Example A-72 4-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol GENTTUTSHTRULE01) WO98/52940 PCT/US98/10436 131 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) 5 1H-pyrazol-4-yl]pyridine; Example A-75 4-[5-(4-chlorophenyl)-3-methyl-lH-pyrazol 4-yl]-2-methoxypyridine; Example A-76 4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol 4-yl]-2-methoxypyridine; 10 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-lH-pyrazol 4-yl]pyridin-2-ol; Example A-79 4-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol 15 4-yl]pyridin-2-ol; Example A-80 4-[5-(3-methylphenyl)-3-methyl-lH-pyrazol 4 -yl]pyridin-2-ol; Example A-81 4-[5-(2-methylphenyl)-3-methyl-lH-pyrazol 4-yl]pyridin-2-ol; 20 Example A-82 4-[5-(4-chlorophenyl)-3-methyl-lH-pyrazol 4-yl]pyridin-2-ol; Example A-83 4-[5-(4-fluorophenyl)-3-methyl-lH-pyrazol 4-yl]pyridin-2-ol; Example A-84 4-[5-(4-methoxyphenyl)-3-methyl-lH-pyrazol 25 4-yl]pyridin-2-ol; Example A-85 5-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol 4-yl]pyridine-2-methanamine; Example A-86 4-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol 4-yl]pyridine-2-methanamine; 30 Example A-87 4-[5-(3-methylphenyl)-3-methyl-lH-pyrazol 4-yl]pyridine-2-methanamine; Example A-88 4-[5-(2-methylphenyl)-3-methyl-lH-pyrazol 4-yl]pyridine-2-methanamine; Example A-89 4-[5-(4-chlorophenyl)-3-methyl-lH-pyrazol 35 4-yl]pyridine-2-methanamine; Example A-90 4-[5-(4-fluorophenyl)-3-methyl-lH-pyrazol msnfUTESHEET(RULE26) WO98/52940 PCT/US98/10436 132 4-yl]pyridine-2-methanamine; Example A-91 4-[5-(4-methoxyphenyl)-3-methyl-lH-pyrazol 4-yl]pyridine-2-methanamine; Example A-92 5-[5-(3-chlorophenyl)-3-methyl-lH-pyrazol 5 4-yl]pyridine-2-carboxamide; Example A-93 4-[5-(3-chlorophenyl)-3-methyl-IH-pyrazol 4-yl]pyridine-2-carboxamide; Example A-94 4-[5-(3-methylphenyl)-3-methyl-lH-pyrazol 4-yl]pyridine-2-carboxamide; 10 Example A-95 4-[5-(2-methylphenyl)-3-methyl-lH-pyrazol 4-yl]pyridine-2-carboxamide; Example A-96 4-[5-(4-chlorophenyl)-3-methyl-lH-pyrazol 4-yl]pyridine-2-carboxamide; Example A-97 4-[5-(4-fluorophenyl)-3-methyl-lH-pyrazol 15 4-yl]pyridine-2-carboxamide; Example A-98 4-[5-(4-methoxyphenyl)-3-methyl-lH-pyrazol 4-yl]pyridine-2-carboxamide; Example A-99 4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl 1H-pyrazol-4-yl]pyridine; 20 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 25 methyl-lH-pyrazol-4-yl]pyridine; Example A-103 4-[5-(benzofuran-6-yl)-3-methyl-IH pyrazol-4-yl]pyridine; Example A-104 4-[5-(3-fluoro-5-methoxyphenyl)-3-methyl 1H-pyrazol-4-yl]pyridine; 30 Example A-105 4-[5-(3-chloro-5-methoxyphenyl)-3-methyl 1H-pyrazol-4-yl]pyridine; Example A-106 4-[5-(l-cyclohexyen-l-yl)-3-methyl-lH pyrazol-4-yl]pyridine; Example A-107 4-[5-(l,3-cyclohexadien-1-yl)-3-methyl-lH 35 pyrazol-4-yl]pyridine; Example A-108 4-[5-(5,6-dihydro-2H-pyran-4-yl)-3-methyl sumUMSHEET(RULE2) WO98/52940 PCT/US98/1 0436 133 1H-pyrazol-4-yl]pyridine; Example A-109 4-(5-cyclohexyl-3-methyl-lH-pyrazol-4 yl)pyridine; Example A-110 4-[5-(4-methoxy-3-methylphenyl)-3-methyl 5 1H-pyrazol-4-yl]pyridine; Example A-111I 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; 10 Example A-113 4-[5-(3-furanyl)-3-methyl-lH-pyrazol-4 yl]pyridine; Example A-114 2-methyl-4-(3-methyl-5-phenyl-lH-pyrazol 4-yl)pyridine; Example A-115 2-methoxy-4-(3-methyl-5-phenyl-1H-pyrazol 15 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-lH-pyrazol-4 yl)pyridine-2-carboxamide; 20 Example A-118 1-[4-(3-methyl-5-phenyl-lH-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 25 4-yl)pyridine; Example A-121 3-methoxy-4-(3-methyl-5-phenyl-lH-pyrazol 4-yl)pyridine; Example A-122 methyl 4-(3-methyl-5-phenyl-lH-pyrazol-4 yl)pyridine-3-carboxylate; 30 Example A-123 4-(3-methyl-5-phenyl-lH-pyrazol-4 yl)pyridine-3-carboxamide; Example A-124 1-[4-(3-methyl-5-phenyl-lH-pyrazol-4 yl)pyridin-3-yl]ethanone; Example A-125 3-bromo-4-(3-methyl-5-phenyl-lH-pyrazol-4 35 yl)pyridine; Example A-126 N,N-dimethyl-4-(3-methyl-5-phenyl-lH 84UTUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 134 pyrazol-2-yl)pyridin-3-amine; Example A-127 2-methyl-4-(3-methyl-5-phenyl-lH-pyrazol 4-yl)pyrimidine; Example A-128 4-(3-methyl-5-phenyl-lH-pyrazol-4 5 yl)pyrimidine; Example A-129 2-methoxy-4-(3-methyl-5-phenyl-lH-pyrazol 4-yl)pyrimidine; Example A-130 4-(3-methyl-5-phenyl-lH-pyrazol-4 yl)pyrimidin-2-amine; 10 Example A-131 N,N-dimethyl-4-(3-methyl-5-phenyl-lH pyrazol-4-yl)pyrimidin-2-amine; Example A-132 4-(5,6-dihydro-2H-pyran-4-yl)-3-methyl-5 phenyl-lH-pyrazole; Example A-133 3-methyl-5-phenyl-4-(3-thienyl)-lH 15 pyrazole; Example A-134 4-(3-furanyl)-3-methyl-5-phenyl-lH pyrazole; Example A-135 3-methyl-5-phenyl-4-(2-thienyl)-lH pyrazole; 20 Example A-136 4-(2-furanyl)-3-methyl-5-phenyl-lH pyrazole; Example A-137 4-(3-isothiazolyl)-3-methyl-5-phenyl-lH pyrazole; Example A-138 4-(3-isoxazolyl)-3-methyl-5-phenyl-lH 25 pyrazole; Example A-139 4-(5-isothiazolyl)-3-methyl-5-phenyl-lH pyrazole; Example A-140 4-(5-isoxazolyl)-3-methyl-5-phenyl-lH pyrazole; 30 Example A-141 3-methyl-5-phenyl-4-(5-thiazolyl)-lH pyrazole; Example A-142 3-methyl-4-(5-oxazolyl)-5-phenyl-lH pyrazole; Example A-143 2-methyl-4-[3-(3-methylphenyl)-lH-pyrazol 35 4-yl]pyridine; Example A-144 4-(l-methyl-3-phenyl-lIH-pyrazol-4-yl)pyridine; a SUTSHEEF (RULE 2) WO98/52940 PCT/US98/10436 135 Example A-145 4-(3-phenyl-lH-pyrazol-4-yl)pyridine; Example A-146 2-methyl-4-(3-phenyl-lH-pyrazol-4 yl)pyridine; Example A-147 4-[3-(3-chlorophenyl)-l-methyl-pyrazol-4 5 yl]pyridine; Example A-148 4-[3-(4-chlorophenyl)-l-methyl-pyrazol-4 yl]pyridine; Example A-149 4-[3-(3-chlorophenyl)-lH-pyrazol-4 yl]pyridine; 10 Example A-150 4-[3-(4-chlorophenyl)-lH-pyrazol-4 yl]pyridine; Example A-151 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]-2 methylpyridine; Example A-152 4-[3-(3-fluorophenyl)-l-methyl-lH-pyrazol 15 4-yl]pyridine; Example A-153 4-[3-(3-fluorophenyl)-lH-pyrazol-4 yl]pyridine; and Example A-154 4-[3-(3-chlorophenyl)-l-methyl-pyrazol-4 yl]-2-methylpyridine. 20 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 25 corresponding starting reagents: Example A-155 CI H N HN N HN Ph 5-(4-chlorophenyl)-N-phenyl-4-(4-pyridinyl)-lH SSMMTITUTEHEE(RULE 26) WO 98/52940 PCT/US98/10436 136 pyrazol-3-amine: DSC 261 oC. Anal. Calc'd for C 20

H

15 C1N 4 + 0.25 H 2 0 (MW 351.32): C, 68.38, H, 4.30, N, 15.95. Found: C, 68.25, H, 4.41, N, 15.74. 5 Example A-156 CI H N N S HN 5-(4-chlorophenyl)-N-methyl-4-(4-pyridinyl) -1H-pyrazol-3 amine: DSC 260 oC. Anal. Calc'd for C 15

H

13 C1N 4 + 0.125 H 2 0 (MW 287.00): C, 62.77, H, 4.57, N, 19.52. Found: C, 10 62.78, H, 4.33, N, 19.22. Example A-157 CI H N N N

N

5-(4-chlorophenyl)-N,N-dimethyl-4-(4-pyridinyl) -1H 15 pyrazol-3-amine dihydrate: DSC 230 oC. Anal. Calc'd for

C

16

H,

5 C1N 4 + 2 H 2 0 (MW 334.81): C, 57.40, H, 4.52, N, 16.73. Found: C, 57.72, H, 4.85, N, 16.54. cgg E8HE(RLE26) WO 98/52940 PCT/US98/10436 137 Example A-158 F | H N N N ,N 5-(3-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl) -1H pyrazol-3-amine: DSC 227 oC. Anal. Calc'd for C 16

H,,FN

4 + 5 0.125 H 2 0 (MW 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 N /N N N 10 N,N-dimethyl-5-(3-methylphenyl)-4-(4-pyridinyl)-1H pyrazol-3-amine: DSC 222 oC. Anal. Calc'd for C 17

H,

8

N

4 + 0.25 H 2 0 (MW 282.86) : C, 72.19, H, 6.41, N, 19.81. Found: C, 71.99, H, 6.46, N, 19.90. SsU SHEET(RLEu2 WO 98/52940 PCT/US98/10436 138 Example A-160 H N N N , HN N-methyl-5-(3-methylphenyl)-4-(4-pyridinyl) -1H-pyrazol-3 amine: DSC 226 oC. Anal. Calc'd for C 16

H

16

N

4 + 0.125 H 2 0 5 (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 NH I~ NH N Et 10 N-ethyl-5-(3-methylphenyl)-4-(4-pyridinyl) -1H-pyrazol-3 amine: DSC 227 oC. Anal. Calc'd for C 17 Hl 8

N

4 + 0.125 H 2 0 (MW 280.61): C, 72.77, H, 6.47, N, 19.97. Found: C, 72.63, H, 6.40, N, 19.73. MSTIUM EET(RULEM) WO 98/52940 PCT/US98/10436 139 Example A-162 H N I/ N N , Et Et N,N-diethyl-5-(3-methylphenyl)-4-(4-pyridinyl) -1H pyrazol-3-amine: DSC 234 oC. Anal. Calc'd for CH 22

N

4 5 (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 Cl H N / N N , Et Et 10 5-(4-chlorophenyl)- N,N-diethyl-4-(4-pyridinyl)-1H pyrazol-3-amine: m.p. 260-261 0 C. Anal. Calc'd for

C

18

H

19 C1N 4 (MW 326.83): C, 66.15, H, 5.86, N, 17.14. Found: C, 66.03, H, 5.72, N, 17.23.A[ 6 ~EF -dAA WO 98/52940 PCT/US98/10436 140 Example A-164 CI H N N N ~N' 0 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3 yl]morpholine: DSC 279 oC. Anal. Calc'd for C 18

H

17 C1N 4 0 + 5 0.25 H 2 0 (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 CI H N N HN n-Pr 10 5-(4-chlorophenyl)-N-propyl-4-(4-pyridinyl) -1H-pyrazol-3 amine: DSC 244 oC. Anal. Calc'd for C 17

H

17 C1N 4 + 0.125 H 2 0 (MW 315.06): C, 64.81, H, 5.44, N, 17.78. Found: C, 64.94, H, 5.43, N, 17.78. assmTESHEET(RULE2) WO 98/52940 PCT/US98/10436 141 Example A-166 Ci H N N N I - HN Ph Isolated as 5-(4-chlorophenyl)-N-(phenylmethyl)-4-(4 pyridinyl)-1H-pyrazol-3-amine hydrate (2:1): DSC 237 OC. 5 Anal. Calc'd for C 2

,H,

7 C1N 4 + 0. 5 H 2 0 (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 Cl 'H N HN NHN N 'O 10 Isolated as 5-(4-chlorophenyl)-N-(2-methoxyethyl)-4-(4 pyridinyl)-1H-pyrazol-3-amine monohydrate: DSC 223 oC. Anal. Calc'd for C 17

H

17 C1N 4 0 + H 2 0 (MW 346.82): C, 58.87, H, 4.94, N, 16.15. Found: C, 58.59, H, 4.79, N, 16.02. O SH~lUEBEET (RUE WO 98/52940 PCT/US98/10436 142 Example A-168 Cl SNH N N 0 --0 1,1-dimethylethyl 4-[5-(4-chlorophenyl)-4-(4-pyridinyl) 5 1H-pyrazol-3-yl]-1-piperazinecarboxylate: DSC 251 oC. Anal. Calc'd for C 2 3

H

26

CIN

5 0 (MW 439.95): C, 62.79, H, 5.96, N, 15.92. Found: C, 62.40, H, 5.82, N, 15.82. 10 Example A-169 CI NH N N N N H Isolated as 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H pyrazol-3-yl]piperazine trihydrochloride: DSC 99 OC. SUS 8RSEET(RULE24 WO 98/52940 PCT/US98/10436 143 Anal. Calc'd for C 18 HC1N 4 + 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-170 ci CI N I I N/ N N 5 1-[5-(4-chlorophenyl)-4-(4-pyridinyl) -1H-pyrazol-3-yl] -4 methylpiperazine: m.p. 247-249 oC. Anal. Calc'd for Cj 9

H

20 C1N 5 + 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. 10 Example A-171 F NH I I N NN 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 SuNnTUTESHEEf (RULE26) WO 98/52940 PCT/US98/10436 144 oC. Anal. Calc'd for C 2 3

H

2 6

FN

5 0 2 + 0.5 CH 3

CH

2

CO

2

CH

2

CH

3 (MW 467.55): C, 64.22, H, 6.47, N, 14.98. Found: C, 63.90, H, 6.61, N, 14.88. 5 Example A-172 F NH -N N 3HCI N N H 1-[5-(4-fluorophenyl)-4-(4-pyridinyl) -l1H-pyrazol-3 yl]piperazine trihydrochloride: m.p. 204-206 oC. Anal. 10 Calc'd for CzH,,Fn s + 3 HC1 + 0.5 H 2 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-pyridinyl) -1H-pyrazol-3 15 yl]piperazine: m.p. 264-265 oC. Anal. Calc'd for

C

1 8 HC1NsN 5 + 0.125 H 2 0 (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 20 accordance with the chemistry described in Scheme II by selection of the corresponding starting reagents further include the compounds disclosed in Table 2. GASHTUM8HE(R E26) WO 98/52940 PCTIUS98/10436 145 UI~~OD N 0 q 00 - C.14 N N N 00 r ~ e~ - It erN r- ID 00 102 ' t W) 01 'IT W(N NOr N - = e4 - - - - - - Q~ NO6 W) NO 'IN NO L n N 00 - r - - - - - - M o NO N N - 'N - WIN 0 V'I 00 0) 00 00 N~ e'4 'IN NO N - C. V) n I'N i ON VIN N 00 ON ON, en m* en 0n ON 00 0 0 0 1 I 6 NO ~ NO N0 00 NO 0l ONWON M I kn 0N a ,4 '( 0 0 ('4 0 C-4 0 ZZ Az z N 2 ~ 'IN 'IN c N) o u) (' U u 0 CN UU 4C) ('N ~ I/N O N 0 ON - (4 (' P2 m It Sr B fl1UTES00 C( 0 L14 m WO 98/52940 PCT/US98/10436 146 Example A-173 F NH I I -N HN N HN N H HN 3HC I N- [5- (4-chlorophenyl)-4- [2- (phenylmethyl)amino] -4 5 pyridinyll] -1H-pyrazol-3-yl] -1,3-propanediamine, trihydrochloride Example A-174 CI NH /N N N N Bn 10 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3 yl] -4- (phenylmethyl)piperazine m1MESHEET(RULE2% WO 98/52940 PCT/US98/10436 147 Example A-175 F SNH N NN N N H Isolated as 4-[3-(4-fluorophenyl)-5-(1-piperazinyl)-1H pyrazol-4-yl]pyrimidine, dihydrochloride 5 Example A-176 CI SNH N N HN NHBoc 1,1-dimethylethyl [3- [ [5-(4-chlorophenyl)-4-(4 pyridinyl) - 1H-pyrazol-3-yl] amino] propyl] carbamate SBffTSHEE(FRA£26) WO 98/52940 PCT/US98/10436 148 Example A-177 Cl NH N N / HN

NH

2 Isolated as N-[5-[4-chlorophenyl)-4-(4-pyridinyl)-1H 5 pyrazol-3-yll] -1,3-propanediamine, trihydrochloride monohydrate Example A-178 F NH N HN HN 0 0 10 1,1-dimethylethyl [2-[[5-(4-chlorophenyl)-4-(4 pyridinyl) -1l-pyrazol-3-yll]amino] ethyl] carbamate SLOTWEEr (RUE26) WO 98/52940 PCT/US98/10436 149 Example A-179 CI OH N 1 1N N (N) N Boc 1,1-dimethylethyl 4-[5-(4-chlorophenyl)-1-(2 5 hydroxyethyl)-4-(4-pyridinyl) -1H-pyrazol-3-yl] -1 piperazinecarboxylate Example A-180 F NH I I N N N Boc 10 1,1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4 pyrimidinyl) - 1H-pyrazol-3-yl] -1 -piperazinecarboxylate SfmumHEET(RULE28) WO 98/52940 PCT/US98/10436 150 Example A-181 c I NH N N / HN F NHBoc 1,1-dimethylethyl [3-[[5-(4-chlorophenyl)-4-(2-fluoro-4 5 pyridinyl) -1H-pyrazol-3-yl] amino] propyl] carbamate Example A-182 CI NH N\ N~ CN) I Et 1- [5-(4-chlorophenyl)-4-(4-pyridinyl) -1H-pyrazol-3-yl]-4 10 ethylpiperazine SUBSTfUTESHEET(RLE26) WO 98/52940 PCT/US98/10436 151 Example A-183 CI NH N , HN 3HC I

H

2 N 5 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 10 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 N ~ 15 4-[3- (2,6-difluorophenyl)-5-methyl-lH-pyrazol-4 yl]pyridine: Anal. Calc'd for C 1 ,HuF 2

N

3 : C, 66.42; H, 4.09; N, 15.49. Found: C, 66.20; H, 3.94; N, 15.16; m.p. SUB T ESHEST(RULE26) WO 98/52940 PCT/US98/10436 152 236.67 oC. Example A-185 NH N N/ 5 4-[3-(3-ethylphenyl)-5-methyl-1H-pyrazol-4-yll]pyridine: Anal. Calc'd for C 17

H,

7

N

3 : C, 77.54; H, 6.51; N, 15.96. Found; C, 77.16; H, 6.27; N, 15.69. m.p. (DSC): 189.25 OC. 10 Example A-186 CI NH N \i 4- [3-(3-chlorophenyl)-5-ethyl-1H-pyrazol-4-yl]pyridine: Anal Calc'd for C 16

H

14 C1N 3 * 0.1 mole H 2 0: C, 67.15; H, 4.91; N, 14.33. Found: C, 66.95; H, 5.00; N, 14.36. DSC: 15 176.18 oC. susMUTSHEET

(RULEM

WO 98/52940 PCT/US98/10436 2153 Example A-187 NH N 4-[3-ethyl-5-(3-ethylphenyl)-1H-pyrazol-4-yl]pyridine: 5 Anal. Calc'd for C 18

H

19

N

3 00.1 mole H 2 0: C, 77.44; H, 6.93; N, 15.05. Found: C, 77.39; H, 6.94; N, 14.93. m.p. (DSC) : 192.66 OC. Example A-188 Cl NH N 10 4-[3-(4-chlorophenyl) -- (1-methylethyl) -lH-pyrazol-4 yl]pyridine: Anal. Calc'd for C 1

,

7

H

6 C1N 2 *0.4M EtOAc: C, 67.08; H, 5.81; N, 12.62. Found: C, 67.40; H, 6.15; N, 12.34. WOOMTUTEHEit(R1JLE"O) WO 98/52940 PCT/US98/10436 154 Example A-189 F S NH N N 5 4-[3-cyclopropyl-5-(4-fluorophenyl) -1H-pyrazol-4 yl]pyridine: Anal. Calc'd for C, 7

H

14

FN

3 : C, 73.1; H, 5.05; N, 15.04. Found: C, 73.23; H, 4.89; N, 14.63; m.p.: 239 240 oC. 10 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: 15 Example A-190 N HN CF 3 F N 4-[3-(4-fluorophenyl)-5-(trifluoromethyl) -l1H-pyrazol-4 yll]pyridine 20 This compound was prepared by the same procedure as SMSWUTEHEEr(RULE26) WO98/52940 PCT/US98/10436 155 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). 5 Anal. Calc'd for CiHF 4

N

3 : C, 58.64; H, 2.95; N, 13.68. Found: C, 58.57; H, 3.07; N, 13.31. m.p. (DSC): 281.94 oC. The compounds of Examples A-191 through A-198 were 10 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 N , 15 4-[5-(cyclopropyl-3-(4-(fluorophenyl)-l-methyl-lH pyrazol-4-yl]pyridine Step 1: Preparation of 1-(4-fluorophenyl)-2-(4 20 pyridinyl)ethanone methylhydrazone F NNHMe N , I 1-C4-fluorophenyl)-2-C4-pyridinyl)ethanone methylhydrazone SUBSU M HEET(RUU 2) WO98/52940 PCT/US98/10Q436 156 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 5 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 10 concentrated and the crude product was recrystallized from diethyl ether and hexane to afford 7.5 g of a yellow solid product (77% yield), l-(4-fluorophenyl)-2-(4 pyridinyl)ethanone methylhydrazone. 15 Step 2: Preparation of 4-[5-(cyclopropyl-3-(4 (fluorophenyl)-l-methyl-lH-pyrazol-4-vllpyridine To a solution of sodium hexamethyldisilazide (5.5 mL, 1.0 M in THF) at 0 oC was added a solution of the compound prepared in step 1 (0.67 g, 0.0028 mol) in 10 mL 20 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 25 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 30 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 oC; 1H NMR (CDCL 3 ) : 6 8.53 (m, 2H) 7.32 (m, 2H), 7.14 (m, 2H), 6.97 (m, 2H), 4.00 (s, 3H), 35 1.83 (m, 1H), 0.95 (m, 2H), 0.36 (m, 2H); Anal. Calc'd For C,,H, 6

FN

3 : C, 73.70; H, 5.50; N, 14.32. Found: C, aMfTSHEET (RULE26) WO98/52940 PCT/US98/10436 157 73.63; H, 5.57; N, 14.08. Example A-192 F N -I N ,N N O H 5 5-cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridinyl)-lH pyrazole-1-ethanol Step 1: Preparation of 1-(4-fluorophenv1)-2-(4 pyridinyvl)ethanone (2-hydroxyethyl)hydrazone F

NNHCH

2

CH

2 0H N , 10 1-c4-f luorophenyl)-2-C4-pyridinyl)ethanone (2-hydroxyethyI]hydrazone To a flask containing hydroxyethyl hydrazine (3.4 g, 0.04 mol) at 80 OC 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 15 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 oC. m~snUTEHT (Rim WO98/52940 PCTIUS98/1 0436 158 Step 2: Preparation of 1-(4-fluorophenyl)-2- (4 pyridinvyl)ethanone [2- [[(1,1 dimethylethyl)dimethylsilyll oxy] ethyll] hydrazone 5 F

NNHCH

2

CH

2 OSi -t- BuMe 2 N , 1-C4-fluoropheny )-2-(4-pyridinyl)ethanone [2-E[(1, 1-dimetlhylethy I[Ddimethylsily I]oxy]ethy I] hydrazone 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 10 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 15 with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to give 3.8 g of crude product, 1-(4-fluorophenyl)-2-(4-pyridinyl)ethanone [2 [[(1,1-dimethylethyl)dimethylsilyl] oxy] ethyl] hydrazone, as a yellow oil that was used in the next step without 20 further purification. annmumSEE(RUL26 WO 98/52940 PCT/US98/10436 159 Step 3: 5-cyclopropyvl-1l- [2-[[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyll -3,4-diphenvl-lH-pyrazole N

NCH

2

CH

2 0Si-t-BuMe 2 5-cyclopropyl-1-[2-[[C1,1-dimethylethyID dimethylsilyI]oxy]ethyl]-3,4-diphenyI-1H-pyrazole To a solution of sodium hexamethyldisilazide (4.2 5 mL, 1.0 M in THF) at 0 oC was added a solution of the compound prepared in step 2 (0.78 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 methyl cyclopropanecarboxylate (0.27 g, 0.0026 mol) in 5 10 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 15 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-l-[2-[[(l,l dimethylethyl) dimethylsilyll] oxy] ethyl] -3,4-diphenyl-1H pyrazole, as a light yellow oil (35% yield), 'H NMR 20 (CDCL 3 ) : 6 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 C 2 5

H

32

FN

3 OSi: C, 68.61; H, 7.37; N, 9.60. Found: C, 68.39; H, 7.81; N, 9.23.

SUBSTITUTESHEET(RULEM)

WO 98/52940 PCT/US98/10436 160 Step 4: Preparation of 5-cyclopropyl-3-(4-fluorophenyl) 4-(4-pyridinyl) -1H-pvrazole-1-ethanol To a solution of the compound prepared in step 3 (0.27 g, 0.00062 mol) in 5 mL of THF was added 5 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 10 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 OC; 1 H NMR (CDCL 3 ) : 6 8.53 (br s, 2H), 7.32 (m, 2H), 7.14 (d, J = 5.6 Hz, 2H), 6.97 15 (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 C 19

H

18

FN

3 0: C, 70.57; H, 5.61; N, 12.99. Found: C, 70.46; H, 5.87; N, 12.84. 20 Example A-193 F N N I OH N OMe 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4 pyridinyl) -lH-pyrazole-1-ethanol 25 To a solution of sodium hexamethyldisilazide (7.4 mL, 1.0 M in THF) at 0 oC was added a solution of the sUsSumSHEE( E28) WO98/52940 PCTIUS98/10436 161 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 5 methoxy)pyridinecarboxylate (0.0.59 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 10 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)-lH-pyrazole-l 15 ethanol, as a yellow solid, mp: 168-169 OC; 'H NMR

(CDCL

3 ): 6 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 C 2 2

H,

9

FN

4 0 2 : C, 20 67.86; H, 4.91; N, 14.35. Found: C, 67.46; H, 5.08; N, 14.03. F N N OSiCt- B u ) Me 2 N , N OMe 4-[l-[2-[[(l,1-dimethylethyl)dimethylsilyl] 25 oxy]ethyl]-3-(4-fluorophenyl-4-(4-pyridinyl)-1H-pyrazol 5-yl]-2-methoxypyridine OU fTUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 162 A second compound, 4- [l- [2-[ [(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl]-3-(4-fluorophenyl-4-(4 pyridinyl) -lH-pyrazol-5-yll]-2-methoxypyridine also was isolated from the above reaction as a yellow oil by 5 chromatography. 1H NMR (CDCL 3 ): 6 8.45 (m, 2H), 8.20 (m, 1H), 7.40 (m, 2H), 7.04 (m, 2H), 6.93 (m, 2H), 6.81 (m, 2H), 4.24 (m, 2H), 4.14 (m, 2H), 3.98 (s, 3H), 0.83 (s, 9H), 0.02 (s, 6H). 10 Example A-194 F I N \. N NOH N 0 N 0 H 4-[3-(4-fluorophenyl)-1- (2-hydroxyethyl)-4-(4-pyridinyl) 1H-pyrazol-5-yl] -2(1H)-pyridinone 15 To a solution of 3-(4-fluorophenyl)-5-(2-methoxy-4 pyridinyl)-4-(4-pyridinyl)-lH-pyrazole-l-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 20 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 2

CI

2 /NH4OH, 5:94:1) 25 to give 0.07 g of product, 4-[3-(4-fluorophenyl)-1-(2 hydroxyethyl)-4-(4-pyridinyl) -lH-pyrazol-5-yll-2 (lH) SMUEHEE(RULE 2) WO 98/52940 PCT/US98/10436 163 pyridinone, as a yellow solid (32% yield), mp: 250-251 oC; 'H NMR (DMSO-d 6 ) : 6 11.74 (s, 1H), 8.45 (d, J = 5.0 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, J = 5.2 Hz, 1H), 5.0 (m, 5 1H), 4.13 (m, 2H), 3.81 (m, 2H); Anal. Calc'd for

C

21

H,

7

FN

4 0 2 *0.2 H 2 0: C, 66.06; H, 4.65; N, 14.67. Found: C, 66.31; H, 4.49; N, 14.27. Example A-195 F N \- N OH N %- N 0 10 0 1-acetyl-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 15 (4-pyridinyl) -lH-pyrazol-5-yl] -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 0 C; 'H NMR (CDC1 3 ) : 6 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 20 (t, J = 6.0 Hz, 2H), 4.43 (t, J = 6.0 Hz, 2H), 2.04 (s,3H); Anal. Calc'd for C 23

H

1 gFN 4 0 3 00.3 H 2 0: C, 65.46; H, 4.63; N, 13.28. Found: C, 65.09; H, 4.64; N, 12.99. SU0BmUTSHEETZ(RULE28) WO 98/52940 PCTIUS98/10436 164 Example A-196 F N \ N 0 \OH N .- o Ethyl 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4 pyridinyl)-lH-pyrazol-5-yl]cyclopropanecarboxylate 5 To a solution of sodium hexamethyldisilazide (17.0 mL, 1.0 M in THF) at 0 oC 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 10 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 15 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 20 [3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl) 1H-pyrazol-5-yl]cyclopropanecarboxylate, as a light yellow oil (35% yield), 'H NMR (CDCL 3 ): 6 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 25 Hz, 3H), (m, 2H), 0.90 (m, 2H); Anal. Calc'd for

C

22

H

22

FN

3 0 3 *0.25 H20: C, 66.07; H, 5.67; N, 10.51 Found: C, BHTUTESHEET

(RUUES)

WO98/52940 PCTIUS98/10436 165 65.89; H, 5.80; N, 9.95. Example A-197 F NH \ N N CO 2 H 5 2-[3-(4-fluorophenyl)-l-(2-hydroxyethyl)-4-(4-pyridinyl) 1H-pyrazol-5-yl]cyclopropanecarboxylic acid To a solution of ethyl 2-[3-(4-fluorophenyl)-l-(2 hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl] 10 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, 15 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 lN sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium and filtered. 20 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)-lH-pyrazol-5-yl]cyclopropanecarboxylic acid, as a white solid (60% yield), mp: 253-255 oC; 1H NMR 25 (CD 3 OD): 6 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 smTUE SHEET(RULE 2) WO 98/52940 PCT/US98/10436 166

C

20

H,

8

FN

3 0 3 : C, 65.39; H, 4.94; N, 11.44. Found: C, 64.92; H, 4.77; N, 11.20. Example A-198 F N N N\OH N / 7' NH 5 N 3-(4-fluorophenyl)-5-(4-imidazolyl)-4-(4-pyridinyl)-1H pyrazole-1-ethanol Step 1: Preparation of methyl 1-f[[2-(trimethylsilyl) 10 ethoxylmethyl]-lH-pyrrole-3-carboxylate C0 2 Me TMS O N N methyl 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrrole-3 carboxylate To a suspension of sodium hydride (1.0 g, 0.025 mol) 15 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-Cl (4.17 g, 0.025 mol) was added dropwise over 5 minutes. The reaction mixture was stirred for 4 hours 20 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 WO98/52940 PCT/US98/10436 167 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. 5 Step 2: Preparation of 4-[l-[2-[[(l,l-dimethylethyl) dimethylsilyl] oxy] ethyll-3-(4-fluorophenyl-5-[I- [[(2 trimethysilyl) ethoxy]vlmethyl-lH-imidizol-4-yl] -lH-pyrazol 4-yl ] pyridine F N OSiCt-BuDMe 2 N N N 0--/ TMS 10 4-[1-[2[[(1,1-dimethylethyl)dimethylsilyll oxy]ethyl]-3-(4-fluorophenyl)-5-[1-[[2 trimethylsilyl)ethoxy]methyl]-lH-imidazol-4-yl]-lH pyrazol-4-yl]pyridine To a solution of sodium hexamethyldisilazide (4.5 15 mL, 1.0 M in THF) at 0 oC 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 20 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 suSmuMTESHEET (RULE 2) WO 98/52940 PCT/US98/10436 168 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 5 solidified upon standing (91% yield), mp: 79-80 oC; 1H NMR

(CDCL

3 ): 6 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 10 Hz , 2H), 0.92 (t, J = 8.0 Hz, 2H), 0.84 (s, 9H), 0.021 (s, 18H); Anal. Calc'd For C 31

H

44 FNsO 2 Si 2 : 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 15 imidazolyl)-4-(4-pyridinyl) -lH-pyrazole-l-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 20 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 25 chloride/methanol, 95:5) to give 0.22 g of the product, 3-(4-fluorophenyl)-5-(4-imidazolyl)-4-(4-pyridinyl) -lH pyrazole-l-ethanol, as a white solid (63% yield), mp: 227-228 oC; 'H NMR (DMSO-d 6 ): 6 8.45 (m, 2H), 7.83 (s, 1H), 7.35 (m, 2H), 7.15 (m, 4H), 7.09 (s, 1H), 5.20 (br 30 s, 1H), 4.32 (s, 2H), 3.81 (m, 2H); Anal. Calc'd For

C

1 ,H1 6

FN

5 0: 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 35 accordance with the chemistry described above (particularly in Scheme VI) by selection of the 8UBsmTUSHEE[(RLME26) WO 98/52940 PCT/US98/10436 169 corresponding starting reagents: Example A-199 NH X N H N CI 5 4-[3-(4-chloro-3-methylphenyl) -lH-pyrazol-4-yl]pyridine Anal. Calc'd for C,,H 2

N

3 C1 (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 oC. 10 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: 15 Example A-200 N 0 OH N N H F 5-(4-fluorophenyl)-4-(4-pyridinyl) -l1H-pyrazole-3 carboxylic acid agfTUTEHfREE(26) WO98/52940 PCT/US98/10436 170 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 5 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 10 was extracted with ethyl acetate to remove unreacted starting material. The aqueous layer was acidified with 1N HC1 to increase the pH to about 6. A white precipitate formed, was collected by filtration, washed with water, and dried in a vacuum oven to give 5-(4 15 fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-3-carboxylic acid (isolated as the monohydrate salt) (2.9777 g, 43.7 %). Anal. Calc'd for C 15 HIoN 3 FO2.H 2 0 (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) 20 Example A-201 N OH I .IN H F 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-methanol 25 To a suspension of 5-(4-fluorophenyl)-4-(4 pyridinyl)-lH-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, BUB8Tff HEE(RULE 26 WO 98/52940 PCT/US98/10436 171 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 5 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 10 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 MgSO 4 to 15 give a crude product (0.45 g). Recrystallization of the crude product from methanol gave 5-(4-fluorophenyl)-4-(4 pyridinyl)-lH-pyrazole-3-methanol (0.2808 g, 56.5%). DSC: 260.26 oC; Anal. Calc'd for C 1 5 sH, 2

N

3 FO (269): C, 66.91; H, 4.49; N, 15.60; Found: C, 66.07; H, 4.63; N, 15.20. MS 20 (MH) : 270 (base peak). Example A-202 - N NH NN H F 25 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3 yl]carbonyl]piperazine 8 USTIUE SHEET (RULE 26) WO 98/52940 PCT/US98/10436 172 Step 1: Preparation of 1,1-dimethylethyl 4-[[5-(4 fluorophenvyl)-4-(4-pyridinyl)-1H-pyrazol-3-vll]carbonyll] 1-piperazinecarboxylate N NBoc I I H F 5 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 oC under nitrogen, 1-(3-dimethylaminopropyl)3 10 ethylcarbodiiminde hydrochloride (0.6984 g, 3.57 mmol, Aldrich Chemical Co.) was added. The solution was stirred at 0 oC 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 15 reaction was stirred from 0 oC 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 3 solution, water and brine, and dried over MgSO 4 . After filtration, 20 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]carbonyl] 1-piperazinecarboxylate (1.2372 g, 78.4%) was obtained by chromatography. Anal. Calc'd for C 24

H

26

N

5 0 3 F. (451): C, 25 63.85; H, 5.80; N, 15.51; Found: C, 63.75; H, 5.71; N, 15.16. MS (MWH) : 452 (base peak) SOMITUTSEET(RULE26) WO98/52940 PCT/US98/10436 173 Step 2: Preparation of 1-[[5-(4-fluorophenyl)-4-(4 pyridinyl)-1H-pyrazol-3-vl]carbonyl]piperazine bis(trifluoroacetate), monohydrate A solution of the compound prepared in step 1 5 (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 10 dried in a vacuum oven overnight to give 1-[[5-(4 fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3 yl]carbonyl]piperazine (isolated as the bis(trifluoroacetate), monohydrate salt) (0.2400g, 100%) as a white solid. Anal. Calc'd for 15 C 19

H

1

N

5 0sOF.2CF 3

COOH.H

2 0(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 20 synthesized in accordance with the chemistry described above (particularly in Scheme VIII) by selection of the corresponding starting reagents: 25 Example A-203 N 7N II N 4-(l,5-dimethyl-3-phenyl-lH-pyrazol-4-yl)pyridine STMUMTESEET(RULE26) WO 98/52940 PCTIUS98/10436 174 N N \ / N 4-(1,3-dimethyl-5-phenyl-1H-pyrazol-4-yl]pyridine A 60% dispersion of sodium hydride (41 mg, 0.00172 5 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 CH31 (122 mg, 10 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 Na 2 S0 4 , filtered 15 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-(l,3-dimethyl-5 phenyl-lH-pyrazol-4-yl]pyridine, and the second material 20 off the column was 4-(l,5-dimethyl-3-phenyl-lH-pyrazol-4 yl)pyridine. Major isomer (4-(l,5-dimethyl-3-phenyl-lH-pyrazol-4 yl)pyridine): m.p.: 94-99 oC. Anal. calc'd for 25 C 16

H

15

N

3 0.1MH20: C, 77.08; H, 6.06; N, 16.85. Found: C, 76.59; H, 5.70; N, 16.62 8U6SRTIUTESHEEr(RULE26) WO98/52940 PCT/US98/10436 175 Example A-204 N 4-[3-(4-chlorophenyl)-1,5-dimethyl-1H-pyrazol-4 yl]pyridine CI IN N 5 N 4-[5-(4-chlorophenyl)-1,3-dimethyl-1H-pyrazol-4 yl]pyridine (the compound of Example A-32) 10 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 15 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-lH pyrazol-4-yl]pyridine): Anal. calc'd for C 16 Hl 4

N

3 C1 20 (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 oC. SusmuTESHEE (UE26) WO 98/52940 PCT/US98/10436 176 Minor Isomer (4-[5-(4-chlorophenyl)-1,3-dimethyl-1H pyrazol-4-yl]pyridine): m.p.: 82-88 oC. Anal. calc'd for C 16 Hl 4

N

3 C1: C, 67.72; H, 4.97; N, 14.81; Found: C, 67.56; H, 4.96; N, 14.73. 5 Example A-205 N /- "N- NNN 4-[5-ethyl-1-methyl-3-(3-methylphenyl) -1H-pyrazol-4 yl] pyridine NN N 10 4-[3-ethyl-1-methyl-5-(3-methylphenyl) -1H-pyrazol-4 yl] pyridine 4- [5-ethyl-1-methyl-3-(3-methylphenyl) -1H-pyrazol-4 15 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 SUBSTITUTSWi=£T (RULE 26) WO 98/52940 PCT/US98/10436 177 as set forth in Example A-45). Major Isomer (4-[5-ethyl-l-methyl-3-(3-methylphenyl)-1H pyrazol-4-yl]pyridine): Anal. Calc'd for C 18

H

1 9 gNO300.45 5 MH20: 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 10 C 18 HgNO 3 *0.30MH 2 0: C, 76.46; H, 6.99; N, 14.86. Found: C, 76.58; H, 6.98; N, 14.63. Example A-206 N 7 N-Et Cl N 15 4-[3-(4-chlorophenyl)-1-ethyl-5-methyl-1H-pyrazol-4 yl]pyridine: Anal. Calc'd for C, 7

H

1 ,6N 3 C1 (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 oC. 20 Example A-207 NN N \ / N Et CI aWmUTEET(RUEL() WO 98/52940 PCTIUS98/10436 178 4-[3-(4-chlorophenyl)-2-ethyl-5-methyl-lH-pyrazol-4 yl]pyridine: Anal. Calc'd for C 17 Hl 6

N

3 C1 (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 oC. 5 The compounds of Examples A-208 and A-209 were prepared in accordance with the chemistry described above (particularly in Scheme IX): 10 Example A-208 F N /N-H N ,/ H 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine Step 1: Preparation of 4-fluorobenzoyl-4'-pyridyl 15 methane To a mixture of 4-picoline (32.6 g, 0.35 moles) and ethyl-4-fluorobenzoate (50.45g, 0.3 moles), maintained at 20 OC, was added lithium bis(trimethylsilylamide) (600 mL (lM)) in a steady but rapid stream so as to maintain 20 ambient 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 OC. The reaction mixture was quenched with concentrated HCI at 0 oC to lower the pH to 25 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- WO98/52940 PCT/US98/10436 179 fluorobenzoyl-4'-pyridyl methane, in 90% yield (58g). 'H NMR was consistent with the proposed structure. Step 2: 5 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 10 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%). 'H NMR was consistent with the proposed structure. 15 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 oC. Hydrazine hydrate (8.0g of anhydrous or 16.0g. of 20 hydrate, 0.25 moles) was then 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 25 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 oC for 10 minutes, filtered through celite and neutralized cautiously to pH 7 - 8 with vigorous stirring and cooling (20% sodium hydroxide was used). The 30 fine off-white precipitate was filtered and dried to give 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine. Yield: 27.3g. (91%). Mass spectrum: m/z = 240. 'H NMR was consistent with the proposed structure. Anal. calc'd for

C,

4 H,oFN 3 : C, 70.28; H, 4.21; N, 17.56. Found: C, 70.11; H, 35 4.33; N, 17.61. s1U 8ta( % WO 98/52940 PCT/US98/10436 180 Example A-209 C I NH N N , 4-[3-(2-chlorophenyl) -l1H-pyrazol-4-yl]pyridine 5 This compound was prepared by the same procedure described for Example A-208 using the corresponding starting reagents. Anal. Calc'd for C 14

H

10 C1N 3 : C, 65.76; H, 3.94; N, 16.43. 10 Found: C, 65.22; H, 3.91; N, 16.50. m.p. (DSC): 208.46 oC. The compounds of Examples A-2i0 and A-211 illustrate 15 were prepared in accordance with the chemistry described above (particularly in Scheme X): Example A-210 F N N OH N . H 20 3-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-1-ethanol SU8SITU8TE8HEE (RULE26) WO98/52940 PCT/US98/10436 181 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 5 acetic acid in a 500 mL Erlenmeyer flask. After gentle boiling (1 hour), a small sample was evacuated at high vacuum and examined by 'H NMR to confirm completion of hydrazone formation. On cooling to ambient temperature, the reaction mass solidified to a yellow cake. DMF 10 dimethylacetal (36 mL, 0.27 moles) was then added and the mixture heated to 80C for 10min, 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 oC, and water (20 mL) was added 15 dropwise with stirring, at which point a cloudy yellow oily suspension was obtained. The solution was now warmed to approximately 50-60 oC, whereupon the solution turned clear yellow. Slow cooling to ambient temperature with stirring (a crystal seed if available speeds up the 20 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)-liH-pyrazole-l-ethanol as a light yellow crystalline solid. Re-heating the filtrate 25 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)-lH-pyrazole 1-ethanol. Total yield: {12.3 + 3.3 + 0.4 + 0.4} = 30 16.4g. (97.6%). Mass spectrum, m/z = 284. 1H NMR was consistent with the proposed structure. Anal. calc'd for C1 6

H,

4

FNO

3 0 + H 2 0: C, 63.78; H, 5.35; N, 13.95. Found: C, 63.55; H, 5.07; N, 13.69. a HUTESHEET (RULE 2d) WO 98/52940 PCT/US98/10436 182 Example A-211 F N I N. N>N 3-(4-fluorophenyl)-4-(4-pyrimidinyl)-lH-pyrazole-1 ethanol 5 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. 10 The compound of Example A-212 was prepared in accordance with the chemistry of Scheme XI: Example A-212 F N

-CH

3 N ,/ H 15 4-[3-(4-fluorophenyl)-l-methyl-liH-pyrazol-4-yl]pyridine The vinyl amine prepared in Step 2 of Example A-208 20 (5.0g, 0.0185 moles) was taken up in ethanol (75mL) and cooled to 0 oC. Methyl hydrazine (l.7g, 0.037 moles) in ethanol (75mL) was added in one portion while maintaining the temperature at 0 to 10 oC. After 3 hours at ambient temperature the solvent was removed and the residue taken 25 up in methylene chloride (150 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 SUBBEUMSHEET(FH.E W) WO98/52940 PCT/US98/10436 183 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 with good stirring and cooling. The cream colored precipitate 5 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 oC. Scratching the sides of the flask starts the crystallization process. After 2 hours of standing, 10 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. 'H NMR confirmed the structure (including regiochemistry using NOE experiments). Yield: 2.1g. (45%). Mass spectrum, m/z = 15 254 (base peak). Anal. calc'd for C,,H, 2

FN

3 + 0.2 H 2 0: 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 20 accordance with the chemistry of Scheme XII: Example A-213 F N / "N-H N HN H OH 2-[[4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2 pyridinyllamino]-1-butanol W SEET(RULE

M)

WO 98/52940 PCT/US98/10436 184 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 5 4-methylpyridine) and (R,S)-2-amino-l-butanol (4 fold molar excess) was heated to 210-220 oC in a sealed vial for 1.5 hours. After cooling to 100 oC 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 10 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 15 structure. The compound of Example A-214 was prepared in accordance with the chemistry of Scheme XIII: 20 Example A-214 F N

NN-CH

3 N , Br 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-1H-pyrazol-4 yl]pyridine 25 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 OC overnight. TLC indicated SUiTUTESHEET(RLE28) WO 98/52940 PCT/US98/10436 185 that the reaction was complete. The mixture was quenched slowly with K 2

CO

3 (25g). When pH was about 5, a precipitate was formed. The precipitate was washed with water (50mL x 5) to give 4-[5-bromo-3-(4-fluorophenyl)-1 5 methyl-lH-pyrazol-4-yl]pyridine (1.24g, 35%): mp 174.38 0 C; Mass spectrum m/z = 332, 334; 'H NMR was consistent with the proposed structure. Anal. Calc'd for C 5 isHlN 3 FBr*0.2

H

2 0: C, 53.66; H, 3.42; N, 12.51. Found: C, 53.58; H, 3.12; N, 12.43. 10 The compound of Example A-215 was prepared in accordance with the chemistry of Scheme XIV: Example A-215 F N N-CH3 N 15 CN 4-[3-(4-fluorophenyl) -1H-pyrazol-4-yl] -2 pyridinecarbonitrile Step 1: 20 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 oC for overnight. 25 The mixture was concentrated. K 2

CO

3 (10%, 100 mL) was added to the residue. A precipitate was formed, filtered and washed with water (30 mL x 3) to give the u mTE SHEET (RULE 26) WO 98/52940 PCT/US98/10436 186 corresponding N-oxide (3.764g, 81.66%). Step 2: To a suspension of the N-oxide prepared in step 1 5 (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 OC. Dimethylcarbamyl chloride (0.8 mL, 8.69 mmol) was added. The mixture was stirred at 25 oC for 2 hours. TLC indicated that the 10 starting materials were gone. The mixture was partitioned into ethyl acetate:water (100 mL:20 mL). The organic layer was washed with K 2 CO3 (10%, 20 mL), water (50 mL), brine (50 mL), dried over MgSO 4 , filtered and concentrated to give 4-[3-(4-fluorophenyl)-lH-pyrazol-4 15 yl]-2-pyridinecarbonitrile (0.23 g, 56 % yield): mp 209.22 OC ; Mass spectrum (chemical ionization): m/z = 265; 1 H NMR was consistent with the proposed structure. Anal. Calc'd for CzsH 9

N

4 F*0.2 H 2 0: C, 67.26; H, 3.54; N, 20.92. Found: C, 67.44; H, 3.40; N, 20.69. 20 The compound of Example A-216 was prepared in accordance with the chemistry of Scheme XV: Example A-216 F _N SN N 0 25 4- [2- [3-(4-fluorophenyl)-4-(4-pyridinyl) -lH-pyrazol-1 yl] ethyl] morpholine I FMTUT EET (R UL E26) 0 WO98/52940 PCTIUS98/10436 187 Step 1: 3-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-l ethanol (prepared in accordance with Example A-210) (10.0 g, 0.0353 moles) was suspended in pyridine (100 mL) and 5 cooled to 0 oC. Methane sulfonyl chloride (4.4 g, 0.0388 moles) was added slowly while maintaining the temperature at 0 oC. After stirring overnight at 10 oC, chilled water (100 mL) and methylene chloride (150 mL) was added and the two layers separated. The water layer was re 10 extracted with 100 mL of methylene chloride and the organic layer dried and concentrated to a paste. After drying at high vacuum, a light tan colored cake was obtained which was triturated with ether (75 mL), filtered and dried to furnish a cream colored solid in 15 79% yield (10.1g) .

1 H NMR was consistent with the proposed structure. The compound was used as such for step 2. Step 2: The mesylate prepared in step 1 (5.0 g, 0.0138 20 moles) was dissolved in an eight fold excess of morpholine (9.6 g, 0.11 moles) in methanol (50 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 25 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)-lH-pyrazol-l yl]ethyl]morpholine as a solid. Yield: 4.5g (86%). Mass spectrum, m/z = 353. 1 H NMR was consistent with the proposed structure. Anal. calc'd for C 20

H

21

FN

4 0: C, 68.16; 35 H, 6.01; N, 15.90. Found: C, 68.20; H, 6.21; N, 15.80. SUBS1UTESHEEU (RULE 26) WO98/52940 PCT/US98/10436 188 The compound of Example A-217 was prepared in accordance with the chemistry of Scheme XVI: Example A-217 F N N N HO 5 3-(4-fluorophenyl)-1-methyl-a-phenyl-4-(4-pyridinyl)-lH pyrazole-5-methanol To solid magnesium (60 mg, 5 mmol) under nitrogen 10 was added a solution of 4-[5-bromo-3-(4-fluorophenyl)-l methyl-lH-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 oC for 2 hours. Benzaldehyde (1 mL) was added. The mixture 15 was heated to 45 OC 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 4 , filtered and concentrated to give a residue. 20 The residue was purified with a silica gel column to give the title compound (59 mg, 12% yield). MS: m/z = 360 (M+1); 'H NMR was consistent with the proposed structure. Anal. Calc'd for C 22

H,,N

2 0F*0.6EtOAC: C, 71.1; H, 5.6; N, 10.2; Found: C, 70.9; H, 5.47; N, 10.2. SUMERJTE8HEET(RULE26) WO 98/52940 PCT/US98/10436 189 The compound of Example A-218 was prepared in accordance with the chemistry described above (particularly Scheme XVII): 5 Example A-218 F N N- H N / HN N O N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4 morpholineethanamine 10 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 oC (dry ice-aqueous isopropanol). N chlorosuccinimide (0.62 g, 0.0046 moles) was added in one 15 portion while maintaining the temperature at -10 oC. After 5 minutes the thiosemicarbazide (0.0046 moles) was added in one portion at 0 oC 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)-lH-pyrazol-3-yl]-4 morpholineethanamine, which was re-filtered and dried. SUBMUESHEET(RULE26) WO98/52940 PCT/US98/10436 190 Yield: 0.95g. (56%). Mass Spec. m/z: 368 (base peak). Anal. Calc'd for C 20

H

22

FN

5 0. C, 65.38; H, 6.04; N, 19.06. Found: C, 64.90; H, 5.92; N, 18.67. 5 Example A-219 N CI H2NHN N H 4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-2(lH)-pyridinone hydrazone 10 Step 1: Preparation of (E)-2-(2-bromo-4-pyridinyl)-N,N dimethylethenamine NMe 2 N Br 4-Methyl-2-bromopyridine (1.0 g, 5.8 mmol) and t butoxybis(dimethylamino)methane (5 ml) were heated to 150 15 OC 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 20 water. The organic layer was dried over magnesium sulfate and solvent removed in vacuo to give 1.0 g of (E)-2-(2-bromo-4-pyridinyl)-N,N-dimethylethenamine as an SUMMTUMESHEET(RULE20 WO 98/52940 PCT/US98/10436 191 oil suitable for use in step 2. Step 2: Preparation of (Z)-2-(2-bromo-4-pyridinyl)-l-(3 chlorophenyl)-3-(dimethylamino)-2-propen-l-one 0 NMe 2 CI 5 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 OC, followed by the addition of 3-chlorobenzoyl chloride (350 mg, 4.5 mmol). 10 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 15 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-l-one, as a glass which was used in step 3 without further purification. 20 Step 3: Preparation of 2-bromo-4-[3-(3-chlorophenyl)-1H pyrazol-4-yl]pyridine NNI Br N I H SUBSTITUTESHEFf (RU.E) WO 98/52940 PCTIUS98/10436 192 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 5 mixtures of ethyl acetate and toluene as eluents to give 2-bromo-4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]pyridine (190 mg, 31%) as an oil: Anal. Calc'd for C 14

H

9 BrClN 3 : C, 50.25; H, 2.71; N, 12.56. Found: C, 50.10; H, 2.60; N, 12.40. 10 Continued elution with mixtures of ethyl acetate and methanol gave 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl] 2(1H)-pyridinone hydrazone (190 mg, 36%) as a crystalline solid: m.p. 163-164 OC.; MS (M+H) = 286. Anal. Calc'd 15 for C 14

H

12 NsC1: C, 58.85; H, 4.23; N, 24.51. Found: C, 58.53; H, 4.28; N, 24.87. Example A-220 N/ ClI PhH2CHN N I H 20 4-[3-(3-chlorophenyl) -lH-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 25 (5 ml) was heated at 175 oC 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 SUS5TUTESHEE (RULE26) WO98/52940 PCT/US98/10436 193 and the residue chromatographed on silica gel using mixtures of ethyl acetate and toluene to give 4-[3-(3 chlorophenyl)-lH-pyrazol-4-yl]-N-(phenylmethyl)-2 pyridinamine (110 mg, 61%) as a solid, m.p. 179-180 OC. 5 Anal. Calc'd For C 21 Hl 7 C1N 4 : C, 69.90; H, 4.75; N, 15.53. Found: C, 69.69; H, 4.81; N, 15.11. Example A-221 N / CI PhH2CH2CHN N N I 10 H 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]-N-(phenylethyl)-2 pyridinamine A solution of the bromopyridine compound prepared in 15 step 3 of Example A-219 (250 mg, 0.75 mmol) in phenethylamine (5 ml) was heated at 175 OC 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 20 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)-lH-pyrazol-4-yl]-N-(phenylethyl)-2 pyridinamine (230 mg, 81%) as a solid, m.p. 185-186 OC. 25 Anal. Calc'd For C 22 Hg 19

CN

4 : C, 70.49; H, 5.11; N, 14.95. Found: C, 70.29; H, 5.15; N, 14.66. SUBSTUMTESHEET(RULE2) WO 98/52940 PCT/US98/10436 194 Example A-222 N C Cl EtHN N I H 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]-N-ethyl-2 pyridinamine 5 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 OC in a sealed tube for 9 hours. The solvent was removed in 10 vacuo and the residue chromatographed on silica gel with 70 ethyl acetate/30 toluene to give 4-[3-(3 chlorophenyl)-lH-pyrazol-4-yl]-N-ethyl-2-pyridinamine (125 mg, 46%) as a solid, m.p. 186-187 OC. 15 Anal. Calc'd For C 16 H,,C1N 4 : 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 20 above (particularly in Scheme XVIII) by selection of the corresponding starting reagents: MIUTE (RU.E) WO98/52940 PCT/US98/10436 195 Example A-223 F NH N N 0 NH 2 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2 pyridinecarboxamide 5 Step 1: To a suspension of 4-[3-(4-fluorophenyl)-lH-pyrazol 4-yl]pyridine (prepared as set forth in Example A-208) (8.8 g, 0.037 mol) in methylene chloride was added m 10 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%), 15 mp: 207-2090C. Step 2: Preparation of 4-[3-(4-fluorophenyl)-lH-pyrazol 4-yl]-2-pyridinecarbonitrile To a solution of the product of step 1 (5.1 g, 0.02 20 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 UesmUE SHEET(RULE26) WO98/52940 PCT/US98/10436 196 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 5 filtered. The filtrate was concentrated and the crude was triturated with hexane and filtered to give 4.3 g of 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2 pyridinecarbonitrile (90%) as a pale yellow solid, mp: 238-2390C. 10 Step 3: Preparation of 4-[3-(4-fluorophenyl)-lH-pyrazol 4-vl1-2-pyridinecarboxamide: To a solution of 4-[3-(4-fluorophenyl)-lH-pyrazol-4 yl]-2-pyridinecarbonitrile from step 2 (0.45 g, 0.0017 15 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 0 C. The mixture was stirred for 1 hour while allowing it to warm to room temperature. Water was added and the precipitate was 20 collected by filtration and air-dried to give 0.32 g of 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2 pyridinecarboxamide as a white solid (67% yield), mp: 230-231 oC. Anal. Calc'd for C 15 sHnFN 4 0: C, 63.83; H, 3.93; N, 19.85. Found C, 63.42; H, 3.66; N, 19.58. 25 Example A-224 F S NH N N 0 CH 3 SUWEffSHEET (RULE26) WO98/52940 PCT/US98/10436 197 Methyl 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2 pyridinecarboxylate To a suspension of 4-[3-(4-fluorophenyl)-lH-pyrazol 4-yl]-2-pyridinecarboxamide prepared as set forth in 5 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 10 filtration and air-dried to give 2.0 g of methyl 4-[3-(4 fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinecarboxylate as a white solid (69% yield), mp: 239-241 0 C. Anal. Calc'd for

C

16

H

12

FN

3 0 2 : C, 64.64; H, 4.07; N, 14.13. Found: C, 64.36; H, 4.10; N, 14.27. 15 Example A-225 F SNH NN N 0 H 4-[3-(4-fluorophenyl) -l1H-pyrazol-4-yl]-N-methyl-2 pyridinecarboxamide 20 A mixture of methyl 4-[3-(4-fluorophenyl)-lH 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 1200C in 25 a sealed tube for 16 hours. After cooling, water was EU SHEET(RFU2) WO98/52940 PCT/US98/10436 198 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)-lH 5 pyrazol-4-yl]-N-methyl-2-pyridinecarboxamide as a white solid, mp: 88-89 0 C. Anal. Calc'd for C 16

H

13

FN

4 0 + 0.4 H 2 0: C, 63.32; H, 4.58; N, 18.46. Found C, 63.10; H, 4.62; N, 18.35. 10 Example A-226 F NH NK, 0 OH 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl] -2 pyridinecarboxylic acid 15 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 20 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 25 was purified by treating with ether to give 0.62 g of 4 [3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinecarboxylic SussMauTESEET(RUJLE26W) WO 98/52940 PCT/US98/10436 199 acid as a white solid (73% yield), mp: 245 0 C(dec). Anal Calc'd for C 1 5 HoFN 3 0 + 0.2 H 2 0: C, 62.80; H, 3.65; N, 14.65. Found: C, 62.77; H, 3.42; N, 14,58. 5 Additional compounds of the present invention which were prepared according to one or more 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 10 analysis results for each compound also are disclosed in Table 3. SussTUTESHEEf (i LM6 WO 98/52940 PCT/US98/10436 200 Ln In Q)~ (H H H H- H H w Hn H H (1 o 0 *m) . U') Cl'(Y . . 0) m mm 0 Y) N 0 mm N w H H H (u C ~ y o 0 U- f 0 II )L r)L )> im im c rd ry L co U 0')0 y ()0 ()r)m 0 > u i nL o D U)w n r-iW- D 1~ un o)')o H mmD (d DCN C cN H cN r-i () H- co H~ m H0 H~ Hn w H w m< H 14 mHHH m) w 0U owr 0 : ) H H~ H H)c J m -q4WCNMHa 0HWriH0 0 wC oL 44 LnmwL nL nwr-W W j w w w 1. w w I- CI Io I. w I . u WO 98/52940 PCTIUS98/10436 201 CH 0 'L0 (N H mn I Ln Lfl LOn *HH *.(j( o a 0D 00 00 00 HN J ~i r-C Dm i W H o m o m wm O-L HHH H NHH HHHMH NHHH(N HHH H m m m m nm m Lome wH W D - Ln ;i - 0 w o w a-H NHH H HHHHN N~lO Oc WNO ti:-Nm 000 OONO HH>H HylL N m0 DC m y H 0 H H H NHH HHHH(wHHHM H H (N~kDHH HWW H wM M -m ~ H (N (N m ZIICN m . ND w*(N o nmm emo mmm m oH CD wr mHmmmammmmmememom(N H QC~~mHH *Ln w.~ N m m * * NNNNNNNN NNN NN WNNNNN NNNN ~C) m m -IH "t(N N 'nCN r mo ( m oqL m C m w d 0 ~q m NN N; M,~ H N (N NN 0 Ln N C)( O m 1 1 1 . 1 1 . .. I I I I I I 1 . 1 I I I I I I .I I , Su.fUTESHEET (RULE 26) WO 98/52940 PCT/US98/1 0436 202 0 0 L n ko m c~im in L Lf)L l CD . . cq * CN r 0 C C 0 000~ 0 H 0 D *CN Kvm w . .e~ . M a n . . H- H H H HHriHHH H H H H H H H H H cqH Lnw H LC in N in w m H mNrm- 1 C -r -w m HD0 co Lnc Hl H H HH HHH H HH HH H HH H cl H mH m N 0 A f c H wn mW N m NN r Hn *n * * nu) Q Itin c t G m c'lqc HzliH m H~ o m co o w w tIZ w wri N-i n r-w in w wo m ra w w 0mOLn w W HLI ()r-L ND - O(N-Cq O H L l 00 Ln r ,[- , ro d,~ WO 98/52940 PCT/US98/10436 203 Example A-227 F

N

N-H N H 4- [3- (3-f luorophenyl) -1H-pyrazol-4-yl]pyridine 5 Example A-228 /--o 0 N N-H N/ H 4-[3-(1,3-benzodioxol-5-yl) -1H-pyrazol-4-yl]pyridine Example A-229 F N/ N

N-CH

3 10 SAUBS UTESHEE B(RULE 26) WO 98/52940 PCT/US98/10436 204 4- [3- (3-f luorophenyl) -1-methyl-1H-pyrazol-4-yll]pyridine Example A-230 CI N N-H N H 5 4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl]pyridine Example A-231 oo 0 0 N / N-CH 3 N/ 4- [3-(1,3-benzodioxol-5-y) -1-methyl-1H-pyrazol-4-yl]pyrid 10 ine Example A-232 CI N

N-CH

3 N SMOTUTSEEr (RULE 26) WO 98/52940 PCT/US98/10436 205 4-[3-(4-chlorophenyl) -1-methyl-1H-pyrazol-4-yl]pyridine Example A-233 Cl N N-CH N + isomer

CH

3 5 4- [3- (3-chlorophenyl) -1-methyl-1H-pyrazol-4-yl] -2-methylp yridine and 4-[5-(3-chlorophenyl)-1-methyl-1H-pyrazol-4 -yll]-2-methylpyridine 10 Example A-234 CI N N-CH N + isomer 4- [3- (3-chlorophenyl) -1-methyl-1IH-pyrazol-4-yl]pyridine and 4-[5- (3-chlorophenyl) -1-methyl-1H-pyrazol-4-yl]pyridine B~Sj TTEHErRLE WO 98/52940 PCT/US98/10436 206 Example A-235

CH

3 N N-CH N/

CH

3 2-methyl-4- [1-methyl-3 (or 5)-(3-methylphenyl) -1H-pyrazol-4 -yl]pyridine 5 Example A-236 N N-H N/ 4-(3-phenyl-1H-pyrazol-4-yl)pyridine Example A-237

CF

3 N N- H N , 10 4-[3-[3-(trifluoromethyl)phenyl] -1H-pyrazol-4-yl]pyridine 8ussmMU SHEET(RULE26) WO 98/52940 PCT/US98/10436 207 Example A-238

CF

3 N N-CH N/ 4- [1-methyl-3- [3- (trifluoromethyl)phenyl] -1H-pyrazol-4 yll] pyridine 5 Example A-239 F F N-H n N/ 4-[3-(3,4-difluorophenyl)-1H-pyrazol-4-yl]pyridine assimTESHEET(FU.EMA) WO 98/52940 PCT/US98/10436 208 Example A-240 CI N) N N-H N/ F 4-[3-(4-chlorophenyl) -1H-pyrazol-4-yl]-2-fluoropyridine 5 Example A-241 Br N) N N- H N/ 4-[3-(4-bromophenyl) -1H-pyrazol-4yl]pyridine Example A-242 F F N

N-CH

3 10 4- [3- (3,4-difluorophenyl) -1-methyl-1H-pyrazol-4-yl]pyridi asmsmWESHEET(RULE WO 98/52940 PCT/US98/10436 209 ne Example A-243 Br N N-CH N/ 5 4- [3- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yl]pyridine Example A-244 F , N N-H N , (E) -4- [3- (4-f luorophenyl) -1H-pyrazol-4-yl] -2- (2-phenyleth 10 enyl)pyridine .JsmlUTESHEET (RULE26) WO 98/52940 PCT/US98/10436 210 Example A-245 c I N

CH

3 HN CH S (S) -4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -N- (2-methylbut yl) - 2-pyridinamine 5 Example A-246 Cl N N-H N OCH HN 4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -N- [(4-methoxy phenyl)methyl] - 2-pyridinamine SWBSTHUTESHEET(RLLE26) WO 98/52940 PCT/US98/10436 211 Example A-247 CI NHN N- H N N N- [4- [3- (4-chlorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] 2-pyridinemethanamine 5 Example A-248 F ~-N NH N NH N N- [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] 2-pyridinemethanamine 10 Anal Calc'd: C, 41.12; H, 3.58; N, 9.22. Found: C, 41.74; H, 5.05; N, 11.11. 8UmTUESHEET(RULE28) WO 98/52940 PCT/US98/10436 212 Example A-249 F N NH N/ H F 2-fluoro-4-[3-(4-fluorophenyl) -1H-pyrazol-4-yl]pyridine 5 Example A-250 IN NH N/ 4- [3- (4-iodophenyl) -1H-pyrazol-4-yl]pyridine Example A-251 N-CH3 N 10 4- [3- (4-iodophenyl) -1-methyl-1H-pyrazol-4-yl]pyridine SalTIIM8HEET(RULE26) WO 98/52940 PCT/US98/10436 213 Example A-252

F

3 C N N-CH N/ 4- [1-methyl-3- [4- (trifluoromethyl)phenyll] -1H-pyrazol-4-yl ] pyridine 5 Example A-253 F N N H N/ F HN R, S

CH

3 N- [1- (4-f luorophenyl)ethyl] -4- [3- (4-f luorophenyl) -1H-pyra zol-4-yl]- 2-pyridinamine ammTuTESHEtr(FOLEM) WO 98/52940 PCT/US98/10436 214 Example A-254 F N N H N H F N-[(3-fluorophenyl)methyll]-4- [3-(4-fluorophenyl) -1H-pyraz ol- 4 -yl]- 2-pyridinamine 5 Example A-255 F N N-CH N H3 C

NH

2 4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yll] -2- (1 methylhydrazino) pyridine SBSTMfESHEET (FM.E2) WO 98/52940 PCTIUS98/10436 215 Example A-256 F N_

-N-CH

3 N F 2-fluoro-4- [3- (4-f luorophenyl) -1-rethyl-1H-pyrazol-4-yllp yridine 5 Example A-257 F F N_ N NH N F 4-[3-(3,4-difluorophenyl)-lH-pyrazol-4-yl]-2-fluoro pyridine q36fTgflMMT(RUE2M WO 98/52940 PCT/US98/10436 216 Example A-258 F N /N-H N/

CH

3 4-[3-(4-fluorophenyl) -1H-pyrazol-4-yll]-3-methylpyridine 5 Example A-259 F \N / "N-CH 3 N/

CH

3 4- [3- (4-fluorophenyl) -1-methyl-1H-pyrazol-4-yll] -3-methylp yridine Example A-260 F F 1/ N 7

NCH

3 N N / 10 F MSlOTUTESHEET (RU.E 2) WO 98/52940 PCT/US98/10436 217 4-[3-(3,4-difluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-flu oropyridine Example A-261 F

CH

3 NN Z N N CH 3 N/ 5 3-(4-fluorophenyl)-N,N-dimethyl-4-(4-pyridinyl) -1H-pyrazo le- 1 -ethanamine Example A-262 F N N-CH N -N N/ F 10 2- [2- (4-fluorophenyl)ethyl] -4- [3- (4-fluorophenyl) -1 methyl-1H-pyrazol-4-yl] pyridine RJ6BTFUTE8HEET (RULE 26) WO 98/52940 PCT/US98/10436 218 Example A-263 F NH N H N HN 4- [3- (4-f luorophenyl) -1H-pyrazol-4-yl] -N- [1 (phenylmethyl)-4-piperidinyll]-2-pyridinamine 5 Example A-264 F NH NN HN NN N' - [4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] N,N-dimethyl - 1,2-ethanediamine mU SHEET(RUUE96) WO 98/52940 PCT/US98/10436 219 Example A-265 F IN NN N F N-NH 2,4-bis [3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine 5 Example A-266 F NH N HN HNN 0 N- [4- [3- (4-f luorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] -4 morpholineethanamine

SUBSITFUITESHEET(RULEM)

WO 98/52940 PCT/US98/10436 220 Example A-267 F N OH N

N/

F 5 3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl) -1H-pyrazole 1-ethanol Example A-268 F NH HN N H N,, N N 10 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N- [2- (1H-imidazol 1-yl) ethyll] -2-pyridinamine THUTES E( 8 ( E) WO 98/52940 PCTIUS98/10436 221 Example A-269 F N\ 0 NN NN F 5 4- [2- [3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-lH pyrazol-1-yll ethyl] morpholine Example A-270 F 'NN N-^VOH N F 10 (E)-3-(4-fluorophenyl)-4- [2-[2-(4-fluorophenyl)ethenyl] 4-pyridinyl] -lH-pyrazole-1-ethano1 WO 98/52940 PCT/US98/10436 222 Example A-271 F N

CH

3 N N CH 3 Na F 3- (4-f luorophenyl) -4- (2-f luoro-4-pyridinyl) -N,N-dimethyl 1H-pyrazole- 1-ethanamine 5 Example A-272 F I N N OH F 3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl)ethyl] -4 pyridinyl] -1H-pyrazole-1-ethanol 8 TUTESHEET(RULE2 WO 98/52940 PCT/US98/10436 223 Example A-273 F N I N N NI N 4-[1-[2-(dimethylamino)ethyl] -3-(4-fluorophenyl) -lH pyrazol-4-yl]-N,N-dimethyl-2-pyridinamine 5 Example A-274 F N N

N'

N HN F 4- [1- [2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -lH 10 pyrazol-4-yl] -N- [(4-f luorophenyl)methyll -2-pyridinamine SUWBSTTUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 224 Example A-275 F N ¢N N F 3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4 pyridinyl] -N,N-dimethyl-lH-pyrazole-1-ethanamine 5 Example A-276 F N N N N - O HN F N-[(4-fluorophenyl)methyl]-4-[3(or 5)-(4-fluorophenyl)-1 [[2- (4-morpholinyl)ethyl] -1H-pyrazol-4-yl] -2-pyridinamine SUBSTITUTSHEET(RULE26) WO 98/52940 PCT/US98/10436 225 Example A-277 F N N H N HN NH 4-[3-(4-fluorophenyl) -l1H-pyrazol-4-yl]-N-4-piperadinyl-2 pyridinamine 5 Example A-278 F N N - " NN F N,N-diethyl-3- (4-fluorophenyl) -4- (2-f luoro-4-pyridinyl) 1H-pyrazole- 1-ethanamine SUBS1TTHEET(RULE) WO 98/52940 PCT/US98/10436 226 Example A-279 F N N HN F 4- [1- [2- (diethylamino)ethyl] -3- (4-fluorophenyl) -lH pyrazol-4-yl] -N- [(4-f luorophenyl)methyl] -2-pyridinamine ss ESHEET(RULE26) WO 98/52940 PCT/US98/10436 227 Example A-280 F N N H N HN OH 2- [[4- [3- (4- (fluorophenyl) -lH-pyrazol-4-yl] -2 pyridinyl] amino] ethanol 5 Example A-281 F N

N-CH

3 HN OH 2- [[4- [3- (4-fluorophenyl) -1-methyl-lH-pyrazol-4-yl] -2 10 pyridinyl] amino] ethanol RSITfUTESHEE(RULE26) WO 98/52940 PCT/US98/10436 228 Example A-282 F NNH NN N 0 H HN OH 3- [[4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2 pyridinyl] amino] -1-propanol 5 Example A-283 F N SOH N NH N/ F HN 3 (or 5)-(4-fluorophenyl)-4-[2-[[(4 10 fluorophenyl)methyl] amino] -4-pyridinyl] -1H-pyrazole-1 ethanol WO 98/52940 PCT/US98/10436 229 Example A-284 F

CH

3 NS N C I N N . N,N-diethyl-3-(4-fluorophenyl)-4-(4-pyridinyl) -1H 5 pyrazole-1-ethanamine Example A-285 F 0 N N NN F HN 10 N- [(4-fluorophenyl)methyl] -4-[3-(4-fluorophenyl)-1-[2-(4 morpholinyl) ethyl] -1H-pyrazol-4-yll] -2-pyridinamine Example A-286 F _N N-H 0 N N / HN N N N 15 N- [5- (4-f luorophenyl) -4- (4-pyridinyl) -1H-pyrazol-3-yl] -4 morpholinepropanamine anmESHEETULE) WO 98/52940 PCT/US98/10436 230 Example A-287 F NN N-H C

CH

3 N HNCH 3 N' - [5-(4-fluorophenyl)-4-(4-pyridinyl) -1H-pyrazol-3-yll] N,N-dimethyl-1,3-propanediamine 5 Example A-288 F \N N- H HN N 5- (4-fluorophenyl) -N-2-propynyl-4- (4-pyridinyl) -1H pyrazol-3-amine Example A-289 F N OH N 0N F HN 10 S1E (UE 6 WO 98/52940 PCT/US98/10436 231 3- (4-fluorophenyl) -4- [2- [ [ (4-fluorophenyl)methyl] amino] 4-pyridinyl] -1H-pyrazole-1-ethanol Example A-290 F N OH N HN 5 5- (4 - f luorophenyl) -4- [2- [ [ (4 -fluorophenyl)methyll amino] 4-pyridinyl] -1H-pyrazole-1-ethanol Example A-291 F N N NN-H N. 10 4- [3- [(4-f luorophenyl) -1H-pyrazol-4-yllquinoline .MTUESHEET (RULE26) WO 98/52940 PCT/US98/10436 232 Example A-292 F K N\ N- H N / N

CO

2 Me N-[5-(4-fluorophenyl)-4-(4-pyridinyl) -lH-pyrazol-3 5 yl]glycine methyl ester Example A-293 F N NH N HN C0 2 H N-[5-(4-fluorophenyl)-4-(4-pyridinyl) -l1H-pyrazol-3 10 yl] glycine Example A-294 F N NN SEfITUTESHiEEf(RULE26) WO 98/52940 PCT/US98/10436 233 4- [3- (4-fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4 yl ] pyridine Example A-295 F N N NN 5 4-[5-(4-fluorophenyl) -1- (2-propynyl) -1H-pyrazol-4 yl ] pyridine Example A-296 N \ N NH N/ 10 4,4' - (1H-pyrazole-3,4-diyl)bis[pyridine] Example A-297 CI CI N NH N/~ 15 ue1mUE8SHEEr(RuLE) WO 98/52940 PCT/US98/10436 234 4-[3-(3,4-dichlorophenyl) -lH-pyrazol-4-yl]pyridine Example A-298 CI N NH N / HN NH N-[E5-C4-chlorophenylI-4 C4-pyridinyl)-IH-pyrazol-3-yl] -4-piperidinamine 5 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: 10 Example A-299 F N I \ NH N N Cl 2-Chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine 15 Step 1: WWUTE8HEET(RUU26) WO98/52940 PCT/US98/10436 235 "NMe 2 N 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 5 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 10 yellow crystal (50% yield); mp: 47-49 OC. Step 2: Preparation of 2-(2-chloro-4-pyrimidinyl)-1-(4 fluorophenyl)ethanone F 0 N N CI 2-(2-chloro-4-pyrimidinyI)-1-(4-fluorophenyDethanone 15 To a solution of lithium diisopropylamide (generated from BuLi (0.045 mol) and diisopropylamine (0.048 mol) in THF) at -78 oC 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 20 fluorobenzoate (7.62 g, 0,045 mol) in THF was added and SUBLSlMTTESHEET(RULE2) WO98/52940 PCT/US98/10436 236 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 5 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 (51% yield), mp: 112-113 oC. 10 Step 3: Preparation of (E)-2-(2-chloro-4-pyrimidinyl)-3 (dimethylamino)-1-(4-fluorophenyl)-2-propen-l-one F 0 N N NMe 2 CI C ED- 2-C 2-ch Ior o-4-pyr i m i d i ny I D- 3-Cdimet hy I am i no)-1-C4-f I uoropheny I ]-2-propen- 1-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-pyrazol-4-yl]pyrimidine 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)-lH-pyrazol-4 JSMUMSHEETRULE26) WO98/52940 PCT/US98/10436 237 yl]pyrimidine as a yellow solid, mp: 204-205 oC; Anal. Calc'd for C 13 HClFN 4 : C, 56.84; H, 2.94; N, 20.40; Cl, 12.91. Found: C, 56.43; H, 2.76; N, 20.02; Cl, 12.97. 5 Example A-300 F NH N N

NHNH

2 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2(1H)-pyrimidinone hydrazone 10 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. 15 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 20 0.5 g of product, 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl] 2(1H)-pyrimidinone hydrazone, as a pale yellow solid (38% yield), mp: 149-150 oC; Anal. Calc'd for C 13 HzzFN 6 : C, 57.77; H, 4.10; N, 31.10. Found: C, 57.70; H, 4.31; N, 30.73. stmU SEHEET(RU 26) WO98/52940 PCT/US98/10436 238 Example A-301 F NH /N N N N 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N,N-dimethyl 2-pyrimidinamine 5 Step 1: Preparation of NMe 2 N '- N NMe2 A solution of the compound prepared in step 2 of Example A-299 (3.0 g, 0.02 mol) and tert 10 butylbis(dimethylamino)methane (10.45 g, 0.06 mol) in 40 mL of DMF was stirred at 110 oC 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 15 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 0 C; Anal. Calc'd for CoH 16

N

4 : C, 62.47; H, 8.39; N, 29.14. Found: C, 62.19; H, 8.58; N, 29.02. MSSTESHEET(RULE26) WO98/52940 PCTIUS98/10436 239 Step 2: Preparation of 4-[3-(4-fluorophenvl)-lH-pyrazol 4-yll-N,N-dimethyl-2-pyrimidinamine To a solution of the compound prepared in step 1 of the present Example (1.2 g, 0.0064 mol) and triethylamine 5 (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 10 magnesium sulfate and filtered. The filtrate was concentrated and the crude (1.6 g) was then dissolved in 50 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, 15 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 20 of product, 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N,N dimethyl-2-pyrimidinamine, as a yellow solid (33% yield), mp: 155-156 oC; Anal. Calc'd for C 15 Hl 4 FN,: C, 63.59; H, 4.98; N, 24.72. Found: C, 63.32; H, 4.92; N, 24.31. 25 Example A-302 F N \ NH N N HN

CH

3 SMUTESHEET(RuLE28) WO 98/52940 PCT/US98/10436 240 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N-methyl-2 pyrimidinamine A suspension of 2-chloro-4-[3-(4-fluorophenyl)-1H 5 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 oC overnight. The mixture was then cooled to room temperature and the precipitate was filtered, air-dried 10 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 oC; Anal Calc'd for C 14 Hl 2

FN

5 : C, 62.45; H, 4.49; N, 26.01. Found: C, 62.58; H, 4.36; N, 25.90. 15 Example A-303 F N -I NH N HN N 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N-(phenylmethyl) 2-pyrimidinamine 20 This compound was synthesize by refluxing 2-chloro 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 in benzylamine overnight. The product, 4-[3-(4-fluorophenyl)-1H 25 pyrazol-4-yl]-N-(phenylmethyl)-2-pyrimidinamine, was obtained as a white solid in 95% yield; mp: 216-217 oC; SMfUTESHEE(L2) WO 98/52940 PCT/US98/10436 241 Anal. Calc'd for C 20

H

1 6 FNs: C, 69.55; H, 4.67; N, 20.28. Found: C, 69.73; H, 4.69; N, 19.90. Example A-304 F NH N. N N 5N HN 5 N-cyclopropyl-4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2 pyrimidinamine This compound was synthesized by stirring 2-chloro 10 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyrimidine prepared in accordance with Example A-299 with excess cyclopropylamine in methanol at 50 oC for 12 hours. The product, N-cyclopropyl-4-[3-(4-fluorophenyl)-lH-pyrazol 4-yl]-2-pyrimidinamine, was obtained as a white solid in 15 26% yield, mp: 203-204 oC; Anal. Calc'd for C 16

H

14 FNs: C, 65.07; H, 4.78; N, 23.71. Found: C, 64.42; H, 4.82; N, 23.58. ag1UTE8EE(RULE26) WO 98/52940 PCT/US98/10436 242 Example A-305 F NH I HNO 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N- [(4 methoxyphenyl)methyl] -2-pyrimidinamine 5 This compound was synthesized by refluxing 2-chloro 4-[3-(4-fluorophenyl) -l1H-pyrazol-4-yl] pyrimidine prepared in accordance with Example A-299 in 4-methoxybenzylamine overnight. The product, 4- [3-(4-fluorophenyl)-1H 10 pyrazol-4-yl]-N-[(4-methoxyphenyl)methyl] -2 pyrimidinamine, was obtained as a off-white solid in 80% yield, mp: 183-185 oC; Anal. Calc'd for C 21

H

18

FN

5 0: C, 67.19; H, 4.83, N, 18.66. Found: C, 67.01; H, 5.11; N, 18.93. 15 Example A-306 F NH N N N N

NH

2 AwImMESHEET(RULE WO 98/52940 PCTIUS98/10436 243 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyrimidinamine A solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4 yl]-N-[(4-methoxyphenyl)methyl]-2-pyrimidinamine prepared 5 in accordance with Example A-305 (0.35 g, 0.00093 mol) in 15 mL of trifluoroacetic acid was heated at reflux for 16 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 oC; Anal. 15 Calc'd for C 13 HoFN 5 0.25 H 2 0: 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 O N 20 N-[4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyrimidinyl] N-(phenylmethyl)acetamide To a mixture of 4-[3-(4-fluorophenyl)-lH-pyrazol-4 yl]-N-(phenylmethyl)-2-pyrimidinamine prepared in 25 accordance with Example A-303 (0.15 g, 0.00043 mol), DMAP am1UEHEET(RULE 26) WO98/52940 PCT/US98/10436 244 (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 5 residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO 3 , 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 10 (4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyrimidinyl]-N (phenylmethyl)acetamide, as a white solid (60% yield), mp: 176-178 oC; Anal. Calc'd for C 22 Hl 8 FNs: C, 68.21; H, 4.68; N, 18.08. Found: C, 67.67; H, 4.85; N, 17.79. 15 Example A-308 F NH I ,N HN N0 H N

-

o 0 Ethyl [4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2 pyrimidinyl]carbamate 20 To a suspension of 4-[3-(4-fluorophenyl)-lH-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 U SHEET(RULEM) WO 98/52940 PCT/US98/10436 245 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 5 was trituated with ether to give 0.15 g of product, ethyl [4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2 pyrimidinyl]carbamate, as a white solid (46% yield), mp: 163-165 oC; Anal. Calc'd for C, 16

H

4

FN

5 0sO 2 : C, 58.71; H, 4.31; N, 21.04. Found: C, 59.22; H, 4.51; N, 21.66. 10 Example A-309 NH N NN 4-[3-(3-methylphenyl)-lH-pyrazol-4-yl]pyrimidine 15 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 20 pyridinyl methane. Anal. Calc'd for C 14

H

12

N

4 (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 oC. SUSMUTE8HMEET(RUE26) WO 98/52940 PCT/US98/10436 246 Example A-310 N N / NH cII N CI 4-[3-(4-chlorophenyl) -l1H-pyrazol-4-yl]pyrimidine 5 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. 10 Anal. Calc'd for Cz 13

HN

4 C1*O.25MH 2 0: C, 59.78; H, 3.67; N, 21.45. Found: C, 59.89; H, 3.32; N, 21.56. m.p. (DSC): 218.17 oC. Example A-311 N N "N NH 15 F 4- [3-(3-fluorophenyl) -l1H-pyrazol-4-yl]pyrimidine This compound was prepared according to the chemistry described in Schemes VI and IX by selection of slmn IESHEET (FU.EN21) WO 98/52940 PCT/US98/10436 247 the corresponding pyrimidine starting material in place of the pyridine starting material. Anal. Calc'd for C 13 HgN 4 F (240.24): C, 64.99; H, 3.78; N, 5 23.22. Found: C, 64.78; H, 3.75; N, 23.31. m.p. (DSC): 168.58 oC. Example A-312 N! N N NH F 10 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 15 of the pyridine starting material. Anal. Calc'd for C 13 Hg 9

N

4 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 oC. 20 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: SmmESHM (R L WO 98/52940 PCT/US98/10436 248 c I N NH N,,,5 , N N ) N H 4-F3-CA-chlorophenylD-5 Cl-p iperaz inyl I 1H-pyrazolI 4- ylI]pyr imid ine B r N N H N ~- N CN H 1-[5-C4-bromophenyl)-4 C4-pyridinyI>-IH-pyrazol-3-yI~piperazine WO 98/52940 PCT/US98/10436 249

F

3 C N NH N N/ O H 1-E4-C4-pyridiny ID -5 [ 4-(trif I uoromethy IDpheny Il] 1H-pyrazol-3-y l]piperazine NC N NH N N N H 4-[ 5-(1-piperaziny l-4-(4-pyridiny ID -1H-pyrazol-3-yl]benzonitrile suesmUTESHEET

(FRUEW

WO 98/52940 PCTIUS98/1 0436 250 HCC NJ N NH N ~- N NN H 1-[5-C(4-ethynylphenyID-A-C4-pyridinyvD -IH-pyrazol-3-yI]piperazine F N N NH N ,- HN 5-C4-flIuoropheny 1J-4 CI-pyridinyID-N-3-pyrrolidinyl IH-pyrazolI- 3-amine cI NH NH 5-C4-chlorophenyID-4 C 4-pyr idinfl - N- 3-pyrroliIdi nylI 1H-pyrazo 1-3-amine WO 98/52940 PCTIUS98/1 0436 251 F N N H N F1 HN _NH N-5-C 4-f luoropheny ID-A (4-pyridinylD-1H-pyrazol-3-yI] -4-p iper idiramine F N O N N N H 3-C4-flIuorophenylI -5 (1--piperazinyl)-4 C 4- pyr id flD- 1 H- pyr azo I 1-ethanol 8LegfTUTESHW(RULE26) WO 98/52940 PCTIUJS98/1 Q436 252 N OH

SN

N N C) N H 3-(4-chlorophenyl)>5 C 1--p iperaz inyID- 4 (4-pyr idinl -1H-pyrazoleI 1-ethanol F N N OH

NH

2 4-L2-aminoethylD-2-CA-fluoro phe-nyID-4,5,6,7-tetrahydro 3-C(4-pyr Idi nylIDpyrazo to E1. 5-alpyr imid in- 6-o1 W~8~EEF(RULE% WO 98/52940 PCT/US98/1 0436 253 c I N N N N H 2 4-[2-amjnoethyl)>2-C--chloro phe-nyI)- ,5,5,7-tetrahydro 3-(4-pyr idiny iDpyrazo 10 [1. 5-a]pyr imi din-6-o I cI N N O H N N 3-(4-chlorophenylD-4-C4-pyrimidinyID IH-pyrazole-1-ethanol WO 98/52940 PCT/US98/10436 254 F ~N9 N NH NN

NH

2 5-C4-fluorophenyl)-4-(4-pyrimidinyID IH-pyrazole-3-ethanamine c I N NH N,,,5,N

NH

2 5-C4-chlorophenyl)-4-CAI-pyrimidiny ID IH-pyrazole-3-ethanamine 4-[3-(4-fluoropheny[D-5-C4-piperidinylD IH-pyrazol-4-yI]pyrimidine WO 98/52940 PCT/US98/10436 255 Cl N NH N N NH 4-[3-(4-chlorophenyl)-5-(4-piperidinyI) 1H-pyrazol-4-yl]pyrimi dine F N NH N N NHCOMe N-[4-[3-C4-f luoropheny l)- H-pyrazol-4-yl I] 2-pyrimidinyl]acetamide Cl N NH N N NHCOMe N-[4-[ 3-(4-ch I oropheny I)- 1H-pyrazol-4-y I] 2-pyrimidinyl]acetamide S ITIUTE SHEET (RULE ) WO 98/52940 PCT/US98/1 0436 256 F N 7 N NHCOEt N-L4-[3-C4-fluorophenyl)-1H-pyrazol-4-yI] 2-pyr imidinylIpropanam ide clI N N H N XN NH COEt N-[4-[3-C4-fluorophenylD-IH-pyrazol-4-yl] 2-pyr imid infy i]propanam ide NH NNH N N 6-E3-C4-fluorophenylD-1H-pyrazol-4-yl]-1H-purine ~u~rrwTEHE~(FULE) WO 98/52940 PCT/US98/1 0436 257 c I N N_ N ~ N 6-[3-C1-chlorophenyID-1H-pyrazo-4-y]-H-pur ine N NH N -N N COMe N-L4-[3-C4-chlorophenylD-IH-pyrazol-A4-yl] 2-pyrimidinyl]-N-CphenylmethyI~acetamide F N" -~NH N sN nN COEt N-[,4-[3-C,4-fluorophenyI)-lH-pyrazoI-AI-yI] 2-pyrimidinyl]-N-Cphenylmethyl~propanamide MOglTUTE SKM (RULEi26) WO98/52940 PCT/US98/10436 258 CI N / NH N N NCOEt Bn/ N-[4-[3-(4-ch I oropheny I)- 1H-pyrazo I -4-y l] 2-pyrimidinyl]-N-(phenylmethyl)propanamide BIOLOGICAL EVALUATION p38 Kinase Assay 5 Cloning of human p38a: 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 10 synthesized from total RNA as follows: 2 gg of RNA was annealed to 100 ng of random hexamer primers in a 10 pl reaction by heating to 70 oC for 10 minutes followed by 2 minutes on ice. cDNA was then synthesized by adding 1 pl of RNAsin (Promega, Madison WI), 2 pl of 50 mM dNTP's, 4 15 pl of 5X buffer, 2 pl of 100 mM DTT and 1 pl (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 OC for 1 hour. 20 Amplification of p38 cDNA was performed by aliquoting 5 pl of the reverse transcriptase reaction into a 100 pl PCR reaction containing the following: 80 pl dH 2 0, 2 pl 50 mM dNTP's, 1 pl each of forward and reverse primers SUTlUTE8HEF.RULE26) WO98/52940 PCT/US98/10436 259 (50 pmol/pl), 10 jil of 10X buffer and 1 pl 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. The 5 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 oC for 1 10 minute, 60 oC for 1 minute and 68 oC 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 15 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. 20 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 25 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, 30 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. STuTESEET(RULEM) WO98/52940 PCT/US98/10436 260 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 grown 5 in Luria Broth (LB) containing 100 mg/ml ampicillin. The next day, 500 ml of fresh LB was inoculated with 10 ml of overnight culture, and grown in a 2 liter flask at 37 oC with constant shaking until the culture reached an absorbance of 0.8 at 600 nm. Expression of the fusion 10 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 15 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 20 from five 1 L shake flask fermentations was resuspended in a volume of PBS (140 mM NaCl, 2.7 mM KC1, 10 mM Na 2

HPO

4 , 1.8 mM KH 2

PO

4 , 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 25 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). 30 Glutathione-Sepharose Affinity Chromatography: 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. 35 The resin was collected by centrifugation (600 x g, 5 min) and washed with 2 x 150 ml PBS/1% Triton X-100, SWSTUTSMH (RU.E26) WO98/52940 PCT/US98/10436 261 followed by 4 x 40 ml PBS. To cleave the p38 kinase from the GST-p38 fusion protein, the glutathione-sepharose resin was resuspended in 6 ml PBS containing 250 units thrombin protease (Pharmacia, specific activity > 7500 5 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 10 0.3 mM PMSF. Mono Q Anion Exchange Chromatography: The thrombin-cleaved p38 kinase was further purified by FPLC-anion exchange chromatography. Thrombin-cleaved 15 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 20 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 S100 Gel Filtration Chromatography: 25 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% glycerol)). Protein was eluted from the column with 30 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 oC. Typical purified protein yields from 5 L E. coli shake 35 flasks fermentations were 35 mg p38 kinase. SUTSTEMMSHEET(RULE26) WO98/52940 PCTIUS98/10436 262 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 5 phosphorylates a biotinylated substrate, PHAS-I (phosphorylated heat and acid stable protein-insulin inducible), in the presence of gamma 32 P-ATP ( 32 P-ATP). PHAS-I was biotinylated prior to the assay and provides a means of capturing the substrate which is phosphorylated 10 during the assay. p38 Kinase was activated by MKK6. Compounds were tested in 10 fold serial dilutions over the range of 100 AM to 0.001 AM using 1% DMSO. Each concentration of inhibitor was tested in triplicate. All reactions were carried out in 96 well 15 polypropylene plates. Each reaction well contained 25 mM HEPES pH 7.5, 10 mM magnesium acetate and 50 AM unlabeled ATP. Activation of p38 was required to achieve sufficient signal in the assay. Biotinylated PHAS-I was used at 1-2 jg per 50 il reaction volume, with a final 20 concentration of 1.5 AM. Activated human p38 kinase alpha was used at 1 jg per 50 Al reaction volume representing a final concentration of 0.3 AM. Gamma 32 p ATP was used to follow the phosphorylation of PHAS-I. 32 P-ATP has a specific activity of 3000 Ci/mmol and was 25 used at 1.2 jCi per 50 il reaction volume. The reaction proceeded either for one hour or overnight at 30 oC. Following incubation, 20 Al of reaction mixture was transferred to a high capacity streptavidin coated filter plate (SAM-streptavidin-matrix, Promega) prewetted with 30 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 32 P incorporated, each well was washed to remove unincorporated 32 P-ATP three times with 35 2M NaCl, three washes of 2M NaCl with 1% phosphoric, three washes of distilled water and finally a single wash s MIwmUTES EET(RU LE2) WO98/52940 PCT/US98/10436 263 of 95% ethanol. Filter plates were air dried and 20 pl 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 5 based on p38 kinase alpha induced phosphorylation of EGFRP (epidermal growth factor receptor peptide, a 21 mer) in the presence of 33 P-ATP. Compounds were tested in 10 fold serial dilutions over the range of 100AM to 0.001pM in 1% DMSO. Each concentration of inhibitor was 10 tested in triplicate. Compounds were evaluated in 50Al reaction volumes in the presence of 25 mM Hepes pH 7.5, 10 mM magnesium acetate, 4% glycerol, 0.4% bovine serum albumin, 0.4mM DTT, 50AM unlabeled ATP, 25 yg EGFRP (200ptM), and 0.05 uCi gamma 33 P-ATP. Reactions were 15 initiated by addition of 0.09 pg of activated, purified human GST-p38 kinase alpha. Activation was carried out using GST-MKK6 (5:1,p38:MKK6) for one hour at 30 oC in the presence of 50AM ATP. Following incubation for 60 minutes at room temperature, the reaction was stopped by 20 addition of 150Al 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 50pl of clarified solution head volume was transferred 25 from the reaction wells to Microlite-2 plates. 150p1l of Microscint 40 was then added to each well of the Microlite plate, and the plate was sealed, mixed, and counted. SUBSmUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 264 TABLE 4 Example p38 kinase IC50 (uM) 1 4.6 5 2 1.5 8 <0.1 16 3.8 23 1.5 25 2.6 10 26 0.7 28 0.3 33 2.5 34 8.0 36 12.1 15 38 0.8 39 1.1 40 1.3 42 0.3 43 <0.1 20 44 <0.1 45 <0.1 46 <0.1 47 3.2 48 1.8 25 50 2.3 51 <0.1 52 0.1 53 0.9 54 0.7 30 55 6.4 143 <0.1 TNF Cell Assays 35 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 40 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 45 magnesium. The cells were centrifuged at 400 x g for 10 minutes at room temperature. The cells were resuspended SU6STILJTEHEC( mZ WO98/52940 PCT/US98/10436 265 in Macrophage Serum Free Medium (Gibco BRL) at a concentration of 2 million cells/ml. LPS Stimulation of Human PBMs: 5 PBM cells (0.1 ml, 2 million/ ml) were co-incubated with 0.1 ml compound (10-0.41 AM, 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 10 (Calbiochem, 20 ng/ml, final concentration) was then added at a volume of 0.010 ml. Cultures were incubated overnight at 37 oC. Supernatants were then removed and tested by ELISA for TNF-a and ILl-b. Viability was analyzed using MTS. After 0.1 ml supernatant was 15 collected, 0.020 ml MTS was added to remaining 0.1 ml cells. The cells were incubated at 37 oC for 2-4 hours, then the O.D. was measured at 490-650 nM. Maintenance and Differentiation of the U937 Human 20 Histiocytic Lymphoma Cell Line: U937 cells (ATCC) were propagated in RPMI 1640 containing 10% fetal bovine serum, 100 IU/ml penicillin, 100 Ag/ml streptomycin, and 2 mM glutamine (Gibco). Fifty million cells in 100 ml media were induced to 25 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 30 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 AM, final concentration) 35 for 1 hour in 96 well microtiter plates. Compounds were prepared as 10 mM stock solutions in DMSO and diluted in m TUEsHEE (RULEM 2) WO98/52940 PCTIUS98/10436 266 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 0 C, the amount of TNF-a 5 released in the culture medium was quantitated by ELISA. Inhibitory potency is expressed as IC50 (AM). Results of these TNF Cell Assays are shown in Table 5. gamumSEET(RULE26) WO 98/52940 PCT/US98/10436 267 TABLE 5 Example. Human PBM Assay U937 Cell Assay IC50 (aM) IC50 ((AM) 1 0.5 5 2 1.6 0.578 4 0.1 0.222 5 0.274 7 0.2 0.201 8 <0.1 10 9 0.4 10 0.7 1.687 12 8.5 13 4.8 14 1.2 15 17 1.1 19 0.3 0.484 20 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 25 30 2.6 31 0.8 1.053 32 2.696 33 0.4 34 0.5 30 35 0.7 36 1.4 37 1.5 0.099 38 0.2 0.208 39 0.7 0.244 35 40 0.4 41 1.0 42 0.7 43 <0.1 0.243 44 0.4 0.477 40 45 <0.1 0.04 46 0.329 47 2.359 48 2.2 0.522 49 6.8 45 50 0.9 51 0.074 54 0.2 0.13 55 <0.1 0.228 143 0.301 SSmMUTE SHEE(RU WO98/52940 PCT/US98/10436 268 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 5 [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 10 instances) 1 to 24 hours prior to the LPS challenge. Rats were administered 30 jg/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 oC until 15 quantitative analysis of TNF-u 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. 20 Mouse Assay Mouse Model Of LPS-Induced TNF Alpha Production: TNF alpha was induced in 10-12 week old BALB/c 25 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 30 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 35 allowed evaluation of compound potency at Cmax plasma levels whereas the 6 hour protocol allowed estimation of SMMTESHWEET(RLU28) WO98/52940 PCTIUS98/10436 269 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. 5 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 IC 50 (pm). Mouse-LPS assay results are expressed as percent inhibition. ~W~uTE8M (M)LaE"O WO 98/52940 270 PCT/US98/10436 TABLE 6 Example p38 1 p38 2 U937 mLPS nLPS mLPS 8h 6h dose lh, 30mpk A-212 0.49 0.74 0.0967 20 10 93 A-208 0.104 0.049 0.1896 98 30 97 A-227 0.06 96 A-228 0.76 0.339 0.4173 32 30 92 A-229 1.4 0.4622 76 91 A-230 0.42 0.178 96 A-231 0.174 0.3225 86 30 94 A-232 0.048 96 A-233 0.044 53 A-234 0.103 A-235 0.104 56 A-236 0.237 94 A-237 0.093 0.087 60 A-238 0.177 0.4016 A-239 0.034 51 30 87 A-240 0.961 78 30 85 A-241 0.338 79 30 87 A-242 0.047 95 30 87 A-243 0.729 82 A-244 0.099 A-245 <.001 0.0337 65 A-246 0.403 0.592 0.4952 A-247 <0.01 0.166 A-249 0.432 73 30 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 0.2976 38 30 80 A-256 0.813 0.4562 A-257 1.081 <.01 0.5167 A-213 0.22 57 A-258 0.48 1.2083 68 A-259 0.17 0.7574 62 A-210 0.16 0.1983 85 30 93 A-260 0.23 1.2821 47 30 79 A-214 0.06 1.4006 70 A-261 0.008 0.2542 48 30 92 A-216 0.018 1.8287 27 30 91 A-262 <0.1 0.3267 45 A-263 <0.01 <0.1 0.5434 49 8LASMlnESEET(RULE26) WO 98/52940 PCT/US98/1 )436 271 Example p38 1 p38 2 U937 mLPS mLPS mLPS 8h 6h dose lh, 30mpk A-264 0.2594 61 A-265 <0.1 0.6016 32 A-266 0.5393 0 A-267 0.43 2.6681 80 A-268 <0.01 0.0074 11 A-217 0.697 0.3486 9 A-269 >10 uM 51 A-270 0.015 0.3466 53 A-271 0.216 4.2144 68 A-272 0.073 0.583 -8 A-273 6.98 >10 43 A-274 <0.1 0.92 21 30 10.14 A-275 2 >10 A-276 0.176 0.45 -24 30 A-277 0.026 33 30 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 0.0973 30 30 A-283 <0.1 0.7998 -20 30 A-284 0.98 0.5088 -1 A-285 <0.1 0.1795 11 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 A-290 6.0191 4 30 A-291 0.388 1.1309 36 30 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-296 26 A-297 0.52 0.17 89 30 p38c in vitro assay results based on PHAS-I assay procedure 2 p38c in vitro assay results based on EGFRP assay procedure SUMTITUTESHEET(RULE26) WO98/52940 PCT/US98/10436 272 Induction And Assessment Of Collagen-Induced Arthritis In Mice: Arthritis was induced in mice according to the procedure set forth in J.M. Stuart, Collagen Autoimmune 5 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 pg of chick type II collagen (CII) (provided by Dr. Marie Griffiths, Univ. of Utah, Salt 10 Lake City, UT) in complete Freund's adjuvant (Sigma) on day 0 at the base of the tail. Injection volume was 100 tl. Animals were boosted on day 21 with 50 pg of CII in incomplete Freund's adjuvant (100 Al volume). Animals were evaluated several times each week for signs of 15 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 20 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 25 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. 30 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 35 oral gavage in a volume of 0.1 ml b.i.d. Administration began on day 20 post collagen injection and continued SUSTUMSHEEr(RLULE WO98/52940 PCTIUS98/10436 273 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. 5 TABLE 7 Compound % Inhibition of Arthritis A-210 58.5 @ 15 mpk A-172 49.3 @ 100 mpk A-189 51.6 @ 30 mpk 10 A-208 97.5 @ 60 mpk A-208 75.0 @ 60 mpk Also embraced within this invention is a class of pharmaceutical compositions comprising the active 15 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 20 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 25 (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 30 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) 35 as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier. The pH of SUmnTUTESHEET(RLE) WO98/52940 PCT/US98/10436 274 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 5 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 10 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 15 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, 20 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 25 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, 30 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 35 ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. SUB50TUTESHEET (RULE26) WO98/52940 PCT/US98/10436 275 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 5 propylene glycol, butane-l,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. 10 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 15 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 20 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 25 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 30 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 35 and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and 8 MU SHEET (RULE 2) WO98/52940 PCT/US98/10436 276 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 5 formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl 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, 10 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 15 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 20 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 25 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 30 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 35 administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, suesnU SHEET(UL2 WO98/52940 PCT/US98/10436 277 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, 5 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 10 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 15 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 20 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 25 respect to specific embodiments, the details of these embodiments are not to be construed as limitations. SUBSTUTESHEE (RULE26) WO98/52940 PCT/US98/10436 278 Description of parallel array synthesis methodology utilized to prepare compounds of Examples B-i, B-ii, and B-iii. 5 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 Examnples B-1575 through B-2269. 10 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 Bl. Each reaction vessel B1 is made of either 15 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 B4 is either opened or 20 closed by controlling the leur-lock position or by the opening or closing of levers B5 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 25 pressure beneath the valve assembly plate by control of inert gas flow through the inert gas inlet valve B6. The parallel reactions that are performed in these reaction blocks are allowed to progress by incubation in a jacketed, temperature controlled shaking station. 30 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 SEslUTESHEEf(RULE=) WO 98/52940 PCTIUS98/10436 279 mantle B7. Mixing is effected at the shaking station by either vertical orbital shaking of the up-right reaction block or by lateral shaking of the reaction block tilted on its side. 5 Functionalized resins are optionally added to each reaction vessel B1 during the course of reaction or at the conclusion of the reaction. These functionalized resins enable the rapid purification of each reaction 10 vessel product. Vacuum filtration of the reaction block apparatus by opening of the vacuum valve B8 allows purified products to be separated from resin-sequestered non-product species. Valve B8 is located on the bottom reaction block chamber B10 which houses the quadrant 15 collection vial racks B11. The desired products are obtained as filtrates in unique collection vials B9. Removal of solvent from these collection vials affords desired products. 20 SU9SSfUTESHEET(RU.EM) WO 98/52940 PCT/US98/10436 280 Scheme B-I BI BI B5 B6:inert gas inlet S~valve. BS: vacuum valve. chamber BI. Scheme B-2 illustrates the various utilizations of functionalized resins to purify reaction vessel products 5 B22 prior to filtration from the fritted vessels E1 into collection vials Bg. Said functionalized resins perform as 1) resin-bound reagents E12, which give rise to resin bound reagent byproducts B13; 2) sequestrants B14 or B15 of excess solution-phase reactants E16 or E17, 10 respectively. Solution-phase reactants E16 and E17 contain inherent reactive functionality -rfv and -rf 2 smnT SHET (RULE WO98/52940 PCT/US98/10436 281 which enable their chemoselective sequestration by the complementary reactive functionality -Crf, and -Crf 2 attached to resins B14 and B15; 3) sequestrants B18 of solution-phase byproducts B19. Byproduct B19 contains 5 molecular recognition functionality -mr 2 which enables its chemoselective sequestration by the complementary functionality -Cmr 2 attached to resin B18; 4) reaction quenching resins B20 which give rise to quenched resins B21. Resin B20 contains functionality -Q which mediates i0 reaction quenching (for instance, proton transfer) of product B22 to form a desired isolable form of product B22. Upon performing reaction quench, the resin B20 is converted to resin B21 wherein -q represents the spent functionality on resin B21 ; 5) sequestrants B23 of 15 chemically-tagged reagents B24 and their corresponding reagent byproducts B25. 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 sequestration of B24 by the complementary 20 functionality -Ctag attached to resin B23. Additionally, the soluble reagent byproduct B25, formed during the course of reaction, contains the same chemical function tag that also enables its sequestration by resin B23. Additionally, some reactants BI16, particularly 25 sterically-hindered reactants and/or electron deficient nucleophiles, contain poorly sequestrable functionality (rfl in this case is a poorly sequestable functionality). These poorly sequestable reactants B16 can be transformed in situ to more robustly sequestrable species B27 through 30 their reaction with sequestration-enabling-reagents B26. B26 contain highly reactive, complementary functionality Crf, which reacts with B16 to form B27 in situ. The ggyggrUESHiEEF{(R.E 26) WO98/52940 PCT/US98/10436 282 bifunctional molecular recognition functionality, mr, contained within B26 is also present on the in situ derivatized B27. Both B26 and B27 are sequestered by the complementary molecular recognition functionality 5 attached to resin B28. By analogy, some reactions contain poorly sequestable byproducts B19, wherein the molecular recognition functionality mr 2 in this case is not able to mediate the direct sequestration of B19 by the complementary functionality attached to resin B18. 10 Similar use of the bifunttional sequestration-enabling reagent B29 transforms B19 into the more readily sequestrable species B30. The imparted molecular recognition functionality, mr, present in B30 is readily sequestered by the complementary functionality, Cmr, 15 attached to resin B31. In some reactions, multiple sequestration resins are utilized simultaneously to perform reaction purifications. Even resins containing incompatible (mutually reactive) functional groups can be used simultaneously because these resins scavenge 20 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 25 reactants, products, or byproducts faster than resin cross-neutralization. waTUEHEET(RULE 26) WO 98/52940 PCT/US98/10436 283 Scheme B-2 A-Ser-mr -- Cmr-O Cmr-Q-- BPSer-mr B27 B28 B31 B30 Crf Ser-mr Cmr 2 *Ser-mr B26 R Rbp B29 B12 B13 A-rfl + B-rf 2 P + PB-mr 2 B16 B17 B22 B19 R-tag Rbp-tag Crfo Crf 2 B24 B25 Cmr2 B14 B15 Q-0 q B18 I I• B18 B20 B21 Ctag-0 SDenotes insoluble resin B23 Scheme B3 describes the modular robotics laboratory 5 environment that was utilized to prepare compounds of Examples B0001 through Bxxxx. 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 10 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. 15 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, 20 solvents, and resin slurries are also mounted at Station #2 or #2 DUP. Under the control of a chemical eunTUmESHEr (RULE 26) WO98/52940 PCT/US98/10436 284 informatics mapping file, reactions are initiated by the transfer of reactant solutions, reagent solutions, solvents, and/or resin slurries into each mounted reaction block vessel. The transfer of known volumes of 5 solutions, suspensions, or solvents is mediated by syringes which control a one-up septum piercing/argon purging cannula, a wide-bore resin slurry-despensing cannula, or by a six-up cannula which can simultaneously deliver volumes to a row of six reaction vessels. The 10 reaction block and/or chemical solution racks may be optionally cooled below room temperature during the chemical solution transfer operations. After the transfer of chemical solutions and solvents has been performed by Station#2 or #2DUP, incubation of the 15 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 20 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 25 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 30 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 SLITTUESHEET (RULE26) WO98/52940 PCT/US98/10436 285 collection vial is prepared as a solution of known molarity as directed and recorded by the chemical informatics system. These product solutions may be subsequently mounted at Station #2 or #2DUP for 5 subsequent reaction steps or taken to Station #7 or #7DUP for analytical processing. Rapid solvent evaporation of product-containing collection vials is accomplished by mounting the 10 collection racks at Savant Automated Solvent Evaporation Stations #4, #4 DUP, or #4 TRIP, wherein #4DUP and #4TRIP 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 15 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 20 functions. Station #7DUP is defined as a duplicate of Station #7 to increase capacity within the robotics laboratory. Product-containing collection racks are mounted at either of these stations. Each product containing collection vial is then prepared as a solution 25 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 30 chemical informatics mapping file, transfers aliquots of each product vial into unique and identifable microtiter plate wells that are utilized to perform analytical determinations. SmUTESHEET(RULE2) WO98/52940 PCT/US98/10436 286 One such microtiter plate is prepared at .Station #7 or #7DUP for subsequent utilization at the Automated HPLC/Mass Spectrometer Station #8 or #8DUP. Station #8DUP is a duplicate of Station #8 to increase the analytical 5 capacity of the robotics laboratory. Stations #8 and #8DUP 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# G1322A solvent 10 degasser, model # G1312A binary pump, a model # Gl316A 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 #8DUP is utilized for the 15 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. 20 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). 25 Proton, 13 -Carbon, and/or g-Fluorine NMR 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 30 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 $Umnm hBE (( WO98/52940 PCTIUS98/10436 287 recorded by the chemical informatics system for retrieval by biologists who perform the biological assaying of products. 5 The Fourier Transfrom InfraRed (FT-IR) Spectrometer Station #11 is utilized to analyze resins for the identity of organic functional groups chemically attached to these resins. The resins, as mentioned above, contain chemical functionality utilized as reagents, 10 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 InspectlR microscope for resin mounting and positioning). Scheme B-3 The lines interconnecting the modular Stations denote the 20 transfer of chemical racks, reaction blocks, and/or collection vial racks from one modular Station to another. SUMMUflTESHEET(FU.E26) WO 98/52940 PCT/US98/10436 288 Automated Automated Chemistry Prep Reaction Building Station #1 Station #2 Automated Automated Offline Reaction weighing/archival 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 #11 NMR Mass Spec Station #10 Station #8 DUP The ChemLib IT system is a composite of software running on the client's desktop and software running on a remote 5 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. 10 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 15 electronic data for the robotics chemistry unit. This ME rU SHE (FRU E2M ) WO98/52940 PCTIUS98/10436 289 server, a Silicon Graphics IRIX station v6.2, runs the database software, Oracle 7 v7.3.3.5.0, that warehouses the data. Connection from the client's desktop to the server is provided by Oracle's TCP/IP Adapter v2.2.2.1.0 5 and SQL*Net v2.2.2.1.0A. SQL*Net is Oracle's network interface that allows applications running on the client's desktop to access data in Oracles' database. The client's desktop is Microsoft Windows 95. The ChemLib IT system client software is composed of Omnis7 10 v3.5 and Microsoft Visual C++ v5.0. This composition on the client side is what is herein referred to as ChemLib. ChemLib communicates with the server for its data via Oracle's PL/SQL v2.3.3.4.0. These PL/SQL calls within ChemLib creates a network socket connection to Oracle's 15 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 20 defines a library in a module called the Electronic 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). 25 The chemist begins by populating the Electronic Spreadsheet with those components required for the compound synthesis. The identity and the availability of these components are defined in the Building Block 30 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 e TUTESHEE(LE6) WO98/52940 PCTUS98/10436 290 declare the quantity of each component to be utilized. The quantity of each component can be identified by its molarity and volumetric amounts (ul) or by it's solid state form (mg). Therefore a well in the Electronic 5 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 for each compound in the Electronic Spreadsheet is defined in 10 the WS Sequence module of ChemLib. The Define WS Sequence module identifies the synthesis steps to be performed at the robotics workstations and any activities to be performed manually or off-line from the robotics workstation. With this module we identify which 15 components 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 performed 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 25 robotics terminology is stored in 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 MMU SHEET(RUU 26) WO98/52940 PCT/US98/10436 291 robotics workstation in the reaction block is then captured into collection vials. The collection vials are first tarred then grossed on 5 the robotics workstation after collecting their products from the reaction block. These weights (tare and gross) are recorded into the ChemLib system with the Tare/Gross Session module. The Tare/Gross Session module then calculates the product or compound yields and its final 10 mass. Preparation of the compound for analytical analysis and screening is defined by the Analytical WS Setup module in ChemLib. The Analytical WS Setup module identifies the 15 dilution factor for each well in the Electronic Spreadsheet, based on the compound's product yield and the desired molar concentration. This identifies the quantity, in uL, to be transferred at the robotics workstation, to a specific location on the MTP 20 (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. 25 The Dilute/Archive 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. 30 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 SJMilT)ESHEET(RU.EM) WO98/52940 PCT/US98/10436 292 the robotics workstations. Reports generated by the robotics workstations are also placed on the server where the ChemLib system can read these files to record the data generated. Each robotics workstation consists of 5 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 10 server for file access only. General Scheme B4 Scaffold C-i with a primary amine functionality 15 contained within the R 4 substituent is reacted in spatially addressed, parallel array reaction block vessels with excess of electrophiles R3-Q wherein Q is chloro, bromo, or an acid activating group including but not limited to N-hydroxysuccinimide. R-Q includes acid 20 chlorides, alkyl chloroformates, sulfonyl chlorides, activated esters of carboxylic acids, activated carbamates, and isocyanates. Reaction of scaffold C-i with Ra-Q'is effected in the presence of a tertiary amine base at room temperature in a mixture of a polar aprotic 25 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 30 adduct B35, and also by the addition of a primary amine functionalized resin B33 which covalently sequesters any remaining electrophile Ra-Q from each reaction mixture as S~ilTUTEHEEN(SM WO 98/52940 PCT/US98/10436 293 resin-bound adduct B34. Resin B33 also sequesters the HQ byproduct from the reaction mixture by proton transfer from solution-phase Base-HQ. Incubation at room temperature, filtration, rinsing of the resin cake, and 5 concentration of the filtrates affords purified products B-i filtered away from resin-bound adducts B32, B33, B34, B35, and B36. Scheme B-4 N-- NH N-NH R2 R4 + a- R2 R4

R

3

R

3 Base Base-HQ C-i B-i

R

4 contains a primary

R

4 contains a derivatized amine function -NH 2 -NH-R J function e-CHO -NH 2 NH2 B32 B33 B33 N-NH N -4

%

2 NH-R' 0 NH 2 . HQ B35 R 3 B34 B36 10 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 MUTMUESHEET(RULE2) WO98/52940 PCT/US98/10436 294 addressed format. A solution of the desired primary amine-containing scaffold C1 (limiting amount,) in dimethylformamide (DMF) is added to the reaction vessels followed by a 4.0 fold stoichiometric excess solution of 5 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 fold 10 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 scaffold C1 to products B-0001-B-0048 compared to reactions that do not utilize stoichiometric excesses of electrophiles and 15 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 B33 and the aldehyde-functionalized resin B32. The 20 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 R -Q and any unreacted scaffold amine C1 are removed from the reaction 25 medium as insoluble adducts B34 and B37 respectively. In 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 B33. Simple filtration of the 30 insoluble resin- adducts B32, B33, B34, B36, and B37, rinsing of the resin cake with dichloroethane, and evaporation of the filtrates affords the desired products B-i in purified form. mgESHIEET(RULE 26) WO 98/52940 PCT/US98/10436 295 Scheme B-5 N-NH N NH

NH

2 + R/Q NH-RJ F F N (0. 1]) N N OO N I N B-i C-1 CH3 V NH 2 -CHO B33 B32 NH-HR 0-NHRJ B33 N-NH N B34 3 F

NH

2 . HQ B37 B36 N Scheme B-6 illustrates a general synthetic method 5 involving the parallel array reaction of a scaffold C-ii containing a secondary amine functionality within the definition of the R substituent. Each reaction vessel is charged with the secondary amine-containing scaffold C ii, followed by the introduction of a stoichiometric 10 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, agUTESHiEEr (u.L8) WO98/52940 PCT/US98/10436 296 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 5 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 10 isocyanate-functionalized resin B38 which covalently sequesters remaining secondary amine scaffold C-ii as resin-bound adduct B39, and also by the addition of the primary amine-functionalized resin B33 which (ovalently sequesters remaining electrophile RL -Q from each reaction 15 vessel as resin-bound adducts B40. Resin B33 also sequesters the HQ byproduct in each vessel as B36, formed by proton transfer from solution-phase Base-HQ. Incubation with these resins, either simultaneously or sequentially, followed by filtration, rinsing, and 20 concentration of the filtrates affords purified products B-ii filtered away from resin-adducts B33, B36, B38, B39, and B40. 25 StIMITEMSEET(RULE2) WO 98/52940 PCT/US98/10436 297 Scheme B-6 N-NH N-NH R2 R 4 + R-Q R2

R

4

R

3

R

3 Base Base-HQ C-ii B-ii

R

4 contains a secondary R contains a derivatized amine function -NH -N-R amine function O N=C=O NH 2 NH2 B38 B33 B33 N-NH 0 R4

R

2 , 4 ' N 2 H

R

4 R NH-RL NH.HQ NH B40 B36 B39 B40 Scheme B-7 illustrates the conversion of the secondary 5 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 10 (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 15 is an acid chloride or alkyl chloroformate, or a 1.5 fold stoichiometric excess when RL-Q is a sulfonyl chloride, or a 1.25 fold stoichiometric excess when RL-Q is an isocyanate. The reaction mixtures are incubated at T1UTESHEET(RULE26) WO98/52940 PCT/US98/10436 298 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 5 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 RL-Q and unreacted scaffold amine C-2 are removed from the reaction medium 10 as insoluble adducts B40 and B39, respectively. Resin B33 also sequesters the HQ byproduct in each vessel as B36, formed by proton transfer from solution-phase Base HQ. Incubation with these resins, followed by filtration and rinsing with solvent mixtures of DMF and/or DCE, 15 affords purified product solutions in collection vials filtered away from resin-adducts B33, B36, B38, B39, and B40. Concentration of filtrates affords purified products B-ii. 20 amanESEU (B.E26) WO 98/52940 PCT/US98/10436 299 Scheme B-7 N-NH

N-

N H + R -Q F NH F N.RL N O O) N I N B-ii

CH

3 1 C-2

CH

3 O NH 2 -CHO B33 B38

NH

2 / / F NH-R NH.RL B33 O N B40 N NH HN N NH 2 . HQ B39 B36 5 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 R 4 substituent. Each reaction vessel is charged with the secondary amine-containing scaffold C 10 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. 9jB5M=T8HEVr(RULE-s) WO98/52940 PCTIUS98/10436 300 Excess 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 5 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 10 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 RL-Q, HQ, B41, and B42 as the 15 resin-bound adducts B40, B36, 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, B36, B40, 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 B-ii. 25 M IIUMSHEET (RULE 26) WO 98/52940 PCT/US98/10436 301 Scheme B-8 N- NH N-NH R2,

R

4 + RL -Q R2

R

4

R

3 1 Base Base-HQ C-li B-ii R contains a secondary R 4 contains a derivatized amine function -NH -N-R amine function

O-SO

2 N=C=O

-NH

2 NH2 B41 B33 B33 o O N NH-RL

%-NH

2 . HQ S R4 2 B40 B36 H I4 RR B42 NHNH R4", 2

R

4 ' R 3 ,Wp NH2 N3 O B43 B33 O-11 NHNH B44 5 Scheme B-9 illustrates the method of Scheme B-8 using scaffold C-2. A solution of the scaffold C-2 (limiting SU lUTESHEEf (RULE26) WO98/52940 PCT/US98/10436 302 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 5 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 RL-Q is a sulfonyl chloride, or a 1.25 fold stoichiometric excess when RL-Q is an 10 isocyanate. The reaction mixtures are incubated at ambient temperature for 2-6 h. After solution-phase reactions have progressed to afford crude product mixtures, each reaction vessel is then charged with a dichloroethane solution of the sequestration-enabling 15 reagent phenylsulfonylisocyanate B41. This reagent B41 reacts with remaining secondary amine scaffold C-2, converting C-2 to the in situ-derivatized compound B45. Subsequent incubation of these vessel mixtures with a large excess (15-20 fold stoichiometric excess) of the 20 amine-functionalized resin B33 sequesters the solution phase species R L-Q, HQ, B41, and B45 as the resin-bound adducts B40, B36, B44, and B46, respectively. The resin charged reaction block is shaken vertically for 20 h on an orbital shaker at ambient temperature to allow optimum 25 agitation of the resin-containing vessel mixtures. Filtration of the insoluble resin- adducts B33, B36, B40, B44, and B46 and subsequent rinsing of the vessel resin bed with DCE affords filtrates containing the purified products B-ii. Concentration of the filtrates affords 30 the purified products B-ii. SITRHl1TESHEET(RULE26) WO 98/52940 PCT/US98/10436 303 Scheme B-9 N NH N-NH II N 4 C-2 K>B-ii

R

4 contains a secondary O R contains a derivatized

R

4 cotin ascodayN

N

m H-Q -N-R L amine function amine function -NH. H 3

H

3 NR amine function S 2N=C=o NH2 NH2 B41 B33 B33 HN N % NH 2 HQ O) 0O NH-RL NHw H SB40 B36 H F B45 N H--N o \ NH2 Q N N I N F B33 Ge

-NH

3 \J NH 2 O B46 B33 0-NH NH B44 5 Another general method for the parallel array reaction block synthesis is illustrated in Scheme B-10 for the derivatization of the carboxylic acid-containing scaffold WO98/52940 PCT/US98/10436 304 C-iii. Scaffold C-iii with a free carboxylic acid functionality is reacted in spatially addressed, parallel array reaction block vessels with excesses of optionally different primary or secondary amines B47 in the presence 5 of the polymer-bound carbodiimide reagent B48 and a tertiary amine base in a mixture of a polar aprotic solvent and/or a halogenated solvent. After filtration of each crude vessel product misture away from resins B48 and B49, each reaction mixture is purified by treatment 10 with the sequestration-enabling-reagent B50 (tetra fluorophthalic anhydride). The reagent B50 reacts with remaining excess amine B47 to afford the in situ derivatized intermediates B51 which contain carboxylic acid molecular recognition functionality. Subsequent 15 incubation of each reaction mixture with a 15-20-fold stoichiometric excess of the primay amine-functonalized resin B33 sequesters B51, B50, and any remaining acid scaffold C-iii as resin-bound adducts B52, B53, and B54, respectively. Filtration of soluton-phase products B-iii 20 away from these resin-bound adducts and rinsing of the resin beds with a polar aprotic solvent and/or halogenated solvent affords filtrates containing purified products B-iii. Concentration of the filtrates affords purified B-iii. 25 Smmum t( E2) WO 98/52940 PCT/US98/10436 305 Scheme B-10 0 RA OH N-N R2 / R 4 RB( N-C N Base R R + NH + N N DMF/DCM excess B48 B47 C-iii RA N O in Io R2 f4 B49 P1 3 B-iii F O 3-NH 2 R NH OH B33 zNH2 N F O F O B47 F N

B

c (remaining) R F B51 H 3 N F F H3NPRo B50 / F )N F \BC F O0

O-NH

2 B52 B33 F H FO F

HN-

F OH F 0 0 B53 . OH RN 3 NH 2 RA 0O H3N N- N B33 4 / R2 / 4 C-iii

B

3 54 (remaining) aM mN1TESHF£T(FU£E26) WO98/52940 PCT/US98/10436 306 Scheme B-11 illustrates the conversion of the acid containing scaffold C-49 to the desired amide products B iii in a parallel synthesis format. A limiting amount of the scaffold C-49 is added as a solution in 5 dimethylformamide to each reaction vessel containing the polymer bound carbodiimide reagent B48 (5 fold stoichiometric excess). A solution of pyridine (4 fold stoichiometric excess) in dichloromethane is added to this slurry, followed by addition of an excess amount of 10 a dimethylformamide solution of a unique amine B47 (1.5 fold stoichiometric excess) to each vessel. The parallel reaction block is then agitated vertically on an orbital shaker for 16-18 h at ambient temperature and filtered to separate the solution phase product mixture away from 15 resin-bound reagent B48 and resin-bound reagent byproduct B49. The resulting solutions (filtrates) containing a mixture of the desired amide products B-iii, excess amines B47 and any unreacted acid containing scaffold C 49, are treated with tetrafluorophthalic anhydride B50. 20 B50 converts the excess amines B47 in each filtrate vessel to its respective sequestrable half acid form B51. After two h incubation time, an excess of the amine functionalized resin B33 and dichloromethane solvent are added to each reaction vessel. The amine-containing 25 resin B33 converts B51, any remaining B50, and any remaining C-49 to their resin-bound adducts B52, B53, and B55, respectively. The resin-charged reaction block is shaken vertically for 16 h on an orbital shaker at ambient temperature to allow optimum agitation of the 30 resin-containing vessel mixtures. Filtration of the insoluble resin- adducts B33, B52, B53, and B55 and subsequent rinsing of the vessel resin-bed with SM fUTESHEE (RULE6) WO 98/52940 PCT/US98/10436 307 dimethylformamide affords filtrates containing the purified products B-iii. Concentration of the filtrates affords the purified products B-iii. 5 SI1TSMMUTE SHEET (RULE 26) WO 98/52940 PCT/US98/10436 308 Scheme B-11 OH

N-

N O CH RB N=C =N Base + NH + DMF/DCM F RC C excess B48 B47 C-49 N RB 5

N-R

c 0 CH30

-

+ B49 B-iii N RB F O 0 NH2 NH 5 F OH B33 RF O O F F B47 F N- Bc F4II (remaining) F R B F O B51 F O HzN F F RB B50 / F O BC

-NH

2 B52 B33 F F 'N HN Q F ' OH-4, F 0 OH B53 -O NH2 O H3 N

CH

3 B33 F *CH 3 N F C-49 (remaining) N 55 B55 WO98/52940 PCT/US98/10436 309 Although Schemes B-I through B-11 describe the use of parallel array chemical library technology to prepare 5 compounds of general formulae B-i, B-ii, and B-iii, it is noted that one with ordinary skill in the art of classical synthetic organic chemistry would be able to prepare B-i, B-ii, and B-iii by conventional means (one compound prepared at a time in conventional glassware and 10 purified by conventional means such as chromatography and/or crystallization). A general synthesis of pyridylpyrazole scaffolds C-i, C 15 ii, and C-iii is depicted in Scheme C-l. Step A: Picoline is treated with a base chosen from but not limited to n-butyllithium (n-BuLi), lithium di-iso propylamide (LDA), lithium hexamethyldisilazide (LiHMDS), potassium t-butoxide (tBuOK), or sodium hydride (NaH) in 20 an organic solvent such as tetrahydrofuran (THF), diethyl ether, t-butyl methyl ether, t-BuOH or dioxane from -78 OC to 50 'C for a period of time from 10 minutes to 3 hours. The metallated picoline solution is then added to a solution of ester B56. The reaction is allowed to stir 25 from 30 minutes to 48 hours during which time the temperature may range from -20 'C to 120 'C. The mixture is then poured into water and extracted with an organic solvent. After drying and removal of solvent the pyridyl monoketone B57 is isolated as a crude solid which can be 30 purified by crystallization and/or chromatography. asnMUTESHEET(RULE26) WO98/52940 PCTIUS98/10436 310 Step B: A solution of the pyridyl monoketone B57 in ether, THF, tBuOH, or dioxane is added to a base chosen from but not limited to n-BuLi, LDA, LiHMDS, tBuOK, or NaH contained in hexane, THF, diethyl ether, t-butyl 5 methyl ether, or t-BuOH from -78 °C to 50 oC for a period of time from ranging from 10 minutes to 3 hours. An appropriately substituted activated ester or acid halide derived from R 4

-CO

2 H is then added as a solution in THF, ether, or dioxane to the monoketone anion of B57 while 10 the temperature is maintained between -50 'C and 50 'C. The resulting mixture is allowed to stir at the specified temperature for a period of time from 5 minutes to three hours. The resulting pyridyl diketone intermediate B58 is utilized without purification in Step C. 15 Step C: The solution containing the pyridyl diketone B58 is quenched with water and the pH is adjusted to between 4 and 8 utilizing an inorganic or organic acid chosen from HOAc, H 2 S0 4 , HC1, or HNO 3 . The temperature during 20 this step is maintained between -20 oC and room temperature. Hydrazine or hydrazine hydrate was then added to the mixture while maintaining the temperature between -20 'C and 40 'C for a period of 30 minutes to three hours. The mixture is then poured into water and 25 extracted with an organic solvent. The pyridyl pyrazole C-i or C-ii is obtained as a crude solid which is purified by chromatography or crystallization. Step: D In some cases the pyridyl pyrazole C-i or C-ii is 30 alkylated with Q-C(RA) -(CH2)nCO 2 alkyl wherein Q is halogen. C-i or C-ii is treated with a base chosen from NaH, NaOEt, KOtBu, or NEt 3 in an organic solvent such as THF, methylene chloride, dioxane, or DMF at temperatures 111ittWESHEET(RUJLE26) WO98/52940 PCTIUS98/10436 311 between -20 oC and 150 oC and reaction times between 30 minutes and 12 hours. The resulting alkylated pyridyl pyrazole ester is then hydrolyzed to the acid by treament with NaOH or LiOH in aqueous/alcohol solvent mixtures or 5 in THF/water solvent mixtures. Alternatively, the ester function is removed by treatment with an organic or inorganic acid if the alkyl residue is t-butyl. Acidification, followed by extraction with an organic solvent affords C-iii which may be purified by 10 chromatography or crystallography. In some cases, regioisomeric alkylated products C-iv are also formed. The desired C-iii can be separated away from C-iv by chromatographic purification or by fractional crystallization. 15 aMMUE8EE(RULE26) WO 98/52940 PCT/US98/10436 312 Scheme C-1 Step A 0 1) Base R 2 N\ 2) ON R2IUO R B57 N R OR B56 Step B 1) Base 2) XCOR 4 N-NH Step C O O R2 R R 4

NH

2

NH

2 R2 R N N B58 Ci or Cii A Ci or Cii 1) QCH(RA)-(CH2)nCO 2 alkyl (B59) B58 Step D 2) saponification or acid hydrolysis 3) neutralization RA CO 2 H "+-) n HO2c ,RA N-N n / 4 nN-N

R

2 / R \ 4 R 2 R + N N C-iii C-iv 5 A synthesis of pyridylpyrazole scaffold C-1 is depicted in Scheme C-2. Step A: WO98/52940 PCT/US98/10436 313 Picoline is added to a solution of LiHMDS in THF at room temperature over a time period ranging from 30 minutes to 1 hour. The resulting solution is stirred for an additional 30 minutes to 1 hour at room temperature. 5 This solution is then added to neat ethyl p fluorobenzoate B60 at room temperature over 1-2 h. The mixture is then allowed to stir at room temperature for 16-24 h. Equal portions of water and ethyl acetate are then added to the reaction and the mixture is partitioned 10 in an extraction funnel. The organic layer is dried, filtered, and evaporated to give an oily solid. Hexanes are then added and the solid is filtered and washed with cold hexanes leaving the pyridyl monoketone B61 for use in Step B. 15 Step B: The pyridyl monoketone B61 is added as a solution in THF to a flask maintained at room temperature which contains t-BuOK in a THF/ t-BuOH cosolvent. A yellow precipitate forms and stirring at room temperature is continued for 20 1-3 h. After this time, N-Cbz-protected glycine N hydroxysuccinimide B62 is added dropwise at room temperature as a solution in THF over 1-3 h. This solution, containing crude diketone B63, is used directly in Step C. 25 Step C:. The solution from step C is treated with water and the pH is adjusted to between 6 and 7 with acetic acid. Hydrazine hydrate is then added dropwise to the mixture as a solution in water over 30 minutes to lh at room temperature. Water and ethyl acetate are then added 30 to the flask and the mixture is then partitioned in a separatory funnel. The organic layer is dried, filtered, and evaported to give a crude oil which is purified by IIm iESHEER(RULEM) WO98/52940 PCT/US98/10436 314 silica gel chromatography, giving rise to purified C 1Cbz. Step: D 5 The Cbz protecting group contained in compound C-iCbz is cleaved using hydrogen gas under pressure and Pd-C in methanol solvent. The resulting amine C-1 is obtained by filtration and concentration.

WO 98/52940 PCT/US98/10436 315 Scheme C-2 StepA 0 1) LiHMDS/THF 2) F 0 B61 N OEt F B60 1) t-BuOK/t-BuOH Step B 2) O NH-Cbz [ N-O B62 O N-NH Step C O O N-NH NH-Cbz 1) MeCO 2 H, pH = 6.5 NH-Cbz

NH

2

NH

2 -hydrate . F F F N N C-1Cbz B63

H

2 , Pd-C, MeOH Step D N-NH

NH

2 F N C-1 5 MU TUTESHEE (RILE 26) WO98/52940 PCT/US98/10436 316 A number of pyridyl pyrazole scaffolds of type C-v are prepared as shown in Scheme C-3. Step A: Picoline is treated with a base chosen from but not limited to n-BuLi, LDA, LiHMDS, tBuOK, or NaH in an 5 organic solvent such as THF, ether, t-BuOH or dioxane from -78 OC to 50 'C for a period of time from 10 minutes to 3 hours. The metallated picoline solution is then added to a solution of an appropriately activated ester analog of a carboxylic acid CbzNRH-(CH 2 ) nCR F(RG) -CO 2 H or 10 BocNRH- (CH 2 ) nCRF(RG)-CO 2 H, preferably but not limited to the N-hydroxysuccinimide B64. The reaction is allowed to stir from 30 minutes to 48 hours during which time the temperature may range from -20 oC to 120 'C. The mixture is then poured into water and extracted with an organic 15 solvent. After drying and removal of solvent the pyridyl monoketone B65 is isolated as a crude solid which can be purified by crystallization and/or chromatography. Step B: A solution of the pyridyl monoketone B65 in 20 ether, THF, tBuOH, or dioxane is added to a base chosen from but not limited to n-BuLi, LDA, LiHMDS, tBuOK, or NaH contained in hexane, THF, ether, dioxane, or tBuOH from -78 OC to 50 oC for a period of time from 10 minutes to 3 hours. The anion sometimes precipitates as a yellow 25 solid. An appropriately substituted activated ester such as the N-hydroxysuccinimide B66 is then added as a solution in THF, ether, or dioxane to the monoketone anion while the temperature is maintained between -50 'C and 50 'C. The resulting mixture is allowed to stir at 30 the specified temperature for a period of time from ranging from 5 minutes to 3 hours. The resulting pyridyl diketone intermediate B67 is utilized without further purification in Step C.

WO98/52940 PCT/US98/10436 317 Step C: The solution containing the pyridyl diketone B67 is quenched with water and the pH is adjusted to between 4 and 8 utilizing an inorganic or organic acid chosen 5 from HOAc, H 2 S0 4 , HC1, or HNO 3 . The temperature during this step is maintained between -20 'C and room temperature. Hydrazine or hydrazine hydrate is then added to the mixture while maintaining the temperature between -20 'C and 40 oC for a period of 30 minutes to 10 three hours. The mixture is then poured into water and extracted with an organic solvent. The pyridyl pyrazole C-vBoc or C-vCbz is obtained as a crude solid which is purified by chromatography or crystallization. 15 Step: D The carbamate protecting groups from C-vBoc or C-vCbz are removed to afford the scaffolds C-v containing either a free primary amine (RH is hydrogen) or a free secondary amine (RH not equal to hydrogen). The Boc protecting 20 carbamate groups are cleaved utilizing 1:1 trifluoroacetic acid (TFA)/methylene chloride at room temperature for several hours. The CBZ carbamate protecting groups are cleaved using hydrogen gas under pressure and Pd-C in an alcoholic solvent. The resulting 25 amines C-v are then optionally crystallized or purified by chromatography. SLMITIESEET (RULEs) WO 98/52940 PCT/US98/10436 318 Scheme C-3 n O Step A Boc or Cbz.N 1) Base H RF RG N 2) B65 N nO O Boc or Cbz' N O-N 1) Base RH RF RG O Step B 2) O O B64K 4 B64 jN-O R O B66 n N-NH BocorCbz N. NG R4 d NH 2

NH

2 , n O O H R R Boc or Cbz H Step C RH R F RG Cv-Boc 'N or Cv-Cbz N

H

2 , Pd-C, MeOH B67 or TFA, CH 2

CI

2 Step D n N-NH HN R4 H R F R G/' RM RE RG N C-v 5 81BIfTUTE8HEET2(R6U) WO98/52940 PCTIUS98/10436 319 The synthesis of scaffolds C-vi is accomplished as shown in Scheme C-4. 5 Step A: A Boc protected pyridylpyrazole B68 is treated with benzaldehyde in methylene chloride at room temperature in the presence of a drying agent for a period of time 10 ranging from 1-24 h. Solvent is then evaporated and the resulting imine B69 is used in step B without further purification. Step B: 15 The pyridylpyrazole imine B69 is dissolved in THF and stirred under nitrogen at temperatures ranging from -78 to -20 'C. A base such as LDA, n-BuLi, or LiHMDS is added dropwise to the mixture which is then stirred for an additional 10 minutes to 3 h. Two-five equivalents of an 20 alklyating agent R F-Q are then added to the mixture and stirring is continued for several hours. The mixture is then quenched with acid and allowed to warm to room temperature and stirred several hours until cleavage of the Boc and the imine functions is complete. The pH is 25 adjusted to 12 and then the mixture is extracted with an organic solvent, which is dried and evaporated. The crude pyridylpyrazole is then crystallized and/or chromatographed to give C-vi. 30 .J~flu~h~fE~r 0%0%~ WO 98/52940 PCT/US98/10436 320 Scheme C-4 N-NBoc N-NHBoc Ph R 2 NH 2 HCOPh- R 2

N

/ Step A B68 B69 Step B 1) Base 2) RF-Q is an alkyl halide, alkyl sulfonate, or dihaloalkane 3) Acid, H 2 0 N-NH R 2

NH

2 R3 RF RF C-vi 5 The synthesis of maleimide-containing scaffolds C-vii is accomplished as shown in Scheme C-5. The maleimide pyrazole scaffolds C-vii are 10 synthesized as depicted in scheme C-5. Condensation reaction of a primary amine H 2 N-R with a maleic anhydride B70 that is substituted at position 3 with either a bromo, chloro, or triflate group generates compound B71. The formed maleimide derivative B71 then reacts with an 15 acetophenone derivative B72 in the presence of a Pd(0) I IlUI'E8HEET(RLUE26)4 WO 98/52940 PCT/US98/10436 321 catalyst and base to afford compound B73. The methylene position of B73 is then acylated with an acid anhydride B74 or an activated acid ester B75, forming the di-ketone derivative B76 . The di-ketone B76 condenses with 5 hydrazine to afford the desired maleimide pyrazole scaffold C-vii. Scheme C-5 0 0 Ar 0 H2N-R N, R B72 O ' N-RN X 1. acid X Pd (0)/base Ar 0 0 2. acid anhydride 0 0 B73 B71 B70 (X is chloro, bromo, or triflate) 0 0 0R4 4 N-NH a4 o 0 Ar R 4 B74 0 N-R NH 2

NH

2 Ar / 0 4 Ar / 00 H 4 00 or o R

R

4 O-N B76 C-vii 0 B75 10 Scheme C-6 illustrates the synthesis of the maleimide pyrazole scaffold C-63 wherein R 4 is hydrogen. The synthesis starts with the condensation reaction of 15 bromomaleic anhydride B77 with 2, 4-dimethoxybenzylamine in acetic acid and acetic anhydride, giving rise to intermediate B78. The maleimide B78 is then treated with 4'-fluoroacetophenone in the presence of catalytic amount SITIU E8HEET(RLE 26) WO 98/52940 PCT/US98/10436 322 Pd 2 (dba) 3 and sodium t-butoxide to form the fluoroacetophenone substituted maleimide B79. The B79 is treated with tert-butoxybis(dimethylamino)methane to yield the a-ketoenamine B80. The a-ketoenamine B80 is 5 condensed with hydrazine to form the maleimide pyrazole skeleton B81. The 2, 4-dimethoxybenzyl group protecting group is optionally removed with ceric ammonium nitrate (CAN) to give compound C-63. Scheme C-6 OMe O H OMe OMe

H

2 N < 0 I2- N F Br o- 1. AcOH Br Pd 2 (dba) 3 / NaOBu-t 0 2. AC20 0 , Me B77 B78 0 0 OMe OMe O N OMe (CH 3

)

3

COCH[N(CH

3

)

2 ]2 O N OMe O OMe O OMe F B79 F N- B80 N-NH / N-NH

NH

2

NH

2 "CAN" / F / O N F /O 0 \ OMe NH 0 -0 MeO B81 C-63 10 Scheme C-7 illustrates the synthesis of maleimide 15 containing scaffolds C-64 and C-65. These scaffolds C-49 and C-50 are synthesized according to the general methods ammumaLqUE2a9) WO 98/52940 PCT/US98/10436 323 illustrated in Scheme C-5 and exemplified with the utilization of N-hydroxysuccinimides B82 and B83 to afford the maleimide-containing pyrazoles B86 and B87, respectively. Optional removal of the 2,4 5 dimethoxylbenzyl groups with CAN and subsequent removal of the Boc-protecting groups with trifluoroacetic acid (TFA) affords the scaffolds C-64 and C-65. Scheme C-7 O O OMe SB82 o NH-Boc OMe ON0 OMe orO FB84 ONH-Boc F B79 N O or ON O Me t-Boc' 0 N B83 0W B83 O OMe F 0 N B85 Boc N-NH N-NH S NH-BOC

NH

2 I F / 0 1) CAN F 7 0 N - 2) TFA NH

NH

2

NH

2 B86 O \ / OMe C-64 O MeO N-NH N-NH NH ' N-BOC F /0 F 0 / NH N -o B87 0 OMe C-65 MeO 10 WERTUESHEET(RULE28) WO 98/52940 PCT/US98/10436 324 The various functionalized resins and sequestration enabling-reagents utilized to prepare and purify parallel 5 reaction mixtures are more fully described below, including their commercial source or literature reference to their preparation. B32 4-benzyloxybenzaldehyde functionalized polystyrene. CHO Novabiochem cat. #01-64-0182 B33 NNH 2 Prepared as reported in D. L. Flynn et al, N J. American Chemical Society (1997) 119, 4874-4881.

NH

2 Methylisocyanate functionalized polystyrene. B38 Novabiochem cat. # 01-64-0169 N-C-O Cl (D B48 Polymer bound EDC, prepared as reported N N- C- N- by M. C. Desai et al, Tetrahedron Letters H 3 (1993) 34, 7685. 3C

CH

3 B41 S2N=C= Benzenesulfonylisocyanate, purchased from B41 / SO 2 NC Aldrich Chemical Company. Cat# 23,229-7 F F FB0 I Tetra-fluorophthalic anhydride, purchased B50 O from Aldrich Chemical Company. Cat # 33,901-6 F 0 F 10 SHEET (RULE M) WO98/52940 PCT/US98/10436 325 5 10 Experimental procedure for the parallel synthesis of a series of amides, carbamates, ureas and sulfonamides B 0001 through B-0048 from scaffold C-1. 15 Examples B-0001 through B-0048 To each reaction vessel (polypropylene syringe tubes fitted with a porous frit, closed at the bottom) of a parallel reaction apparatus was added 200 uL of dimethylformamide. A stock solution of the scaffold 20 amine C-1 in dimethylformamide (0.1 M, 500 uL) was added to each reaction vessel followed by the addition of a stock solution of N-methylmorpholine in dimethylformamide (1.0 M., 200 uL). A stock solution of each of the electrophiles was then added to the appropriate reaction 25 vessels: a) 500 uL of a 0.2 M solution of the acid chlorides in dichloroethane or b) 500 uL of a 0.2 M solution of the chloroformates in dichloroethane or c) 313 uL of a 0.2 M solution of the isocyanates in dichloroethane or d) 375 uL of a 0.2 M solution of the 30 sulfonyl chlorides in dichloroethane. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop orbital shaker) at 200 RPM at ambient S W U SHEEr(RULE26) WO 98/52940 PCT/US98/10436 326 temperature (23-30 'C) for a period of 2-3 h, under a gentle flow of nitrogen. At this time each reaction vessel was treated with approximately 250 mg of polyamine resin B33 (4.0 meq N/g resin) and approximately 100 mg of 5 polyaldehyde resin B32 (2.9 mmol/g resin). Each reaction vessel was diluted with 1 mL dimethylformamide and 1 mL dichloroethane and the orbital shaking was continued at 200 RPM for a period of 14-20 h at ambient temperature. Each reaction vessel was then opened and the desired 10 solution phase products separated from the insoluble quenched byproducts by filtration and collected in individual conical vials. Each vessel was rinsed twice with dichloroethane (1 mL) and the rinsings were also collected. The solutions obtained were then evaporated 15 to dryness in a Savant apparatus (an ultracentrifuge equipped with high vacuum, scalable temperature settings and a solvent trap to condense the volatile solvent vapors). The resulting amide, carbamate, urea and sulfonamide products were then weighed and characterized. 20 The yields and analytical data for the products obtained using this method are shown below. 25 30 ammUWSHEEt

(RUL)

WO 98/52940 PCT/US98/10436 327 N-NH NH R2 N H R N Observed Calcd. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) B-0001 F 85 397 398 B-0002 F 94 412 413 B-0003 F 91 340 341 O B-0004 F 79 368 369 L0 .000 B-0005 F 92 498 499 B-0006 F 92 416 417 _ _ _ _ _ 0 B-0007 F Br 86 450 451 Br WO 98/52940 PCT/US98/10436 328 S Calcd. Observed Example# R 2

R

J %Yield Mass Spec Mass Spec Mass Spec (+H (M+H) B-0008 F 86 448 449 B-0009 F o 83 368 369 -O-O B-0010 F - 86 338 339 B-0011 F 92 402 403 0 0 B-0012 F 74 442 443 IOI 1 H1 B-0013 F 91 446 447

-

\ /0 B-0014 F 84 352 353 0 B-0015 F 94 380 381 0 CF 3 B-0016 F 89 440 441 B-0017 F 83 498 499 0 Km~ru&sEEr (RUL~E3) WO 98/52940 PCT/US98/10436 329 Observed Called. Example# R R %Yield aS Mass Spec Mass Spec (+H (M+H) O O B-0018 F -H 24 439 440 B-0019 F cI 89 474 475 A CI B-0020 IF o90 440 441 0 B-0021 F 85 386 387 B-0022 F 35 417 418 N B-0023 F - - /94 397 398 0 O No 2 B-0024 F 87 417 418 0 B-0025 F 0 5 354 ' 0 B-0026 F- F 87 426 427 B-0027 F -89 350 351 ammUEHEEt

(RL)

WO 98/52940 PCT/US98/10436 330 2 Calcd. Observed Caled.MasSe Example# R R %Yield Mass Spec (M+H)Spec (M+H) B-0028 F o92 456 457 B-0029 F 89 428 429 B-0030 F 37 498 499 0 B-0031 F - 18 407 408 B-0032 F 86 462 463 B-0033 F 3 352 101 B-0034 F -- 92 446 447 0 /L \ B-0035 F 28 569 570 B-0036 F 0- 93 416 417 B-0037 F 91 422 423 0MIUESE(RULE WO 98/52940 PCT/US98/10436 331 Observed Example# R R %Yield Calcd Mass Spec Mass Spec (M+H) (M+H) B-0038 F 84 390 393 B-0040 F 92 416 417 B-0041 F I\c0 \ 75 444 445 o B-0042 F 54 390 391 O B-0043 F o 80 396 397 O B-0044 F 81 310 311 0 F B-0045 F 91 408 409 0 CF 37 B-0046 F 25 464 465 B-0047 0 88 430 431 WO 98/52940 PCT/US98/IQ436 332 Observed Example# R R %Yield Mass Spec Mass Spec Mass Spec (+) (M+H) B-0048 F 95 414 415 I ) WO 98/52940 PCT/US98/10436 333 5 10 By analogy to the procedure identified above for the preparation of Examples B0001-B0048, the following examples B-0049 through B-1573 were prepared. 15 20 25 30 ajmFUTESH-EE(RUL2) WO 98/52940 PCT/US98/10436 334 N-NH NH-R R2RJ N Example# R2 ield Calcd. Observed MRa %Yield Mass Spec Maass Spec (M+H) B-0049 F 85 414 415 0 B-0050 F9 458 459 B-05F 91 426 427 F B-0051 F F 91 426 427 0 F B-0052 9 407 408 CI B-0054 F 92 363 364 0 o F / C1 B-0055 F / N 86 505 506 0M I 0 WO 98/52940 PCT/US98/10436 335 Example# 2 Cald Observed R R %Yield Mass Spec Mass Spec Mass Spec (MH (M+H) 8-0056 ,F o , 86 487 488 B-0057 F 83 394 395 o B-0058 F o 86 462 463 Cif B-0062 F 74 456 457 0 0 -F B-0062 F 3 94 458 459 B-0063 F- " 87 372 373 1 -0 B-0064 F ' - 5 394 395 0 B-0065 F c 87 420 395 asmllUTESHEET (RULE2) WO 98/52940 PCT/US98/1Q436 336 Example# 2 Cald Observed R R %Yield Calcd. Mass Spec Mass SpecM (M+H) B-0066 F 89 350 351 B-0067 F-o -92 386 387 B-0068 F 89 432 433 B-0069 F 37 390 391 B\ L 0 B-0070 F" 18 432 433 O Cl _ _ _ _ _ _ I I -0071 F 86 440 441 B-0072 F - 3 432 433 0N I O\ B-0073 F - Br 92 450 451 B-0074 F 28 390 391 B-0075 F 93 402 403 sMITRIESHEE(RULE26) WO 98/52940 PCT/US98/10436 337 Example# 2 Calcd Observed R R %Yield Mass Spec Mass Spec Mass Spec (MH (M+H) B-0076 F 91 400 401 o B-0077 F / 84 382 383 1 0 B-0078 F 87 396 397 SO O o 0 B-0079 F 1 92 364 365 B-0080 F . O 75 447 448 10 ,i o B-0081 !F 'I ' 815 382 383 B-0082 F 80 430 431 ' O B-0084 F o 91 464 465 0 B-0085 F o00- 25 462 463 M SHET(RLE2) 5ufl111TESHEEr (RULEs) WO 98/52940 PCT/US98/10436 338 Example# 2 RCalcd Observed R R %YieldMass Spec Mass Spec (M+H) I / B-130086 88 432 433 O B-0087 F o95 416 417 I O B-0088 F 438 439 o - >0 B-0089 F O 336 337 B-0090 F '/ 444 445 0B4 B-0091 F 0368 369 0 B-0092 F /\- 0506 507 B-0093 F r 436 437 0 0 B-09 F-- I CF, B-09'Fb' 461 462 F B-0095 F0 - 408 409 0 F oUMMooTRUEM WO 98/52940 PCT/US98/10436 339 Example# R2 %Yield Calcd. Observed MRa %Yield Mass Spec Mass Spec (MH (M+H) B-0096 410 411 0 0 £NgTUEHEEr (FU.E2) WO 98/52940 PCT/US98/10436 340 Example# S Calcd. Observed R YlMass Spec Mass Spec Maass Spec (M+H) 00 B-0097 F 14 486 487 H I I - NH B-0098 F-o-'-- \ 8 465 0

I

B-0099 F---- j 75 464 465 0 o B-0100 F 72 388 389 0 0 B-0101 F- - 23 408 409 0 Nq B-0102 F 37 487 488 _________0_ C C1 B-0103 F 0" _ 11 492 493 HO CI SHEETSM.LE26) WO 98/52940 PCT/US98/10436 341 Example# Calcd. Observed

R

2 R %Yield Malcd. Mass Spec Maass Spec Mass Spec (M+H) O B-0104 F - F 59 426 427 O 0 B-0105 F 79 360 361 0 B-0106 F 56 374 375 / \ I____/ O B-0107 F - 33 346 347 0 B-0108 F o 12 466 467 B-0109 F 65 450 451 O 0 B-0110 F 55 458 459 0 L B-0111 iF ii41 458 459 B-0112 F - 19 467 468 r _ B-0113 F / 78 453 454 aMUTEsHEETr(RULE 26) WO 98/52940 PCT/US98/10436 342 Example# Observed R R j %Yield Calcd, Mass Spec Mass Spec (M+H) (M+H) 0 B-0114 F 14 453 454

NO

2 B-0115 F -0 33 453 B-0116 F 11 459 487 0 O/ B-0117 F /o0 77 438 439 0 o B-0118 F 0 52 422 423 0 B-0119 F - 82 434 435 0 \ B-0120 F 49 422 423 0 s B-0121 F S 64 414 415 0 B-0122 F 87 501 502 B-0123 F 100 450 451 RIBUSIEET

(WU.IM)

WO 98/52940 PCT/US98/10436 343 Example# Observed Called.

R

2 R %Yield Ma Mass Spec Mass Spec (M+H) (M+H) 0 B-0124 F 1 87 456 457 S-i CI / \ B-0125 F -45 472 473 B-0126 F -100 476 477 B-0127 F 100 433 434 CN CI o B-0128 F c 100 482 O B-01 29 F -- 96 480 481 0 B-0130 F 93 468 469 L/ 0/ FO B-0131 F / \ 90 468 469 0 B-0132 F - 78 436 437 B-0133 F-!\ - 76 426 427 O SHEE(RULE26)

SUSMUTESHEET(FM.EMS)

WO 98/52940 PCT/US98/10436 344 Example# Observed R R J %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) F B-0134 F _ 87 444 445 B-0135 F / c ' 67 476 477 o-E0 C' O B-0136 F 100 570 B-0137 F- 35 480 481 B-0138 F 60 500 7nBu B-0139 F n 73 585 586 o 0 iO B-0140 F 62 434 459 0 B-0141 F 100 483 484 o 0 9 /S B-0142 F _ 90 444 445 B-0143 F- I// 61 492 493 CFe 11WUESHMEET(RULE) WO 98/52940 PCT/US98/10436 345 Example# Observed R R j %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) B-0144 F 49 448 449 SBMUESHE.ETU(RULE 26) WO 98/52940 PCT/US98/10436 346 Observed Example# R R %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) B-0145 F 48 433 434 0 B-0146 F 32 415 416 o B-0147 F 0 67 471 472 B-0148 F 79 465 B-0149 F - 65 353 354 B-01501 F 53 465 466 B-0151 F 68 401 402 aimUESHEET(RULE26) WO 98/52940 PCT/US98/10436 347 SCalcd. Observed Called. Example#

R

2 R %Yield Mass Spec Mass Spec (MH (M+H) B-0152 F 39 383 B-0153 F 96 427 428 B-0154 F 0 44 459 460 B-0155 F 74 479 480 / \ B-0156 F 44 459 460 B-0157 F 72 415 416 0 B-0158 F 96 445 446 0 0 B-0159 F 97 411 412 B-0160 49 417 418 YH B-0161 F o: 93 459 460 0 8UBSITUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 348 Observed Example# R 2 RJ %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) B-0162 F 91 405 406 - NI i 0 C B-0163 F ce094 455 456 H C1 B-0164 F 0 84 455 456 B-0165 F 52 411 412 0 B-0166 F HN 72 417 418 B-0167 F I66 447 448 B-0168 F 27 415 416 B-0169 F 91 415 416 LS H B-0170 F 8 351 352 B-0171 F 10 437 438 MTITUSHEET (RULE M) WO 98/52940 PCT/US98/10436 349 Calcd. Observed Example# R R %Yield Mass Spec Mass Spec (M+H) (M+H) CF3 B-0172 F o 62 471 472 700 B-0173 F /, 40 455 456 B-0174 F 92 405 406 B-0175 F 96 387 388 - -0 B-0176 F NH 25 415 416 O B-0177 F 100 397 398 B-0178 F 34 429 430 7 H B-0179 F 72 429 430 B-0180 F 91 463 464 B-0181 F 100 463 464 8UBSTnUTESHEET (RULE 26) WO 98/52940 PCT/US98/10436 350 Observed Calcd. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) B-0182 F 50 447 448 B-0183 F 22 455 456 B-0184 F 63 465 466 Fi F C B-0185 F 65 471 472 B-0186 F - 42 429 430 H B-0187 F - 62 481 482 0 :: B-o188 F o 0 98 439 440 0 B-0189 F 21 453 454 B-0190 F __57 417 418 B-0191 F 24 477 478 SImSImUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 351 Observed Called. Example#

R

2 R %Yield ad Mass Spec Mass Spec(MH (M+H) B-0192 F a 35 455 456 LumVIESHEERU

)

WO 98/52940 PCT/US98/10436 352 Observed Example# R R %Yield Calcd. Mass Spec Mass Spec (M+H) OI B-19 S\ 437 39 B0194 F H 65 365 366 B-0195 F 93 587 588 0 B-0196 F 82 365 366 B-0197 F 100 587 588 B-0198 F 86 373 374 0 B-0199 F-Q N 81 373 374 0

SORUITESHEET(FU£MW)

WO 98/52940 PCT/US98/10436 353 2 Calcd. Observed Called. Example# R R %Yield Mass Spec Mass Spec (M+H) B-0200 F 78 373 374 0 N B-0201 F c 95 352 353 O L I o B-0202 F o 100 416 417 0 B-0203 F o 69 354 355 LO B-0204 F 93 340 341 B-0205 F o 94 354 355 B-0206 F 79 424 425 0 o B-0208 F88 378 379 B-0209 F 0 83 362 363 o SMTHnUTESHEEf(RU.E28) WO 98/52940 PCT/US98/10436 354 Observed Called. Example# R 2 R %Yield Ma Mass Spec Mass Spec (M+H) (M+H) B-0210 F CF 3 100 364 365 L0 O / \ NH B-0211 F NH 60 325 326 O B-0212 F 79 339 340 O B-0213 F NH 71 353 354 B-0214 F NH 2 77 311 312 0 B-0215 F N 24 353 354 O B-0216 F o 339 340 B-0217 F 381 382 - 0, 0_ _ _ B-0218 F N 365 366 0 B-0219 F NH401 402 T E E401 402(RULE SLWMT=USH 'r(RLUE WO 98/52940 PCT/US98/10436 355 Observed Called. Example# R 2 J %Yield Ma Mass Spec Mass Spec (M+H) (M+H) B-0220 F 415 416 L- 2- -I-%_ 0 B-0221 F 367 368 " II CF 3' 0s ( E26) 8UBSnrUTEHEEr(LE) WO 98/52940 PCT/US98/10436 356 Observed Called. Example# R R %Yield aS Mass Spec Mass Spec(MH (M+H) B-0222 F 0 96 486 487 B-0223 F o o0 ' _ 100 465 466 r B-0224 1,F / 75 486 509a CI B-0225 F c 100 442 443 o I II B-0226 iF / . / o 88 482 483 0 B-0227 F o 73 482 483 B-0228 F Q oH 37 452 - WO 98/52940 PCT/US98/10436 357 Observed Caled.MasSe Example# R R j %Yield Mass SpecMass Spec Mass Spec (MiH (M+H) CI B-0229 'F / \ o c 100 476 477 0 -O-II " -= B-0230 F 11 Cli 94 476 477 CI B-0231 F F o 100 460 461 B-0232 F F 90 440 441 Ci B-0233 F / II 0 cl 99 476 477 SBr B-0234 F - ' "?II O 100 486 487,489 o O B-0235 F Bri L Bri 89 486 487,489 B-O O ~0, (_f_ ) , B-0236 F O C5 100 476 477 0 B-0237 F - -c - -~ 0 100 476 477 0 B-0238 F 0 92 438 nJMTESHEET(RULESS) WO 98/52940 PCT/US98/10436 358 Observed Called. Example# R 2 R %Yield aS Mass Spec Mass Spec (M+H) (M+H) B-0239 F o ci 100 442 443 CI B-0240 F / \ o 100 442 443 Cl B-0241 F 0 c 100 476 477 O B-0242 F- F c, 100 460 461 F 0 C __ __ _ __ __ _ II B-0243 F /s o 87 456 457 B-0244 F S 0 100 436 437 B-0245 F / O 100 422 423 / 0 0 B-0246 F / 100 452 453 0 B-0247 F c - I 100 476 477 0 B-0248 F frl O__ __ 0 73 1468 SMUTUTESHEET(RULE26) WO 98/52940 PCT/US98/1 0436 359 2 Calcd. Observed Example# R Rj %Yield msSpcMass Spec Br B-0249 F / S ~ ______ _________ 100 516 517,519 B-0250 F ~ ~ /~ 0 N, B-0251 IF /1 __ o 0-10 427 428 0 B-0252F 0 ____IN-0 100 450 451 CI B-0253 F \ 0 _____100 472 473 L- C _________ 100 433 434 B-0255 F- /\ -o~r'1>r'o 184 547 548 B-0256 F 0 _____100 484 507a 0 B-0257 FX/ ______ ________1_ 85 534 535 B-0258 F1/1 ___ ___ __ ___ __ ___ ___ __ ___ __ 100 491 492 WO 98/52940 PCT/US98/10436 360 Observed Called. Example# R R %Yield aS Mass Spec Mass Spec (+H (M+H) O B-0259 F 100 554 555 B-0260 F o 0S" 0""1 91 500 501 0 , _ _ o B-0261 F 0 100 486 487 B-0262 F S 100 481 482 0 B-0263 F / O100 554 555 O B-0264 F L 0 75 375 376 N B-0265 F /s 0 71 459 460 B-0266 F O- N 100 412 413 SUBSnMUSHEEM

(RJLES)

WO 98/52940 PCT/US98/10436 361 Observed Example# R R %Yield Mass Spec lcd. Mass Spec Mass Spec (M ) (M+H) B-0267 IF 100 386 387 0O B-0268 F / c 89 406 407 0 B-0269 F 84 386 387 B-0270 F - CF 3 92 440 441 B-0271 F 98 428 429 0 B-0272 F 57 498 499 Cl B-0273 Fc--( - 100 440 441 o WmlUSHET(FU.EZ WO 98/52940 PCT/US98/10436 362 Observed Example# R R %Yield Calcd. Mass Spec Mass Spec (M+H) j CN B-0274 F O CN 94 397 398 B-0275 F / 90 422 423 0 / F B-0276 F OF 100 408 409 LF B-0277 F 88 408 409 F ~F B-0278 F 100 426 427 F CI CI B-0279 F 54 440 441 0 B-0280 F 79 414 415

SCF

3 I B-0281 F /82 458 459 O F B-0282 F 89 426 427 O B-0283 F CF3 90 458 459

-

F 0U WO 98/52940 PCT/US98/10436 363 2 Calcd. Observed Called. Example# R R %Yield Mass Spec Mass Spec (M+H) 0 B-0284 IF 100 458 459 F 0 F B-0285 F , CF 3 94 458 459 0 CF 31 B-0286 F 100 458 459 F 0 B-0287 IF - / : CF3 96 458 459 F 0 CF 3 B-0288 IF 100 458 459 F Co B-0289 F 96 406 407 O B-0290 F 96 386 387 B-0291 F C 95 440 441 O F B-0292 F -94 390 391 F F B-0293 F 100 408 409 S0 U ET(UE SUB~flUTSHETr(RULE 2B) WO 98/52940 PCT/US98/10436 364 Observed Example# R R j %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) CI B-0294 F 100 440 441 O C 0 B-0295 F 91 408 409 O F B-029 F, FF942-42 F F B-0298 96 426 427 o F F B-0297 F 88 390 391 0 F B-029308 F 95 408 409 O B-0301 F 99 450 451,453 B-0302 F CF 94 440 441 B-0303 F 100 378 379 O R1,il1itlfESHEET W(FUM.E S) WO 98/52940 PCT/US98/10436 365 Calcd. Observed Called. Example# R 2 J %Yield Mass Spec Mass Spec (M+H) (M+H) B-0304 F 100 391 392 SUMITUTESHEr(RULE26) WO 98/52940 PCT/US98/10436 366 Observed Example# R R %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) B-0305 70 326 327 B-0306 59 340 341 B-0307 c59 354 355 C C B-0308 60 368 369 Cl B-0309 61 352 353 CI B-0310 61 366 367 B-0311 65 356 357

CR

WO 98/52940 PCT/US98/10436 367 Calcd Observed Called. Example# R R %Yield Mass Spec Mass Spec (+H (M+H) B-0312 c- 75 342 343 CI B-0313 o 68 356 357

C

1 B-0314 31 370 371 Cl B-0315 o 61 384 385 CI0 B-0316 75 368 369 C o B-0317 0 62 366 367 Cl B-0318 52 388 389 C1 0 F B-0319 53 424 425 -i101l I 0 F 0 F B-0320 50 424 425 C1 F _________ F F B-0321 54 442 443 c 0 F 8UBS~lT E SHEET(RULEA26 WO 98/52940 PCT/US98/10436 368 Observed Example# R R %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H)

F

3 C B-0322 64 474 475 Cl O CF 3 B-0323 58 474 475 Cl FI O CI B-0324 -60 422 423 CI < CI1 B-0325 64 422 423 Cl B-0326 /58 422 423 Cl /0 B-0327 63 378 379 Cl 0 B-0328 68 389 390 o B-0329 I 63 362 363 C1 0 cl O O B-0330 /-\ 48 376 377 Cl B-0331 cS 66 424 425 0 CI SBNTEDtELT(RULEs) WO 98/52940 PCT/US98/10436 369 Observed Called. Example# R R %Yield Ma Mass Spec Mass Spec (M+H) (M+H) 0 B-0332 61 442 443 CI B-0333 60 458 459 Cc B-0334 ,55 502 503 CI C1 _ _ _ A o O0 B-0335 60 454 455 Cl B-0336 100 500 501 B-0337 c c 65 458 P 0 CCI B-0338 c 69 502 503 B-0339 / 69 454 - 0 B-0340 c 77 492 493 B-0341 / c 64 458 459 CI 8 l HEET(RuLE20 WO 98/52940 PCTIUS98/10436 370 2 Calcd. Observed Example# R j%Yield MascSpe Mass Spec B-0342 -\ / 41 438 0 CI B-0344 -6 430 431 B-0346 96 464 465 B-0347 2 0 0 B-0348 N 56 497 49 H N B-0350 f 57 403 404 CI B-0351 /31 355 356 SUS~fUSHEET(RULE 2M WO 98/52940 PCT/US98/10436 371 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (+) (M+H) B-0352 -51 397 398 CI SUBWfSHEET(RULE) WO 98/52940 PCT/US98/10436 372 N-NH N N H R2

R

J

CH

3 N Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) 0 B-0353 F 71 382 383 B-0354 F -35 512 513 , c, 0 B-0355 F -37 352 353 o B-0356 F 57 404 405 B-0357 F 88 366 367 0 B-0358 F1 88 410 411 B-0359 F 100 324 325 8MIIUIEHEE T(FU.E WO WO 98/52940 PCT/US98/10436 373 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) B-0360 F 56 364 365 o 0 B-0361 F r 100 44350 351 0 B-0362 F 100 464 465 B-0363 F /73 512 513 O 0 B-0364 F 88 377 378 0 B-0365 F 70 396 397 I0 B-0366 F 100 354 355 0 B-0367 F / 71 416 417 B-0368 F 86 454 455 B-0369 F 40 440 441 0 F ti eS'UTESHEi (IU.E WO 98/52940 PCT/US98/10436 374 2 Calcd. Observed Called. Example# R 2

R

j %Yield ss Spec Mass Spec Mass Spec (MH (M+H) B-0370 F 94 364 365 O B-0371 F o 88 460 461 i6 B-0372 F 69 430 431 O B-0373 F 100 430 431 B-0374 F 75 400 401 O B-0375 F 74 386 387 O B-0376 F 1 53 378 379 0 N B-0378 F 69 387 388 O N B-0379 F 66 387 388 0 mQUEH.Er (RUL WO 98/52940 PCT/US98/10436 375 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) B-0380 F 85 416 417 -o 0, B-0381 F 93 430 431 B-0382 F 84 382 383 B-0383 F - 74 583 584 B-0384 F 63 438 439 M RUSHETeT(RUlE) WO 98/52940 PCT/US98/10436 376 Observed Example# R 2

R

J %Yield Calcd. Mass Spec Mass Spec (M+H) B-0385 F - F 83 440 441 0 0 B-0386 IF - 99 422 423 0 B-0387 iF S 47 388 389 0 B-0388 IF 100 448 449 L0 B-0389 F 71 436 437 B-0390 FF10/45 45 F-Q--- o // 0 5 5 0 B-0390 F 11 ~ B-0391 F C -cF 45 414 415

-C

3 : IUTE E (RULE26) 8tWTITUESHEETR .E6 WO 98/52940 PCT/US98/10436 377 Observed Example# R R %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) F 0 B-0392 F 100 440 441 / \ II O B-0393 F - 75 388 389 0 B-0394 F 92 402 403 o B-0395 F 87 374 375 0 B-0396 F S 86 360 361 O 0 0 B-0397 F 81 452 453 O 0 B-0398 F 88 428 429 0 B-0399 F 99 436 437 0 B-0400 F 82 482 483 0- 0 B-0401 F N 94 367 368 H L~gf~EHE RL 6 WO 98/52940 PCT/US98/1Q436 378 Observed Called. Example# R 2 R %Yield a c Mass Spec Mass Spec (M+H) (M+H) 0 B-0402 F NH 73 325 326 - NH 2 B-0403 F 91 415 416 B-0405 F 88 395 396 O B-0406 F - /100 419 420 0 B-0407 N 52 353 354 B-0410 F F 100 419 420 B-0411 F 94 429 430 SS IF0 EHEET6) 8UBSTMITESHEET (ULE26) WO 98/52940 PCT/US98/10436 379 Observed Called. Example# R 2 J %Yield a c Mass Spec Mass Spec (M+H) -(M+H) B-0412 F 91 365 366 0 H B-0413 F - 79 367 368 o . IH N B-0414 ii F'-//'/ ;\ o ,... 85 429 430 B-0415 F /82 401 402 B-0416 F I 93 429 430 B-0417 F -- - N97 429 430 O B-0418 F 100 419 420 B-0419 F 100 431 432 B-0420 F '' 36 381 382 B-0421 F NH 96 353 354 0ET(R E26) SUmsmUTE8EETt- WO 98/52940 PCT/US98/10436 380 Observed Example# R R %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) /o B-0422 F 100 461 462 B-0423 F 1 00 406 407 B-0424 F 76 366 367 B-0425 F o 21 368 369 B-0426 F o 100 354 355 o Ii HN B-0427 F 100 379 380 B-0428 F 100 379 380 0 B-0429 F 86 368 369 8SSMUTESET( FES) WO 98/52940 PCT/US98/1 0436 381 2 Calcd. Observed Example# R j%Yield MascSpe Mass Spec MassSpec(M+H) B-0430 1F- ~ i 51 500 501 00 B-0431 IF-\r- y / 76 479 480 Br' B-0432 F / ' ZO 90 500 501 C1 B-0433 iF - 96 456 457 B-0434 IF-~r- ~ ~ 75 496 497 0 B-0436 73'--~i~s\C 506 ~J~BHEr(RLE WO 98/52940 PCT/US98/10436 382 Calcd. Observed Example# R R %Yield Mass SpecMass Spec Mass SpecM (M+H) B-0437 F 19 466 OH___ 00 B-0438 F - 100 490 491 0 B-0439 F

-

67 464 465 B-0440 F / 96 472 473 0 '-0-0 B-0441 F 87 472 473 B-0442 F 72 481 482 I I O I B-0443 F -66 473 474 B-0444 F / 80 515 516 CI ClI B-0445 F 94 490 491 O 0 B-0446 F 84 464 465 O (R~a2 WO 98/52940 PCT/US98/10436 383 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) Cl

°

0 B-0447 F ___ 89 470 471 0 / 0 C B-0448 F \ 100 490 491 CI 0 B-0449 F 100 474 475 C1 B-0450 F -< 100 447 448 F B-0451 F 100 454 455 -, I B-0452 F 0< 95 496 497 C1 B-0453 F - 100 490 491 0 B-0454 F 100 500 501 BrBr B-0455 F 96 500 501 0 B-0456 F o 89 494 495 0 O UBSTU8SHEET(RULE) WO 98/52940 PCT/US98/10436 384 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) B-0457 F o 93 482 483 0 CF. B-0458 F /100 490 491 CF1 B-0459 F c 100 490 491 O SUBSTHUTESHEET(FU.E26) WO 98/52940 PCT/US98/10436 385 Calcd. Observed Example# R 2

R

J %Yield Cacd. Mass Spec Mass Spec (MH (M+H) B-0460 F 93 450 451 B-0461 F 84 452 453 O B-0462 F 96 456 457 CI B-0463 F\ 66 456 457 0 C1 B-0464 F - 69 490 491 CI B-0466 F 78 474 475 Cl I a.MUTESHEEI

RUL

WO 98/52940 PCT/US98/10436 386 Cd Observed Calcd. Mass Spec Example# R 2 J %Yield Mass Spec (M+H)Spec (M+H) C' B-0467 F - / \ 78 470 471 B-0468 F 91 450 451 B-0469 F _ 85 436 437 0 B-0470 F - 99 466 467

CF

3 B-0471 F 100 490 491 0 I B-0472 F o... 37 482 483 0 B-0473 F \ c0 92 462 463 o N B-0474 F o 99 530 532 B-0475 F - 55 472 473 0 B-0476 F 89 441 442 S MUrESHEET(RULEEM WO 98/52940 PCT/US98/10Q436 387 Observed Called. Example# R 2 R %Yield a c Mass Spec Mass Spec (M+H) B-0477 F 79 464 465 0 B-0478 F 92 486 487 B-0479 F \ / 97 447 448 H B-0480 F 75 561 562 0 B-0481 F 74 498 499

°

0 B-0482 F 57 548 549 B-0483 F 83 505 506 O O B-0484 F o 100 568 569 o1 0 B-0485 F 100 495 496 0 B-0486 F \ 100 426 427 0SUESEET(RE3) WO 98/52940 PCT/US98/10436 388 Observed Example# R R %Yield Calcd Mass Spec Mass Spec (MH Bs048 100 56 S0 o _ B-0489 F7o 91 500 501 B-0490 F- HS 40 473 474 B-0491 F s o 73 514 515 SUBSlTUTE8HEEr(RULE26) WO 98/52940 PCT/US98/10436 389 Calcd. Observed Example# R R %Yield Mass Spec Mass Spec (M+H) (M+H) B-0492 F 89 400 401 0 B-0493 F c 100 420 421 B-0494 F 100 400 401 Ir 0 B-0495 IF CF 100 454 455 B-0496 F S 100 442 443 B-0497 !F 50 512 513 B-0498 F c 100 454 455 8USSmTUSHEETr(RULEM) WO 98/52940 PCT/US98/10436 390 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) B-0499 F 98 411 412 B-0500 F 100 436 437 0 oF B-0501 F OF 100 422 423 B-0502 F 100 422 423 F B-0503 F 92 440 441 0 F C1 C B-0504 F 67 454 455 O B-0505 F 68 428 429 CF3 B-0506 F 98 472 473 0 F F B-0507 F 82 440 441 B-0508 F C3 99 472 473 I o mgTHUEHEET

(RULES)

WO 98/52940 PCT/US98/10436 391 Observed Called. Example# R R %Yield ad Mass Spec Mass Spec (+) (M+H) 0 B-0509 F 100 472 473 F 0 F B-0510 F CF 3 96 472 473 0 B-0511 F 100 472 473 F 0 B-0512 F cF 100 472 473 S CF 3 B-0513 F - 100 472 473 F CI B-0514 F 100 420 421 B-0515 F 100 400 401 o cI B-0516 F C 100 454 455 F B-0517 F - 100 404 405 F B-0518 F 99 422 423 8 &JIESHM7"(RLE9M WO 98/52940 PCT/US98/10436 392 Observed Called. Example# R R %Yield aS Mass Spec Mass Spec (MH (M+H) CI B-0519 F 100 454 455 B-0520 F /98 422 423 - N'T o F F B-0521 F 99 440 441 F B-0522 F 88 404 405 O B-0523 F 100 422 423 F B-0524 F F 100 422 423 B-0525 F - 100 420 421 B r B-0526 F - 100 464 465 0 B-0527 F CF 3 100 454 455 B-0528 F 100 392 393 L0 l o |H E (LL~ WO 98/52940 PCT/US98/10436 393 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) B-0529 F 94 405 406 O SmESE(RULE24) WO 98/52940 PCT/US98/1Q436 394 N- NH H N N N Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) 0 B-0530 F 67 382 383 B-0531 F 66 512 513 O B-0532 F 37 352 353 _____ 1@_I O B-0533 F 56 404 405 B-0534 F i 100 366 367 o 0 B-0535 F 100 410 411 B-0536 F O 41 324 325 S ITIUTESHET(IR.EM) WO 98/52940 PCT/US98/10436 395 S Calcd. Observed Example# R R %Yield aSpec Mass Spec Mass Spec (MH (M+H) B-0537 F 100 364 365 o B-0538 F 29 350 351 B-0539 F 70 464 465 o Bd / \/ B-0540 F - 50 512 513 0 B-0541 F 61 377 378 O B-0542 F- - 61 396 397 B-0543 F 59 354 355 B-0544 F -! 45 416 417 0 F 3 B-0545 F 100 454 455 F B-0546 F F 44 440 441 0 F SuBSWUS.Er (RULE2s) WO 98/52940 PCT/US98/10436 396 2 Cald. Observed Caled.MasSe Example# R R %Yield Mass Spec Mass Spec (M+H) B-0547 F 64 364 365 B-0548 F 89 460 461 0 '-C > - I - IV B-0549 F 100 430 431 O B-0550 F 100 430 431 0 B-0551 /\ 81 400 401 B-0552 F 38 386 387 B-0553 F 31 378 379 L0 B-0554 F 100 387 388 0 B-0555 F 66 387 388 0 B-0556 F 32 387 388 ammNlUESHET(RUUEa) WO 98/52940 PCT/US98/10436 397 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (+H (M+H) B-0557 F - -. a 70 416 417 0 B-0558 F- 57 430 431 B-0559 F - 74 382 383 B-0560 F 36 583 584 B-0561 F 51 438 439

SUBSMUTESHEET(RULEN)

WO 98/52940 PCT/US98/10436 398 Observed Exampe# 2Caled. Example# R 2

R

J %Yield Mass Spec Mass Spec (M+H) O B-0562 F 88 440 441 0 0 B-0563 F \ / 68 422 423 0 0 B-0564 I F 47 388 389 0 B-0565 F100 448 449 0 B-0566 F 76 436 437 F B-0567 F IS 99 458 459 0 _ 0 B-0568 |F - S - CF 3 45 414 415 ajmu=SHEE(RULE2M WO 98/52940 PCT/US98/10436 399 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) F B-0569 F __ 88 440 441 II o 0 . O B-0570 F61 388 389 O B-0573 F - 72 360 361 O B-0574 F -5o 97 452 453 B-0575 F - 71 428 429 / \ 1 O B-0576 F 88 436 437 O B-0577 F - a 72 482 483 0 B-0578 F 89 367 368 VjRt EMT9H WO 98/52940 PCT/US98/10436 400 Observed Example#R R %Yield Calcd. Mass Spec Mass Spec (MH (M+H) B-0579 FNH 2 100 325 326 - NH 2 B-0580 F 75 415 416 B-0581 F o 44 379 380 B-0582 F 75 395 396 O B-0583 F F 80 419 420 B-0584 F 57 353 354 B-0585 F -83 339 340 H B-0586 F 71 415 416 I B-0587 F 100 419 420 B-0588 F 94 429 430 0MUSHE(.E GSJW SHM (RULE 9) WO 98/52940 PCT/US98/10436 401 S Calcd. Observed Example# R R J %Yield mass Spec MSpec Mass Spec (MH (M+H) / H B-0589 F 78 365 366 H B-0590 F N 82 367 368 B-0591 F ,, 72 429 430 YH B-0592 F 82 401 402 o B-0593 F 88 429 430 B-0594 F 100 429 430 B-0595 F- 99 419 420 F B-0596 F 93 431 432 B-0597 F - .. 40 381 382 B-0598 F NH93 353 354 0

SUSTTEHEE(RULES)

WO 98/52940 PCT/US98/1Q436 402 S Calcd. Observed Called. Example# R R %Yield Mass Spec Mass Spec (MH (M+H) B-0599 F 100 461 462 B-0600 F - 98 406 407 B-0601 IF 66 366 367 O B-0602 F o 25 368 369 B-0603 F o 90 354 355 o B-0604 F .86 379 380 O B-0605 F 87 379 380 0 B-0606 F 72 368 369 SUBSHTUTEStET(FUE) WO 98/52940 PCT/US98/1 Q436 403 2Yel Calcd. Observed Example# RRYedMass Spec Mass Spec (M+H) B-0607 IF/\ III)N4 50 51 B-0608 1F / ,oI 100 479 480 \o / ~ ~~Bri B-0609 F - F 82 500 501 0 B-061 0 FQ-- -S CI 100 456 457 0 B-0611 F-Q-- ~~\> 76 496 497 0 B-0612 !F-O-- 69 496 497 0 C1 B-0613 !F ~ 61 506 ____ _ _ _ _ _ _ _J 3 WO 98/52940 PCT/US98/10436 404 Observed Example# R R %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) o B-0614 F 18 466 0 _ OH C1 B-0615 F -I100 490 491 B-0616 F , - 77 464 465 B-0617 F 93 472 473 B-0618 F - 84 472 473 B-0619 F - 71 481 482 - NO 0 B-0620 F 89 473 474 O B-0621 F- 68 515 516 Cl B-0622 F J 70 490 491 I o B-0623 F 92 464 465 0 suesm1HTE8HEE(RULESS) WO 98/52940 PCT/US98/10436 405 Observed Called. Example# R R %Yield ac Mass Spec Mass Spec (M+H) (M+H) l~ci B-0624 F /98 470 471 0 B-0625 IF"-- 96 490 491 cI B-0626 IF-- -- \ / 100 474 475 OI B-0627 F 100 447 448 S / F B-0628 F - a 64 454 455 ClC B-0629 F 100 496 497 C1 0 CI B-0630 F85 490 491 B-0631 F 0 75 500 501 Br i<Br B-0632 F - 83 500 501 0 B-0633 F - o 58 494 495 0 SSUBITE Er( 2 suesmnUTESHEET RULEN ) WO 98/52940 PCT/US98/10436 406 Cald. Observed Example# R R %Yield Calcd Mass Spec Mass Spec(+) B-0634 IF -o- 63 482 483 / B-0634 F-- '- /-i _ 63 482 483 CF B-0635 F 95 490 491 B-0636 F 100 490 491 SUSTrUTESHEEr

(RULER

WO 98/52940 PCT/US98/10436 407 Observed Example# R R %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) O B-0637 F 1 B-0637 F / 91 450 451 0 0 B-0638 F 96 436 437 O IC B-0639 F 100 456 457 CC B-0640 F - 100 456 457 - 1 0 -c~C' B-0641 F 88 490 491 CI B-0642 IF 99 490 491 CI B-0643 IF 92 474 475 Cl 8 t_( Ld WO 98/52940 PCT/US98/10436 408 Cald Observed Example# R R %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) CI B-0644 F - 100 470 471 0I B-0645 Fo - 92 450 451 B-064 F 094 490 491 0 B-0649 F 100 43 o/ 0 B-0650 F 8290 462 463

CF

3 B-0648 F 00 94 490 491 0 B-0649 F - 57 482 0 I, B-0653 F - 84 46241 46342 SMB-0651 S \T 100 530 531(RULES) 0 B-0652 P 53 472 0C B-0653 IF 1-"-- 1 84 441 442 0 6LUBMWTE8EET ("UEs WO 98/52940 PCT/US98/10436 409 Observed Example# R R %Yield Calcd Mass Spec Mass Spec (M+H) (M+H) o B-0654 F 92 464 465 11l 0 B-0655 F /\ \0 100 486 487 0 B-0656 F 98 447 448 B-0657 F 85 561 562 0 B-0658 F 92 498 499 B-0659 FI 46 548 549 B-0660 F 80 505 506 0 B-0661 F- 100 568 569 o B-0662 F- \ S 98 495 496 B-0663 F - - 74 426 427 TEHEET(RLE) &WU =WUtT(RMU WO 98/52940 PCT/US98/10436 410 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (+H (M+H) O B-0664 F 30 389 390 0 B-0665 F 100 568 569 B-0666 F 93 500 501 B-0667 F /_ - 54 473 474 B-0668 F - s 66 514 515 SUBSnUTESHEET(RULE M) WO 98/52940 PCT/US98/10436 411 Observed Example# R R %Yield Cacd Mass Spec Mass Spec(+H (M+H) B-0669 F 65 400 401 0 1 o o B-0670 F c 45 420 421 0 B-0671 F 43 400 401 0 B-0672 F - CF 45 454 455 B-0673 F Q- 41 442 443 0 B-0674 F - 16 512 513 0 __C1 s8afmuSHEET(RULE26) WO 98/52940 PCT/US98/10436 412 Observed Called. Example# R R %Yield Ma Mass Spec Mass Spec (+) (M+H) CN B-0676 F 34 411 412 0 B-0677 F - 46 436 437 0 O o/ F B-0678 F 37 422 423

-

0 \/ F F B-0679 F 34 422 423 F B-0681____ F 31______ 454 ____455 F O\F B-0680 F 60 440 441 0 0F C I C B-0681 F31 454 455 0 B-0682 F N37 428 429 CF 3 B-0683 F-/ 46 472 473 F B-0684 F F 50 440 441 0 C F 3 B-0685 F0 - 1 44 472 473 SrrruTE SEfZ (F- 26) WO 98/52940 PCT/US98/10436 413 Observed Example# R R %Yield Calcd. Mass Spec Mass Spec (MH (M+H) 0 B-0686 F 66 472 473 F O F B-0687 F

CF

3 57 472 473 0 F B-0689 F CF 3 42 472 473 F 0 CF 3 B-0690 F 34 472 473 F C1 B-0691 F 52 420 421 B-0692 F 41 400 401 B-0693 F Cl 56 454 455 o B-0694 F 38 404 405 B-0695 FF 3 422 423 suegrfsnm$HEEr(RUL2s) WO 98/52940 PCT/US98/10436 414 Observed Example# R R %Yield Calcd Mass Spec Mass Spec (M+H) (M+H) C1 B-0696 F 57 454 455 CI 1 0 B-0698 F F 59 440 441 OF B-0699 F 5 420 423 O 0 -F F I F B-069 F - - 4 44 441 F B-0701 F F 46 422 423 0 F B-0702 F 43 420 421 B r O B-0703 F 57 464 465 F B-0704 F - F3 44 454 455 I I B-070S FUBST 3U T E EF .E SUBSTffUTESIIETF(RALE26) WO 98/52940 PCT/US98/10436 415 Observed Example# R R %Yield Calcd Mass Spec Mass Spec (+H (M+H) N B-0706 F o 35 405 406 O SUSSfThUTE SHEET (RULE 26) WO 98/52940 PCT/US98/10436 416 N-NH 2 NH R R N Observed Example# R 2 J %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) 0 o o_ o_ _ _ o B-0707 F F, 76 516 517 - - I , , O O B-0708 F 61 498 499 O B-0709 F - s37 464 465 0 / \ -O-O B-0710 F 76 524 525 0 B-0711 F 75 512 513 F B-0712 F-O! /\ F 91 534 535 0 B-0713 F - S CF 3 42 490 491 0 SUBSITUTEHEET(RULE

)

WO 98/52940 PCT/US98/10436 417 Observed Called. asSe Example# R 2 J %Yield Mass Spec Mass Spec (M+H) F B-0714 F 87 516 517 0 B-0715 F S 60 464 465 0 B-0716 F 59 478 479 0 B-0717 F I 61 450 451 O 0 B-0718 F - -65 436 437 0 0 B-0719 F - /84 528 529 B-0720 F 69 504 505 O 0 B-0721 F 63 512 513 0 B-0722 F - 88 558 559 0 B-0723 F 68 443 444 N 0 H SUBSMTE SHEET (RULE 26) WO 98/52940 PCT/US98/10436 418 S Calcd Observed Called. Example# R R %Yield Mass Spec Mass Spec (M+H) (M+H) 0 B-0724 F N , 75 401 402 - NH 21 B-0725 F0 - N 83 491 492 /

\\

B-0726 F 24 455 456 o B-0727 F N 67 471 472 B-0728 F 89 495 496 H N B-0731 F 60 491 492 N B-0732 F F 86 495 496 B-0733 F 81 505 506 SUBTMTESHEE~(RULEs) WO 98/52940 PCT/US98/10AQ436 419 Observed Called. Example# R R %Yield Ma Mass Spec Mass Spec (+H (M+H) B-0734 F - 87 441 442 H B-0735 F 83 443 444 0 o 7 B-0736 F H 91 505 506 H B-0737 F 9 477 B-0738 F 87 505 506 I[1 B-0739 F 82 505 506 F B-0740 F y85 495 496 B-0741 F-0- -- 68 507 508 N B-0742 F 14 457 B-0743 F H77 429 430 SUBSmUTESHEET (RUUE216) WO 98/52940 PCT/US98/10436 420 S Calcd. Observed Called. Example# R 2 R %Yield ss Spec Mass Spec Mass Spec (MH (M+H) / \ B-0744 F - 86 537 538 B-0745 F 82 482 483 B-0746 F - 74 442 443 0 B-0747 F83 444 445 - 0 B-0748 F o 94 430 431 O F HN B-0749 IF 100 455 456 B-0750 F 100 455 456 B-0751 F 48 444 445 o I( L WO 98/52940 PCT/US98/10436 421 N-NH S NH R

R

2 AH N Calcd. Observed Example# R R %Yield Mass Spec Mass Spec Masss Spec - l '-L'-o B-0752 F 84 516 517 -O-/O 0 B-0753 F - 67 498 499 0 B-0754 F 31 464 465 B-0755 F 85 524 525 B-0756 F 77 512 513 0 B-0757 F - bF 57 534 535 o 0 0 B-0758 F - C3 36 490 491 o SUBgS UTESHEE(RULE26) WO 98/52940 PCT/US98/10436 422 Example# Calcd Observed Example# R R J %Yield aSpec Mass Spec Mass Spec (MH (M+H) F 0 B-0759 F 79 516 517 / \II i B-0759 F 3 46 6 0 B-0760 F-- 53 464 465 B-0761 F -o 50 478 479 0 B-0762 F 60 450 451 0 B-0763 F S 75 436 437 0 B-0764 F 43 528 529 0 0 B-0765 F 75 504 505 O B-0766 F 67 512 513 0 0 B-0767 F / 43 558 559 B-0768 F 78 443 444 H SUBSTIUTEET(F E26) WO 98/52940 PCT/US98/10436 423 Observed Calcd. Example# R R %Yield ad Mass Spec Mass Spec (M+H) (M+H) 0 B-0769 F 76 401 402 NH 2 B-0770 F 57 491 492 B-0771 F N 14 455 456 / \o B-0772 F N 72 471 472 B-0773 F HH 100 495 496 0 0 B-0774 F 41 429 430 N 0 B-0775 F 91 415 416 H B-0776 F 6 4 491 492 B-0777 F 90 495 496 B-0778 F 19 505 506 SU0 TE(R E ) SU6MlUTSHET(RLU26) WO 98/52940 PCT/US98/10436 424 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) H B-0779 F 79 441 442 / \ H B-0780 F H 40 443 444 o )7 H I B-0781 F 93 505 506 O B-0782 F 57 477 478 B-0783 F 99 505 506 B-0784 F U 100 505 506 _ _ _ _ _ o j _ _ _ _ / \ OF B-0785 F --- ! 92 495 496 B-0786 F 91 507 508 B-0787 F -15 457 458 B-0788 F 48 429 430 SMTUTESHEET (RULE 26) WO 98/52940 PCT/US98/10436 425 Observed Called. Example# R R %Yield aS Mass Spec Mass Spec (MH (M+H) B-0789 F 91 537 538 B-0790 F p/ 93 482 483 B-0791 F 76 442 443 0 B-0792 F o 96 444 445 B-0793 F o 54 430 431 HN B-0794 F .. 100 455 456 O 0 B-0795 F - 100 455 456 IO B-0796 F 094 444 445 SUBBTUTESHEET(RULE2) WO 98/52940 PCT/US98/10436 426 Observed Example# R R %Yield Calcd. Mass Spec Mass Spec (M+H) B-0797 'F 90 458 459 B-0798 F o 90 588 589 B-0799 F 82 428 429 0 B-0800 F 92 480 481 0 o B-0801 F 82 442 443 0 B-0802 F 95 486 487 O B-0803 'F 89 400 401 ggymHESHEET(RULE26) WO 98/52940 PCT/US98/10436 427 Observed Called. Example# R R j %Yield ad Mass Spec Mass Spec (M+H) (M+H) B-0804 F 87 440 441 0 B-0805 F 100 426 427 o B-0806 F 99 540 541 0 B-0807 F / 96 588 589 0 ON B-0808 F 82 453 454 0 B-0809 F 92 472 473 0 B-0810 F 98 430 431 ii B-0811 88 492 493 o FC B-0812 F 81 530 531 B-0813 F F 98 516 517 0 F SUBSTTUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 428 Observed Example# R R %Yield Cacd Mass Spec Mass Spec (M+H) B-0814 F - 100 440 441 0 B-0815 F 0 100 536 537 B-0816 F 99 506 507 O B-0817 F /98 506 507 0 B-0818 F 86 476 477 IIo O B-0819 F 90 462 463 0 B-0820 F 91 454 455 0 N B-0821 F69 463 464 0 B-0822 F 79 463 464 f0 N B-0823 F 79 463 464 sUBsTmUTESHEE(RUE26) WO 98/52940 PCT/US98/10436 429 Observed Example# R 2 J %Yield Calcd Mass Spec Mass Spec (+H (M+H) B-0824 F - 82 492 493 ,ooo B-0825 F 100 506 507 B-0826 F -97 458 459 B-0827 F 100 659 660 B-0828 F97 514 515 SUsgmgTESWt

(RUL

WO 98/52940 PCT/US98/10436 430 2 Calcd. Observed Example# R R %Yield Mass Spec Mass Spec (M+H) (M+H) B-0829 F S 63 458 459 B-830 'F o70 588 589 B-0831 F 0 100 428 429 B-0832 F 81 480 481 B-0833 F 73 442 443 B-0834 F o 79 486 487 B-0835 F S 5 400 401 USTT SHEET(RUtLE26) WO 98/52940 PCT/US98/10436 431 Observed Example# R R %Yield Calcd Mass Spec Mass Spec (M+H) (M+H) B-0836 F o 28 440 441 B-0837 F o 81 426 427 B-0838 F Br 0o 84 540 541 B-0839 F o 80 588 589 B-0840 F o 71 453 454 B-0841 F 55 472 473 B-0842 F 71 430 431 0/ B-0843 F 68 492 493 0 F3C I B-0844 F 61 530 531 F B-0845 F /0 \ F O0 F 84 516 517 8UBSITUTESHEEr(RULE26) WO 98/52940 PCT/US98/10436 432 Observed Called. Example# R R %Yield ad Mass Spec Mass Spec (+H (M+H) B-0846 F 87 440 441 B-0847 F o - 86 536 537 B-0848 F / o 79 506 507 B-0849 F o - 81 506 507 B-0850 F-/ I 0 69 476 477 B-0851 F o 83 462 463 B-0852 F 0 77 454 455 B-0853 F o 87 463 464 B-0854 F o 73 463 464 B-0855 F o 92 463 464 SUsTfTULTESHEEr(RULEi

)

WO 98/52940 PCT/US98/1 0436 433 2 Calcd. Observed Exam ple# R j%Yield MasSc Mass Spec 0 75 492 493 B-0857 F / I__________ 86 506 507 B-0858 F ___________84 458 459 B-0859F ______ ___________80 659 660 B-0860 F / I ___ __ _ __ ___ __ __ _ ___ __ __ __ 94 514 515 BUBqfTUE EET (RULE 6) WO 98/52940 PCT/US98/10436 434 N-NH H N R R2 .'W/H3 O NHCH31

N

Calcd. Observed Called. Example# R R %Yield Mass Spec Mass Spec (MH (M+H) O B-0861 84 583 584 F B-0862 F 96 475 476 ... .. .. . . . .. . . .. 0 ! B-0863 69 423 424 0 B-0864 Fo 86 437 438 B-0865 62 395 O B-0866 F 81 421 422 0 B-0867 F Br 100 535 536 o 0susmmSH RUM) suSMMUMSEHEff(RUSE) WO 98/52940 PCT/US98/10436 435 Observed Called. Example# R R %Yield aS Mass Spec Mass Spec (M+H) (M+H) B-0868 F 89 583 584 O 0 / \ / B-0869 F 100 448 449 N 0~~ B-0870 F 100 425 426 B-0871 F 100 487 488 O B-0872 IF 78 501 502 0 B-0873 IF / 78 471 472 I 0 B-0874 F 92 475 476 O F B-0875 F 37 458 459 OO 0 B-0876 F 69 507 508 0 B-0877 F 70 445 446 I ( F-M UET ( RUE26) WO 98/52940 PCT/US98/10436 436 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) O B-0878 F 91 431 432 0 F -O-IO B-0879 IF 92 511 512 0 B-0880 F 89 410 411 N B-0881 F 84 490 491 B-0882 F 85 500 501 F / 0 B-0883 F85 424 425 B-0884 F 86 532 533 0 WO 98/52940 PCT/US98/10436 437 N-NH H N 2 R N O

NHCH

3 Calcd. Observed Called. Example# R 2 J %Yield Mass Spec Mass Spec (M+H) (M+H) B-0885 F 51 583 OF B-0886 F 97 475 O B-0887 F - 29 423 424 O B-0888 F o- 82 437 438 B-0889 F 93 395 396 B-0890 F 91 421 422 0 B-0891 F S43 535 536 0 WO 98/52940 PCT/US98/10436 438 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) B-0892 F 62 583 584 0 $0 B-0893 F 95 448 449 0 B-0894 F 100 425 426 O B-0895 F 76 487 488 B-0896 F 62 501 502 B-0897 F 80 471 472 0 B-0898 F 79 475 476 -/ 9 O F B-0899 F 70 458 459 0 B-0900 F 62 507 508 B-0901 F 43 445 446 SUBTU HEo(RULE) SUST.oSEE(RLE6 WO 98/52940 PCT/US98/10436 439 Observed Called. Example# R R %Yield ac Mass Spec Mass Spec (M+H) (M+H) 0 B-0902 F - - 93 431 432 07 F B-0903 F o -II j / 100 511 512 0 O B-0904 F 95 410 411 , N / H B-0905 F 89 490 491 B-0906 F 69 500 501 0 B-0907 F K 28 424 425 -F-K _ _5 B-0908 F / /64 532 5 suesmUTESHEET(RAEM) WO 98/52940 PCT/US98/10436 440 N-NH H N 2J R2 ."I/H R

OCH

3 N Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) B-0909 F 83 542 543 OF B-0910 F 80 434 435 o B-0911 F 91 382 383 0 B-0912 F 100 396 397 B-0913 F 94 354 355 0 B-0914 F -95 380 381 0o B-0915 F 98 494 495 MEMWE0SHEET(RULE8) WO 98/52940 PCT/US98/10436 441 Observed Example# R R %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) B-0916 F 84 542 543 0 /o B-0917 IF 79 407 408 N B-0918 F 89 384 385 0 B-0919 F 91 446 447 B-0920 F 99 460 461 B-0921 F 84 430 431 0 B-0922 F 81 434 435 O F B-0923 F 76 417 418 B-0924 F 70 466 467 0 B-0925 F 64 404 405 0 SUBSTITUTESHEET(RUE26) WO 98/52940 PCT/US98/10436 442 S Calcd. Observed Called. Example# R R %Yield Spec Mass Spec Mass Spec (MH (M+H) B-0926 F - 47 390 391 0 F 0 0 B-0927 !F 89 470 471 O B-0928 F ' 53 369 370 H B-0929 F 100 449 450 B-0930 F 14 459 460 B-0931 F H 41 383 384 B-0932 F H \ 0 94 491 492 SUBSTrrUTESHEET(RULEM) WO 98/52940 PCT/US98/10436 443 N-NH J.. ,k-..-", /H N N Observed Calcd. Mass Example# R R %Yield c Mass Spec Spec (M+H) 44,/ B-0933 F H 48 447 448 0 H B-0934 F o 44 429 430 o B-0935 F 33 485 486 HN On B-0936 F 30 479 /0 B-0937 F 68 367 368 Br B-0938 F 72 479 480 H B-0939 F 76 415 416 8UBSMTUMTESHEET(RtLE2) WO 98/52940 PCT/US98/10436 444 Observed Calcd. Mass Example# R R %Yield c Mass Spec Spec (M+H) 0 B-0940 F - o 36 397 398 B-0941 F o 41 441 442 B-0942 F 27 473 474 B-0943 F 55 493 494 B-0944 F H 473 474 0 H B-0945 F 82 429 430 B-0946 F 100 459 460 0 /\ ( 0 B-0947 F 60 425 426 0 H B-0948 F 100 431 432 0 B-0949 F 98 473 474 SUBSTrfuTESHEET(RULE26) WO 98/52940 PCT/US98/10436 445 Observed Example# 2 1 Caled. Mass Osre Example# R 2 R %Yield Calcd. Mass Mass Spec Spec (M+H) F I H B-0950 F 64 419 420 CF, B-0951 F 100 469 470 0 B-0952 F a 61 469 470 I0 B-0953 F o 67 425 426 o\ B-0954 F N 62 431 432 0 B-0955 F o _ 39 461 462 B-0956 F 66 429 430 H /o B-0957 F 93 429 430 B-0958 F 86 365 366

:HN----

B-0959 F 73 451 452 A iRTITUMSHEET(RULE26) WO 98/52940 PCT/US98/10436 446 Observed Example# R R %Yield Calcd. Mass Mass Spec Spec (M+H) B-0960 F " 98 485 486 B-0961 F / 100 469 470 B-0962 F F 100 419 420 0- B-0963 F N 83 401 402 B-0965 F 90 411 412 H So B-0966 F --- 4 76 443 444 B-0967 F 100 443 444 \ ' r-o B-0968 F 100 477 478 B-0969 F - 77 477 478 SUBSTRUTESHEET(M

)

WO 98/52940 PCT/US98/10436 447 Observed Calcd. Mass Example# R R %Yield c Mass Spec Spec (M+H) B-0970 F - 38 461 462 C1 B-0971 F oc 95 469 470 B-0972 F 98 479 480 B-0973 F 96 485 486 B-0974 F H 74 443 444 B-0975 F 100 495 496 B-0976 F 70 453 454 0 B-0977 F 100 467 468 Sc B-0979 F 54 491 492 SUSMUTEUSHET(RULE2S) WO 98/52940 PCT/US98/10436 448 Observed Called. Mass Example# R R %Yield Mass Spec (M+H) CB B-0980 F 65 469 470

H(

WO 98/52940 PCT/US98/10436 449 2 Calcd. Observed Example# R 2 R %Yield Calcd. Mass Observed Mass Spec Mssp (M+H) B-0981 F o 78 382 383 0 B-0982 F 82 512 513 0 B-0983 94 352 353 B-0984 F 81 404 405 0 B-0985 84 366 367 B-0986 F 80 410 411 -r C 0 B-0987 85 324 325 suwnTUTEHEERMLE WO 98/52940 PCT/US98/10436 450 Observed Example# R 2 R%Yield Calcd. Mass Spec Mass Spec MH) (M+H) B-0988 F 91 364 365 0 B-0989 F 88 350 351 0 Br B-0990 F 68 464 465 0 B-0991 F 86 512 513 0 -II B-0992 F 79 377 378 0 B-0993 Fc 81 396 397 B-0994 F0100 354 355 B-0995 F 75 416 417 0 CF 3 B-0996 F 65 454 455 SIM I TESHEET(RULE2 WO 98/52940 PCT/US98/10436 451 Observed Example# R 2 R%Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) 0 F B-0997 F 64 440 441 0 B-0998 F 81 364 365 B-0999 F o 79 460 461 B-1 000 F 84 430 431 B-1001 F-0 - 0 78 430 431 0 B-1002 F-85 400 401 ____ _ ' _ 0 B-1003 F i83 386 387 0 B-1004 F 87 378 379 0 B-1005 F <57 387 388 U N WO 98/52940 PCT/US98/10436 452 Observed Example# R 2

R

J %Yield Mass Specld. Mass Spec Mass Spec (MH (M+H) 0 B-1006 F 80 387 388 0 0 B-1009 F-- / 81 430 431 B-1010 F 81 382 383 / \ B-1011 F66 583 584 B-1012 F lo69 438 439 suBS=TrESHEET(RULE2) WO 98/52940 PCT/US98/1 0436 453 2 Calcd. Mass Observed Example# R R %Yield Spc Mass Spec Spec (M+iH) B-1013 F H ~ /~53 440 441 B-i1014 !F - S 61 422 423 0 B-10i5 'F-( - S 47 388 389 0 B-1016 F74 448 449 B-1017 / 63 436 437 F B-10i8 I F Q--- V / \ 82 458 459 0 B-i1019 F-Q -- --- F3 41 414 415 __________________ 3!_______________ I _________ ___________ __________ ________ ______________0 _____ _____ WO 98/52940 PCT/US98/10436 454 Observed Calcd. Mass Example# R 2 J %Yield c Mass Spec Spec (M+H) F B-1020 F 100 440 441 S II 0 o B-1 021 F s100 388 389 O B-1022 F - 74 402 403 0 O B-1023 F -. 76 374 375 0 B-1024 F 73 360 361 - II O o B-1025 F o 100 452 453 0 B-1026 F 95 428 429 O 0 0 B-1027 F- -- ~i /98 436 437 O O B-1028 F 100 482 483 0 0 B-1 029 F -N 98 367 368 su~snT8HEU(RULE90 WO 98/52940 PCT/US98/10436 455 Observed 2ape % Calcd. Mass Mass Spec Example# R 2 Rj %Yield Spec Mass Spec Spec (M+H) 0 B-1030 F- NH 88 325 326 B-1031 97 415 416 L o B-1034 F 67 419 420 S0 0 B-1035 F /-73 353 354 0 B-1036 F 79 339 340 H B-1037 F /78 415 416 B-1038 100 419 420 /., \- N B-1039 F 95 429 430 SUSS0 UTESHEE( ) SUBrUTSHE7(AE WO 98/52940 PCT/US98/10436 456 Observed Calcd. Mass Observec Example# R R j %Yield Spec Mass Spec e(M+H) / H B-1040 F -91 365 366 0 B-1041 F 88 367 368 o B-1042 F 78 429 430 H B-1 043 F 79 401 402 B-1044 F 93 429 430 -7 B-1045 F N 100 429 430 O B-1046 F 94 419 420 F B-1047 F 100 431 432 B-1048 F 58 381 382 B-1049 F 97 353 354 SUBSTITUTESHEE (RLE26) WO 98/52940 PCT/US98/10436 457 Observed Calcd. Mass Example# R R %Yield c Mass Spec Spec (M+H) B-1050 100 461 462 B-1051 F - 88 406 407 B-1052 F 82 366 367 0 rj, B-1053 F o 21 368 B-1054 F o 98 354 355 HN B-1055 F 100 379 380 B-1056 F 85 379 380 0 B-1057 F 30 368 369 OTTE0f UE suesTUTESHEE(RULEM) WO 98/52940 PCT/US98/10436 458 Observed Calcd. Mass Observed Example# R R %Yield Sc Mass Spec Spec (M+H) B-1058 F \35 500 501 o 0 B-1059 F - 77 479 480 H Br B-1060 F 37 500 501 O B-1 061 IF' \ Il86 456 457 __ _ F<S \\_ __ 0 B-1064 F /c, 58 49506 497 HO SST UESHF0T(R E ) o 1 0 B-1 064 F 58 506 HO

C

WO 98/52940 PCT/US98/10436 459 Observed Example# R R %Yield Calcd. Mass Mass Spec Spec (M+H) B-1065 F 24 466 OOH B-1066 F 100 490 491 S B-1069 F 74 464 465 B-1070 F 54 47281 482 0 B-1069 F 0 97 472 473 B-1 070 F-54 481 482 B-1071 67 473 474 O B-1072 F0/ 35 515 516 \ / N\ O B-i 073 F 11 \ 100 490 491 0 B-1074 F 100 464 465 0 SUB1TmUTESHEET (FU.E ) WO 98/52940 PCT/US98/10436 460 Observed Example# R R %Yield Calcd. Mass Mass Spec Spec (M+H) CI O B-1075 F - 100 470 471 III O B-1076 F c 93 490 491 I - 0 C1 0 B-1077 I F 100 474 475 Cl 0 B-1 078 F80 447 448 I I B-1 079 F 85 454 455 o CI B-1080 F // 100 496 497 C1 B-1081 F / F 100 490 491 - Ns B-1 082 F 0 r1 100 500 501 Br B-1083 F 93 500 501 I 0 B-1084 F 0 81 494 495 0 BTUTSHEET(RULE6) WO 98/52940 PCT/US98/10436 461 Observed Calcd. Mass Example# R R %Yield c Mass Spec Spec (M+H) o B-1085 F - 93 482 483 CF 0 B-1086 1F 92 490 491 B-1087 F c 100 490 491 8UesIUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 462 Observed Calcd. Mass Observed Example# R R %Yield Sc Mass Spec Spec (M+H) 0 B-1088 F 97 450 451 0 B-1089 iF - 100 436 437 0 B-1090 F 100 456 457 o B-191 100 456 457

C

B-1094 F 100 474 45 0 S T0 E B-1 091 IF Q --- 100 45645 B-1 092 F96 490 491 CI B-1093 IF 0 CI; 100 490 491 CI CI B-1094 jF / F! 100 474 475 0 USrM T SHEE (RULE 26) WO 98/52940 PCT/US98/10436 463 Observed Calcd. Mass Observed Example# R R %Yield Sc Mass Spec Spec (M+H) B-1095 F-- / 81 470 471 0 B-1096 F / !-- 77 450 451 / O B-1 097 F O 100 436 437 B-1098 F [1 93 466 467

CF

3 B-1099 F _1 / \ 100 490 491 0 0 B-1100 F 47 482 B-1101 F /\ 64 462 463 B-1102 F 98 530 531 / \ O 0 B-1103 F 1 -IQ )65 472 B-1104 F ___ 88 441 442 SUBSTITTE SHEE (RULE2) WO 98/52940 PCT/US98/10436 464 Observed Example# R 2 J %Yield Calcd. Mass Mass Spec Spec (M+H) B-1105 F 100 464 465 __ _ __ _ __ _N N 0 B-1106 F , /91 486 487 B-1107 F 96 447 448 B-1108 F 55 561 562 0 0 S 0 8-1109 F /\/~ - 100 498 499 0 /0 B-1il1 F - 73 548 549 B-1111 F 94 505 506 /N ,I I-r I B-1112 F 100 568 569 B-1113 F c\ 100 495 496 0 B-1114 F - / 73 426 427 SUBSTITUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 465 Observed Calcd. Mass Example# R R %Yield c Mass Spec Spec (M+H) 0 B-1115 F - - N 30 389 390 i0 -Q-II B-1116 F 100 568 569 O S0 O B-1117 F 83 500 501 B-1118 F 55 473 B-1119 F -70 514 515 SUMTfJTESHEET(RULE26) WO 98/52940 PCT/US98/10436 466 Observed 2 ~~Caled. Mass Osre Example# R 2

R

j %Yield Cacd M Mass Spec Spec MasSe (M+H) B-1120 F ' - / 84 400 401 B-1121 F c 86 420 421 B-1122 F -90 400 401 0 0 B-1123 F CF 3 100 454 455 B-1124 F 91 442 443 0 B-1125 F 50 512 513 B-1126 F 85 454 455 SUBSTff UTESHEE (RULE 26) WO 98/52940 PCT/US98/10436 467 Observed Example# R R %Yield Calcd. Mass Mass Spec Spec (M+H) 5" CN B-1127 F 93 411 412 0 B-1128 F 87 436 437 0 B-1129 F o 78 422 423 B-1130 F F 96 422 423 F __ F F B-1131 F 84 440 441 F C I B-1132 F 77 454 455 10 S o B-1133 F 62 428 429 CF3 B-1134 F 91 472 473 o F F B-1135 F 85 440 441 F 0 B-1136 F CF3 82 472 473 8UBSTU SE (RULE26) WO 98/52940 PCT/US98/10436 468 Observed Calcd. Mass Example# R R %Yield c Mass Spec Spec (M+H) 0 B-1137 F- F 95 472 473 F 0 F B-1138 F / \ - CF 3 100 472 473 0 F 3 B-1139 F 100 472 473 FF 0 B-1140 F CF 3 92 472 473 - / N CF 3 CFe B-1141 F 100 472 473 CI B-1142 F 88 420 421 B-1143 F -0 - 90 400 401 F B-1145 93 404 405 ' F B-1146 F 90 422 423 I No ___8UBST__lESHEET(RULE26) WO 98/52940 PCT/US98/10436 469 Observed Example# R R %Yield Cald. Mass Mass Spec Spec (M+H) C1 B-1147 F 100 454 455 B-1148 F 87 422 423 O F F B-1149 IF- 87 440 441 o F B-1150 F 90 404 405 o B-1151 F82 422 423 0 F F1 B-1152 F F 85 422 423 T)

-

I B-1153 F1cl 90 420 421 B r B-1154 F 78 464 465 O B-1155 F 79 454 455 B-1156 F- 995 392 393 O SUBSTITUTES8HEET (RULE 26) WO 98/52940 PCT/US98/10436 470 Observed Calcd. Mass Osre Example# R R %Yield Cacd Mass Mass Spec Spec (M+H) B-1157 F 81 405 406 8UBSITfUTEHEET(RULE26) WO 98/52940 PCT/US98/10436 471 N-NH I Ji R H N N S Calcd. Observed Example# R R j %Yield aSpec Mass Spec Mass Spec (+H (M+H) 0

/@

B-1158 F o 54 396 397 O B-1159 F o-42 526 527 B-1160 F 27 366 367 0 0 B-1161 F 58 418 419 F. B-1162 F Q0 62 380 381 o B-1163 F o 58 424 425 B-1164 F 67 338 339 ujET (U IE 26) WO 98/52940 PCT/US98/10436 472 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) B-1165 F 66 378 379 0 B-1166 F 65 364 365 0 0 rBr B-1167 F -64 478 479 0 B-1168 F 76 526 527 0 B-1169 F 70 391 392 B-1170 F 76 410 411 B-1171 F 82 368 369 0 B-1172 F 73 430 431 O CF 3 B-1173 F 74 468 469 0 F OFF B-1174 F 83 454 455 F

SUBSTTTESHEET(FUE)

WO 98/52940 PCT/US98/10436 473 Observed Example# R 2 R %Yield Calcd. Mass Spec Mass Spec (M+H) B-1175 F 76 378 379 o I B-1176 F o 96 474 475 A B-1177 F94 444 445 0

O

o B-1178 F 90 444 445 B-1179 F /57 414 415 B-1180 F 75 400 401 0 B-1181 F 1 66 392 393 0 B-1182 F 74 401 402 N 0 B-1183 F 62 401 402 N B-1184 F 51 401 402 SSUSHEF(RU2 suSfl~T SEHEETIRULE ) WO 98/52940 PCT/US98/10436 474 Calcd. Observed Example# R R %Yield Mass Spec Mass Spec (M+H) (M+H) 0 0 B-1185 F - 90 430 431 B-1186 F 86 444 445 B-1187 F 74 396 397 B-1188 F I-76 597 598 B-1189 F 60 452 453 SUSSMT&TESHEE=(RULE26) WO 98/52940 PCT/US98/10436 475 2 Calcd.Observed Example# R j%Yield Mascdpe Mass Spec MassSpec (M+H) 0 B-1190 !F - / 47 436 437 0 B-1191 *F -45 402 437 B-1 192 F F 61 472 473 ________________________________ 0 0 B-1 193 F -6 -- F 2 462 429 B-1___ 194 F0 49 405 FUSIUESEE RL 6 WO 98/52940 PCT/US98/10436 476 Observed Caled.MasSe Example# R

R

j %Yield Mass Spec Mass Spec (M+H) B-1197 F 54 454 455 O 0 ____7 0 B-1198 F - 44 402 403 B-1199 F 67 416 417 0 -- 0 B-1200 F 45 388 389 0 o B-1201 F 52 374 375 o 0 B-120 F 100 466 467 0 B-1204 F II 100 450 451 0 O B-1205 F o 83 496 497 B0- 0 B-1206 F N 97 381 382 gggUTESEET(RULEM) WO 98/52940 PCT/US98/10436 477 Observed Calcd.MasSe Example# R R %Yield Mass SpecMass Spec (M+H) 0 B-1207 F N 100 339 340 - NH 2 B-1208 F 90 429 430 B-29 F N69 393 394 1 F - -35 409 410 0 B-1211 F 100 433 434 0 B-1212 F N 83 367 368 0 B-1213 F 78 35 H B-1214 Fo68 429 430 B-1215 F 65 433 434 B-1216 F N 91 443 444 SustmUTE SH-EE (RULE26) WO 98/52940 PCT/US98/10436 478 Observed Cald. Example# R R %Yield Mass Spec Mass Spec (M+H) B-1217 99 379 380 B-1218 F 92 381 382 0 H I B-1219 F 74 443 444 -12 F ! , 19 443 44 O H N B-1220 F o 67 415 416 B-1221 IF 14 443 444 B-1222 F 19 443 444 O B-1223 F o 71 433 434 F B-1224 F 100 445 446 B-1225 F -75 395 396 0 B-1226 IF NH 58 367 368 VASM~rSHEUr(MLEB) WO 98/52940 PCT/US98/10436 479 Observed Called. Example# R R %Yield aS Mass Spec Mass Spec (M+H) S(M+H) B-1227 F o 98 475 476 B-1228 F 71 420 421 B-1229 F 85 380 381 0 B-1230 F o 10 382 B-1231 F 66 368 369 HNi B-1232 IF 100 393 394 0 B-1233 F,96 393 394 B-1234 F 66 382 383 SUBSTrUfESHEEFT(RULE26) WO 98/52940 PCT/US98/10436 480 Observed Called. Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) B-1235 F 50 514 515 0 B-1236 F 100 493 494 0 H Br B-1237 F - 91 514 515 ' 0 B-1238 !F c 100 470 471 0 B-1239 F o 71 510 511 0 0 0 B-1240 F 27 510 511 / 0 B-1241 'F c 73 520 SU nT 8 (RULE WO 98/52940 PCT/US98/10436 481 Observed Cal2d. Mass Spec Example# R2 R %Yield Mass Spec (M+H) 0 OOH B-1244! - 52 478 4=79 B -1245 O 100 5447 B-1244 56 48 487 B-1247 F / 43 495 496 CII B-1246 56 486 487 B-1247 F / - I 43 495 496

-

NOO B-1248 F-0 61 487 488 B-1249 32 529 530 C1 Cil / B-1250 F _-- 56 504 505 0 B-1251 F 58 478 479 0 SMMnUTESH (PULE26) WO 98/52940 PCT/US98/10436 482 Cald Observed Example# R R %Yield a c Mass Spec Mass Spec (M+H) (M+H) B-1252 F 98 484 485 o B-1253 F 59 504 505 O B-1254 F100 488 489 CI B-1255 F 96 461 B-1257 F - 63 510 511 od 0 B-1258 F 100 504 505 B-1259 F 95 514 515 BBr B-1260 F/ 92 514 515 FO B-1261 o 98 508 509 USsTUTESHEE

(RULEM

WO 98/52940 PCT/US98/10436 483 Observed Caled.MasSe Example# R R %Yield Mass SpecMass Spec Mass Spec (iH (M+H) B-1262 F 97 496 497 CF B-1263 F - 100 504 505 0CC B-1264 F c 100 504 505 BUBliUTSHEER ULE26) WO 98/52940 PCT/US98/10436 484 Observed Called. Cac.Mass Spec Example# R R %Yield Mass Spec Mas ec (M+H) 0 B-1265 F

-

100 464 465 0 B-1266 F

-

79 466 451 II 0 B-1267 F 100 470 471 o II 0 B-1268 F 87 470 471 CI B-1269 100 504 505 o CI C1 B-i1270 F 2 /\ c 100 504 505 0 CI B-1271 F 56 488 489 O S~gg ggSEET(RULE 2

R

WO 98/52940 PCT/US98/10436 485 S Calcd. Observed Caled.MasSe Example# R 2

R

J %Yield Mass Spec Mass Spec (M+H) B-1272 F - 98 484 485 Cl B-1273 F - 90 464 465 O B-1274 F 87 450 451 B-1275 F \ / 94 480 481

CF

3 0 B-1276 F -- ~ 100 504 505 0 00 0 B-1277 F -- 60 496 511 C1 S B-1278 F- - 68 476 477 \J: 0 B-1279 F / 100 544 545 O B-1280 F- - - 68 486 0 B-1281 F 98 455 456 WO 98/52940 PCT/US98/1 0436 486 2 Calcd.Observed Example# R j%Yield MascSpe Mass Spec MassSpec(M+H) B-18 F-- 0 100 478 479 B-1283 F -/ \ 58 500 501 -Io _,CN B-24F-/ 58 461 462 B-1285 F -1 65 575 576 B-1286 F - 87 512 513 B-1287 F /79/\ 562 563 B-1288 F-0 11/ 100 519 520 B-1289 F -77 582 583 B-1290 FK s100 509 510 0i B-1291 F 91 440 441 SUTW % (RULE2) WO 98/52940 PCT/US98/10436 487 Observed Ca led.MasSe Example# R 2 J %Yield Mass SpecMass Spec (M+H) B-1292 F S - N 35 403 404 B-1293 F- - 73 582 583 o 0 B-1294 F - 49 514 515 B-1295 F / 48 487 B-1296 F - 76 528 529 SUSUTESHEET(RULE26 WO 98/52940 PCT/US98/10436 488 Observed Ca led.MasSe Example# R 2 J %Yield Mass SpecMass Spec Mass Spec (MH /(M+H) B-1297 'F - 62 447 448 B-1298 F 66 452 453 N B-1299 F 65 479 431 0 B-1300 F 71 444 445 \, _ _\_ _ __ _ 0 H B-1301 F 100 472 473 NH B-1302 F 75 410 411 0 B-1303 F N- 74 424 425 _ _ _ \H _ _S74 44 2 B-1303 F 7 2 2 WO 98/52940 PCT/US98/10436 489 Observed Caled.MasSe Example# R R %Yield a c Mass Spec B-1304 F 11 430 431 B-1305 F 2 424 B-1306 30 433 434 B-1307 100 522 523 B-1308 F 100 508 509 /- \ -I K/ 7 B-1309 F 100 448 449 i

F

N / / 0 B-1310 FI 26 430 431 - NH B-1311 F 45 397 398 O B-1312 14 507 508 B-1313 F - N r 67 450 451 jaImTME SHEET (RULE26) WO 98/52940 PCT/US98/10436 490 Observed Called. Example# R R %Yield Ma Mass Spec Mass Spec (+) (M+H) 0 / \, B-1314 F 69 444 445 B-1315 F 57 450 451 0 B-1316 F -N 75 393 394 B-1317 F 100 461 462 B-1318 F i_31 450 451 B-1319 F /23 464 465 B-1320 F 59 512 513

H

WO 98/52940 PCT/US98/10436 491 Observed Called. Example# R 2 R %Yield Calcd. Mass Spec Mass Spec (M+H) B-1321 F 63 414 415 0 B-32 Fcl 45 434 435 B-1323 F 53 414 415 0 B-1324 F

CF

3 32 468 469 B-1325 F j 45 456 457 0 B-1326 F o50 526 527 B-1327 F 55 468 469 8U~gf=SHE(RULE 26) WO 98/52940 PCT/US98/10436 492 Observed Caled.MasSe Example# R R %Yield Mass Spec Mass Spec (M+H) ON B-1328 F CNK 29 425 426 0 B-1329 F67 450 451 o B-1330 F F 59 436 437 B-1331 F 45 436 437 F F B-1332 F 81 454 455 B-1333 F F I< 3 6 6 F B-1333 F 23 468 469 0 B-1334 F Q53 442 443 o F F B-1336 F 69 454 455 F

CF

3 B-1337 FCF 67 486 487 SUST SHFE(RULE2 $U~ffWBHEU(RULE26) WO 98/52940 PCTIUS98/10436 493 2 Calcd.Observed Example# R j%Yield Mas Spe Mass Spec MassSpec(M+H) 0 B-1 338 F39 486 487 0F B-1 339 F ~CF 3 61 486 487 0 B-1 341 F54 486 487 F B-i 341 & Fj--- 55 486 487 B-1 344 51 486 487 C1 B-1345 F 72 4 434 435 B-1346 40--- NI 5 414 415 F B-1347 F-7-F--~ ~ bN 67 436 437 0LO M ERL 9 WO 98/52940 PCT/US98/10436 494 Observed Called. Example# R R %Yield ad Mass Spec Mass Spec (M+H) (M+H) CI B-1348 F 39 468 469 B-1349 F 68 436 437 FF B-1350 F 73 454 455 o F OF F B r B-1355 - 73 454 455 F3 B-1351 F 54 418 419 0 B-1 352 IF iI 77 436 43 F B-1353 F F 66 436 437 Cl B-1354 'F ~I58 434 435 B-1355 F NI 77 478 479 0 B-1356 F c~ 50 468 469 B-1357 F 36 406 407 0g HETRL WO 98/52940 PCT/US98/10436 495 Observed Called. Example# R R %Yield Cas Mass Spec Masss Spec (M+H) B-1358 F 39 419 420 UBSMUESHE(RULE26) WO 98/52940 PCT/US98/10436 496 N-NH R 2 I N./-, L /

R

2 RL N Observed Example# R RL %Yield Calcd. Mass Mass Spec Spec (M+H) 0 B-1359 F - 95 552 553 S.1 o0 B-1360 F 77 444 445 -01 O / \ B-1361 F 100 392 393 I 0 B-1362 F 85 406 407 B-1363 F 100 364 365 0 B-1364 F 99 390 391 0 B-1365 F 92 504 505 susmUTEHEET(RULES) WO 98/52940 PCT/US98/10436 497 Observed 2L Calcd. Mass sev Example#

R

2 R %Yield Spec Mass Spec (M+H) O B-1366 F 100 552 553 B-1367 F 100 417 418 O B-1368 F 0 86 394 395 / K 0 B-1369 F 0-- 100 456 457 B-1370 F 100 470 471 B-1371 F 77 440 441 F j B-1372 F 100 444 445 =7\ jjrr B-1373 F o 42 427 428 B-1374 \ - 60 476 477 F.0 B-1375 - S-O 94 414 415 SUBBTT RNTLE 28 WO 98/52940 PCT/US98/10436 498 Calcd. Mass Observed Cald. Mass s Spec Example# R R %Yield Spec Mass SpecH) Spec (M+H) B-1376 - 87 400 401 F S0 B-1377 - F 100 480 481 0 FO B-1378 - 95 379 380 NH F- H F B-1379 FN 93 459 460 0 F o B-1380 - 89 469 470 B-1381 FN 84 393 394 0 N S 9jwnT=WEE(RULEffi) WO 98/52940 PCT/US98/10436 499 Observed Calcd. Mass Observed Example# R R %Yield ScMass Spec Spec (M+H) B-1383 F 46 416 417 O B-1384 IF 56 432 433 0 B-1385 F 59 426 427 B-1386 F50 427 428 B-1387 F 12 427 428 0 B-1388 F r' rBl 66 504 505 B-1389 F jCl 48 460 461 0 SUsmU1TESHEr(RULER) WO 98/52940 PCT/US98/10436 500 Observed 2 LCalcd. Mass Mass Spec Example# R RL %Yield Spec Mass SpecH) Spec (M+H) B-1390 F CF 44 494 495 0 B-1391 F 50 456 457 B-1392 F 47 451 452 O F B-1393 F 44 444 445 L--- 0 CI B-1394 F 52 460 461 0 B-1395 F 77 440 441 N B-1396 F - 58 451 452 0 B-1397 F 64 460 461 o 0 B-1399 F 655045 B-1399 F 50 494 495 0 SUBSTITUTSHET(RULE26) WO 98/52940 PCT/US98/1Q436 501 Observed Called. Mass Example# R RL %Yield c Mass Spec Spec (M+H)

H

3 C B-1400 F - 74 440 441 - 0 F B-1401 F 76 462 463 o F F B-1402 F /F 65 462 463 OF 0 B-1403 F o 64 445 446 0

F

3 C B-1404 F-I 70 512 513 0 F

CF

3 B-1405 F ---4. 57 512 513 o F O CF, B-1406 F 73 512 513 o F B-1407 F 80 512 513 F3C 0 B-1408 F 2 512 513 0

F

3 C B-1409 F 62 512 513 0

I

WO 98/52940 PCT/US98/10436 502 Observed Calcd. Mass Observed Example# R 2 RL %Yield c Mass Spec Spec (M+H) B-1411 F 19 462 463 0 oF B-1412 F 74 462 463 <FF B-1413 IF /\ N 75 494 495 OF B-1414 F 68 462 463 O B-1415 F 48 462 463 C1 B-1416 F48 494 495 0 o B-1417 F 57 494 495 0 C1 B-141875 B-1418 F 49 494 495

C

B-1419 F-/\- ci 39 494 495 O N SU~SSTTUTESHEEr(gM.E2a WO 98/52940 PCT/US98/10436 503 Observed Example# R RL %Yield Calcd. Mass Mass Spec Spec (M+H) B-1420 F 72 378 379 B-1421 F /C- 74 406 407 0 o B-1422 F O68 394 395 0 B-1423 F - 57 408 409 0 B-1424 F O 77 422 423 B-1425 F O 26 408 409 S0 CF3 B-1426 F O . 41 406 407 B-1427 F O37 404 405 B-1429 F 2 418 419 sUssnSWS(RUE 26) WO 98/52940 PCT/US98/10436 504 Observed Example# R RL %Yield Calcd. Mass Spec Spec Mass Spec (M+H) 0 B-1430 61 442 443 0 B-1431 F 64 428 429 0 B-1432 F 71 429 430 O 0 B-1433 F 74 462 463 O 0 0 B-1434 F S- 88 466 467 /0. B-1435 F 75 481 482 0 B-1436 F 71 504 505 O ST0 VSTES8EE(RLULEM WO 98/52940 PCT/US98/10436 505 Observed Called. Mass Example# R2 RL %Yield Calcd. Mass Mass Spec Spec (M+H) B-1437 F 63 468 469 B-1438 F c1 78 502 503 *~' '~II S CI 0 -O -I O B-1439 F 70 545 546 B-1440 F -N 62 535 536 B-1441 F 82 608 o o N / B-1442 'F 79 555 556 S 0 B-1443 F 28 513 514 o /O B-1444 F --- 75 522 523 LO B-1 445 'Fa 74 526 527 0o o B r B-1446 F o 70 570 571 T S E0RULE ) sueflTflSHEWr(LE 26) WO 98/52940 PCT/US98/10436 506 Observed 2xample# L Calcd. Mass Observed Example# R R L %Yield Sc Mass Spec Spec (M+H) B-1447 F o73 506 507 0 IF o B-1448 F cl 76 530 531 Cl B-1449 F i 82 530 531 C B-1450 F 83 530 531 0 cI B-1450 F -- 7 530 531 0 0 CI B-45/ c\76 530 53 B-1453 F 73 530 531 0 CI / \ F B-1454 F F 81 498 499 0 F F B-1455 F 83 49F9 B-1456 F F0 p 78 498 499 SUBST0S R E26) 8UOSlTiUTSHEEF (RULE 2S) WO 98/52940 PCT/US98/10436 507 Observed Calcd. Mass Example# R 2 R %Yield c Mass Spec Spec (M+H) CI B-1457 F 74 496 497 O Br B-1458 F 82 540 541 O 0 B-1459 F 80 476 477 O 0 0 B-1460 F 78 530 531

CFN

3 ON B-1461 F .82 487 488 0 0 Lo B-i 62 F71 540 541 0 B-1465 F Co8o49=49 B-1466 F 78 546 547 B-1463 s oeO-HE( ' F B-1464 F __ 83 480 481 B-1465 g' CC 84 496 497 0 B-1 466 F 80 540 541 11 Br 0 SUBBlrrUTEBHEET (RUUE=) WO 98/52940 PCT/US98/10436 508 Observed 2x L ~Calcd. Mass Observed Example# R 2 R %Yield Mass Spec Spec (M+H) B-1467 F 79 476 477 0 O B-1468 F CF 3 79 530 531 F B-1470 F o 80 480 481 O 0 B-1471 F ._cl 74 496 497 o 1Br B-1472 F 75 540 541 O 0 B-1 473 F 77 476 477 B-1474 F CF3 11 81 530 531 o CN B-1475 oF 70 487 488 0 B-1476 F s- 54 540 541 O S ITI'UTESHEET(RULE26) WO 98/52940 PCT/US98/10436 509 Observed 2L Calcd. Mass Observed Example# R 2 R %Yield Spec Mass Spec (M+H) B-1477 F - 79 546 547 S 0BTIUTESHEET(RULE26) 8LueffM'u EUrlRLUE WO 98/52940 PCT/US98/10436 510 L Calcd. Observed Called. asSe Example# R R %Yield Mass Spec Mass Spec (M+H) - 0 B-1478 87 394 395 ____________________Br B-1 479 41 504 505 0 o B-1480 o 87 451 452 0 o B-1481 I18 416 417 0 - 0 B-1482 F-& / 77 427 428 Nj B-1483 \ 4406 407 B-1484 \ /82 422 423 WO 98/52940 PCT/US98/10Q436 511 Observed Example# R 2 RL %Yield Calcd. Mass Spec Mass Spec (M+H) (M+H) C1 B-1485 / 85 460 461 B-1486 / 64 406 407 I 0 B-1487 71 392 393 o B-1488 82 427 428 O B-1489 / 87 444 445 0 B-1490 81 462 463 B-1491 87 462 463 B-1492 69 364 365 B-1493 \Y 53 417 418 0 B-1494 17 426 427 SUBSIuTESHEET(RULE26) WO 98/52940 PCT/US98/10436 512 Observed Called. Example# R 2 RL %Yield a c Mass Spec Mass Spec (M+H) (M+H) B-1495 / 79 460 461 O CI B-1496 F 80 444 445 0 B-1497 es\ /82 460 461 B-1499 \o70 432 433 0 -0 B-1500 / 68 390 391 B-1501 \ /63 394 395 B-1502 78 408 409 B-1503 \ / o 55 404 405 - 0 B-1504 CF 39 418 419 uesmUT8CF ET(RE) 8STJTE88EF. (RULEs) WO 98/52940 PCT/US98/10436 513 2 L Calcd. Observed Example# R R %Yield Mass Spec Mass Spec (M+H) (M+H) B-1505 69 540 541 B-1 506 69 462 463 I o B-1507 c 70 496 497 F B-1508 65 480 481 B-1509 56 414 415 o B-1510 - 62 400 401 0 B-1511 \ 30 468 469 O1 S 0 B-1512 0 50 476 477 B-1513 \ 44 540 541 O Br B-1514 / CF, 42 530 531 12 005

SUSURHE

WO 98/52940 PCT/US98/10436 514 Observed Called. asSe Example# R 2 RL %Yield Mass Spec Mass Spec (M+H) o B-1515 / // 68 496 497 0 B-1516 F- - N 27 429 430 B-1517 - 92 466 467 O H 'yN B-1518 ' 33 379 380 O B-1519 / 50 393 394 O B-1 520 82 435 436 O 0 o ' B-1521 c 86 509 510 H B-1522 H 12 405 406 O 0 B-1524 81 459 460

IF

WO 98/52940 PCT/US98/10436 515 Calcd Observed Called. Example# R 2

R

L %Yield Mass Spec Mass Spec (M H) (M+H) B-1525 / 57 419 420 0 Ia~lgM='ESH (RUM20) WO 98/52940 PCT/US98/10436 516 Cd Mass Observed Example# R RL %Yield c Mass Spec Spec (M+H) o B-1526 I73 410 411 CI O B-1527 66 520 521 CI CN B-1528 91 467 468 I0 Cl i B-1529 73 432 433 > 0 CI B-1530 91 443 444 B-1531 74 422 423 ______ c, 0, I I B-1532 o 68 438 439 _ _ _ L CI 0 SBSMTUT'ESH.ET (ROLE26) WO 98/52940 PCT/US98/10436 517 Observed Calcd. Mass Observed Example# R 2 RL %Yield Spec Mass Spec (M+H) CC B-1 533 84 476 477 cI I0 B-1534 C 72 422 423 B-1535 78 408 409 0 CI B-1536 77 443 444 ______ - CI 0 B-1537 86 460 461 CI O B-1538 F 74 478 479 I0 CI B-1539 85 478 479 CI 0 CI B-1540 71 380 381 B-1541 71 433 434 CI 0 B-1542 89 442 443 CI SUSfm)TUESHEET(RULE26) WO 98/52940 PCT/US98/10436 518 Observed Calcd. Mass Observed Example# R RL %Yield Mass Spec Spec (M+H) B-1543 82 476 477 0 Cl CI B-1544 76 460 461 CI o B-1545 77 476 477 CI C 0 B-1546 76 394 395 Cl B-1547 58 448 449 B-1548 83 406 407 CI B-1549 o 67 410 411 CI O B-1550 I i037 424 425 CI B-1551 o55 420 421 B-1552 cF , 23 434 435 CFI SCilTUTE8HEET(FU.EM WO 98/52940 PCT/US98/10436 519 Observed 2 L %ed Calcd. Mass sSp Example# R R %Yield Mass Spec Spec (M+H) B-1553 83 556 557 CI B-1554 84 478 479 0 CI B-1555 c 93 512 513 CI B-1556 83 496 497 B-1 557 - 62 430 431 ci 0 B-1558 - 45 416 417 ci [ 0 0 B-1559 - 67 484 485 CI 0 V0 B-1560 0 16 492 493 0 B-1561 84 556 557 CI O Br CFa B-1562 c 74 546 547 SU8BTUESHEET(RULES) WO 98/52940 PCT/US98/1Q436 520 2 L Clcd.Mass Observed Example# RR L%Yield ScdMs Mass Spec Spec (M+H) B-1 563 I / s 72 512 513 B-1564 57 445 446 B-1 565 64 482 483 B-1 566 71 395 396 B-5754 409 410 B-56 N76 451 452 791 42142 B-1 569 I70 525 526 H B-1 570 y 79 421 422 B-510 60 475 476 B-1 572 077 475 476 C I _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ WO 98/52940 PCT/US98/10436 521 Observed Calcd. Mass Example# R 2 RL %Yield c Mass Spec Spec (M+H) B-1573 N 65 435 436 CI0 SUBmUESHEEr(RULE 26) WO 98/52940 PCT/US98/10436 522 5 10 Proton NMR data for selected members from Examples B-0001 through B-1573 are shown in the following table. 15 20 25 30 sumUTESHEET(RULEI) WO 98/52940 PCT/US98/10436 523 Plate ID 1H NMR(solvent), d ppm (DMF-d7) d 8.53(bd, J = 4.99Hz, 2H), 7.44-7.24(m, 11H), 4.41 (s, 2H), 4.31 (br, B-0120 2H) (DMF-d7) d 8.56(bd, J = 4.98Hz, 2H), 7.78-7.69(m, 4H), 7.39-7.19(m, 6H), B-0224 4.23(br, 2H) (DMF-d7) d 8.47(br, 2H), 7.91-7.75(m, 3H), 7.57-7.53(m, 1H), 7.38-7.34(m, B-0235 2H), 7.21-7.13(m, 4H), 4.20(br, 2H) (CDCI3/CD3OD) d 8.38(d, J = 5.38 Hz, 1H), 7.62-7.32(m, 9H), 7.04-6.95(m, B-0244 4H), 6.86-6.80(m, 2H), 4.52(q, J = 6.96 Hz, 1H), 1.40(d, J = 6.88 Hz, 3H) (DMF-d7) d 8.45(bd, J = 2.85, 2H), 7.87(br s, 4H), 7.76-7.75(m, 2H), 7.53 B-0256 7.33(m, 5H), 7.18-7.13(br, 4H) (DMF-d7), 1.32(br, 3H), 1.67(br, 3H), 4.17(br, 2H), 5.12(br, 1H), 7.50(m, 6H), B-0426 8.77(m, 2H), 13.54(br, 1H). (DMSO), 1.14(t, J = 6.9 Hz, 3H), 4.54(m, 1H), 6.99(br, 2H), 7.21(br, 4H), B-0438 7.45(s, 1H), 7.61(q, J = 8.7 Hz, 2H), 8.52(d, J = 5.2 Hz, 2H). (DMF-d7), 1.61 (brd, J = 30.6 Hz, 3H), 4.61 (br, 1H), 7.25(m, 6H), 7.65(m, 3H), B-0466 8.59(br, 2H), 13.34(brd, J = 34.8 Hz, 1H). (CD3OD), 1.53(d, J = 7.2 Hz, 3H), 4.59(q, J = 7.2 Hz, 1H), 6.88(d, J = 4 Hz, 1H), 7.09(m, 3H), 7.15(dd, J = 4.4, 1.6 Hz, 2H), 7.26(m, 2H), 8.46(d, J = 6.0 B-0473 Hz, 2H). (DMF), 1.80(br, 3H), 2.35(s, 1H), 4.98(br, 1H), 7.38(m, 6H), 7.85(m, 2H), B-0477 8.45(br, 1H), 8.75(d, J = 6.0 Hz, 2H). (Methanol-d4), 1.57(d, J = 5.6 Hz, 3H), 4.74(br, 1H), 7.23(m, 4H), 7.60(m, 2H), B-0479 7.81 (m, 4H), 8.67(br, 2H). (DMF), 1.78(s, 3H), 2.76(br, 6H), 4.85(br, 1H), 7.42(br, 2H), 7.54(br, 2H), B-0487 7.66(br, 3H), 8.82(s, 2H). (CD3OD), 1.38(d, J = 7.2 Hz, 3H), 4.15(br, 2H), 4.50(br, 1H), 7.04(br, 2H), B-0566 7.18(br, 2H), 7.30(m, 7H), 8.45(m, 2H). (CD3OD), 1.56(br, 3H), 4.66(q, J = 6.7 Hz, 1H), 7.17(m, 8H), 7.56(m, 2H), B-0569 8.47(s, 2H). (Methanol-d4), 1.49(br, 3H), 3.86(br, 3H), 4.60(br, 1H), 6.92(br, 2H), 7.19(br, B-0574 2H), 7.31 (br, 2H), 7.76(m, 4H), 8.60(br, 2H). (DMF-d7), 1.58(brd, J = 30.0 Hz, 3H), 4.62(br, 1H), 7.25(m, 6H), 7.60(m, 4H), B-0639 8.59(br, 2H), 13.30(brd, J = 12.3 Hz). 7.18(m, 2H), 7.32(dd, J = 6.0, 4.4 Hz, 1H), 7.70(dd, J = 9.0, 5.8Hz, 1H), B-0643 8.43(dd, J = 4.8, 3.2 Hz, 2H). (CD3OD), 1.58(br, 3H), 4.62(q, J = 6.6 Hz, 1H), 6.93(br, 1H), 7.17(m, 5H), B-0650 7.31 (br, 2H), 8.51 (br, 2H). (CDCI3/CD3OD) d 8.48 (d, J = 5.30 Hz, 2H), 7.72-7.59(m, 4H), 7.14-7.10(m, B-0656 2H), 7.03-6.97(m, 4H), 4.60(q, J = 7.57Hz, 1H), 1.43(d, J = 7.26Hz, 3H) (CD3OD), 1.52(d, J = 6.8 Hz, 3H), 3.75(s, 3H), 7.21 (m, 2H), 7.42(m, 2H), B-0663 7.57(s, 1H), 7.76(s, 1H), 7.98(br, 2H), 8.76(br, 2H). Hz, 2H), 3.06(m, 1H), 3.43(q, J = 6.1 Hz, 2H), 7.02(m, 2H), 7.14(m, 2H), B-1165 7.41(m, 2H), 8.59(d, J = 5.6 Hz, 2H). = 1.6 Hz, 1H), 7.04(t, J = 8.6 Hz, 2H), 7.14(m, 2H), 7.36(m, 2H), 8.39(d, J = 1.8 B-1169 Hz, 1H), 8.60(m, 2H). 6.83(br, 1H), 7.02(t, J = 8.7 Hz, 2H), 7.15(d, J = 5.6 Hz, 2H), 7.40(m, 2H), B-1171 8.59(d, J = 5.0 Hz, 2H). SUTmT UTSHEET(RULEm) WO 98/52940 PCT/US98/10436 524 Plate ID 1H NMR(solvent), d ppm (CDCI3), 1.94(br, 2H), 2.53(s, 3H), 2.85(t, J = 6.2 Hz, 2H), 3.65(br, 2H), B-1179 6.15(br, 1H), 7.04(m, 3H), 7.22(m, 3H), 7.41(br, 4H), 8.60(br, 2H). (CDCI3), 2.00(br, 2H), 2.85(br, 2H), 3.64(br, 2H), 7.03(br, 3H), 7.17(br, 2H), B-1183 7.36(br, 2H), 7.66(br, 2H), 8.60(br, 2H), 8.77(br, 2H). (DMSO), 1.76(br, 2H), 2.66(br, 2H), 2.91(br, 2H), 4.30(s, 2H), 7.18(br, 5H), B-1194 7.35(m, 6H), 8.54(d, J = 5.8 Hz, 2H). (DMSO), 1.17(br, 3H), 1.76(br, 2H), 2.71(br, 2H), 2.97(br, 4H), 7.18(br, 4H), B-1200 7.36(br, 2H), 8.54(br, 2H). (DMSO), 1.03(s, 6H), 1.68(br, 2H), 2.63(br, 2H), 3.00(br, 2H), 3.65(br, 1H), B-1206 5.69(m, 2H), 7.16(br, 4H), 7.35(br, 2H), 8.54(br, 2H). (DMSO), 1.75(m, 2H), 2.14(s, 6H), 2.66(br, 2H), 3.10(br, 2H), 7.04(br, 3H), B-1216 7.18(br, 4H), 7.35(m, 2H), 7.47(br, 1H), 8.54(d, J = 4.8 Hz, 2H). (DMF), 1.25(br, 3H), 2.01(br, 2H), 3.35(br, 4H), 6.20(s, 1H), 6.30(s, 1H), B-1226 7.42(br, 4H), 7.65(br, 2H), 8.77(s, 2H). (DMSO-d6), 1.80(br, 4H), 2.82(br, 1H), 2.94(br, 1H), 3.10(br, 1H), 3.60(br, 1H), B-1360 4.54(br, 1H), 7.18(m, 4H), 7.30(m, 4H), 7.46(m, 2H), 8.54(br, 2H). (DMSO-d6), 0.99(br, 6H), 1.73(br, 4H), 2.89(br, 2H), 3.03(m, 1H), 4.04(br, 2H), B-1361 4.44(m, 1H), 7.18(m, 4H), 7.30(m, 2H), 8.57(d, J = 4.64 Hz, 2H). (DMSO-d6), 1.78(br, 4H), 2.01(s, 3H), 2.89(br, 1H), 3.05(br, 1H), 3.34(br, 1H), B-1363 3.85(br, 1H), 4.48(br, 1H), 7.12(br, 2H), 7.21(br, 2H), 7.30(br, 2H), 8.69(br, 2H). (CDCI3), 0.78(dd, J = 3.0, 2.9 Hz, 2H), 1.00(s, 2H), 1.78(m, 1H), 1.86(b, 4H), 2.64(m, 1H), 2.99(m, 1H), 3.16(m, 1H), 4.33(br, 1H), 4.70(br, 1H), 6.99(m, 2H), B-1364 7.14(s, 2H), 7.29(m, 2H), 8.64(s, 2H). (CDC3), 1.89(s, 4H), 2.65(m, 1 H), 2.96(m, 1 H), 3.06(m, 1 H), 3.43(s, 3H), 3.93(d, J = 13.2 Hz, 1H), 4.09(d, J = 13.5 Hz, 1H), 4.18(d, J = 13.5 Hz, 1H), B-1368 4.68(d, J = 12.4 Hz, 1H), 7.60(m, 2H), 7.12(s, 2H), 7.26(m, 2H), 8.63(s, 2H). S LnTTUTESHEET(RULE2) WO 98/52940 PCT/US98/10436 525 5 10 By analogy to the procedure identified above for the preparation of Examples B0001-B0048, the following 15 examples B-1574 through B-2269 are prepared. 20 25 30

SUBSTRUTESHEET(RULEM)

WO 98/52940 PCT/US98/10436 526 N-NH R2/ N RL N Examples B-1 574 through B-1 597 are prepared from Scaffold C-27 Example# R

R

L Br 10 B-1574 B Br 0 B-1575 - F Br0 B-1576 Br i o B-1 577 Br I B-1578 B r [0 B-1579 Br Br 0_ B-1580 Br SUBBSnTTESHiET (RULE26) WO 98/52940 PCT/US98/10436 527 Br B-1581 L I Br o B-1582 "o Br B-1 583 B r o B-1584 B Br B-1587 Br o B-1588 o Br B-158 9 BrO Br B-158 S*O o Br B-i 589 /\ - 0 B-i591 Br SUSBrU SHEETRUE ) B-1590 zi 0 MMMM1UTSHMTE(RJLE 26) WO 98/52940 PCT/US98/1 0436 528 Br 0 01 B r B-1 593 /\ I ________ ~NH __ BrF B-1 594 Br O H B-1595 L/ Br Br 0 B-i 597 / jIII 0/ _______ _______ ______ WO 98/52940 PCT/US98/10436 529 N-NH R2 NR~R N Examples B-1 598 through B-i 621 are prepared from Scaffold 0-28 Example# R L

H

3 C 0 B-1 598I

H

3 0 B-1 599 b - ~ F,

H

3 C B-1 600 H 3 C o B-1 601 __ _ _ _ _

H

3 C B-1602

H

3 C0 B-1603

H

3 C{ B-1 604 SU9STUE8HEEM(RLE91) WO 98/52940 PCTIUS98/10436 530 Example# R2RL

H

3 0 0 B-1605 N

H

3 C0 B-i1606 701

H

3 0 B-1607 0 H1 3 C0 B-1609 5 H3C B-i1610 H1 3 C F B-i1611 ~ 1- 3 C B-1612 50

H

3 C B-1613 5 - 0 1- 3 C r B-1614 %:-S VU8WfTUTESEET(RLE28) WO 98/52940 PCT/US98/10436 531 Example#

R

2 R

H

3 C B-1616 F -0 H3N B-1617

H

3 C 0 B- -61 H3H B-1619 ry

H

3 C B-1620 N H H3C B-1621 0 I , ImITUTESHEEr(RULEM) WO 98/52940 PCT/US98/10436 532 N-NH R2/ / ~N RL N Examples B-1 622 through B-1645 are prepared from Scaffold C-38 Example#

R

2 RL 0 B-1622 F I _ 0 B-1623 F F B-1624 F B-1625 IF B-1626 F 0 o B-1627 F 0 B-1628 F /E 8UBfITUTE8HEET(RULE26) WO 98/52940 PCT[US98/10436 533 Example# R2RL 0 B-1629 N 'FI B-1 630 F 0 B-1631 F 0 0 B-1 632 IF % 0-.. B-1633 F B-1634 FP B-1635 / - F B-1636 F / ' F-0 N -o B-1 638 -l: -,jflTSHE (\\E28 WO 98/52940 PCTIUS98/1 0436 534 Example# R 2 R L F /1 B-i 639 s;, 0 0I B-1 641 -1 HH B-1 6452 H N ________________0 ___________ B -1645 0'E T (R L E WO 98/52940 PCT/US98/10436 535 S N-NH 2 R R / m; R L; N Examples B-1646 through B-1 669 are prepared from Scaffold C-39 Example#

R

2

R

L 0 B-1646 F 0 B-1647 F F 0 B-1648 F 1 0 O B-1649 F B-1650 F B-1651 F B-1652 F / BR SMMUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 536 Example#

R

2 RL B-1653 !o __1____- _-_ 0sG 0 B-1656 F/\ B-1655 F O c B-1 657 jF B-1658 F_ F j B-1659 F o B-1660 F /No B-1661 -I 0 B-1662 F suesmTESHEET(

M

WO 98/52940 PCT/US98/10436 537 Example#

R

2 RL B-1663 F -O 0 F SO B-1664 F \ i 0 B-1665

F-O-N

O NH B-1666 F Ij B-1667 F B-1668 F N HNO -0- B-1669 F) HN 8UBOMMUTSHEET(R~LE26) WO 98/52940 PCT/US98/10436 538 N-NH R 2 N-'RL 7 0 NH 0 Examples B-1670 through B-1693 are prepared from Scaffold C-65 Example# R

R

L 0 B-1670 F B-1671 F F F 0 B-1672 F B-1673 F / I.-O-N 0 B-1674 F B-1675 F B-1676 IF / BR sueBMUTESHEEr (IRUEs) WO 98/52940 PCT/US98/1Q436 539 Example#

R

2

R

L 0 B-I 677 0 , o B-1678 F I Q B-1679 'F O F B-1680 Fao B-1 681 F 0.F0-0 - o B -1 68 5 F/o 0 B-1683 'F /o B-1684 FNo B-1 685 F O 0 B-1686 8tUTUTESHEET(RE6) WO 98/52940 PCTIUS98/1 0436 540 Example# R R B-1 687 s0 %0 F-/ s B-1 688 - IF \\ 0 1 B-1 689 N H B-1 690 B-1 6921 B-1692 H N SUM~fHEMW(RULEs) WO 98/52940 PCT/US98/10436 541 N NH R NRL N 0 H Examples B-1694 through B-1717 are prepared from Scaffold C-66 Example#

R

2 RL 0 B-1694 F I o_ _ _ _ _ _ B-1695 F F 0 S o B-1696 F B-1697 Fo B-1698 F 0 B-1 699 F 0 B-1700 F 8 TSUMfU1 SHEE1 (RULE26) WO 98/52940 PCTIUS98/1 0436 542 Example# R 2 RL ;0 B-1 702 F 1 0 B-1703 F 0o B-1700 B-1705 F 0 B-1706 IF / a B-1707F/ B-1708 FP ~ F/ B-1709

-

I IO 0 B-1710 0 SU8SMM-EEff(RULE2) WO 98/52940 PCTIUS98/1 0436 543 Example# RRL B-1711 z: 0 B-1712 -F % . B-1713- I 0 NH' B-1714H Y iH B-1715 -J/ H N B-1717 - )0N aSLnTMTE8HMT(RULEgM WO 98/52940 PCT/US98/10436 544 N-NH

R

L 2 / N R2 0 NH O Examples B-1718 through B-1741 are prepared from Scaffold C-69 Example# R 2 RL B-1718 IF B-1719 F F B-1720 F i0 B-1721 F 0 B-1722 F B-1723 F B-1724 F BR " SUBSTRUTESHEET(RLE 2) WO 98/52940 PCT/US98/1 0436 545 Example# R2RL B-1725 / 1

F

B-1 726 IF - 7 0 B-1727 F0" B-1728 IF B-1729 I B-1 730 F / F B-1731 F / \ B-1732 IFI /\ - N, B-1733 -o 0 B-1 734 -z: -, \ WO 98/52940 PCTIUS98/10436 546 Example# RRL B-1735 -i: 0 B-1 737 N H B-1738 F-0

-

y

F

B-1740 H N 0-/\ B-1 741 /

HN

WO 98/52940 PCT/US98/10436 547 N-NH

R

L R2 / 'N 0 NH 0 Examples B-1 742 through B-1 765 are prepared from Scaffold C-70 Example#

R

2 RL 0 B-1742 F B-1 743 F F o B-1744 F B-1 745 F 0 B-1746 F 0 B-1747 F B-1748 F SUMs SW(RuBR suasnTSHEET(FRAEM) WO 98/52940 PCTIUS98/1 0436 548 Example# R RL 1 0 B-1 749 FN 0 B-1750 F I J ol :0 B-1 751 iF -O 0 B-1752

F

B-1753 F B-1754 F B-1 755F/ FJX B-1756 F/~ > I~ - ~ ' IN B-175 IF 0 B-1758 0 WO 98/52940 PCT/US98/10436 549 Example#

R

2

R

L B-1 759 F ,O O B-1760 F \\ B-1761 F O NH B-1762 F B-1 763

L/N

B-1764 HN 0 F Oi B-1765 SUBUTSHHN(RU _ _ _ _ _ _ _ _ _ _ 0 _ _ _ _ _ _ _ _ _ WO 98/52940 PCT/US98/10436 550 N-NH

R

2 RL NRR / 0 N 0 CH 3 Examples B-1766 through B-1789 are prepared from Scaffold C-71 Example# R 2 RL 0 B-1766 F 0 B-1767 F F F B-1768 F 0 B-1769 F 0 B-1770F B-1771 F-Qo B-1772 F BR

RUMMUTESHE.ET(RULEM

WO 98/52940 PCT/US98/10436 551 Example# R

R

L 0 B-1773 F I 0 B-1774 F o 0 B-1775 F O 0 B-1776 F o B-1 777 F B-1778 IF B-1779 F o B-1780 F N 0 B-1781 FCO J,- 0 B-1782 F 6WfUESHEERUEN) WO 98/52940 PCTIUS98/1 Q436 552 Exam ple# R R B-1 783 -- :o B-1 784 -F \ F' B-i 785 ___ ~NH H~N B-1786 B-1787- i B-1788 F'

HN

0 B-1789 HN01 _____ ____/

_____

WO 98/52940 PCT/US98/10436 553 N-NH RL R2 N -j N 0 'CH 3 Examples B-1790 through B-1813 are prepared from Scaffold C-72 Example#

R

2 RL B-1790 F _ _ _ I_ __ 0 B-1791 F O B-1792 F B-1793 F 0 B-1794 F 0 B-1795 F B-1796 F L BR SUBSHlU'TESHEETrUl.EE) WO 98/52940 PCTIUS98/1-0436 554 Exam ple# R RL B-1 797 /\ F B-1798 F 0 B-1799 JF- 0 B-1800 IF B-1 802 F B-1 803 ,F B-1804 F B-1805 F s 0 B-1 805 - I . -0 W~ffffM8EU(RLLE6 WO 98/52940 PCTIUS98/1 0436 555 Example# R 2 RL B-1 807 0 B-1808 -6 \ 0 FF B-1 810 F-

-

N B-1810 -H B-1811 HN B 1 8 1 3 0/ HN 1 U I ESHEET(RULE10 WO 98/52940 PCT/US98/1 0436 556 N -NHRL / 0 0 OCH 3 Examples B-i 814 through B-i 837 are prepared from Scaffold 0-73 Example# R2R L 0 B-1 814 I F B-1 815 F/ - F B-1 816 F B-1 817 F / 0 B-1 818 0 B-1 819 FP -. 0 B-1820 F ~ SEt(RULE 26) WO 98/52940 PCTIUS98/10Q436 557 Example# R 2 RL 0 B-1 821 0 B-1822 FO 0 B-1824F B-i1825 F B-1 826 iF FF B-1829 F /\\ 0 B-1 830 8UBSTIMJTSHEEr(MUEBM WO 98/52940 PCT/US98/10Q436 558 Example# R2RL B-1 831 -z F S/ B-i 832 F6 0 B-1 833 ______ ~NH _ _ _ F yN B-1834 B-1 835 ~- _ _ _ _ _ _ HN B-1837 HN ________ __ ___________09 _ _ _ _ _ _ _ _ _ _ _ SMM88EEZ (ULE26) WO 98/52940 PCT/US98/10436 559 N-NH R2 / R 7 N'RL N N Examples B-1838 through B-1861 are prepared from Scaffold C-33 Example#

R

2

R

L 0 B-1838 F B-1839 F F O B-1 840 F B-1841 F B-1842 F 0 B-1843 F 0 B-1844 F / UBMITUTESHEET(RULE26) WO 98/52940 PCTIUS98/10Q436 560 Example# R2RL 0 B-1 845 /\ ) B-1 846 F B-1 847 [F0 B-1848 F -i B-1849F B-1 850 F

JJ

0 B-1851 B-1853 0 B-1854 SUM8TMMTEHEMr(RULEW) WO 98/52940 PCT/US98/10436 561 Example# R2 RL B-1855 F - 0 F SO B-1856 F \ - O B-1857 O NH B-1858 F F B-1859 B-1860 F HN 0 B-1861 F) UgfMUTESHEET(RULE 2

)

WO 98/52940 PCT/US98/10436 562 N-NH R / N O R L , R N Examples B-1862 through B-1885 are prepared from Scaffold C-45 Example#

R

2 RL B-1862 F B-1863 F F B-1864 F B-1865 1F / B-1 866 F B-1867 F B-1868 F SSUTME(RMEBR SU.BSlTUTESHET(RUL-E26) WO 98/52940 PCTIUS98/1 0436 563 Example# R R 0 B-1 869[/\ B-1 870 F/\ - ,',Lo, 0 B-1871 !F 0 0 B-1 872F B-1 873 F/ B-1875 F l IFF B-1 876 F 0\c - NC B-1 877 S 0 B-1 878 -'~ SMMglUMrSHMTO (UE2 WO 98/52940 PCTIUS98/10436 564 Example# R 2 RL B-1 879-[ i 0 B-1 88.

-

~\ B-1 881

-

IY NH B-1 882 B-1883 B-1884 B-1885 -) SU35WES-ET (RUL2) WO 98/52940 PCT/US98/10436 565 N-NH RL R2 N N Examples B-1 886 through B-1 909 prepared from Scaffold C-42 Example#

R

2 RL 0 B-1886 F B-1887 F-F 0 B-1888 F B-1 889 F B-1 890 F- 0 B-1891 F / 0 B-1892 F 8UBSTMJTEHEET(RUE28) WO 98/52940 PCTIUS98/1 0436 566 Example# R R 0 B -18 9 3 I \l

-

0 B-1 894F/ 0 B-1895 F /\ 0 B-1896 F -a.. B-1 897F/ B-1898 F -0 F B-i1899 B-1900 F B-i1901 -I IZ 0 B-1902 -Ir 8S"TffUME8iW(RuLE9) WO 98/52940 PCTIUS98/1 0436 567 Example# R 2 RL F-- , B-1 903 F -r B-1904 6 F \ 0 B-1905 NH B-1906 -rX 0 B-1 908 0 B-1909 ) 00_____ _____ suB'lTTEHEr(ULM WO 98/52940 PCT/US98/10436 568 RL rR E N-NH I / N

R

2 N Examples B-1910 through B-1933 are prepared from Scaffold C-44 Example#

R

2 RL 0 B-1910 F 0 B-1911 F -O 0 B-1912 F B-1913 F B-1914 F B-1915 F B-1916 F / 2B) -BR SUBSTrTrESHEET (RULES2) WO 98/52940 PCT/US98/1 0436 569 Example# R R B-1917 F 0 B-1919 IF /\ 0 B-1920 B-1921F B-1 922 IF/ B-1923 F/ B-1924 IFF / \ 0 B-1926

-Z-

WO 98/52940 PCT/US98/1 0436 570 Example# R RL B-1927

-.

:Z B-1928 -, % 0 B-1929 ______ ______ ____ NH_ _ ___ _ _ B-1930 B-1 931 -V F B-1932 HN4_ _ 0 B-1 933 F-0 / IN SU6B1TffMSHEE(REW) WO 98/52940 PCT/US98/10436 571 K N-NH RL R 2 / N Examples B-1934 through B-1957 are prepared from Scaffold C-41 Example# R

R

L B-1934 F B-1935 F F 0O B-1936 F B-1937 F B-1938 F 0 B-1939 F B-1940 F

BR

WO 98/52940 PCTIUS98/1 0436 572 Example# R 2 RL 0 B-1 941 FI~ B-1942 F-0 B-1943 IF-O B-1944 'F lb K B-1945 FI B-1946 FK B-1 947 F-- B-1948F/ 0 F r B-1950 -zr. 0 qX~ffUMHET(RULE2 WO 98/52940 PCT/US98/10436 573 Example#

R

2 RL B-1 951 F -, F S B-1952 F B-1953 O NH B-1954 F o F <9 B-1957 - I OH Us S E L B-1 956 SU8BSTUTESHEU(RU1EN WO 98/52940 PCT/US98/10436 574 RL

R

E N-NH I

R

2 N N Examples B-1958 through B-1981 are prepared from Scaffold C-43 Example#

R

2 RL B-1958 F B-1959 F F F B-1960 F 0 B-1961 F B-1962 F / \ B-1963 F / B-1964 F / SUBSU TESHEE(RULES) WO 98/52940 PCTIUS98/1 0436 575 Example# R2RL 0 B-1966 F " ________ 0 B-1968 B-1969 B-98F / 011 B-1970 F B-1971 B-1972 F-0 I C B-1973 0 B-1 974 SUSMnhTEHEW(Ruam WO 98/52940 PCTIUS98/1 0436 576 Example# R2RL B-1975 -z_ B-1 976 -6\ F 0 B-1977 N H F OH B-1979-/ F-0 I _ B-1980 B-1981 0 HN ,qUMTHJMW(RLUW) WO 98/52940 PCT/US98/10436 577 N-NH R2 / NRRL N Examples B-1982 through B-2005 are prepared from Scaffold C-30 Example#

R

2 RL 0 B-1982 S B-1983 S / F B-1984 S / L I 0 B-1985 S / B-1986 S B-1 987 S 0 B-1988 s SUWff=TSKU(RULaE2) WO 98/52940 PCT/US98/10436 578 Example#

R

2

R

L 10 B-1989 O B-1990 S0 o .___ I B-1991 O B-1992 S /o I o B-1993 S / B-1994 So B-1995 S N. B-1997 S / -... B-1998 S O StBMTMUTESHEE

RULEL)

WO 98/52940 PCTIUS98/1 Q436 5709 Example# R2RL B-1999 S /%r B-2000 S /6\ B-2001 S 0-:Y _ _ ~~NH_ ___ OH B-2003 ~ V B-2004 s / 0 B-2005s/ &8BTff8MEEr(RLILEA WO 98/52940 PCTIUS98/10436 580 N -NH H 2N'R R2 / N Examples B-2006 through B-2029 are prepared from Scaffold C-60 Example# R2 RJ 0 B-2006 F 0 B-2007 F F 0 B-2008 F 0 B-2009 F B-2010 F-/ \ 0 B-2011 F 0 B-2012F/ ______ __ ___ ______ _____BR _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Vj~n=S8EEV (RULF-2) WO 98/52940 PCT/US98/10436 581 Example# R2R 0 B-2013 F/ B-01 F 0 13-2015 0 B-21016 F/ 0 B-2017 B-2018 IF Q 0 B-2019 i B-2020F/ 0 ____________ 0 B-2022F ajefUE8%E(RLU6) WO 98/52940 PCTIUS98/1 0436 582 Example# R 2Rj B-,2023 IF / \:: B-2024 F6 1 0 B-2025 F/ B-2026 FI -~ H B-2027 F / \

HN

8U8B11TMJTEUE(RULE26) WO 98/52940 PCT/US98/10436 583 N-NH R2/ R2/ NH N Examples B-2030 through B-2053 are prepared from Scaffold C-36 Example# R R 0 B-2030 F 0 B-2031 F F B-2032 F 0 B-2033 F B-2034 F 0 B-2035 F-/ 0 B-2036 F / \ I BR

SUBSITRJTESHEET(RUEW

WO 98/52940 PCT/US98/1 0436 584 Example# R2R B-2037 F' B-2038 F / \ 0 B-2039 ' F /\0 B-2040 B-2041 B-:2043 F/\ I B-2044 B-2045 FF SjJ B-05F / z B-2046 F-~--S 0 SUUMM~nUTE8SEERULE 6) WO 98/52940 PCTIUS98/1 0436 585 Example# R2R B-2047 F0 F6 % B-2048 F o Jj/ B-2049 F/\ NHN B-2050 F/ -~ H 0 VuJ&MMMSEHE7(RULE 26) WO 98/52940 PCT/US98/10436 586 N-NH R 2/ NH R N Examples B-2054 through B-2077 are prepared from Scaffold C-34 Example# R 2

R

J 0 B-2054 F / 0 B-2055 F F 0 B-2056 F / \ 0 B-2057 F B-2058 F B-2059 F B-2060 F _ _STUTESHEET(RULE) WO 98/52940 PCTIUS98/1 0436 587 Example# R2R 0 B-2062 F/ 0 B-2064 0 13-2065 . B-2066

-

0/ B-2068 F B-:2069 F / 0 B-2070 F/\s0 ~0 WO 98/52940 PCTIUS98/1 0436 588 Example# R 2Rj B-2071 1F0 :' B-2072 IF IF / \\ B-2073 IFo NH B-2074F/\ O H B-2075 :F / \JN B-2076 i

HN

____________0 B-2077 1IF HN suMfTWfEBHEM r(RULEff) WO 98/52940 PCT/US98/10436 589

R

J N -NH I HN R R2 N Examples B-2078 through B-2101 are prepared from Scaffold C-57 Example# R R 0 B-2078 H 0 B-2079 H F B-2080 H 0 B-2081

H

0 B-2082 H B-2083 H B-2084 H UJBnTLTSHEEV(RULEM~) WO 98/52940 PCTIUS981 0436 590 Exam ple# R2 0 B-2085 H 0 B-2087 H 0 B-2088 H - 0 0 B-2089 ... B-2090 H B-2091 H 0 B-2092 B-2093 H I r ,::::iL a WO 98/52940 PCTIUS98/10436 591 Example# R2R B-2094 H-z~ B-2095 H B-2096 H- \ 0 B-2097 Hr-y NH B-2098 H B-2099 H-L11 B-21 00 H HN 0 _ _ _ _ _ _ _ _ _ 0 B-21 01 H WO 98/52940 PCT/US98/10436 592 R N-NH HN 2 R- i N Examples B-2102 through B-2125 are prepared from Scaffold C-52 Example# R 2 R B-2102 H _ _ I B-2103 H F B-2104 IH 0 B-2105 H L B-2106 H B-2107 H 0 B-2108 H SUBSmUTESIEET (K L6O) WO 98/52940 PCTIUS98/1 0436 593 Example# R2R 0 B-21 09I B___21_ 10__ _ 0 B-2112 0 0 B-2113 B-2114 B-2115 6 0 B-2116 ,\ 0 IN B-2117 H-r- 0 B-2118 S:: 0-gIUTBET(RL 6 WO 98/52940 PCT/US98/1 0436 594 Example# R2R B-2119 0I B_10_$j F 0 B-2121 H NH' B-2122 ' B-2123 H- J B-2124

H

HN U B I T TE H E (0LE WO 98/52940 PCT/US98/10436 595 R N-NH HN 2 N Examples B-2126 through B-2149 are prepared from Scaffold C-56 Example# R R 0 B-2126 H 0 B-2128 H 0 B-2129 H O B-2130 H 0 B-2131 H 0 B-2132 H BR su~s~nSHEE(RULE26) WO 98/52940 PCTIUS98/1 0436 596 Example# R2R B-2133 H EH B __2134__ I- _____ 0 B-2134 H B-21350 0 B-2136 H I- 01~ B-2137 B-2138 H B-2139 H B-2140 \ 0 B-2141 H- ' B-2142 Pjm mffF~w-=T(RUL9) WO 98/52940 PCTIUS98/10436 597 Example# R2R B-2143 H tzrf 0 B-2144 B-2145 H iFF B-2146 HI B-2147

H

B-2 148 H I 0 B-2149 H 0"H WO 98/52940 PCT/US98/10436 598 N -NH H 2 / R R N N Examples B-2150 through B-2173 are prepared from Scaffold C-32 Example# R R 0 B-2150 F 0 B-2151 F F F 0 B-2152 F B-2153 F B-2154 F 0 B-2155 F / \ 0 B-2156 F / N BR SUSTRUTEEE(RU)LE26) WO 98/52940 PCT/US98/1 0436 599 Example# R 2 0 B-2158 F/\ 0 ,0 B-2161F B-2162 B-2163 B-2165 F / \o 0 B-2166 F /\Iszz~0 - j 0 WO 98/52940 PCT/US98/10436 600 Example# R2R B-2167 F/\ISZO B-2168 F / \ B-2169 F NH B-2170F/ I B-2171F/ B-2172 FH B-2173F/ I O\HN ________ ______________0 WO 98/52940 PCTIUS98/1 0436 601 N-NH H 7 0 NH 0 Examples 2174 through B-2197 are prepared from Scaffold C-64 Example# R2R 0 B-2174 B-2175 F-0 0 B-2177 B-2178 F 0 B-2179 F-/0 0 B-21 80 F /-- BR SUMBTUTESET (RUE28 WO 98/52940 PCTIUS98/1 0436 602 Example# R2R 0 B-2181 F / \ B_218 K-, _ 0 B-2184 B-2186 B-2184 F /0 B-21895 B-2190 F / 0 8-21 87 F-QL---- WO 98/52940 PCTIUS98/10436 603 Example# R2R B-2191 F0 B-2192 F /6 %) B-2193 F 0 IY N H B-2194 F/\ - ~0 0 B-2196 HN 0 B-2197 F) / \ SUBS11Mi1SWSE- (RULE 26) WO 98/52940 PCT/US98/10436 604 N-NH H R2 / S N N Examples B-2198 through B-2221 re prepared from Scaffold C-22 Example# R2 R 0 B-2198 F 0 B-2199 F F F 0 B-2200 F 0 B-2201 F / B-2202 F / \ 0 B-2203 F 0 B-2204 F-/ B R WO 98/52940 PCT/US98/10436 605 Example# R R 0 B-2205 F- - \ I-I 0 B-2206 F/\ o 0 B-2207 F O 0 B-2208 F B-2209 F B-2210 F -I B-2211o B-2212 FN o B-2213 F --... O 1r0 B-2214 F7

OJ--

0 sUB MESHEEf(RULE ) WO 98/52940 PCTIUS98/I 0436 606 Example# R 2 B-2:215 F/ B-2216 F J-\o B-2217 I F 0I NH B-2218 B-2219 F-0 /J B-2220F 'H B-2221 F-Q--) SUeBnTuTE8EET(RLU20~ WO 98/52940 PCT/US98/10436 607 N-NH H R 2 /N R2 'R N Examples B-2222 through B-2245 are prepared from Scaffold C-29 Example# R R B-2222 S / 0 B-2223 S F 0 B-2224 S / 0 B-2225 S B-2226 0 B-2227 S/ 0 B-2228 S / BR SU THU SHEET(RULE26) WO 98/52940 PCT/US98/1 0436 608 Example# R 2 - 0 B-2229s/ 0 B-2230s/ /0 0 B-2231 sk" / 0 B-2232 s/0~ B-2233 0-/ B-2234 S/ F B-2235s B-2236s/ 0 NC, B-2237 0 fJJ 0 sawnMuES-IMr(MUEs WO 98/52940 PCT/US98/10436 609 Example# R 2 B-2238 S / J-o 0 B-2239 s

:

/0 B-2240 S /F ~ j ____ __ __ B-2241 S / 0 NH N B-2242 /I B-2243 s / B-2244 s/H 0 B-2245s/ 0 WO 98/52940 PCT/US98/10436 610 N-NH

R

2 "'NH I Rj N Examples B-2246 through B-2269 are prepared from Scaffold C-35 Example# R R 0 B-2246 F 0 B-2247 F F B-2248 F 0 B-2249 F / B-2250 F-/ 0 B-2251 F 0 B-2252 F

BR(

WO 98/52940 PCT/US98/10436 611 Example# R 2 R 0 B-2253 F B-2254 F - 0 B-2255 F-0 O B-2256 B-2257 N.o B-2258 F 0 B-2259 F Do B-2260 F N o B-2261 F OO 'N. 0 B-2262 F-- O SUBIMUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 612 Example# R 2 R B-2263 F /*0 O NH B-2266 F o B-2267 F-Q--- B-2268 F DN 0 B-2269 F o HN __________________0 _ ___ _____ Sjj65~Tff SWEr (RLEw) WO98/52940 PCTIUS98/10436 613 5 10 Examples B-2270 through B-2317 15 In a parallel array reaction block containing 48 fritted vessels, each reaction vessel was charged with 250 mg of polymer bound carbodiimide B48 (1.0 mmol/g resin) and a solution of the acid-containing scaffold C 20 49 in dimethylformamide (0.1 M, 500 uL). To each slurry was added a solution of pyridine in dichloromethane (0.2 M, 1000 uL) followed by a solution of a unique amine B47 (0.2 M, 375 uL) in dimethylformamide. The reaction mixtures were agitated on a Labline benchtop orbital 25 shaker at 250 RPM for 16-20 h at ambient temperature. The reaction mixtures were filtered into conical vials and the polymer was washed with 1.5 mL of dimethylformamide and 2.0 mL of dichloromethane. The filtrates were evaporated to dryness in a Savant 30 apparatus and dimethylformamide (350 uL) was added to each conical vial to dissolve the residue. A solution of tetrafluorophthalic anhydride (1.0 M, 150 uL) in suemTHEET(RULE) WO98/52940 PCT/US98/10436 614 dimethylformamide was added to the reconstituted conical vials and the mixture incubated for 2 hours at ambient temperature. Polyamine polymer B33 (4.0 meq N/g resin, 250 mg) and 1.0 mL dichloromethane was then added to the 5 reaction mixture in each conical vial. After agitating the reaction mixtures for 16 h at 250 RPM on an orbital shaker at ambient temperature, the mixtures were filtered through a polypropylene syringe tube fitted with a porous frit. The polymers were washed twice with 10 dimethylformamide (1.0 mL each) and the filtrates and washings collected in conical vials. The filtrates were evaporated to dryness and weighed to afford the desired amide products B-2270 through B-2317 as oils or solids. The analytical data and yields for the products prepared 15 in this manner are listed below. 20 25 30 &SsmUTESHEff(RUJLE26) WO 98/52940 PCT/US98/10436 615 R N -Rc N N R 2 CH 3 CI N RB I- c Observed N-RCaled. Mass Osre N-R R Yield Calcd. Mass Mass Spec Spec. M+H NM+H , O B-2270 F 12 352 353 iI\i B-2271 F 39 432 433 B-2272 F L 26 400 /- 11NH B-2273 F 14 396 397 0 B-2274 F L /30 434 435 0 B-2275 F 43 443 B-2276 F 35 364 365 SUBSITUESHEET (RULE 26) WO 98/52940 PCT/US98/10436 616 RB c- Observed N-R Caled. Mass R2 Yield Calcd. Mass Mass Spec Spec. M+H O B-2277 FNH/ 33 490 B-2278 F 53 460 461 B-2279 F 10 420 H B-2280 F /N07 435 436 - -JLNH 0 B-2281 F \Jr& /18 401 402 B-2282 F 22 390 41 3a F HN aM+Na <, N/ 417 a B-2283 / 10 394 a F, aM+Na B-2284 F N423 B-2285 F 23 450 0

H

B-2286 0 4 506 HI SUBS1TUTESHEET (RULE26) WO 98/52940 PCT/US98/10436 617 RB C dObserved R2 N-R Yield Calcd. Mass Mass Spec Spec. M+H M+H O B-2287 F 5 437 438 B-2288 F 8 435 436 B-2289 F o 4 450 451 B-2290 F 9 456 457 N B-2291 F 9 415 416 0 H 0 B-2292 F 5 368 369 B-2293 F 5 366 367

-

NH 0 B-2294 F 5 381 382

N

B-2295 F 0 41 0 16 410 411 B-2296 F O NH 4 483 s u-r(m SUBS Ir E8SHEmr(R-Et~ WO 98/52940 PCT/US98/10436 618 RB I c Observed N2R Calcd. Mass R2 Yield Sc. Mass Spec Spec. M+H 0 0 B-2297 F0 o 7 490 F -- IJ~ 0 B-2298 IF 4 537 H HO B-2299 F /o 4 507 508

H

0 B-2300 F 442 0H B-2301 F 20 396 397 0 O II B-2302 F 30 459 H CI C1 B-2303 F / 6 482 / -N B-2304 F I5 395 396 0 0 B-2305 F\/10 460 B-2306 F 11 466 467 StI I ME (RLEM WO 98/52940 PCT/US98/10436 619 RB i c Observed

N

' -R Caicd. Mass Observed R24N Yield Spec. Mass Spec Spec. M+H O B-2307 F 5 421 422 B-2308 s 26 470 0 H B-2309 F/\j24 424 425 B-2310 F 9 348 B-2311 F N 21 338 339

S

B-2312 F s 28 398 399 B-2313 F 6 410 CN B-2314 F 15 363 364

-

I NH Ho .i.\I u UT .( L B-2315 F 414 H B-2316 F / o11 4184 RUSf1TESH-Er (RL e) WO 98/52940 PCT/US98/10436 620 RB C cObserved

N-R

c Caled. Mass Osre R2 N R Yield Calcd. Mass Mass Spec Spec. M+H 0 B-2317 F /NH 36 428 WO 98/52940 PCT/US98/10436 621 5 10 By analogy to the procedure identified above for the preparation of Examples B-2270 through B-2317, the following examples B-2318 through B-2461 were prepared. 15 20 25 30

MITVESHEET(RU.EM)

WO 98/52940 PCT/US98/10436 622 RB N -RC N -N 0

R

2

CH

3 I N RB c Observed N-R Calcd. Mass

R

2 Yield c. Mass Spec Spec. M+H M+H O ----- f ° B-2318 F HN 23 426 427 /0 B-2319 F NH 23 394 O B-232 ' F- [ ' JAN HI B-2320 F H 50 490 491 O SUBTIUTSHETUL26NH B-2321 49 426 427 B-2322 F NH 40 366 367 B-2323 F /\ 68 410 411 0 K- 0 B-2324 1F 57 456 457 i 0 WO 98/52940 PCT/US98/10436 623 RB I c Observed N- R Calcd. Mass

R

2 Yield c Mass Spec Spec. M+H ~M+H O B-2325 F NH 41 382 383 L-o -0 B-2326 iF ! 71 440 441 B-2327 F 36 464 465 O B-2328 F . 32 467 468 N_ H 0 NH , J 0 0 NH B-2330 F -" 26 364 365 0 B-2331 F 38 464 465 B-2332 F 33 483 484 0 7 i ,-o i N B-2333 F 36 378 379 TUTE EE(RULE26) SWE(UE6 WO 98/52940 PCT/US98/10436 624 B R I i Calcd. Mass Observed R2 - R Yield c. Mass Spec Spec. M+H O 0 1 B-2334 F 44 428 429 3: B-2335 F NH 27 406 407 0 KNH B-2336 F 41 428 429 0 B-2337 F .... NH 27 423 424

LL

-

/ 7 NH i o B-2338 F 33 469 470 B 3-- --- oO B-2339 F s 52 518 519 O o B-2340 F 64 442 443 o B-2341 F NH 41 350 351 0, HCNH B-2342 F -34 414 415 amUTESHEE (RULE26) WO 98/52940 PCT/US98/10436 625 RB I C Observed N-RC[ Calcd. Mass R Yield Mass Spec RR Spec. M+H oN H B-2343 F O -_ -- 29 424 425 O 0 B-2344 F 33 492 493 Br N H B-2345 F 30 420 421 o B-2346 F 35 474 475 No i B-2347 F 34 392 393 / ~ '-JLNH B-2348 F 51 458 459 B-2349 F 73 517 518 o 0 B-2350 IF 22448 449 B-2351 F 64 486 487 SUBSM SHEE(RULE261 WO 98/52940 PCT/US98/10436 626

R

B c Observed N-R Calcd. Mass R Yield Mass Spec Spec. M+H O O B-2352 F o.ANH 0 41 482 483 0 B-2353 F o 57 438 439 o N H B-2354 F 63 484 485 B-2355 F 28 536 537 H B-2356 F NH 29 408 409 1 NH B-2357 F 41 436 437 N-N . NH B-2358 F -41 451 452 O / \ ~ ;tNH 7 B-2359 F 57 502 503 r 0 B-2360 FA'NH B-2360 F -o46 496 497 O O

SUBSTTESH__(F_.EW

WO 98/52940 PCT/US98/10436 627 RB R I c Observed 2 N--R Calcd. Mass R Yield Mass Spec Spec. M+H ,/ O B-2361 F H 13 476 477 B-2363 F O 57 396 397 0 /' ( OH B-2364 F o 61 438 439 B-2365 F 072 424 425 S U SH (RULE ) sU fl1TE$HEET(RULE 26) WO 98/52940 PCT/US98/10436 628 R N -RC N -N 0 R 2 CH 3 I N RB I c Observed

R

2 i Yield Cacd Mass Mass Spec Spec. M+H 0 O B-2366 N 34 380 381 o Ci B-2367 F 52 480 481 B-2368 F 35 407 407 B-2369 F 31 435 436 F B-2370 F N 33 414 415 F I 0 B-2371 F N 28 366 367 F B-2372 -N 37 422 423 F-0 agSTRUTUyps.E26) WO 98/52940 PCT/US98/10436 629

R

B I Observed 2 N-Rc Calcd. Mass R2 Yield Mass Spec Spec. M+H M+H B-2373 F 50 432 433 r O F0 N B-2374 F / 29 382 383 o B-2375 F L 35 395 396 O B-2376 F 36 428 429 B-2377 F o 68 438 439 FO B-2378 FN 55 446 447 .......... . i 0 - 0 o I B-2379 N334 6 B-2380 51 421 422 NO o B-2381 F 52 429 430 1 I 8uBSMnUWSHEET(lUZ) WO 98/52940 PCT/US98/10436 630 RB C Observed 2 R Calcd. Mass Observed

R

2 Yield Mass Spec Spec. M+H O 0 _ B-2382 N 48 407 408 F B-2383 F 53 382 383 B-2384 F 38 447 448 No B-2385 59 498 450 00 B-2386 F 45 429 430 -- N B-2387 F 74 558 / B-2388 53 475 IFO _______ -- 0 ON B-2390 N 53 487 488 SU 0m SHEET (RULEs) WO 98/52940 PCT/US98/10436 631 RB I C Observed N-R Calcd. Mass sSp R Yield Spec. Mass Spec Spec. M+ M+H B-2391 F 30 435 436 B-32F 5744N6 N B-2392 FN57 464 465 0_ 0 N __ __ oN B-2393 F / 50 418 419 o N B-2394 F 65 488 489 O B-2395 F N 59 437 438 00 O B-2396 F 34 534 535 OMe Cl o B-2397 F_ 32 516 517 I0o :-) , 81 533 534 B-2398 F / 8 - N 0 B-2399 F 55 502 SUSnmUESHEET(RULE M6) WO 98/52940 PCT/US98/10436 632 RB R I c Observed N-R Caled. Mass R2 Yield c. Mass Spec Spec. M+H B-2400 F N- 34 381 382 B-2401 F N 32 378 379 B-2402 F 71 519 520 F 0 B-2403 F 68 527 528 O B-2404 F NcI 62 447 448 0 o B-2405 F 71 536 537 _ _"- _ _ _ _ L 43 0 B-2406 F 394 395 o 0 0 N N B-2407 F 65 508 509 O H B-2408 F 34 495 496 o~k SU8SrEUTESHEE(RULF-2) WO 98/52940 PCT/US98/10436 633 B R I Observed N-Rc Calcd. Mass R2 Yield c. M Mass Spec Spec. M+H i M+H 0 o B-2409 47 448 449 o B-2410 F_ o73 542 543 o0 B-2411 F 81 489 490 0 B-2412 N 54 409 410 B-2413 F 4 suWss =Lrr% E.(RuE2 WO 98/52940 PCT/US98/10436 634 R N -R C N N O R CH 3 N I RB I c Observed

N-R

C

, Calcd. MassObserved

R

2 Yield Spec. Mass Spec Spec. M+H O 1 0 B-2414 F 14 473 474 0 -' NH B-2415 F 19 421 422 CI FO 0 B-2416 F 13 386 387 B-2417 F 29 414 415 F _____ II B-2418 F 6 420 421 CI 0 o B-2419 FH 10 454 F 5CF 3 44 B-2420 F \ NH 5 442 443 WO 98/52940 PCT/US98/10436 635 RB R I 0 Observed N-R Calcd. Mass

R

2 Yield Mass Spec iR Spec. M+H \< M+H 0 -LNH B-2421 F 1 Cl 28 454 455 /~ Hw B-2422 F H cl 47 420 421 O SNH B-2423 F 53 400 401 F B-2424 F 15 400 401 o B-2425 F -'- 18 522 523

F

3 C

'

d CF 3 0 N H B-2426 F [38 464 465 Br 0 ___ *'-'-~ NH B-2427 F 26 468 469 B-2428 F s22 432 433 O 0BF B-2429 -Lc o4 0 0 WO 98/52940 PCT/US98/10436 636 RB R C Observed N-Rc.Caled. Mass R2 Yield Calcd. Mass Mass Spec Spec. M+H ! M+H B-2430 F N o 15 476 477 o B-2431 6 446 447 FO 0 0 0 1k o| B-2435 N c 23 42 4 B-243 F 37 404 405 _ ' LL- NH F0 B-2438 5NH 8 422 423 F I!I 0 / \ ~ QANH B-2436 5 , 1 476 47 0 B-2437 F 4 486 487 0 -L NH B-2438 F N 58 422 423 F F &jWM=&E9T(RULEs) WO 98/52940 PCT/US98/10436 637

R

B I c Observed R2Yielc Mass Spec Spec. M+H O NH ©o B-2439 F 12 454 455 CF 3 0 SNH B-2440 F 8 521 522 B-2441 F 6 443 444 B-2442 IF 0 N 37 514 515 0 O B-2443 F i 15 518 B-2444 F ON52 520 B-2445 F 33 517 518 F-00 : c NH B-2446 F 70 500 501 F L~~i o=s- [ ~ 0 F 0 F o

N

B-2447 F 56 488 489 SuMTUTESHEEf(RULEM) WO 98/52940 PCT/US98/10436 638 RB c Observed N-R Calcd. Mass R Yield c. Mass Spec R- Yield Spec. M+H O H B-2448 F 51 522 523 /NH B-2449 F 19 512 513 CI; 0 B-2450 F = 16 538 539 B-2451 F e N 71 511 512 N o B-2452 F71 500 501 1 0 B-2453 F j O 0

CF

3 61 470 0 B-245 \ANH 0 B-2454 F o15 472 473 0 O , NH B-2455 F ce 39 520 I __--_ N-N \N B-2456 F 51 533 534 SUBSTIUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 639 RB I Observed N-R Calcd. Mass R2 Yield Mass Spec Spec. M+H O B-2457 55 540 FO - -0 B-2458 F 0 22 488 489 FF 0 O Vo B-2459 F-8 486 487 :0 B-2460 F j q13 534 535 iu !i S S/ \13 542 B-2461 F N13 542 S MUTESHEEr(RULE26) WO 98/52940 PCT/US98/10436 640 5 10 Example C-1 15 5-AMINOMETHYL-4- (4-PYRIDYL) -3- (4-FLUOROPHENYL) PYRAZOLE N-NH \I/ NH 2 F N 20 1-(4-fluorophenyl)-2-(4-pyridyl)-l-ethanone. 4 picoline (40 g, 0.43 mol) was added to a LiHNDS solution (0.45 mol, 450 mL of a 1.0 M solution in THF) over 30 minutes at room temperature (a slight exotherm was observed) The resulting solution was stirred for 1 h. 25 This solution was added to ethyl 4-fluorobenzoate (75.8 g, 0.45 mol, neat) over 1 h. The mixture was stirred overnight (16 h). Water (200 mL) was added and the mixture was extracted with EtOAc (2x200 mL). The organic layer was washed with brine (1x200 mL) and dried over M-UT (ESHT E N) WO98/52940 PCT/US98/10436 641 Na 2

SO

4 . The organic layer was filtered and the solvent was removed to leave oily solid. Hexane was added to the oil and the resulting solid was filtered and washed with hexane (cold). A yellow solid was isolated (50 g, 54%): 5 1H NMR (CDC1 3 ) 6 8.58 (d, J = 5.7 Hz, 2H), 8.02 (dd, J = 5.5, 8.0, 2H), 7.12-7.21 (m, 4H), 4.23 (s, 2H); "F NMR (CDC1 3 ) 6 -104.38 (m); LC/MS, tr = 2.14 minutes (5 to 95% acetonitrile/water over 15 minutes at 1 mL/min, at 254 nm at 500C), M+H = 216; High Resolution MS Calcd for 10 C 23

H

20

N

4 0 2 F (M+H) : 216.0825. Found: 216.0830 (A mmu = 0.5). N-benzyloxycarbonyl-5-aminomethyl-4-(4-pyridyl)-3 (4-fluorophenyl) pyrazole. A 3L round bottom flask 15 fitted with a mechanical stirrer, N 2 inlet and an addition funnel was was charged wtih 557 mL (0.56 mol) of 1 M t BuOK in THF and 53 mL (0.56 mol) of t-BuOH. The ketone, 1 (60 g, 0.28 mol) was dissolved in 600 mL of THF and added to the stirred mixture at room temperature. A yellow 20 precipitate formed and the mixture was stirred for 1 h. N-benzyloxycarbonyl-glycinyl N-hydroxysuccinimide (128.6 g, 0.42 mol) was dissolved in 600 mL of THF and added dropwise at r.t. over lh. The mixture was stirred for another 5 minutes and 150 mL of water was added. the pH 25 was adjusted to 6.7 with 70 mL of AcOH. Hydrazine monohydrate (41 mL inl00 mL of water) was added via an addition funnel. The mixture was stirred for 1 h and was diluted with 500 mL of water and 500 mL of ethyl acetate. The biphasic mixture was transferred to a sep funnel and 30 the layers were separated. The aqueous layer was extracted with EtOAc (3x300 mL). The organic layer was 8URLTUTESHEET(RULE 26) WO98/52940 PCT/US98/10436 642 dried (Na 2

SO

4 ), filtered and evaporated to leave 157 g of a crude reddish oil. The oil was suspended in CH 2 C1 2 and filtered to remove any insoluble material (DCU, hydrazone of the 5 monoketone). The solution was split into two portions and each portion was chromatographed (Biotage 75L, 3% EtOH/CH 2 Cl 2 then 6% EtOH/CH 2 Cl 2 ) . The appropriate fractions were concentrated (some contamination from the monoketone and the hydrazone) from each portion to leave 10 a yellow solid. The solid was suspended in ethyl acetate and heated to boiling for 10 minutes. The solution was allowed to cool to R.T. overnight. The precipitate was filtered to give 30 g of a white solid (27% yield of 2): 'H NMR (DMF-d7) 6 13.36 (s, 1H), 8.57 (d, J = 5.8 Hz, 2H), 15 7.16-7.52 (m, 11H), 5.11 (s, 2H), 4.48 (d, J = 5.4 Hz, 2H); 19F NMR (DMF-d 7 ) 5 -114.9 (m), -116.8 (m) (split fluorine signal is due to the pyrazole tautomers); LC/MS, tr = 3.52 minutes (5 to 95% acetonitrile/water over 15 minutes at 1 mL/min, at 254 nm at 50 0 C), M+H = 403; High 20 Resolution MS Calcd for C 23

H

20

N

4 0 2 F (M+H): 403.1570. Found: 403.1581 (A mmu = 1.1). 5-aminomethyl-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole. To a IL Parr bottle was added 7 g (17.4 mmol) 25 of 2 and 180 mL of MeOH and 90 mL of THF to give a clear solution. The bottle was purged with nitrogen and 1.5 g of 10% Pd/C (wet Degussa type El01) was added. The Parr bottle was pressured to 40 psi (H 2 ) and was agitated. Hydrogen uptake was 5 psi after 5 h. The bottle was 30 repressured to 42 psi and was agitated overnight. The bottle was purged with N2 and was filtered through Celite. The Celite was washed with MeOH (3x50 mL) and SUBSTUMTESHEET(RULE26) WO 98/52940 PCT/US98/10436 643 the filtrate was concentrated to give 4.5 g of an off white solid (94%). 'H NMR (DMSO-d 6 ) 6 8.52 (d, J = 4.63 Hz, 2H), 7.36 (dd, J = 5.64, 8.1 Hz, 2H), 7.16-7.30 (m, 4H), 3.79 (s, 2H); " 9 F NMR (DMSO-d 6 ) 8 -114.56 (m); LC/MS, 5 t r 1.21 minutes (5 to 95% acetonitrile/water over 15 minutes at 1 mL/min, at 254 nm at 50 0 C), M+H = 269 m/z; High Resolution MS Calcd for C1 5 H1 4

N

4 F (M+H) : 269.1202. Found: 269.1229 (A mmu = 2.7). 10 The following pyridylpyrazoles (C-2 through C-21, Table C-1) were prepared according to the experimental procedure described above for example C-1. 15 Table C-1. Exampl Structure MW, M + 'H NMR (solvent), ppm e No. H Calculat ed Found C-2 N-NH 323.1672 (DMF-d 7 ): 8.77 (t, J F NH 323.1670 4.4 Hz, 2H), 7.60 (m, 2H), 7.44 (t, J = 4.4 Hz, 2H), 7.35 (m, 2H), 3.22 (bd, 2H), 3.01 (septet, J = 5.3 Hz, 1H), 2.74 (m, 2H), 1.95 (m, 4H) suB~rm~ES~E~r 0%,&%E WO 98/52940 PCT/US98/10436 644 C-3 N-NH 282.127 (DMF-d 7 ) 8.77 (br s, I, NH 2 F CH 3 (M) 2H), 7.64-7.62 (m, 2H), I 282.1245 7.50 (br s, 2H), 7.38-7.34 (M, EI) (m, 2H), 4.40-4.37 (m, 1H), 1.56 (br s, 3H) C-4 N-NH 282.127 (DMF-d 7 ): 8.77 (br s, / NH 2 F H 3 (M) 2H), 7.64-7.62 (m, 2H), S282.1147 7.50 (br s, 2H), 7.38-7.35 (M, EI) (m, 2H), 4.40-4.37 (m, 1H), 1.57 (br s, 3H) C-5 N-NH 323.1672 (DHSO-d 6 ) 8.56 (br, 2H) NH F 323.1687 7.32 (m, 2H), 7.18 (m, 4H), 2.91 (m, 2H), 2.71 (m, 2H) 1.88 (m, 1H), 1.65 (m, 2H), 1.40 (m, 2H) C -6 N-NH C-6 N-NH NH 2 359 (DMSO-d 6 ): 8.46 (d, J = F -359 4.6 Hz, 2H), 7.32-7.13 (m, ' 7H), 6.98-6.96 (m, 4H), 4.06 (t, J = 7.0 Hz, 1H), 2.98-2.95 (m, 2H) C-7 N-NH 359 (DMSO-d 6 ) 8.46 (d, J F - 359 5.4 Hz, 2H), 7.32-7.28 (m, I 2H), 7.20-7.12 (m, 5H), 6.98-6.96 (m, 4H), 4.06 (t, J = 7.0 Hz, 1H), 2.98 2.94 (m, 2H) C-8 N-NH 313.1465 (DMSO-d 6 ) 13.83 (bs, I NH 2 F - 313.1492 1H), 8.61 (d, J = 5.7 Hz,

SOCH

3 N 2H), 8.33 (bs, 1H), 7.33 (m, 6H), 4.44 (m, 1H), 3.63 (m, 2H), 3.27 (s, 3H)

SUSTITUESHEE(RULERE)

WO 98/52940 PCT/US98/10436 645 C-9 N-NH 313.1465 (DMSO-d 6 ) : 8.55 (dd, J = I ,NH 2 F -OCH3 313.1457 1.5, 4.4 Hz, 2H), 7.37 7.32 (m, 2H), 7.26 (dd, J = 1.6, 4.4 Hz, 2H), 7.22 7.16 (m, 2H), 4.06 (t, J = 6.5 Hz, 1H), 3.49 (d, J = 6.6 Hz, 2H), 3.20 (s, 3H) C-10 N-NH 354 (DMSO-d 6 ) : 13.03 (bs, F 354 1H), 8.50 (dd, J=1.6, 2.7 CONHCH. N ONHC Hz, 2H), 7.58 (bq, J=4.3 Hz, 1H), 7.3 (m, 2H), 7.12-7.21 (m, 4H), 3.77 (t, J= 6.3 Hz, 1H), 2.45 (d, J=4.5 Hz, 3H), 1.97 (t, J= 7.4 Hz, 2H), 1.85 (dt, J=7.3, 7.1 Hz, 2H) C-11 N-NH NH2 354 (DMSO-d 6 ) : 13.03 (bs, F- ON 354 1H), 8.50 (dd, J=1.6, 2.7 CONHCH, N Hz, 2H), 7.58 (bq, J=4.3 Hz, 1H), 7.3 (m, 2H), 7.12-7.21 (m, 4H), 3.77 (t, J= 6.3 Hz, 1H), 2.45 (d, J=4.5 Hz, 3H), 1.97 (t, J= 7.4 Hz, 2H), 1.85 (dt, J=7.3, 7.1 Hz, 2H) C-12 N-NH 283.1359 (DMSO-d 6 ) : 8.53 (d, J

/NH

2 F 283.1363 5.0 Hz, 2H), 7.37-7.32 (m, N 2H), 7.21-7.17 (m, 4H), 2.83(d, J = 6.0 Hz, 2H), 2.77 (d, J = 6.0 Hz, 2H) C-13 N-NH NH2 297.1515 (DMSO-d 6 ) 8.53 (d, J

/NH

2 F 297.1515 5.4 Hz, 2H), 7.34 (dd, J = N 5.8, 8.2 Hz, 2H), 7.18 SUBST EEEr (RULE26) WO 98/52940 PCT/US98/10436 646 (dd, J = 5.8, 9.8 Hz, 4H), 2.68 (t, J = 7.3 Hz, 2H), 2.52 (m, 2H), 1.64 (m, 2H) C-14 Cl N-NH 284.0829 ( CD 3 OD): 8.74 (br, 2H), / NH 2 N 284.0806 7.77 (br, 2H), 7.45-7.58 (m, 3H), 7.30-7.40 (m, 1H), 4.43 (s, 2H) C-15 N-NH 285 (DMSO-d 6 ) 8.53 (br, 2H), I NH 2 c 285 7.56 (br, 2H), 7.26 (m, 4H), 3.75 (br, 2H) N C-16 N-NH 329, 331 (DMSO-d 6 ) 8.53 (d, J = I NH 2 Br 329, 331 4.4 HZ, 2H), 7.42 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 4.6 Hz, 2H), 3.76 (bs, 2H) C-17 Cl N-NH 339 (DMSO-d 6 ) : 8.53 (t, J = NH 339 4.3 Hz, 2H), 7.33 (m, 3H), 7.19 (t, J = 4.6 Hz, 2H), N 7.14 (d, J = 7.3 Hz, 1H), 3.23 (m, 2H), 2.88, (m, 3H), 1.92, (m, 3H), 1.70 (m, 1H) C-18 N-NH 339 (DMSO-d 6 ): 8.57 (d, J CI NH 339 4.6 Hz, 2H), 7.41 (d, J N 8.3 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 4.8 Hz, 2H), 3.18 (bd, 2H), 2.88 (m, 1H), 2.76 (m, 2H), 1.82 (br, 4H) C-19 N-NH 383, 385 (DMSO-d 6 ) 8.56 (br, 2H) Br H 383, 385 7.52 (br, 2H), 7.14-7.29 N (m, 4H), 2.99 (br, 2H), SUBSTUTESHEE(RULE26) WO 98/52940 PCT/US98/10436 647 2.71 (br, 1H), 2.51 (br, 2H), 1.68 (br, 4H) 5 10 The following pyridylpyrazoles (C-22 through C-40, Table C-2) are prepared utilizing the general schemes C-1 and C-2 and the experimental procedure described for example 15 C-i above. Table C-2 Cmpd. No. Structure C-22 N-NH

UENH

2 F -s NJ C-23 N-NH /

"

NH

2 N C-24 N-NH H 2 F- NH N SU68TUTSHEU (ROU SPW WO 98/52940 PCT/US98/10436 648 C-25 Br N-NH /

NH

2 N C-26 H 3 C N-NH / NH 2 N C-27 Br N-NH NH C-28 H3C N-NH C-29 N-NH / NH 2 S N C-30 N-NH S- NH N C-31 N-NH F3C NH C-32 N-NH / NH2 F N C-33 N-NH F SNH N N C-31 N-NH Ba WO 98/52940 PCTIUS98/10436 649 C-34 N-NH

F

I NH 2 N' N NH C-35 N-NH F I

INH

2 N C-36 N-NH F IN H 2 NI

FN

N C-37 N-NH F -

NH

2 N'NN C-38 N-NH F N H NH ' N C-39 N-NH F - ."GNH

-

I N C-40 N-NH / \ /CO 2 t-BU F -NH 2 N C-41 N-NH H F N N C-43 N-NH H F I N N C - 4 4 N -N H H' -N 'N SUBSTTUTEE(RULE26) WO 98/52940 PCT/US98/10436 650 C-45 N-NH H -N NH N' C-46 N-NH H N' F NCH3 N C-47 N-NH H

/NH

3 N 10 NN CO2 H F

CH

3 N 15 Step A The pyrazole (2.60 g, 10.3 mmol) from example 4 was suspended in 52 mL of dichloroethane and 52 mL of 2.5 M susmTESHE-(FLE2H WO 98/52940 PCT/US98/10436 651 NaOH. Tetrabutylammonium hydroxide (0.5 mL of a 1 M aqueous solution) was added to the stirred mixture. To this mixture was added t-butyl bromoacetate (2.10 g, 10.8 mmol). The reaction mixture was stirred at room 5 temperature for 4 h. The mixture was poured onto 200 mL of CH 2 C1 2 and 200 mL of H 2 0. The phases were separated and the organic phase was washed with water (ixi00 mL) and brine (ix100 mL). The organic layer was dried over Na 2

SO

4 and was filtered. The solvent was removed to leave 10 an off-white solid. This solid was triturated with hexane and the resulting solid isolated by filtration. The solid was washed with hexane to leave 3.4 g of a white solid (90%). 15 Step B 20 The alkylated pyrazole (3.7 g, 10.1 mmol) from Step A was treated with 57 mL of 4 N HCL in dioxane. The solution was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was dissolved in THF. The solution was treated 25 with propylene oxide (10.3 mmol) and was stirred for lh at room temperature. The solvent was removed to leave an oil. The residual solvent was chased with several portions of EtOH. The resulting solid was triturated with Et20 and the title compound Example C-49 was 30 isolated by filtration to afford 3.0 g of an off-white solid (95%). Mass spec: M+H cald: 312; found 312. 'H NMR (DMSO-d6): 8.81 (d, J = 6.4 Hz, 2H), 7.73 (d, J = 8UBSTIUTE8HEET(RULE=) WO 98/52940 PCT/US98/10436 652 5.8 Hz, 2H), 7.40 (m, 2H), 7.23 (t, J = 8.5 Hz, 1H), 5.16 (s, 2H), 2.40 (s, 3H). 5 Example C-50 N-N /

CO

2 H H F N According to the procedure described above in Example C 10 49, Example C-50 was also prepared starting from 4-[3-(4 fluorophenyl)-lH-pyrazole-4-yl]pyridine. Mass spec: M+H cald: 298; found 298. H NMR (DMSO-d6): 8.75 (d, J = 6.4 Hz, 2H), 8.68 (s, 1H), 7.78 (d, J = 6.6 Hz, 2H), 7.52 (dd, J = 5.4, 8.5 Hz, 2H), 7.31 (t, J 8.9 Hz, 2H), 15 5.16 (s, 2H). Example C-51 20

/-CO

2 H N-N F -N Boc NI N Starting with the N-Boc-piperidinyl analog of Example C 2, Example C-51 is also prepared according to the methods described in Scheme C-1. SUBSTTTSHEE-T(FU.E 2S) WO 98/52940 PCT/US98/10436 653 Example C-52 5 N-NH

H

2 N / O H N Step A: Picoline is treated with a base chosen from but not limited to n-BuLi, LDA, LiHMDS, tBuOK, or NaH in an organic solvent such as THF, ether, t-BuOH or dioxane 10 from -78 OC to 50 'C for a period of time from 10 minutes to 3 hours. The picoline solution is then added to a solution of N-Cbz-(L)-phenylalaninyl N hydroxysuccinimide. The reaction is allowed to stir from 30 minutes to 48 hours during which time the temperature 15 may range from -20 °C to 120 oC. The mixture is then poured into water and extracted with an organic solvent. After drying and removal of solvent the pyridyl monoketone is isolated as a crude solid which could be purified by crystallization and/or chromatography. 20 0 HN Cbz -< 7 N 25 Step B: A solution of the pyridyl monoketone in ether, THF, tBuOH, or dioxane is added to a base chosen from but nmMMrrmm=HEET(RULE25) WO98/52940 PCT/US98/10436 654 not limited to n-BuLi, LDA, LiHMDS, tBuOK, or NaH contained in hexane, THF, ether, dioxane, or tBuOH from 78 OC to 50 oC for a period of time from 10 minutes to 3 hours. Formyl acetic anhydride is then added as a 5 solution in THF, ether, or dioxane to the monoketone anion while the temperature is maintained between -50 'C and 50 'C. The resulting mixture is allowed to stir at the specified temperature for a period of time from 5 minutes to several hours. The resulting pyridyl diketone 10 intermediate is utilized without purification in Step C. O O HN Cbz H N Step C: The solution containing the pyridyl diketone is 15 quenched with water and the pH is adjusted to between 4 and 8 utilizing an inorganic or organic acid chosen from HOAc, H 2 S0 4 , HCl, or HNO 3 . The temperature during this step is maintained between -20 oC and room temperature. Hydrazine or hydrazine hydrate is then added to the 20 mixture while maintaining the temperature between -20 °C and 40 OC for a period of 30 minutes to several hours. The mixture is then poured into water and extracted with an organic solvent. The N-Cbz-protected pyridyl pyrazole is obtained as a crude solid which is purified by 25 chromatography or crystallization. SUEstmW SEET(RULE2 WO 98/52940 PCT/US98/10436 655 N-NH Cbz" HN H zH N 5 Step: D The CBZ protecting group is cleaved using hydrogen gas under pressure and Pd-C in an alcohol solvent, affording scaffold C-52 after filtration and concentration. N-NH

H

2 N / H "H 10 N 15 The following compounds C-53 through C-59 in Table C-3 are prepared according to the general procedure described above for the preparation of C-52. Table C-3 Example No. Structure C-53 N-NH

H

2 N ~ H N SUBSTnUESHEET (RULE26) WO 98/52940 PCT/US98/10436 656 C-54 N-NH

H

2 N NIN Boc N C-55 N-NH

H

2 N / N Boc N C-56

H

2 N N-NH H N C-57

H

2 N N-NH H N C-58 N-NH

H

2 N /, NH-Boc N C-59 H 2 N-NH NH-Boc N Example C-60 5 Step A: A Boc protected pyridylpyrazole is treated with benzaldehyde in methylene chloride at room temperature in fml1JE-$HEET(RULE26) WO 98/52940 PCTIUS98/10436 657 the presence of a drying agent for a period of time ranging from 1-24 h. Solvent is then evaporated and the resulting imine is used in step B without further purification. 5 N-NBoc N-NHBoc Ph \ / NH 2 HCOPh N F - F N Step A N N Step B: The pyridylpyrazole imine is dissolved in THF and stirred 10 under nitrogen at temperatures ranging from -78 to -20 'C. A base such as LDA, n-BuLi, or LiHMDS is added dropwise to the mixture which is then stirred for an additional 10 minutes to 3 h. Two equivalents of a methyl iodide are then added to the mixture and stirring is continued for 15 several hours. The mixture is then quenched with acid and allowed to warm to room temperature and stirred several hours until cleavage of the Boc and the imine functions is complete. The pH is adjusted to 12 and then the mixture is extracted with an organic solvent, which 20 is dried and evaporated. The crude pyridylpyrazole is then crystallized and/or chromatographed to give purified C-60. suBSf mTESHEEr(RULEM) WO 98/52940 PCT/US98/10436 658 Step B N-NH N-NHBoc Ph / NH 2 F F N 1) Base N 2) Mel C-60 3) Acid, H 2 0 5 Example C-61 N-NH

NH

2

F

N 10 Example C-61 is prepared according to the method described in example C-60, substituting 1,4-dibromobutane for methyl iodide. 15 20 Example C-62 SULTUMTEMEE (RULE26) WO98/52940 PCT/US98/10436 659 N-NH

NH

2 F N Example C-62 is prepared according to the method described in example C-60, substituting 1,3-dibromoethane for methyl iodide. 5 Example C-63 The synthesis of compound C-63 starts with the 10 condensation reaction of bromomaleic anhydride B77 with 2, 4-dimethoxybenzylamine in acetic acid and acetic anhydride. The maleimide B78 is then treated with 4' fluoroacetophenone in the presence of catalytic amount Pd 2 (dba) 3 and sodium t-butoxide to form the 15 fluoroacetophenone substituted maleimide B79. B79 is then treated with tert-butoxybis(dimethylamino)methane to yield the a-ketoenamine B80. The a-ketoenamine B80 is condensed with hydrazine to form the N-protected maleimide pyrazole B81. The 2,4-dimethoxybenzyl group is 20 cleaved with ceric ammonium nitrate (CAN) to give the title compound C-63. Susm8TuTESHEET(RuL

)

WO 98/52940 PCT/US98/10436 660 OMe 0 O 2 OMe OMe

H

2 N NF,( Br 1. AcOH Br Pd 2 (dba) 3 / NaOBu-t O 2. Ac 2 0 O OMe B77 B78 OMe O O

(CH

3

)

3

COCH[N(CH

3

)

2

]

2 OMe ON 'N SOMe 0 OMe F B79 N- B80 N-NH / N-NH NH2NH2 CAN NF F 0 iNH SOMe NH 0 MeO B81 C-63 Example C-64 5 N-NH / / NH 2 7F 0 F/ N O H Using the method described in Schemes C-6 and C-7, 10 Example 64 is prepared. SUTBWUWHEEf(RUESQ WO 98/52940 PCT/US98/10436 661 Example C-65 N-NH , NH F / O N 5 O H Using the method described in Schemes C-6 and C-7, Example 65 is prepared. I0 Example C-66 N-NH F NH F N 0 15 H Using the method described in Schemes C-6 and C-7, Example C-66 is synthesized, substituting N-2,4 20 dimethoxybenzyl-4-bromopyridone for B78. 25 amrnTE8HEEf(FU.RM) WO 98/52940 PCT/US98/10436 662 Example C-67 5 N-NH / NH 2 F N 0 H Using the method described in Schemes C-6 and C-7, Example C-67 is synthesized, substituting N-2,4 10 dimethoxybenzyl-4-bromopyridone for B78, and substituting N-Boc-glycyl N-hydroxysuccinimide for B82. Example C-68 15 N-NH NH2 H Using the method described in Schemes C-6 and C-7, 20 Example C-68 is synthesized, substituting N-2,4 dimethoxybenzyl-4-bromopyridone for B78. 25 SUBmUTEM HEET( RE2) WO 98/52940 PCT/US98/10436 663 Example C-69 N-NH H NH F / 0 N 5 O H Using the method described in Schemes C-6 and C-7, Example 69 is prepared, substituting N-Boc-nipecotyl N hydroxysuccinimide for B83. 10 Example C-70 N-NH H ''NH F / 0 N O H 15 Using the method described in Schemes C-6 and C-7, Example 70 is prepared, substituting N-Boc-nipecotyl N hydroxysuccinimide for B83. Example C-71 20 N-NH F- NH F /0 N 0

CH

3 SSTIT1UTESHEET (RUU'W26 WO 98/52940 PCT/US98/10436 664 Using the method described in Schemes C-6 and C-7, Example 71 is prepared, substituting N-methyl-3 bromomaleimide for B78. 5 Example C-72 N-NH H NH F / O N o CH 3 10 Using the method described in Schemes C-6 and C-7, Example 72 is prepared, substituting N-methyl-3 bromomaleimide for B78, and substituting N-Boc-nipecotyl N-hydroxysuccinimide for B83. 15 Example C-73 N-NH H F / O N o

'CH

3 Using the method described in Schemes C-6 and C-7, 20 Example 73 is prepared, substituting N-methyl-3 bromomaleimide for B78 and substituting N-Boc-nipecotyl N-hydroxysuccinimide for B83. 25 semTESHrq.EET

(RLESS)

WO98/52940 PCTIUS98/10436 665 Biological data from compounds of Examples B-0001 through B-1573 and of Examples B-2270 through B-2462 are shown in 5 the following tables. In vitro P38-alpha kinase inhibitory data are shown in the column identified as: "P38 alpha kinase IC 50 , uM or % inhib @ conc. (uM)" 10 In vitro whole cell assay for measuring the ability of the compounds to inhibit TNF production in human U937 cells stimulated with LPS are shown in the column 15 identified as: "U937 Cell IC 50 , uM or % inhib @ conc., (uM)" In vivo assessment of the ability of the compounds to inhibit LPS-stimulated TNF release in the mouse is shown 20 in the column identified as: "Mouse LPS Model, % TNF inhib @ dose @ predose time" wherein in the dose is milligram per kilogram (mpk) administered by oral gavage and the predose time indicates the number of hours before LPS challenge when 25 the compound is administered. In vivo assessment of the ability of the compounds to inhibit LPS-stimulated TNF release in the rat is shown in the column identified as: 30 "Rat LPS Model, % TNF inhib @ dose @ predose time" wherein in the dose is milligram per kilogram (mpk) administered by oral gavage and the predose time 8UBTTESHEE(RULE 26

)

WO 98/52940 PCT/US98/10436 666 indicates the number of hours before LPS challenge when the compound is administered.

WO 98/52940 PCT/US98/10436 667 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-0001 53.0%@1.0uM 40.0% @1.0uM B-0002 71.0%@1.0uM 28.0%@10.0uM B-0003 70.0%@1.0uM 76.0% 10.0uM B-0004 80.0%@1.0uM 4.61uM B-0005 95.0%@1.0uM 2.97uM B-0006 82.0%@1.0uM 80%@10.0uM B-0007 74.0%@1.0uM 85.0%@10.0uM B-0008 42.0%@1.0uM 65.0%@10.0uM B-0009 0.04 uM 0.72uM B-0010 0.52 uM 0.65uM B-0011 0.03 uM 4.47uM B-0012 30.0%@1.0uM 44.0% @1.0uM B-0013 70.0%@1.0uM 84.0%@10.0uM B-0014 79.0%@1.0uM 80.0%@10.0uM B-0015 82.0%@1.0uM 80.0%@10.0uM B-0016 94.0%@1.0uM 3.98uM B-0017 56.0%@1.0uM 79.0%@10.0uM B-0018 60.0%@1.0uM 59.0%@10.0uM B-0019 84.0%@1.0uM 100.0%@10.0uM B-0020 73.0%@1.0uM 81.0%@10.0uM B-0021 68.0%@1.0uM 76.0%@10.0uM B-0022 69.0%@1.0uM 44.0@1.0uM B-0023 90.0%@1.0uM 77.0%@10.0uM B-0024 94.0%@1.0uM 52.0%@1.0uM B-0025 89.0%@1.0uM 79.0%@10.0uM B-0026 96.0%@1.0uM 3.27uM B-0027 94.0%@1.0uM 11.0uM B-0028 69.0%@1.0uM 45.0%@10.0uM B-0029 91.0%@1.0uM 58.0%@10.0uM B-0030 92.0%@1.0uM 75.0%@10.0uM B-0031 94.0%@1.0uM 100.0%@10.0uM B-0032 94.0%@1.0uM 78.0%@10.0uM B-0033 97.0%@1.0uM 10.0uM B-0034 95.0%@1.0uM 10.0uM B-0035 94.0%@1.0uM 10.0uM B-0036 92.0%@1.0uM 8.24uM B-0037 91.0%@1.0uM 86.0%@10.0uM B-0038 71.0%@1.0uM 84.0%@10.0uM B-0039 89.0%@1.0uM 72.0%@10.0uM B-0040 93.0%@1.0uM 2.3uM B-0041 65.0%@1.0uM 66.0%@10.0uM B-0042 94.0%@1.0uM 2.76uM rmisTnESti (RULE ) WO 98/52940 PCT/US98/1 0436 668 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % 1C50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Exam le# __________________ ______ ___ B-0043 0.22 uM 0.54uM _________________ B-0044 0.14 uM .l9um ________ _______ B-0045 94.0%@1.OuM 1.OluM____ ____________ B-0046 96.O%@1.OuM 54.O%@1.OuM __ ______________ B-0047 94.0%@1.OuM 74.0%@l0.OuM _______________ B-0048 94.O%@1.OuM 76.0%@10.OuM ________ B-0049 88%@1.OuM 33.0%@1.OuM ________ B-0050 73%@1.0uM 34.O%@1.OuM ________ B-0051 3.3uM 2.1 5uM 47%@ 1 Ompk@-6h 79%@3mpk@-4h B-0052 92%@1.OuM 15.0%@1.OuM ________ B-0053 95%@l.OuM 34.0%@1.OuM ________ B-0054 90%@1.OuM 30.0%@1.OuM ________ B-0055 93%@1.OuM >1.OuM B-0056 96%@1.OuM 21.0%@1.OuM B-0057 96%@1.OuM 29.0%@1.OuM _______ B-0058 79%@1.OuM 18.0%@1.OuM _______ B-0059 83%@1.OuM 35.0%@1.OuM________ B-0060 73%@1.OuM 22.0%@1.OuM _______ B-0061 62%@1.OuM 27.0%@1.OuM _______________ B-0062 94%@1.OuM 36.0%@1.OuM ___ _____________ B-0063 96%@1.OuM 40.0%@1 .OuM ________ _______ B-0064 90%@1.OuM 4.0%@1.OuM ___ _____________ B-0065 83%@1.OuM 21.0%@1.OuM ___ _____________ B-0066 94%@1.OuM 28.0%@1.OuM ___ _____________ B-0067 91%@11.OuM 1.0%@1.OuM ________ B-0068 72%@1.OuM 22.0%@1.OuM ________ B-0069 96%@1.OuM 37.0%@1 .OuM-________ B-0070 92%@1 .OuM 30.0%@1 .OuM B-0071 86%@1.OuM 31.0%@1.OuM B-0072 77%@1.OuM 32.O%@1.OuM B-0073 91%@1.OuM 24.0%@1.OuM________ B-0074 92%@1 .OuM 42.0%@1 .OuM________ B-0075 91%@1.OuM 35.0%@1.OuM ___ _____________ B-0076 58%@1.OuM 21.0%@1.OuM ___ _____________ B-0077 0.8um 10.0uM ________ _______ B-0078 80%@1.OuM 20.0%@1.OuM ___ _____________ B-0079 93%@1.OuM 13.0%@1.OuM ________ B-0080 73%@1.OuM 73.0%@1.OuM ________ B-0081 92%@1.OuM 13.0%@1.OuM ________ B-0082 47%@1.OuM 27.0%@1.OuM _______________ B-0083 0.22uM 6.5lu M ________ 5-0084 56%@1.OuM 30.0%@1 .OuM________ ,SsSTWEUE

(NAJEASM)

WO 98/52940 PCTIUS98/1 0436 669 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib © dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# _______________ ___ B-0085 83%@1.OuM 21.0%@1.OuM ________________ B-0086 91%@1.OuM 37.0%@1.OuM ________________ B-0087 0.55uM 2.26uM 38% @ 3mpk@-6h ________ B-0088 96%@1.OuM 9.0%@1.OuM ________ B-0089 O.O4uM 3.33uM ________ B-0090 98%@1 .OuM 52.0%@1 .OuM ________ B-0091 96%@1.OuM 40.0%@1.OuM ________ B-0092 97%@l1.OuM 34.0%@l1.OuM B-0093 3.18 uM 1.25uM 30%@30mpk@-6h B-0094 96%@1.OuM 52.O%@1.OuM _______________ B-0095 98%@1.OuM 38.O%@1.OuM B-0096 91%@1.OuM 22.O%@1.OuM________ B-0097 72.0% @1 0.OuM 38.O%@l1.OuM B-0098 66.0%@10.OuM 12.0%@1.OuM________ B-0099 43.0% @1.OuM >1.OuM _______________ B-01 00 75.0% @1.OuM 5.OuM _______________ B-0101 71.0% @1.OuM 2.11luM _______________ B-01 02 81.0%@1.OuM 15.0%@1.OuM ________ B-01 03 71.0%@1.OuM 6.0%@1.OuM ________ B-01 04 56.0% @1.0uM 2.78uM _______ B-01 05 78.O%@1.OuM 5.0um ________ B-01 06 62.O%@1.OuM 5.OuM B-01 07 O.27uM 5.OuM B-01 08 61.0%@1.OuM 4.85uM B-01 09 45.0%@1.OuM 19.0%@1.OuM B-01 10 66.O%@1.0uM 13.0%@1.OuM________ B-01 11 57.0%@1.OuM >1.OuM _______ B-01 12 97.0%@1.OuM 1.l2uM _______________ B-01 13 75.0%@1.OuM 43.0%@1.OuM ________________ B-01 14 45.0%@1.OuM 3.92uM _______________ B-01 15 47.0%@1.OuM 2.0%@1.OuM ________ B-01 16 73.O%@1.OuM 35.0%@1.OuM ________ B-01 17 0.46 uMV 1.78 uM 30%@30mpk@-6h B-01 18 1.1 uMI 1.29 uM B-01 1 89.0%@10.OuM 2.78uM B-01 20 0.008 uM 0.21 uM 77%@lO0mpk@-6h 70%@3mpk@-4h B-01 21 79.0%@1.OuM 1.22uM B-01 22 79.0%@10.OuM 2.0%@1.OuM________ B-01 23 59.0%@1.OuM >.OuM _______________ B-01 24 73.0%@1.OuM 15.0%@1.OuM _______________ B-0l 25 70.0%@ 10.OuM 1 7.0%@ 1.OuM _________________ fB-126 1_66.0%@1.OuM 1.57uM________ WO 98/52940 PCT/US98/10436 670 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-0127 82.0%@1.0uM 0.96uM B-0128 78.0%@1.0uM 1.81uM B-0129 51.0%@1.0uM 31.0%@1.0uM B-0130 69.0%@1.0uM 58.0%@1.0uM B-0131 43.0%@1.0uM 46.0%@1.0uM B-0132 76.0%@1.0uM 8.0%@1.0uM B-0133 51.0%@1.O0uM 42.0%@1.0uM B-0134 60.0%@1.0uM 2.17uM B-0135 78.0%@1.0uM 58.0%@1.0uM B-0136 77.0%@1.0uM 44.0%@1.0uM B-0137 41.0%@1.0uM 37.0%@1.0uM B-0138 50.0%@1.0uM 32.0%@1.0uM B-0139 54.0%@10.0uM 17.0%@1.0uM B-0140 67%@10.0uM 9.0%@1.0uM B-0141 78.0%@1.0uM 10.0%@1.0uM B-0142 86.0%@1.0uM 12.0%@1.0uM B-0143 42.0% @1.0uM 3.63uM B-0144 86.0% @1.0uM 43.0%@1.0uM B-0145 54.0% @10.0uM 12.0% @1.0uM B-0146 77.0% @10.0uM 28.0% @1.0uM B-0147 44.0% @1.0uM 22.0% @1.0uM B-0148 51.0% @1.0uM >1.0uM B-0149 1.15 uM 10.0 uM B-0150 27.0% @10.0uM 35.0% @1.0uM B-0151 43.0% @1.O0uM 30.0% @1.0uM B-0152 51.0% @1.0uM 24.0% @1.0uM B-0153 57.0% @1.0uM 21.0% @1.0uM B-0154 65.0% @10.0uM 14.0% @1.0uM B-0155 40.0% @10.0uM 26.0% @1.0uM B-0156 42.0% @10.0uM 13.0% @1.0uM B-0157 48.0% @10.0uM 9.0% @1.0uM B-0158 58.0% @10.0uM 39.0% @1.0uM B-0159 54.0% @10.0uM 5.0% @1.0uM B-0160 59.0% @10.0uM 26.0% @1.0uM B-0161 72.0% @10.0uM 13.0% @1.0uM B-0162 23%@1.0uM 2.05 uM B-0163 20.0% @10.0uM 10.0% @1.0uM B-0164 37.0% @10.0uM 20.0% @1.0uM B-0165 70.0% @10.0uM 19.0% @1.0uM B-0166 45.0% @10.0uM 37.0% @1.0uM B-0167 40.0% @1.0uM 37.0% @1.0uM B-0168 44%@1.0uM 2.36 uM WO 98/52940 PCT/US98/10436 671 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-0169 43.0% @1.0uM 21.0% @1.0uM B-0170 43.0% @1.0uM 30.0% @1.0uM B-0171 61.0% @10.0uM 21.0% @1.0uM B-0172 16.0% @10.0uM 11.0% @1.0uM _ B-0173 33.0% @10.0uM 48.0% @1.0uM B-0174 54.0% @10.0uM 43.0% @1.0uM B-0175 41.0% @10.0uM 31.0% @1.0uM B-0176 50.0% @1.0uM 30.0% @1.0uM B-0177 70.0% @10.0uM 27.0% @1.0uM B-0178 12.0% @10.0uM 35.0% @1.0uM B-0179 27.0% @10.0uM 37.0% @1.0uM B-0180 34.0% @10.0uM 23.0% @1.0uM B-0181 5.0%@1.0uM 2.0% @1.0uM B-0182 39.0% @10.0uM 40.0% @1.0uM B-0183 12.0% @10.0uM 34.0% @1.0uM B-0184 66.0% @10.0uM 17.0% @1.0uM B-0185 65.0% @10.0uM 25.0% @1.0uM B-0186 40.0% @1.0uM 25.0% @1.0uM B-0187 4.0% @10.0uM 14.0% @1.0uM B-0188 70.0% @10.0uM 35.0% @1.0uM B-0189 42.0% @10.0uM 9.0% @1.0uM B-0190 59.0% @10.0uM 31.0% @1.0uM B-0191 40.0% @1.0uM 29.0% @1.0uM B-0192 12.0% @10.0uM 47.0% @1.0uM B-0193 0.54 uM 6%@1.0uM B0194 1.31 uM 22%@1.0uM B-0195 1.03 uM 55%@1.0uM B-0196 2.24 uM >1.0uM B-0197 2.0 uM 14%@1.0uM B-0198 1.2 uM 2%@1.0uM B-0199 1.34 uM 3%@1.0uM B-0200 1.31 uM 16%@1.0uM B-0201 0.29 uM 59%@1.0uM B-0202 0.55 uM 2.26 uM_ B-0203 0.16 uM 65%@1.0uM B-0204 0.21 uM 48%@1.0uM B-0205 0.096 uM 54%@1.0uM B-0206 5.76 uM 14%@1.0uM B-0207 0.12 uM 52%@1.0uM B-0208 0.067 uM >1.0uM B-0209 0.29 uM 8%@1.0uM B-0210 0.057 uM 67%@1.0uM gmjtESHEEr(RULEM) WO 98/52940 PCT[US98/1 0436 672 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib © dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# _________ ______ ___ B-0211 0.25 uM 30%@1.OuM B-0212 0.12 uM 28%@1.OuM B-0213 0.31 uMV 39%@1.OuM ________ B-0214 0.16 uMV 50%@1.OuM B-0215 0.11 uM 51%@1.OuM B-0216 0.56 uMV >1.Oum _______ B-0217 0.55 uM >1.OuM B-0218 0.53 uMV 18%@1.Oum B-0219 0.91 uM 18%@1.Oum ________ B-0220 0.13 uMV 40%@1.OuM B-0221 2.4 uM >1.OuM ________ B-0222 0.4uM 29.0%@1.OuM ________________ B-0223 0.2uM 1.0%@11.OuM ______________ B-0224 <0.l Um 93.0%@1.OuM ________________ B-0225 0.047uM 37.0%@1.OuM ________________ B-0226 0.074uM 20.0%@1.OuM ________________ B-0227 0.045uM 1.0%@1.OuM _______________ B-0228 0.l1SuM 44.0%@1.OuM ________________ B-0229 <0.l Um 61.0%@1.OuM ________________ B-0230 0.041luM 30.0%@1.OuM ________________ B-0231 0.055uM 40.0%1 .OuM ________ B-0232 0.O4BuM 24.0%@1.OuM B-0233 0.095uM 43.0%@1.OuM B-0234 0.llUM 68.0%@1.OuM B-0235 1.31luIV 90.0%@1.Oum B-0236 0.077uM 46.0%@1.OuM B-0237 0.l3uM 60.0%@1.OuM B-0238 0.47uM 82.0%@l1.OuM B-0239 5.73uM 84.0%@1.OuM B-0240 0.2uM 70.0%@1 .OuM B-0241 0.luMV 45.0%@1.OuM _______________ B-0242 <0.1 uM 78.0%@1 .OuM ________ _______ B-0243 0.039uM 53.0%@1 .OuM ________ _______ B-0244 0.O2uM 57.0%@1.OuM _______________ B-0245 0.l3uM 24.0%@1.OuM ________________ B-0246 <O.luM >1.OuM ________ _______ B-0247 0.OB2uM 75.0%@1.OuM ________________ B-0248 <O.lUM 11.0%@1.OuM _______________ B-0249 <0.l uM 75.0%@1.OuM ________________ B-0250 0.28uM 36.0%@1 .OuM ________________ B-0251 0.31luMV 1.0%@1.OUM B-0252 0.0O1lUM 54.0%@1.OuM________ 8bwftfilsET(RLE WO 98/52940 PCT/US98/10436 673 P38 alpha kinase U937 Cell 1C50,uM Mouse LPS Model % Rat LIDS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# ________ ________ _________ B-0253 0.061luM 74.O%@1.OuM ________ B-0254 .2uM 59.O%@1.OuM ________ B-0255 O.32uM 68.O%@1 .OuM ________ B-0256 <O.luMI 88.O%@1.OuIM ________ B-0257 1.71luMV 11.O%@1.OuM B-0258 O.37uM 63.O%@1.OuM B-0259 0.35uM 58.O%@1 .OuM B-0260 O.56uM 23.O%@1 .OuM B-0261 O.49uM 23.O%@l1.OuM ________ B-0262 O.4luM 89.O%@1.OuM B-0263 O.62uM 64.O%@1 .OuM ________ B-0264 .l4uM 18.O%@1.OuM _______ B-0265 O.92uM 24.O%@ 1.OuM _________________ B-0266 O.25uM 24.O%@1.OuM ________________ B-0267 O.48uM 11.O%@1.OuM________ B-0268 3.39uM 19.O%@1.OuM________ B-0269 9.81luMV 19.O%@1.OuM________ B-0270 5.7guM 13.O%@1.OuM________ B-0271 7.55uM 12.O%@1 .OuM B-0272 1.8luMI 48.O%@1.OuM________ B-0273 5.O3uM 13.O%@1.OuM________ B-0274 2.6BuM 25.O%@1 .OuM _________________ B-0275 2.67uM 33.0%@ 1 .OuM _________________ B-0276 1 .25uM 26.O%@1 .OuM ________________ B-0277 O.68uM 34.O%@l.OuM ________________ B-0278 1 .26uM 36.O%@ 1.OuM ________ B-0279 1 .39uM 33.O%@1 .OuM ________ B-0280 O.86uM 18.O%@1 .OuM ________ B-0281 7.37uM 24.O%@1.OuM ________ B-0282 O.75uM 38.O%@1 .OuM ________ B-0283 6.66uM 29.O%@1 .OuM ________ B-0284 O.OB3uM 65.O%@1 .OuM ________ B-0285 4.57uM 29.O%@1.OuM B-0286 .33uM 50.O%@l1.OuM B-0287 4.OuM 22.O%@1.OuM B-0288 4.46uM 26.O%@1 .OuM ________ B-0289 Oi15UM 55.O%@1.OuM________ B-0290 O.66uM 44.O%@1 .OuM _________________ B-0291 1 .33uM 20.O%@l1.OuM _________________ B-0292 O.22uM 28.O%@1 .OuM _________________ B-0293 O.66uM 53.O%@1.OuM________ B-0294 0.68uM 45.O%@l1.OuM ________ WMBfl=&4sEE(RLE- WO 98/52940 PCTIUS98/1 0436 674 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Exam ple# ________ ________ _________ B-0295 O.82uM 45.O%@1 .OuM ________ B-0296 8.O3uM 36.O%@1.OuM ________ B-0297 O.78uM 30.O%@1 .OuM ________ B-0298 O.5BuM 48.O%@1 .OuM _____ ____ ________ B-0299 .87uM 54.O%@1.OuM ____ ____________ 8-0300 0.78uM 32.O%@1 .OuM _____ ____ ________ B-0301 0.l9uM 50.O%@1.OuM ___ _____ _______ B-0302 4.O2uM 24.O%@1.OuM ________ B-0303 0.22uM 1O.0%@1.OuM _______ B-0304 O.56uM 28.O%@1 .OuM ________ ______ B-0305 _________ B-0306 __________________ B-0307 __________________ B-0308 _________ _______ __ B-0309 ________ B-031 0 _______ ______ __ B-0311 _________ _ _ _ _ _ _ _ B-0312 _______ ______ __ B-0313 _______________ __ B-0314 _ _ _ _ _ _ _ ________ _ _ _ _ _ _ _ _ 8-0315 _________ _______ __ B-0316 ________ ________ _ _ _ _ _ _ _ _ B-0317 ________ ________ B-0318 ________ ________ _ _ _ _ _ _ _ _ B-0319 ________ ______ __ B-0320 ______ __ B-0321 __________________ B-0322 B-0323 ______ __ B-0324 _________________ __ B-0325 _________________ __ B-0326 ________ _______ __ B-0327 ________ _______ __ B-0328 _________ _______ __ B-0329 ________ _________ _______ __ B-0330 ________ _______ __ B-0331 ________ ________ _______ __ B-0332 _________________ __ B-0333 ________ ______ __ B-0334 __________________ B-0335 _________ B-0336 __________________ __________ _________ suSMTFrESEEr(RLE01" WO 98/52940 PCT/US98/10436 675 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-0337 B-0338 B-0339 B-0340 B-0341 B-0342 B-0343 B-0344 B-0345 B-0346 B-0347 B-0348 B-0349 B-0350 B-0351 B-0352 B-0353 1.37uM 55%@1.0uM B-0354 1.0uM O.66uM 51%@30mpk@-6h 54%@3mpk@-4h B-0355 0.75uM 40.0%@1.0uM B-0356 O.66uM 24.0%@ 1.0uM B-0357 1.46uM 0.66uM B-0358 0.37uM 17.0%@1.0uM B-0359 O.45uM 47.0%@1.0uM B-0360 1.6uM 19.0%@1.0uM B-0361 O.33uM 46.0%@1.0uM B-0362 O.52uM 27.0%@1.0uM B-0363 4.67uM 25.0%@1.0uM B-0364 1.44uM 27.0%@1.0uM B-0365 O.96uM 27.0%@1.0uM B-0366 0.7uM 46.0%@ 1.0uM B-0367 1.0uM 23.0%@1.0uM B-0368 1.0uM 0.64uM 37%@30mpk@-6h B-0369 0.16uM 57.0%@1.0uM B-0370 0.65uM 28.0%@1.0uM B-0371 O.49uM 28.0%@1.0uM B-0372 0.35uM 29.0%@ 1.0uM B-0373 O.45uM 18.0%@1.0uM B-0374 1.38uM 12.0%@1.0uM B-0375 1.0uM 19.0%@1.0uM B-0376 2.99uM 12.0%@1.0uM B-0377 1.29uM 36.0%@1.0uM B-0378 1.1uM 36.0%@1.0uM SUeSUlUTESHEET

(RULEM)

WO 98/52940 PCT/US98/10436 676 P38 alpha kinase U937 Cell IC50,uM Mouse LIPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib~conc. (uM) inhib@conc. (uM) @predose time @predose time Example# ________ ________ B-0379 O.53uM 24.O%@1.OuM________ B-0380 1.41luMV 32.O%@1.OuM________ B-0381 0.22uM 47.O%@1.OuM ____ ____________ B-0382 0.4luIM 32.O%@1.OuM ____ ____________ B-0383 1.43uM 1O.0%@1.OuM ____ ____________ B-0384 4.O2uM 16.0%@1.OuM ____ ____________ B-0385 O.O57uM 0.9uM 30%@3Ompk@-6h 0%@3mpk@-4h B-0386 .3uM 54.0%@1.OuM________ B-0387 0.41luM 52.0%@1.OuM ____ ____________ B-0388 <0.l Um 36.0%@1.OuM ____ ____________ B-0389 0.01lUM 0.O5uM ________62%@3mpk@-4h B-0390 0.OB9uM 55.O%@1.OuM ____ ____________ B-0391 O.86uIM 18.O%@1.OuM _______________ B-0392 .3uIM 57.0%@1.OuM ____ ____________ B-0393 O.O43uM 66.0%@l1.OuM ________ _______ B-0394 O.l3uM -45.0%@1.OuM ____ ____________ B-0395 O.OB7uM 48.0%@1.OuM ____ ____________ B-0396 O.097uM 0.44uM _________________ B-0397 O.l7uM 41.O%@1.OuM B-0398 0.O54uM 66.0%@l1.OuM _________________ B-0399 0.l4uM 39.0%@1.OuM ____ ____________ B-0400 0.l6uM 25.0%@1.OuM________ B-0401 O.46uM 52.O%@1.OuM________ B-0402 .4uM 1.5luM________ B-0403 1 .77uM 2.42uM ________ B-0404 0.31luMV 48.0%@1.OuM ________ B-0405 0.79uM 30.0%@1.OuM________ B-0406 O.54uM 35.0%@1 .OuM________ B-0407 O.76uM 27.0%@l1.OuM ________ B-0408 O.5uM 50.0%@l1.OuM ________ B-0409 O.53uM 30.0%@1.OuM________ B-041 0 0.3BuM 44.0%@1.OuM________ B-0411 O.62uM 50.0%@l1.OuM ________ B-0412 O.24uM 48.0%@1.OuM________ B-0413 0.l8uM 55.0%@1.OuM B-0414 2.54uM -25.0%@1.OuM B-0415 O.42L1M 43.0%@1.OuM B-0416 O.32uM 34.0%@1.OuM _______ B-0417 0.9luM 28.0%@1.OuM________ B-0418 0.22uM 27.0%@1.OuM________ B-0419 O.85uM 41.0%21.OuM _______ B-0420 0.83uM 4.0%@1.OuM ________ _______ Wwf S-=r., 11 V- WO 98/52940 PCTIUS98/10436 677 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# __________________ B-0421 0.46uM 57.O%@1.OuM _______ B-0422 <0.l uM 40.O%@1.OuM________ B-0423 0.l8uM 33.0%@1.OuIM________ B-0424 O.O83uM 32.O%@1 .OuM________ B-0425 0.26uM 54.O%@1 .OuM________ B-0426 0.055uM O.74uM 41%@3mpk@-4h B-0427 0.63uM 39.O%@1.OuIM________ B-0428 0.99uMI 27.O%@1 .OuM B-0429 0.27uM 45.O%@1.OuM _______ B-0430 0.29uM 75.O%@1.OuM B-0431 O.2luM 64.0%@1.OuM B-0432 <0OluM 89.O%@1.OuM B-0433 <0.l um 92.0%@1.OuM B-0434 0.l2uM 65.0%@1.OuM B-0435 O.3uM 61.O%@1.OuM _______ B-0436 1.lluM 71.O%@1.OuM B-0437 0.58uM 59.0%@1 .OuM ________ B-0438 <Ol1uMI 91.O%@1.OuM _______ B-0439 2.l2uM 65.0%@1.OuM B-0440 0.66uM 63.O%@1 .OuM ________ B-0441 0.8uM 58.O%@1.OuM _____ ___________ B-0442 <0.l uM 91.0%@1.OuM ________________ B-0443 2.Ol1uM 71.O%@1.OuM _______ B-0444 1.0luMI 51.0%@11.OuM ________ B-0445 <0.l uM 83.0%@l.OuM ________ B-0446 0.78uM 80.O%@1 .OuM ________ B-0447 0.l9uM 71.0%@1.OuM ________ B-0448 O.4uM 79.0%@1.OuM B-0449 0.83uM 81.O%@1.OuM________ B-0450 0.26uM 81 .0%@1 .OuM________ B-0451 0.071 uM 83.O%@l1.OuM 42%@30mpk@-6h________ B-0452 0.7uM 75.0%@1.OuM B-0453 0.47L1M 75.0%@1 .OuM B-0454 0.lluM 80.O%@1.OuM _______ B-0455 <0.l uM 95.0%@1.OuM 36%@3mpk%/-4h B-0456 1.8l1uM 67.O%@1.OuM B-0457 0.089uM 81.0%@1.OuM ________ B-0458 0.033uM 70.O%@1 .OuM ________ B-0459 0.O99uMI 76.0%@1.OuM ________ B-0460 0.061luM 92.0%@1 .OuM ________ B-0461 0.O25uM 96.O%@1.OuM ___ _____ _______ 6B-0462 <0 luM 97.0%@1.OuM _______ amwnirfAHFM4r(MLE2S) WO 98/52940 PCTIUS98/10436 678 P38 alpha kinase U937 Cell IC50,uM Mouse LPDS Model % Rat LPS Model % 1C50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# ________ _________ _________ B-0463 0.O52uM 95.O%@1.OuM ____ ____________ B-0464 <0.1 UM 91.O%@1.OuM ___ _____ _______ B-0465 O.OB4uM 98.O%@1.OuM ____ ____________ B-0466 <0.1 uMI 98.0%@l1.OuM _________0%@3mpk@-4h B-0467 <0.l Um 77.0%@1.OuM ____ ____________ B-0468 0.031luMV 93.O%@1.OuM ____ ____________ B-0469 0.O56uM 92.0%@1 .OuM ____ _____ ________ B-0470 0.063uM 92.0%@1.OuM ____ ____________ B-0471 O.O27uM 97.O%@1 .OuM ____ _____ ________ B-0472 .l9uM 54.0%@1.OuM ____ ____________ B-0473 0.OO4uM 95.0%@1.OuM ____ ____________ B-0474 0.024uM 86.0%@1.OuM ____ ____________ B-0475 O.2luM 74.0%@1.OuM ____ ____________ B-0476 0.56uM 69.0%@1 .OuM _____ ____ ________ B-0477 1 .48uM 96.0%@1 .OuM ____ _____ ________ B-0478 O.O34uM 87.0%@1 .OuM ____ _____ ________ B-0479 0.031 uIVI 90.0%@ 1.OuM ________ 1 5%@3mpk@-4h B-0480 .l2uM 88.0%@1.OuM ____ ____________ B-0481 0.01 4uM 95.0%@l1.OuM _________56%@3mpk@-4h B-0482 0.97uM 68.0%@1 .OuM _____ ____ ________ B-0483 0.57uM 68.0%@1.OuM ___ _____ _______ B-0484 0.28uM 62.0%@1.OuM ___ _____ _______ B-0485 0.O4uM 95.0%@11 .OuM ____ _____ ________ B-0486 0.24uM 80.0%@1.OuM ____ ____________ B-0487 0.lluM 89.0%@1.OuM________ 54%@3mpk@-4h B-0488 0.62uM 88.0%@1 .OuM________ B-0489 0.3uM 80.0%@1.OuM B-0490 0.9luM 74.0%@1.OuM B-0491 0.43uM 66.0%@1.OuM B-0492 0.069uM 42.0%@1 .OuM B-0493 0.3uM 36.0%@1 .OuM B-0494 0.l3uM 30.0%@1.OuM B-0495 0.l2uM 25.0%@1.OuM B-0496 0.B3uM 16.0%@1.OuM B-0497 0.44uM 31 .0%@1 .OuM B-0498 0.33uM 11.0%@1.OuM ________ B-0499 0.39uM 37.0%@ 1.OuM ________ B-0500 0.26uM 41.0%@1.OuM B-0501 0.549uM 52.0%@1 .OuM B-0502 0.065uM 48.0%@l1.OuM ________ B-0503 0.l6uM 73.0%@1.OuM [B-0504 0.4uM 43.0%@1 .OuM ________ _______ MMU ITEHET(RULIESN) WO 98/52940 PCTIUS98/10436 679 P38 alpha kinase U937 Cell 1C50,uM Mouse LIPS Model % Rat LPDS Model % 1C50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example#________ B-0505 0.28uM 44.0%@1 .OuM B-0506 0.94uM 43.O%@1 .OuM B-0507 O.l8uM 75.O%@1.OuM B-0508 2.OuM 48.0%@1.OuM B-0509 0.luM 86.O%@1.OuM ________ B-051 0 0.69uM 61.0%@1.OuM ________ B-051 1 0.OO7uM 90.O%@1.OuM________ B-0512 1.OuM 53.0%@1.OuM _______ B-0513 0.72uM 52.0%@1 .OuM________ B-0514 0.l4uM 87.O%@1.OuM________ B-0515 .42uM 61.O%@1.OuM________ B-0516 0.37uM 84.O%@1.OuM ________________ B-0517 0.094uM 52.0%@1.OuM _______________ B-0518 0.luMI 64.0%@ 1.OuM ________________ B-0519 0.O43uM 87.O%@1 .OuM ________ B-0520 0.4uM 67.O%@1.OuM ________ B-0521 1.37uM 52.0%@1.OuM ________ B-0522 0.l5uM 75.O%@1.OuM ________ B-0523 0.l19uM 83.O%@1 .OuM B-0524 O.4uMI 77.O%@1.OuM B-0525 .l6uM 76.O%@1.OuM B-0526 0.031luM 87.O%@1.OuM B-0527 1.O9uM 63.O%@1.OuM B-0528 0.l4uM 70.O%@1.OuM B-0529 0.ll1UM 73.0%@1.OuM ________ B-0530 5.53uM 45.O%@1.OuM________ B-0531 0.5uM 48.0%@1.OuM________ B-0532 0.45uMI 1.01 uMI 41 %@30mpk@-6h________ B-0533 1 .23uM 47.0%@1 .OuM________ B-0534 0.4luM -54.0%@1.OuM ________________ B-0535 0.44uM O.87uM ________ _______ B-0536 0.46uM 0.l5uM ________________ B-0537 3.44uM 51.0%@1.OuM _______________ B-0538 1.l3uM 45.0%@1.OuM ________ B-0539 2.84uM 21.0%@1.OuM ________ B-0540 3.62uM 54.0%@1 .OuM ________ _______ B-0541 3.24uM 28.0%@1 .OuM B-0542 1 .55uM 50.0%@l1.OuM B-0543 1 .56uM 43.0%@1 .OuM B-0544 1.l2uM 27.0%@1.OuM B-0545 1.06uM 41.0%@1.OuM B-0546 1.O4uM 18.0%@1.OuM B-0547 1.24uM 21.0%@1.OuM B-0548 1 .77uM 28.0%@ 1 OuM________ B-0549 2.22uM 22.0%@1 .OuM ________ _______ WO 98/52940 PCTIUS98/1 0436 680 P38 alpha kinase U937 Cell IC50,uM Mouse LIPS Model % Rat LIPS Model % 1C50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example#________ B-0550 2.4lu M 14.O%@1.OuM B-0551 1.O8uM 56.O%@1.OuM ________ _______ B-0552 .l3uM 46.O%@1.OuM B-0553 1 .44uM 47.O%@1 .OuM B-0554 2.58uM 20.O%@1 .OuM ________ _______ B-0555 1.87uM 34.O%@1.OuM B-0556 O.49uM 39.O%@1.OuM B-0557 1.37uM 32.O%@1.OuM _______ B-0558 O.85uM 33.O%@1.OuM ________ B-0559 O.53uM 49.O%@1.OuIM ________ B-0560 2.57uM 31.O%@1.OuM ________ B-0561 2.O7uM -40.O%@1 .OuM ________ B-0562 O.22uM O.3uM _________ 5%@3mpk@-4h B-0563 .8uM .3uM ________ B-0564 O.82uM 58%@1.OuM _______ B-0565 O.23uM O.59uM _________________ B-0566 <0OluM 0.l7uM ________ %@3mpk@-4h B-0567 .l4uM O.2BuM ________ B-0568 1 .22uM 46.O%@l1.OuM ________ B-0569 .5uM O.26uM ________ B-0570 O.27uM 46.O%@1.OuM _______ B-0571 O.38uM 44.O%@1 .OuM ________ B-0572 O.27uM 41.0%@1.OuM _______ B-0573 O.36uM 1 .7uM ________ B-0574 O.l3uM O.66uM _________37%@3mpk@-4h B-0575 O.O32uM 0.l7uIM _______ B-0576 O.O6BuM O.39uM 65%@3mpk@-4h B-0577 0.091lUm 66.O%@1.OuM B-0578 1.88uM 47.O%@1.OuM _______ B-0579 OAlluM 79.O%@1.OuM________ B-0580 2.23uM O.84uM ________ B-0581 O.26uM 2.l7uM________ B-0582 1.O3uM 37.O%@1.OuM _______ B-0583 3.93uM 26.O%@1 .OuM________ B-0584 O.66uM 54.O%@1 .OuM ________________ B-0585 O.83uM 79.O%@1.OuM 50%@3Ompk@-6h _______ B-0586 0.81luM 51.O%@1.OuM B-0587 6.84uM 38%@1.OuM _______ B-0588 12.8uM 42%@1.OuM B-0589 1.71luM 42%@1.OuM B-0590 1.57uM 38.OuM B-0591 3.59uM 29.O%@1 .OuM B-0592 1.62uM -45.O%@1.OuM B-0593 1.22uM 36.O%@1.OuM _______ B-0594 -41.O%@1.OuM ________ B-0595 2.42uM 22.O%@1 .OuM ________ B-0596 20.OuM 41.O%@1.OuM _______ B-0597 1.68uM 63.O%@1.OuM ________ B-0598 2.l2uM 50.O%@1.OuM _______ j8UBgf f 341-M (RVU 28) WO 98/52940 PCTIUS98/1 0436 681 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % 1C50,uM or % or % TNF inhib © dose inhib @dose inhib@conc. (uM) inhib~gconc. (uM) @predose time @predose time Example# ________________ ___ B-0599 4.l6uM 21.O%@1.OuM________ B-0600 0.OO2uM 28.O%@1 .OuM ____ _____ ________ B-0601 O.OB9uM 1.3luM ________43%@3mpk%-4h B-0602 0.97uM 61.O%@1.OuM ____ ____________ B-0603 O.O9uM 51.O%@1.OuM ____ ____________ B-0604 0.3uM 20.0%@1.0uM _____ ___________ B-0605 .8uM 47.O%@1.OuM ____ ____________ B-0606 .7uM 53.O%@1.OuM________ B-0607 2.79uM 70.O%@1.OuM________ B-0608 0.O59uM 73.O%@1.OuM________ B-0609 <0.l Um 87.O%@1.OuM________ B-061 0 <0luM U 88.0%@1.OuM________ B-0611 0.65uM 60.O%@1 .OuM _____ ____ ________ B-0612 0.l6uM 60.O%@1.OuM________ B-0613 0.l7uM 76.O%@1.OuM________ B-0614 0.76uM 70.O%@l1.OuM _________ %@3mpk@-4h B-0615 0.O8uM 83.O%@l.OuM________ B-0616 O.38uM 87.O%@1.OuM ____ ____________ B-0617 0.045uM 92.O%@1.OuM________ B-0618 0.37uM 80.O%@1.OuM________ B-0619 <0.l Um 88.O%@1.OuM________ B-0620 1 .59uM 58.O%@1 .OuM ________ B-0621 0.36uM 68.O%@1.OuM________ B-0622 0.076uM 78.O%@1.OuM________ B-0623 0.l2uM 76.O%@1.OuM________ B-0624 0.O85uM 54.O%@1.OuM________ B-0625 0.023uM 88.O%@1.OuM ________ B-0626 <0OluM 85.O%@1.OuM B-0627 0.25uM 69.O%@1.OuM B-0628 0.023uM 72.O%@1 .OuM B-0629 0.2uM 79.O%@1.OuM________ B-0630 O.O6uM 77.O%@1.OuM _______ B-0631 0.O65uM 81.O%@1.OuM________ B-0632 <0.l Um 79.O%@1.OuM _______ B-0633 0.6uM 80.O%@1.OuM________ B-0634 0.6uM 40.O%@1.OuM________ B-0635 0.l5uM 55.O%@1.OuM________ B-0636 <0.l Um 86.O%@1.OuM ___ _____ _______ B-0637 0.lluM 92.O%@1.OuM ____ ____________ B-0638 0.25uM 89.O%@1.OuM ____ ____________ B-0639 0.051 uM 93.O%@l1.0uM ________50%@3mpk@-4h B-0640 0.36uM 94.O%@1.OuM________ B-0641 0.58uM 65.O%@1.OuM ____ ____________ B-0642 0.49uM 90.O%@ 1 .OuM ____ _____ _______ B-0643 O.069uM 85.O%@1.OuM ________0%@3mpk@-4h B-0644 O.O58uM 89.O%@1.OuM ____ ____________ B-0645 0.58uM -80.O%@1.OuM ____ ____________ B-0646 0.26uM 94.O%@1.OuM ____ ____________ B-0647 1.6luM 76.O%@1.OuM________ WO 98/52940 PCT/US98/1 0436 682 P38 alpha kinase U937 Cell IC50,uM Mouse LIPS Model % Rat LIPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example#______ ___ B-0648 <0.l uM 83.O%@1.OuM _______ B-0649 0.83uM 39.O%@1.OuM ________ _______ B-0650 0.0O6uM 95.O%@l1.OuM 8%@3mpk@-4h B-0651 1.78uM 81.O%@1.OuM B-0652 0.l9uM 83.O%@1.OuM B-0653 2.OluM 74.O%O1.OuM ________ B-0654 5.97uM 78.O%@1.OuM________ B-0655 1.25uM 76.O%@1.OuM ________________ B-0656 0.007uM 95.0%@1 .OuM 28%@3mpk@-4h B-0657 O.l7uM 83.O%@1.OuM ________ B-0658 1.l4uM 91.0%@1.OuM ________ B-0659 2.64uM 87.O%@l1.OuM ________ B-0660 O.OB8uM 92.O%@ 1.OuM ________ B-0661 <0.1 uM 90.0%@1 .OuM ________ B-0662 <0.l UM 95.0%@1.OuM ________ B-0663 0.88uM 74.0%@1.OuM ________ B-0664 0.39uM 80.0%@11.OuM _______ B-0665 0.47uM 72.0%@1 .OuM ________ _______ B-0666 O.l7uM 73.0%@1.OuM ________ B-0667 0.83uM 75.0%@ 1 OuM ________ B-0668 0.27uM 78.0%@1 .OuM ________ B-0669 0.89uM -34.0%@1.OuM ________ B-0670 3.l5uM 32.0%@1.OuM ________ B-0671 6.38uM 36.0%@1 .OuM ________ B-0672 6.59uM 32.0%@1.OuM ________ B-0673 8.54uM 48.0%@l1.OuM ________ B-0674 2.8lu M -42.0%@1.OuM ________________ B-0675 5.42uM 3.0%@1.OuM ________________ B-0676 2.O9uM 22.0%@1 .OuM _________________ B-0677 1.63uM 25.0%@1.OuM ________________ B-0678 0.3BuM 52.0%@l1.OuM _________________ B-0679 0.062uM 45.O%@1.OuM ________________ B-0680 0.42uM 67.0%@1 .OuM ________ B-0681 1 .96uM 17.O%@1 .OuM ________ B-0682 0.76uM 39.0%@1 .OuM ________ B-0683 13.OuM 32.0%@1.OuM ________ B-0684 0.54uM -68.0%@l1.OuM ________ B-0685 15.4uM 33.0%@1 .OuM ________ B-0686 0.42uM 59.0%@1 .OuM ________ B-0687 10.l1uM 15.0%@1.OuM ________ B-0688 0.66uM 58.0%@l1.OuM ________ B-0689 14.6uM -27.0%@1.OuM ________ B-0690 27.lu M 36.0%@1.OuM ________________ B-0691 0.l6uM 48.0%@1.OuM _______ B-0692 0.38uM 29.0%@1 .OuM________ B-0693 0.39uM 28.0%@l1.OuM ________ B-0694 0.62uM -21 .0%@1 .OuM________ B-0695 0.23uM 32.0%@1 .OuM________ B-0696 0.085UIM 35.0%@1 .OuM_________ WuefmUM &ET (RULE 28) WO 98/52940 PCTIUS98/1 0436 683 P38 alpha kinase U937 Cell IC50,uM Mouse LIPS Model % Rat LIPS Model % 1C50,uM or % or % TINF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# ______________ ___ B-0697 O.45uM 44.O%@1.OuM B-0698 2.33uM 43.O%@1.OuM ________ _______ B-0699 O.34uM 31 .O%@1 .OuM ________ B-0700 O.24uM 56.O%@1 .OuM ________ B-0701 0.39uM 45.O%@1 .OuM ________ B-0702 O.O36uM 39.O%@1.OuM________ B-0703 .2uM 39.O%@1.OuM________ B-0704 2.l9uM 29.O%@1.OuM ____ ____________ B-0705 0.44uM 21.O%@1.OulM ____ ____________ B-0706 O.44uIM 32.O%@1 .OuM ________ B-0707 1.7uM ________ B-0708 2.luM ________ B-0709 O.84uM___ ______ B-071 0 1.99uM ________ B-0711 1.99uM ________ B-0712 2.9uM ________ ________ B-0713 4.3uM ________________ B-0714 3.7uIM ________ _______ B-0715 3.2uM ________________ B-0716 4.6uM___ _____ B-0717 4.3uM ________ B-0718 1.4uM___ _____ B-0719 3.4uM___ _____ B-0720 1 .3uM___ ______ B-0721 3.8uM____ _____ B-0722 0.O7uM >1.OuM________ B-0723 O.47uM ________ B-0724 O.O6uM 17.O%@1 .OuM ________ _______ B-0725 9.7uM____ _____ B-0726 1 .4uM________ _________ ___ ______ B-0727 O.5luM _________________ B-0728 20.OuM________ ___ ______ B-0729 O.87uM________ _________ ___ ______ B-0730 O.25uM 11.O%@1.OuM________ B-0731 O.B7uM >1.OuM B-0732 14.OuM __ ______ B-0733 32.OuM __ ______ B-0734 O.92uM __ ______ B-0735 1.OuM _______ B-0736 26.OuM __ ______ B-0737 2.6uM___ _____ B-0738 2.7uM ________ B-0739 4.luM ________ B-0740 4.4uM____ _____ B-0741 26.OuM ________ B-0742 2.2uM____ _____ B-0743 1 .2uM___ ______ B-0744 23.OuM ________ ________ B-0745 6.OuM ________ ________ ________ WO 98/52940 PCTIUS98/1-0436 684 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example#_______________ ___ B-0746 O.OluM 22.O%@1.OuM________ B-0747 1.l1uM_________________ ___ _____ B-0748 1.2uM__________ _____ B-0749 4.4uM ________ B-0750 O.92uM___________ ______ B-0751 1.6uM _______ B-0752 O.33uM_________ ___ ______ B-0753 O.37uM___________ ______ B-0754 O.55uM___________ ______ B-0755 2.3uM ________ B-0756 O.94uM___________ ______ B-0757 O.54uM 16.O%@1.OuM ________ B-0758 1.5uM ________ B-0759 O.3uM____ _____ B-0760 0.01lum 13.O%@1.OuM ________ B-0761 <0.lu _________ B-0762 O.l3uM 5.O%@1.OuM ________ B-0763 O.Ol5uM 17.O%@1.OuM ________ B-0764 O.67uM 26.O%@l1.OuM ________ B-0765 O.3uM 29.O%@l1.OuM ________ B-0766 O.95uM ________ B-0767 O.O8uM________ __ ______ B-0768 1 .4uM ________ B-0769 12.7uM__________ ______ B-0770 2.3uM ________________ B-0771 O.5uM ________________ B-0772 O.8uM ________________ B-0773 14.OuM__________ ______ B-0774 1 .5uM ________________ B-0775 O.6uM >1.OuM ________ B-0776 O.9uM >1.OuM ________ B-0777 21.OuM _______ B-0778 51 .OuM__ ______ B-0779 O.5uM___ _____ B-0780 1.luM _______ B-0781 48.OuM__ ______ B-0782 22.OuM__ ______ B-0783 8.OuM___ _____ B-0784 7.OuM___ _____ B-0785 23.OuM__ ______ B-0786 24.OuM__ ______ B-0787 1 .5uM__ ______ B-0788 1.2uM__ _____ B-0789 33.OuM __ ______ B-0790 1.OuM 4.0% @1.OuM ________ B-0791 O.3uM >1.OLIM _______ _________ B-0792 1.l1uM _______ _________ _ _ _ _ _ _ _ _ B-0793 O.3uM ________ _________ ________ B-0794 2.9uM 2.O%@1.OuM ______ ___ ________ ISILEIbwrT=TSHET(RfUEfwk WO 98/52940 PCT/US98/10436 685 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-0795 1.9uM 11.0%@1.0uM B-0796 1.4uM B-0797 1.04uM B-0798 1.73uM B-0799 - >1.0uM B-0800 1.01uM >1.0uM B-0801 0.67uM >1.0uM B-0802 - >1.0uM B-0803 0.057uM 53.0%@1.0uM B-0804 0.3uM 32.0%@1.0uM B-0805 0.71uM >1.0uM B-0806 3.28uM >1.0uM B-0807 10.8uM B-0808 3.09uM >1.0uM B-0809 1.22uM 7.0%@1.0uM B-0810 1.11uM >1.0uM B-0811 2.79uM 2.0%@1.0uM B-0812 2.12uM >1.0uM B-0813 3.02uM >1.0uM B-0814 - >1.0uM B-0815 2.11uM >1.0uM B-0816 3.46uM >1.0uM B-0817 3.07uM 33.0%@1.0uM B-0818 4.97uM >1.0uM B-0819 1.08uM >1.0uM B-0820 1.64uM 3.0%@1.0uM B-0821 1.44uM B-0822 1.33uM B-0823 2.39uM >1.0uM B-0824 3.41 uM M B-0825 B-0826 1.74uM B-0827 15.6uM B-0828 7.9uM B-0829 0.61uM 65.0%@1.0uM B-0830 0.54uM 34.0%@ 1.0uM B-0831 0.9uM >1.0uM B-0832 1.49uM B-0833 0.95uM 23.0%@ 1.0uM B-0834 1.25uM B-0835 B-0836 1.24uM B-0837 1.96uM >1.0uM B-0838 3.1uM B-0839 4.3uM B-0840 0.63uM 47.0%@ 1.0uM B-0841 0.32uM 36.0%@1.0uM B-0842 0.74uM 63.0%@1.0uM B-0843 0.61uM >1.0uM SUBBSnUE SHEE (RUL S) WO 98/52940 PCT/US98/1 0436 686 P38 alpha kinase U937 Cell IC50,uM Mouse LIPS Model % Rat LIPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example#______________ ___ B-0844 O.4uM 25.O%@1 .OuM ________ B-0845 1 .7BuM _________________ ________ B-0846 1.8uM__________ _____ B-0847 O.73uM 21.O%@1 .OuM ________ B-0848 1.56uM___________ ______ B-0849 1.25uM___________ ______ B-0850 1.8luM_________ __ ______ B-0851 .9luMV 39.O%@1.OuM ____ ____________ B-0852 1.O2uM___________ ______ B-0853 - 38.O%@1.OuM _______ _________ B-0854 - 25.O%@1.OuM _______ _________ B-0855 - 8.O%@1.OuM _______ _________ B-0856 - 38.O%@1.OuM _______ _________ B-0857 6.25uM_________ ___ ______ B-0858 2.luM 48.O%@1.OuM _____ ___________ B-0859 39.5uM________ _________ __ ______ B-0860 38.luM ________ B-0861 1.32uM 12.O%@1.OuM________ B-0862 2.l5uM 4.O%@1.OuM ________ B-0863 0.81luM 25.O%@1.OuM ________ B-0864 O.39uM 40.%@1.OuM ________ B-0865 O.66uM -46.O%@1 .OuM ________ B-0866 1.38uM 28.O%@1.OuM________ B-0867 O.62uM >1.OuM _______ B-0868 3.2BuM 8.O%@1.OuM ________ B-0869 4.l9uM >1.OuM B-0870 3.l3uM >1.OuM B-0871 1.9uM >1.OuM________ B-0872 3.l3uM 3.O%@1.OuM B-0873 6.92uM >11.OuM B-0874 1.92uM >1.OuM B-0875 2.l3uM 8%@1.Oum B-0876 0.89uM >1.OuM _______ B-0877 1.l7uM 13.O%@1.OuM B-0878 O.65uM 19.O%@1 .OuM B-0879 O.87uM 1.O%@1.OuM B-0880 0.1l5ul -40.O%@1.OuM B-0881 1 .36uM >1.OuM B-0882 __1.48uM 9%@1.Oum B-0883 1.O6uM >1.OuM________ B-0884 1 .B9uM B-0885 ________ _________ _________ B-0886 ________ ________ ________ B-0887 ________ _________ _________ B-0888 ________ _________ _________ B-0889 ________ _________ _________ B-0890 ________ ________ ________ B-0891 I__________________ _________ B-0892 _________ ________ __________ _______ __ 8uBwrrTs-IEEr ("UEv) WO 98/52940 PCTIUS98/1-0436 687 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# _________ _________ __________ _________ B-0893 ___________________ _________ B-0894 _________ _________ _________ B-0895 _________________ __ B-0896 __________________ __ B-0897 _________________ __ B-0898 _________________ __ B-0899 _________________ __ B-0900 ________________ __ B-0901 ________________ __ B-0902 ________ _______ __ B-0903 __________________ __ B-0904 _________ _________ ________ __ B-0905 _________________ __ B-0906 _________ B-0907 _________ B-0908 __________ B-0909________ __ B-091 0 _______ ______ __ B-0911 _______ B-0912 _______ ______ __ B-0913________ _______ __ B-0914 _______ ______ __ B-0915________ _______ __ B-0916 _ _ _ _ _ _ _ _______ ______ __ B-0917 ________ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ B-0918 ________ _______ B-0919 __ _ _ _ _ _ _ ______ __ B-0920 ________ ______ __ B-0921 _________ __________________ B-0922 _________ __________________ B-0923 _________ __________________ B-0924 ________ ________ ______ __ B-0925 ________ ________ ______ __ B-0926 __________________ B-0927 ________ ________ B-0928 ________ ________ B-0929 ___________________ _______ __ B-0930 ___________________ _______ __ B-0931 _________________ ______ __ B-0932 ___________________ _________ B-0933 47.O%@l.OuM 37.0%@1.OuM ________ B-0934 67.0%@1.OuM 36.0%@1.OuM ________ B-0935 69.O%@1 .OuM 54.0%@1 .OuM ________ B-0936 69.O%@1.OuM >1.OuM ________ B-0937 64.O%@1.OuM 1.74uM ________ B-0938 51.O%@l.OuM 29.0%@1.OuM ________ B-0939 78.O%@1.OuM -14.0%@1.OuM ________ B-0940 56.O%@1.OuM 22.0%@1.OuM ________ B-0941 81.O%@1.OuM 25.O%@1.OuM ________ 43tBj3STrTESHE (RILEM WO 98/52940 PCT[US98/10436 688 P38 alpha kinase U937 Cell 1C50,uM Mouse LIDS Model % Rat LPS Model % 1C50,uM or % or % TNF inhib © dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# ________ _______ ________ ________ B-0942 82.0%@1.OuM 2.O%@1.OuM ________________ B-0943 63.0% @1O.OuM 24.0%@1.OuM________________ B-0944 45.O%@1.OuM 27.O%@1.OuM________________ B-0945 96.0%@1 .OuM 0.93uM ____ ____________ B-0946 76.O%@l.OuM 31.0%@1.OuM________________ B-0947 69.O%@1.OuM 34.0%@1.OuM________________ B-0948 68.0%@1.OuM 1.8lum ____ ____________ B-0949 90.0%@1.OuM 17.0%@1.OuM________ B-0950 81 .0%@ 1.OuM 0.58uM ________ B-0951 82.0%@1 .OuM 20.0%@1 .OuM ________ B-0952 44.0%@1.OuM 21.0%@1.OuM________ B-0953 63.0%@1.OuM 25.0%@1.OuM________ B-0954 62.0%@1.OuM 0.52uM ________ B-0955 49.0%@l.OuM 0.54uM ________ B-0956 56.0%@1.OuM 1.33uM ________ B-0957 79.O%@1.OuM 22.0%@1.OuM________ B-0958 74.0%@l.OuM 0.38uM ________ B-0959 83.0%@1.OuM 39.0%@1.OuM________ B-0960 48.0%@l.OuM 4.0%@1.OuM ________ B-0961 79.0%@1.OuM 23.0%@1.OuM _______ B-0962 85.0%@1.OuM 2.7lu M _______ B-0963 76.O%@1.OuM 39.O%@1.OuM________ B-0964 94.O%@1.OuM 5.OuM _______ B-0965 74.0%@1.OuM 1.luM________ B-0966 50.0%@1 .OuM 5.0%@1 .OuM B-0967 8O.0%@l1.OuM 29.0%@l1.OuM B-0968 35.0%@1.OuM 26.0%@1.OuM B-0969 63.0%@1.OuM -35.0%@1.OuM B-0970 76.0%@1O.OuM 0.B8uM B-0971 61.0%@1.OuM 39.0%@1.OuM B-0972 85.0%@1.OuM 2.0%@1.OuM B-0973 66.0%@1O.OuM 48.0%@l.OuM B-0974 57.0%@l1.OuM 47.O%@l1.OuM B-0975 82.0%@1.OuM 32.0%@l.OuM B-0976 79.0%@1.OuM 36.0%@1.OuM B-0977 60.0%@1 .OuM 26.0%@1 .OuM B-0978 59.O%@1.OuM 36.0%@1.OuM B-0979 56.O%@10.OuM 23.0%@1.OuM________ B-0980 68.0%@1.OuM 31.0%@1.OuM________ B-0981 62.0%@1.OuM 57.0%@1.OuM________________ B-0982 65.0%@1.OuM 23.0%@1.OuM________________ B-0983 75.0%@1.OuM 0.8uM____ ____ _______ B-0984 60.0%@1.OuM 51.0%@1.OuM________________ B-0985 86.0%@l1.OuM 0.75uM ____ _____ ________ B-0986 70.O%@l1.Ou M 71 .0%@l1.OuM _________ ________ B-0987 78.0%@l1.OuM 79.0%@ 1.OuM _________ ________ B-0988 72.0%@l1.OuM 65.0%@l1.OuM _________ ________ B-0989 85.O%@1.OuM 0.B5uM ____ ____________ B-0990 -26.0%@1.OuM _________ ________ WO 98/52940 PCT/US98/10436 689 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or% or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-0991 58.0%@1.0uM 33.0%@1.0uM B-0992 77.0%@1.0uM 45.0%@1.0uM B-0993 57.0%@1.0uM 73.0%@1.0uM B-0994 55.0%@1.0uM 43.0%@1.0uM B-0995 53.0%@1.0uM 14.0%@1.0uM B-0996 54.0%@1.0uM 27.0%@1.0uM B-0997 69.0%@1.0uM 22.0%@1.0uM B-0998 67.0%@1.0uM 25.0%@1.0uM B-0999 61.0%@1.0uM 24.0%@1.0uM B-1000 55.0%@1.O0uM 42.0%@1.0uM B-1001 63.0%@1.0uM 31.0%@1.0uM B-1002 70.0%@1.0uM 41.0%@1.0uM B-1003 74.0%@1.0uM 29.0%@1.0uM B-1004 79.0%@1.0uM 45.0%@1.0uM B-1005 58.0%@1.0uM 23.0%@1.0uM B-1006 69.0%@1.0uM 38.0%@1.0uM B-1007 52.0%@1.0uM 34.0%@1.0uM B-1008 54.0%@1.0uM 23.0%@1.0uM B-1009 80.0%@1.0uM 55.0%@1.0uM B-1010 75.0%@1.0uM 1.0uM B-1011 72.0%21.0uM 17.0%@1.0uM B-1012 - 20.0%@1.0uM B-1013 85.0%@1.0uM 7.0%@1.0uM B-1014 88.0%@1.0uM 20.0%@1.0uM B-1015 77.0%@1.0uM 34.0%@1.O0uM B-1016 58.0%@l.OuM 10.0%@1.0uM B-1017 96.0%@1.0uM 58.0%@1.0uM B-1018 88.0%@1.0uM 34.0%@1.0uM B-1019 82.0%@1.0uM 66.0%@1.0uM B-1020 87.0%@1.0uM 36.0%@1.0uM B-1021 82.0%@1.0uM 35.0%@1.0uM B-1022 84.0%@1.0uM 53.0%@1.0uM B-1023 93.0%@1.0uM 70.0%@1.0uM B-1024 89.0%@1.0uM 57.0%@1.0uM B-1025 61.0%@1.O0uM 23.0%@1.0uM B-1026 87.0%@1.0uM 53.0%@1.0uM B-1027 58.0%@1.0uM 18.0%@1.0uM B-1028 70.0%@1.0uM 17.0%@1.0uM B-1029 69.0%@1.0uM 54.0%@1.0uM B-1030 76.0%@1.0uM 60.0%@1.0uM B-1031 69.0%@1.0uM 42.0%@1.0uM B-1032 76.0%@1.0uM 37.0%@1.0uM B-1033 86.0%@1.0uM 34.0%@1.0uM B-1034 66.0%@1.0uM 39.0%@1.0uM B-1035 75.0%@1.0uM 52.0%@1.0uM B-1036 68.0%@ 1.0uM 68.0%@1.0uM B-1037 - 41.0%@1.0uM B-1038 57.0%@1.0uM 0.57uM B-1039 - 1.33uM SUBSTlUTESHEET (RULE ) WO 98/52940 PCT/US98/10436 690 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-1040 72.0%@1.0uM 0.38uM B-1041 70.0%@1.0uM 73.0%@1.0uM B-1042 79.0%@1.0uM 12.0%@1.0uM B-1043 64.0%@1.0uM 53.0%@1.0uM B-1044 94.0%@1.0uM 0.93uM B-1045 78.0%@1.0uM 25.0%@1.0uM B-1046 72.0%@1.0uM 66.0%@1.0uM B-1047 72.0%@1.0uM 58.0%@1.0uM B-1048 67.0%@1.0uM 19.0%@1.0uM B-1049 67.0%@1.0uM 65.0%@1.0uM B-1050 - 0.54uM B-1051 68.0%@1.0uM 41%@1.0uM B-1052 69.0%@1.0uM 66%@1.0uM B-1053 78.0%@1.0uM 0.4uM B-1054 79.0%@1.0uM 55.0%@1.0uM B-1055 89.0%@1.0uM 63.0%@1.0uM B-1056 89.0%@1.0uM 0.76uM B-1057 85.0%@1.0uM 0.72uM B-1058 0.66uM 43.0%@1.0uM B-1059 0.18uM 24.0%@1.0uM B-1060 0.11uM 32.0%@1.0uM B-1061 0.03uM 19.0%@1.0uM B-1062 <0.1uM 26.0%@1.0uM B-1063 0.16uM 44.0%@1.0uM B-1064 0.39uM 50.0%@1.0uM B-1065 0.56uM 40.0%@1.O0uM B-1066 <0.1uM 39.0%@1.0uM B-1067 1.6uM 32.0%@1.0uM B-1068 0.48uM 24.0%@1.0uM B-1069 0.22uM 27.0%@ 1.0uM B-1070 <0.1uM 44.0%@1.0uM B-1071 <0.1uM 48.0%@1.0uM B-1072 0.38uM 28.0%@1.0uM B-1073 <0.1 uM 21.0%@1.0uM B-1074 0.23uM 33.0%@1.0uM B-1075 0.03uM 29.0%@1.0uM B-1076 0.08uM 31.0%@1.0uM B-1077 <0.1uM 38.0%@1.0uM B-1078 0.26uM 48.0%@1.0uM B-1079 <0.1uM 40.0%@1.0uM B-1080 0.19uM 28.0%@1.0uM B-1081 <0.1uM 37.0%@1.0uM B-1082 <0.1uM 54.0%@1.0uM B-1083 <0.1uM 23.0%@1.0uM B-1084 0.43uM 29.0%@1.0uM B-1085 <0.1uM 29.0%@1.0uM B-1086 <0.1uM 42.0%@1.0uM B-1087 0.05uM 32.0%@1.0uM B-1088 0.73uM 49.0%@1.0uM . SUBSTUTESHIEF

RULEE)

WO 98/52940 PCTIUS98/1 0436 691 P38 alpha kinase U937 Cell 1C50,uM Mouse LPDS Model % Rat LIDS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# ________________ ___ B-1 089 <0.l UM 39.0%@l.puM _______________ B-1 090 <0.l uM -90.O%@1.OuM ____ ____________ B-1 091 <0.l UM 73.O%@1.OuM _______________ B-1 092 O.27uM 85.O%@1.OuM _______________ B-1 093 O.33uM 36.O%@1.OuM ____ ____________ B-1 094 O.Ol3uM 69.0%@1.OuM ____ ____________ B-1 095 <0.l UM 70.O%@1.OuM ____ ____________ B-1 096 <0.l uM 32.0%@1.OuM ____ ____________ B-1 097 <0.l UM 4 4.0%@11.O7uM ________________ B-1 098 <0.l UM 82.0%@1.OuM ________________ B-1 099 O.26uM 74.O%@1.OuM _______________ B-1 100 O.22uM 56.0%@1.OuM ____ ____________ B-1 101 O.O26uM 82.0%@1.OuM _______________ B-1 102 O.O35uM 83.0%@1.OuIM ______________ B-1 103 O.O94uM 90.O%@1.OuM ____ ____________ B-1 104 O.l2uM 69.O%@1.OuM ____ ____________ B-1 105 <O.luM 84.0%@1.OuM ____ ____________ B-1 106 <0.l uM 86.O%@1.OuM ________ B-1 107 O.O57uM 84.O%@1.OuM________ B-1 108 O.22uM 81.0%@1.OuM ________ B-1 109 O.O54uM 80.0%@1.OuM B-1110 O.47uM 64.O%@1.OuM B-1111 O.l9uM 64.O%@1.OuM B-1 112 O.58uM 43.0%@1.OuM B-1 113 <0.l uM 72.O%@1.OuM B-1 114 O.O69uM 51.0%@1.OuM B-1 115 O.O24uM 89.O%@1.OuM B-1 116 0.41luM 81.O%@1.OuM B-1 117 O.l3uM 73.O%@1.OuM B-1 118 O.33uM 91.O%@1.OuM _______________ B-1 119 O.35uM 80.O%@1.OuM _______________ B-1 120 O.47uM 9.O%@1.OuM _______________ B-1 121 3.5BuM 29.O%@1.OuM _______________ B-1 122 1.84uM 32.O%@l.OuM ____ ____________ B-1 123 2.93uM 27.0%@1.OuM ________ B-1 124 1.49uM 52.O%@1.OuM _______________ B-1 125 O.56uM 41.O%@1.OuM _______________ B-1 126 1.5uM >1.OuM_______ _________ B-1 127 O.7luM 7.O%@1.OuM _______________ B-1 128 2.55uM 26.O%@1.OuM _______________ B-1 129 1.O7uM 46.O%@1.OuM ________ B-1 130 O.5uM 29.0%@1.OuM ________ B-1 131 O.O76uM -34.0%@1.OuM B-1 132 O.72uM 11.0%@1.OuM B-1 133 O.3BuM 33.0%@1.OuM B-1 134 1.71luM 33.0%@1.OuM B-1 135 O.23uM 38.0%@1.OuM B-1 136 1.l7uM 40.0%@1.OuM B-1 137 O.O38uM 35.O%@1 .OuM ________ 8 UBnTTEHEWr(RULEIS) WO 98/52940 PCT/US98/1 0436 692 P38 alpha kinase U937 Cell IC50,uM Mouse LIPS Model % Rat LIPS Model % IC50,uM or % or % TINF inhib © dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Exam ple#______________ ____ B-1 138 1.82uM >1.OuM ________ B-1 139 0.041luM -29.0%@1.OuM ________________ B-1 140 1.68uM 39.O%@l.OuM ________ B-1 141 2.47uM 32.0%@1.OuM ________ B-1 142 .luM 37.O%@1.OuM________ B-1 143 Ol17uM 40.0%@1.OuM ________ B-1 144 O.44uM 72.0%@1.OuM ________________ B-1 145 1.O7uM 71.0%@1.OuM ________ B-1 146 O.47uM 61.0%@1.OuM ________ B-1 147 0.095uM 53.0%@1.OulM________ B-1 148 O.43uM 61.0%@1.OuM ________ B-1 149 1.55uM 48.0%@1.OuM ________ B-1 150 0.47uM 75.0%@1.OuM ________ B-1 151 O.32uM 72.0%@1.OuM ________ B-1 152 O.73uM 53.0%@1.OuM ________ B-1 153 2.22uM 52.O%@1.OuM _______ B-1 154 0.O85uM 46.0%@ 1.OuM _______ B-1 155 3.22uM 30.0%@1.OuM________ B-1 156 0.27uM 78.O%@1.OuM________ B-1 157 O.26uM 66.0%@1.OuM _______ B-1 158 74%@1.OuM 0.68uM 53%@30mpk@-6h B-1 159 66.O%@1.OuM 1.O3uM 60%@30mpk@-6h B-1 160 79.0%@1.OuM 0.38uM ________ B-i 161 64.O%21 .OuM 0.93uM 40%@30mpk@-6h 45%@3mpk@-4h B-i 162 79.0%@l1.OuM O.59uM 40%@30mpk@-6h B-1 163 74.0%@1.OuM O.37uM ________ B-1 164 - .35uM ________ B-1 165 66.O%@1.OuM O.99uM ________ B-1 166 77.O%@1.OuM 0.39uM 50%@30mpk@-6h 50%@3mpk@-4h B-1 167 70.O%@1.OuM 1.O6uM ________ B-1 168 66.0%@1.OuM 0.63uM B-1 169 80.0%@11.OuM 0.lluM B-1 170 82.0%@l.OuM 0.57uM B-1 171 78.0%@1.OuM 0.23uM B-1 172 68.0%@l.OuM 1.95uM B-1 173 65.0%@l.OuM 62%@1.OuM _______ B-1 174 80.O%@l.OuM 0.86uM________ B-1 175 72.O%@1.OuM 1.83uM________ B-1 176 67.O%@1.OuM 67.0%@1.OuM________ B-1 177 70.0%@1.OuM 1.l6uM________ B-1 178 92.0%@1.OuM 1.6luM________ B-1 179 86.O%@1.OuM 0.4luM________ B-1 180 78.O%@1.OuM 0.53uM________ B-1 181 79.O%@1.OuM 66%@1.OuM________ B-1 182 72.O%@1.OuM 0.65uM _______________ B-1 183 77.0%@l.OuM 0.2uM ________________ B-1 184 69.0%@11.OuM 0.63uM________ B-1 185 71.O%@1.OuM 0.79uM ________________ B-1 186 183.O%@1.OuM 60%@1.OuM _______________ 8UB83TTUMEU(RULE2B) WO 98/52940 PCT[US98/10436 693 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LIPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# ________ B-1 187 76.0%@1.OuM 1.89uM B-1 188 -36.O%@1.OuM________ B-1 189 68.O%@1.OuM 0.83uM________ B-1 190 78.O%@1.OuM 62.O%@1.OuM ________ _______ B-1 191 74.O%@1.OuM 57.O%@1.OuM ________ _______ B-1 192 84.0%@1.OuM 0.47uM____ ____________ B-1 193 69.O%@1.OuM 65.O%@1.OuM _______ B-1 194 87.O%@1.OuM 0.58uM___ _____ _______ B-1 195 52.O%@1.OuM 60.0%@1.OuM _______ B-1 196 74.O%@1.OuM 68.O%@1.OuM ________ B-1 197 77.0%@1.OuM 45.0%@1.OuM _______ B-1 198 92.O%@1.OuM 0.46uM___ _____ _______ B-1 199 87.O%@1.OuM 49.O%@1.OuM __ ______________ B-1 200 95.O%@l.OuM O.64uM____ ____________ B-1201 84.0%@1.OuM 0.5luM____ ____________ B-1 202 71.O%@1.OuM 58.0%@1.OuM __ ______________ B-1 203 84.O%@l.OuM 58.0%@1.OuM __ ______________ B-1 204 68.0%@1.OuM 59.0%@1.OuM __ ______________ B-1 205 74.O%@1.OuM 46.O%@1.OuM ________ _______ B-1 206 81.0%@1.OuM 0.34uM____ ____________ B-1 207 90.O%@1 .OuM 58.0%@1 .OuM ________ B-1 208 82.0%@1.OuM 51.0%@1.OuM B-1 209 86.0%@1.OuM 55.0%@1.OuM B-1 210 82.O%@1.OuM 57.0%@1.OuM B-1211 88.O%@1.OuM 59.O%@l.OuM B-1212 90.O%@1.OuM 57.O%@1.OuM B-1 213 84.0%@1.OuM O.62uM B-1 214 76.O%@l.OuM 58.O%@1.OuM B-1215 86.0%@1.OuM 0.23uM B-1216 88.0%@1.OuM 0.l8uM B-1 217 87.O%@1.OuM 0.46uM B-1218 88.0%@1.OuM 76.0%@1.OuM B-1219 85.0%@1.OuM 37.0%@1.OuM ________ B-1 220 81.0%@1.OuM 53.O%@1.OuM _______ B-1221 82.0%@1.OuM 44.0%@1.OuM _______ B-1 222 65.0%@1.OuM 9.0%@1.OuM ________ B-1 223 80.O%@1.OuM 61.0%@1.OuM _______ B-1 224 82.O%@1.OuM 74.0%@1.OuM ________ _______ B-1 225 89.O%@1.OuM 73.O%@1.OuM ________ _______ B-1 226 89.O%@1.OuM 0.l8uM___ _____ _______ B-1 227 83.0%@1.OuM O.22uM ___ _____ _______ B-1 228 90.0%@11.OuM 0.72uM____ _____ ________ B-1229 87.0%@1.OuM O.65uM ____ ____________ B-1 230 90.0%@11.OuM 0.25uM____ ____________ B-1 231 94.0%@1.OuM 0.56uM____ ____________ B-1 232 81.0%@1.OuMI 54.0%@1.OuM ________ _______ B-1 233 85.0%@1 .OuM 0.36uM ____ _____ ________ B-1 234 89.0%@1.OuM 0.49uM I_______ B-1 235 0.O4uM 76.0%@1.OuM WO 98/52940 PCT/US98/1 0436 694 P38 alpha kinase U937 Cell 1C50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example#________ B-1 236 1 OAluM 53.O%@1.OuM B-1 237 O.22uM 39.O%@1.OuM _________________ B-1 238 O.l4uM 16.O%@1.OuM B-1 239 <0.l uM 38.O%@l.OuM B-1 240 <OAluM 59.O%@1.OuM B-1 241 O.O4uM 81.O%@1.OuM B-1 242 O.O8uM 83.O%@1.OuM _______ B-1 243 O.O4uM 47.O%@1.OuM B-1 244 O.26uM 44.O%@1.OuM ________ B-i 245 O.49uM 42.O%@1 .OuM ________ B-i 246 O.27uM 40.O%@l1.OuM ________ B-1 247 <0.l uM 58.O%@1.OuM B-1 248 <O.Ilum 68.O%@1.OuM B-i 249 O.24uM 60.O%@1 .OuM________ B-1 250 O.i4uM 18.O%@1.OuM _______ B-1251 0.41luM 38.O%@1.OuM _______ B-1 252 O.l7uM 46.O%@1.OuM________ B-1 253 O.l5uM 57.O%@1.OuM________ B-1 254 O.l6uM 68.O%@1.OuM _______ B-1 255 12.9uM 75.O%@1.OuM________ B-1 256 O.l2uM 41.O%@1.OuM _______________ B-1 257 1 .48uM 40.O%@1 .OuM ________ _______ B-1258 O.O7uM 56.O%@1.OuM _______________ B-i 259 <O.luM O.48uM ________________ B-1 260 .lluM 48.O%@1.OuM ________________ B-1261 O.74uM 44.O%@1.OuM ________ B-1 262 <0.l UM 63.O%@1.OuM ________ B-1 263 1 *O5uM 57.O%@1.OuM B-1 264 O.32uM 47.O%@1.OuM B-1 265 O.43uM 51.O%@1.OuM ________ B-1 266 <OAluM 58.O%@1.OuM B-1 267 <0OluM 73.O%@1.OuM B-1 268 <0.l UM -79.O%@1.OuM B-i 269 O.46uM 84.O%@l.OuM B-1 270 O.47uM 83.O%@1.OuM _______ B-1271 O.l3uM 74.O%@1.OuM _______ B-1 272 O.Ol4uM 38.O%@l.OuM _______ B-1i273 <0.l uM 36.O%@1.OuM ________ B-1 274 <0.l UM 41.O%@1.OuM _______ B-1 275 <O.lum 50.O%@l.OuM _______ B-1i276 O.O62uM 11.O%@1.OuM________ B-1 277 <0.l UM 47.O%@1.OuM _______ B-1 278 O.l2uM 85.O%@1.OuM________ B-1 279 <0.l UM 79.O%@1.OuM________ B-1 280 O.O39uM 83.O%@1.OuM ________________ B-1281 <0.l Um 85.O%@1.OuM ________ B-1282 <0.l UM 75.O%@1.OuM _______________ B-1 28,3 <O.luM 64.O%@1.OuM ________ B-1 284 <0.l uM 75.O%@1.OuM I_______ _______ SUBSTS~

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WO 98/52940 PCTIUS98/1 0436 695 P38 alpha kinase U937 Cell 1C50,uM Mouse LPS Model % Rat LIDS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# _________ __________________ B-1 285 0.O57uM 80.O%@1.OuM________ B-1 286 O.l5uM 78.0%21.OuM ________ _______ B-1 287 O.25uM 55.0%@1 .OuM________ B-1 288 0.l5uM 74.0%@1.OuM________ B-1 289 O.73uM 35.0%@1 .OuM ___ _____________ B-1 290 0.26uM 75.0%@1.OuM _______________ B-1 291 0.O97uM 55.O%@1.OuM ____ ____________ B-1 292 0.01lUm 74.0%@1.OuM ____ ____________ B-1 293 0.3luM 48.0%@1.OuM ____ ____________ B-1 294 0.01 UMV 54.O%@1.OuM ____ ____________ B-1 295 0.079uM 74.0%@l.OuM ____ ____________ B-1 296 0.O38uM 48.0%@1 .OuM ___ _____________ B-1297 O.O2uM >1.OuM ________ B-1 298 0.O55uM 20.0%@1 .OuM ________ B-1 299 0.091u Um1.OuM ________ B-1 300 0.071luM 18.0%@1.OuM ____ ____________ B-1301 0.l2uM 15.O%@1.OuM ________ B-1 302 O.O23uM 11.0%@1.OuM ________ B-1 303 0.O8uM >1.OuM ________ B-1 304 0.luMI 10.0%@1.OuM ________ B-1 305 0.64uM 9.0%@1.OuM ________ B-1 306 0.lluM >1.OuM_______ _________ B-1 307 O.OO9uMI 16.0%@1.OuM ________ B-1308 <0.lu Um1.OuM ________ B-1 309 O.O45uM >1.OuM ________ B-1 310 0.l2uM 11.0%@1.OuM ________ B-1311 0.O5uM -57.0%@1.OuM ________ B-1312 0.35uM >1.OuM ________ B-1313 0.035uM 37.0%@1.OuM ________ B-1314 0.O45uM 24.0%@1.OuM ________ B-1315 0.O55uM 12.0%@1.OuM B-1316 O.O26uM 36.0%@1.OuM B-1317 O.Ol9uM 9.0%@1.OuM B-1318 <0.lu UN 1.0%@1.OuM _______ B-1319 O.24uM >1.OuM _______ B-1 320 O.047uM 43.0%@1.OuM________ B-1321 0.47uM -66.O%@1.OuM _______ B-1 322 O.l2uM 87.0%@1.OuM _______ B-1 323 0.Ol3uM 85.0%@1.OuM________ B-1 324 0.l6uM 83.0%@1.OuM ____ ____________ B-1 325 O.27uM 95.0%@1.OuM _______________ B-1 326 0.O92uM 84.0%@1.OuM ________ B-1 327 0.l3uM 65.0%@1.OuM ____ ____________ B-1 328 0.O32uM 86.0%@1.OuM ________ B-1 329 0.66uM 54.0%@1 .OuM ________ B-1 330 0.O53uM 85.0%@1.OuM ________ B-1331 0.OO4uM 85.0%@1.OuM ________ B-1 332 0.OO7uM 81.0%@1.OuM ________ B-1 333 O.45uM 76.0%@1.OuM ________ suwnwmuTSHiEU(RLE" WO 98/52940 PCT/US98/1 0436 696 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib~conc. (uM) @predose time @predose time Example#_________ __________ _______ ___ B-1 334 0.l3uM 73.0%@1.0uM ________________ B-1 335 0.097uM -63.0%@1.OuM ________________ B-1 336 0.072uM 83.0%@1.OuM ________________ B-1 337 0.4uM 90.0%@1.OuM ________________ B-1 338 0.l8uM 73.0%@1.OuM ________ B-1 339 0.l2uM 67.0%@1.0uM _______ B-1 340 0.043uM 63.0%@1.OuM ________ B-1 341 0.42uM 52.0%@1.OuM ________ B-1 342 0.25uM 59.0%@1.OuM ________ B-1 343 0.065uM 83.0%@1.0uM ________ B-1 344 0.Ol4uM 86.0%@1.OuM ________ B-1 345 0.27uM 73.0%@1.OuM _______ 8-1 346 0.043uM 86.0%@1.OuM _______ B-1 347 0.021luM 84.O%@1.OuM ________ B-1 348 O.OO9UM 69.O%@1.OuM B-1 349 0.037uM 86.O%@1.0uM 8-1 350 0.01 9uM 78.O%@1.OuM B-1351 O.O6BuM -78.0%@1.0uM B-1 352 O.Ol3uM 76.0%@1.OuM B-1 353 0.062uM 80.0%@1.OuM B-1 354 O.Ol3uM 83.0%@1.0uM B-1 355 O.O7uM 75.0%@1.OuM B-1 356 0.O59uM -91.0%@1.OuM B-1 357 0.l8uM 84.0%@1.OuM _______________ B-1 358 O.l6uM 76.O%@1.OuM _______________ B-1359 0.005 84.0%@1.OuM ________________ B-1 360 0.11 0.l5uM _________54%@3mpk@-4h B-1 361 0.03 0.29uM_________ ________ B-1 362 0.003 0.29uM_________ ________ 0. 009 0.28uM 51.0%@30pmk @- 53%@3mpk@&-4h B-1 363 _ _ _ _ _ _ _ __ _ _ _ _ __6H _ _ _ _ _ _ _ _ - 0.009 0.27uM 53.0%@3Ompk@- 17%@3mpk@-4h B-1 364 _______ _____ ___6.OH B-1365 0.17 -88.0%@1.OuM _______ B-1 366 0 .04 0.27uM ________ B-1 367 <0.1 0.22uM_________ ________ B-1 368 0.031 0.33uM 44.0%@30mpk @ B-1 369 <0.1 0.29uM B-1 370 <0.1 0.77uM________ B-1371 0.06 83.0%@1.OuM B-1 372 <0.1 0.41luM 48.0%@30mpk @ B-1 373 0.016 0.l7uM B-1 374 <0.1 0.28uM B-1 375 0.01 0.25uM B-1 376 0.009 0.26uM 3.0%@30mpk @-6H B-1 377 0.12 5.OuM ________ B-1378 0.02 1.O4uM________ ________ B-1 379 <0.1 0.092uM _________ ________ FBA-MO 8 <0.1 0.26uM _________________ WO 98/52940 PCT/US98/1 0436 6097 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LIPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) Opredose time @predose time Example# ________ ________ ________ B-1 381 0.055 O.73uM _________________ B-i 382 <0.1 O.44uM _________________ B-1 383 0.0012 0.l5uM _________________ B-1384 0.57 0.37uM _________________ B-1 385 <0.1 0.11u _________________ B-i 386 <0.1 0.25uM _________________ B-1 387 <0.1 O.luM _________________ B-i1388 0.57 1 .38uM B-i 389 0.06 0.57uM B-1 390 <0.1 71.0%@1.OuM B-1 391 0.Ol6uM 82.0%@1.OuM B-1392 0.059uM 82.0%@1.OuM B-1 393 3.l7uM 80.0%@1.OuM B-1 394 0.32uM 78.0%@1.OuM B-1395 1.48 61.0%@1.OuM _______ B-1 396 1.55 73.0%@1.OuIM B-1 397 0.92 85.0%@1.OuM________ B-i1398 0.67 83.0%@1 .OuM B-1 399 0.14 74.0%@1.OuM B-1 400 0.024 83.0%@1 .OuM B-1401 0.033 75.0%@1.OuM _______ B-1 402 0.12 76.0%@1.OuM ________ B-1 403 4.54 71%@1.OuM ________ B-1404 0.6 -70%@1.OuM ________ B-1405 0.28 70%@1.OuM ________ B-1 406 1.39 56.0%@1.OuM ________ B-1407 0.4 71.0%@1.OuM ________ B-1 408 0.27 -69.0%@1.OuM ________________ B-1 409 <0.1 72.0%@1 .OuM ________________ B-1410 <0.1 69%@1.OuM ________________ B-1411 <0.1 81.0%@1.OuM________ B-1412 0.097 80.0%@1.OuM B-1413 0.016 78.0%@1.OuM B-1414 0.025 83.0%@1.OuM B-1 415 1.41 79.0%@1.OuM B-1416 0.14 81.0%@1.OuM ________ B-i 417 0.069 69.0%@1 .OuM ________ B-1418 1.01 -82.0%@1.OuM B-1 419 0.3 84.0%@1.OuM________ B-1420 <0.1 82.0%@1.OuM B-1421 0.014 75.0%@1.OuM B-1 422 0.58 68.0%@1.OuM _______ B-1423 1.58 -84.0%@1.OuM ________ B-1 424 0.86 76.0%@1.OuM _______ B-i1425 0.09 83.0%@1 .OuM ________ B-1 426 0.19 80.0%@l.OuM ________ B-1427 <0.1 84.0%@1.OuM ________________ B-1428 <0.1 86.0%@1.OuM ____ ____ _______ B-1i429 <0.1 -87.0%@1.OuM ____ ____ _______ SUB Tff=&EET("UE,,,) WO 98/52940 PCT/US98/1 0436 698 P38 alpha kinase U937 Cell 1C50,uM Mouse LPS Model % Rat LIPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @ predlose time Example# _________ ____________ ___ B-i 430 0.75uM 35.0% @1 .OuM________ B-1 431 0.36uM 58.0% @1.OuM________ B-1432 0.lluM 51.0% @1.OuM________ B-1 433 0.26uM 21.0% @1.OuM________ B-1 434 0.l9uM 28.0% @1.OuM ____ ____________ B-1 435 1.8uM 45.0% @1.OuM ____ ____________ B-1 436 1.0uM 20.0% @1.OuM________ B-1437 0.3uM 23.0% @1.OuM ____ ____________ B-1 438 2.01luMV 21.0% @1.OuM ________ B-1 439 1.7uM 17.0% @1.OuM ____ ____________ B-1 440 0.87uM 3.0% @1.OuM ____ ____________ B-1 441 1.95uM 66.0% @1.OuM________ B-1442 1.54uM 18.0% @1.OuM________ B-1 443 0.014uM 83.0% @1.OuM________ B-1 444 0.3uM 24.0% @1.OuM________ B-1445 0.43uM 27.0% @1.OuM________ B-1446 0.77uM 36.0% @!.OuM ________ _______ B-1 447 0.5uM 34.0% @1.OuM________ B-1 448 1.43uM 22.0% @1.OuM________ B-1449 1.61luM 50.0%@1.OuM________ B-1 450 2.luM 49.0%@1.OuM B-1451 2.88uM 50% @1.OuM B-1452 2.4lu M 47.0%@1.OuM B-i 453 __2.53uM 49.0% @1 .OuM B-1 454 1.6uM 12.0% @1.OuM B-1 455 1.2luM 8.0% @1.OuM B-1456 1 "29uM >1.OuM B-1 457 0.43uM 43.0% @1.OuM________ B-i1458 0.95uM 65.0% @1 .OuM________ B-1459 0.67uM 46.0% @1 .OuM________ B-1 460 0.96uM 29.0% @1.OuM ________ _______ B-1461 0.4uM 39.0% @1.OuM________ B-1462 0.22uM 50.0% @1.OuM________ B-1463 2.34uM 26.0% @1 .OuM ________ _______ B-1 464 1.l8uM 27.0% @1.OuM ____ ____________ B-1 465 3.23uM 31.0% @1.OuM ____ ____________ B-1466 1.69uM >1.OuM_______ _________ B-1 467 1.22uM 1.0% @1.OuM ____ ____________ B-1 468 1.6luM 10.0% @1.OuM________ B-i 469 0.37uM 14.0% @1 .OuM ________ B-1 470 0.6uM 28.0% @1.OuM ____ ____________ B-i1471 0.85uM 25.0% @1 .OuM_________ B-1472 0.93uM 12.0%@1.OuM________ 8-1 473 1.24uM 14.0% @1.OuM________ B-1474 1.23uM 31.0% @1.OuM________ 8-1 475 2.luM 24.0% @1.OuM ________ _______ B-1 476 0.047uM 42.0% @1.OuM________ 8-1477 2.5uM 34.0% @1.OuM _____ ____ ________ B-1478 _________________ _ _ _ _ _ _ _ _ suBBrlUTEIEU(AYL 26) WO 98/52940 PCT/US98/10436 699 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % IC50,uM or % or % TNF inhib @ dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-1479 suBSmTMESHEEr(RULEU) WO 98/52940 PCTIUS98/1-0436 700 P38 alpha kinase U937 Cell IC50,uM Mouse LIDS Model % Rat LPS Model % Example# IC50,uM or % or % TNF inhib @ inhib @dose inhib@conc. (uM) inhib@conc. (uM) dose @predose time @predose time B-2270 O.72uM 31%@1O.OuM _______ ______ B-2271 O.93uM 38%@1O.OuM _______ ______ B-2272 O.26uM 53.O%@1O.OuM _______________ B-2273 1.92uM 39.O%@1O.OuM _______ ______ B-2274 O.26uM 59.O%@1O.OuM _______ ______ B-2275 2.l6uM 53.O%@1O.OuM _______ ______ B-2276 11.5uM 37.O%@1O.OuM_______ B-2277 14.9uM 44.O%@1O.OuM _______ ______ B-2278 O.8uM 51.O%@1O.OuM _______ ______ B-2279 O.32uM 36.O%@1IO.OuM _______ ______ B-2280 O.4uM 57.O%@1O.OuM _______ ______ B-2281 O.8luM 60.O%@1O.OuM _______ ______ B-2282 .9luMV 41.O%@1O.OuM _______ ______ B-2283 O.O4uM .53.O%@1O.OuM _______ ______ B-2284 4.6lu M 62.O%@1O.OuM _______ ______ B-2285 2.29uM 49.O%@1O.OuM _______ ______ B-2286 O.Ol7uM O.78uM 25%@3Ompk@-lh B-2287 2.56uM 61.O%@1O.OuM _______ ______ B-2288 6.5lu M 46.O%@1O.OuM _______ B-2289 3.OuM 30.O%@1O.OuM _______ B-2290 2.37uM 59.O%@1O.OuM _______ B-2291 O.Ol9uM 41%@1O.OuM________ B-2292 8.82uM 57.O%@1O.OuM _______ B-2293 2.lluM 56.O%@1O.OuM _______ B-2294 1.68uM 50.O%@1O.OuM _______ ______ B-2295 1.79uM 56.O%@1O.OuM B-2296 17.3uM 63.O%@1O.OuM B-2297 3.59uM 57.O%@1O.OuM B-2298 O.29uM 4.22uM _______ B-2299 1.97uM 62.O%@1O.OuM B-2300 O.O7uM 43.O%@1O.OuM B-2301 O.l8uM 44.O%@1O.OuM B-2302 1 .OuM 58.O%@l1.OuM________ B-2303 0.011luM 54.O%@1O.OuM _______ B.2304 1.4luM 50.O%@1O.OuM _______ B-2305 O.54uM 60.O%@1O.OuM _______ ______ B-2306 5.88uM 39.O%@1O.OuM _______ ______ B-2307 2.29uM 69.O%@1O.OuM _______ ______ B-2308 O.66uM 56.O%@1O.OuM _______ ______ B-2309 O.29uM 47.O%@1O.OuM _______ ______ $,5gflMJTEEET (RLE We) WO 98/52940 PCT/US98/1 0436 701 P38 alpha kinase U937 Cell 1C50,uM Mouse LPDS Model % Rat LIDS Model % Example# IC50,uM or % or % TNF inhib @ inhib @dose inhib@conc. (uM) inhib@conc. (uM) dose @predose time @predose time B-231 0 .2uM 1.2uM 50%@30mpk@-6h_______ B-231 1 7.l8uM 60%@1O.OuM _______ B-2312 2.93uM 43.O%@1O.OuM _______ ______ B-2313 42.3uM 58.0%@1O.OuM_______ B-2314 1 1.OuM 66.O%@10.OuM_______ B-2315 0.49uM 36.O%@10.OuM_______ B-2316 0.46uM 58.O%@10.OuM B-2317 1.OuM 60.O%@1O.OuM B-2318 73.O%@10.OuM 25.O%@1O.OuM _______ B-231 9 75.0%@ 10.OuM 40.0%@ 1 .OuM B-2320 44.0%@1O.OuM 35.0%@1O.OuM _______ B-2321 69.O%@1O.OuM 27.O%@1O.OuM _______ B-2322 76.O%@1O.OuM 38.0%@1O.OuM _______ B-2323 69.O%@10.OuM 46.0%@10.OuM _______ B-2324 58.O%@10.OuM 36.0%@1O.OuM B-2325 60.O%@1O.OuM 51.O%@1O.OuM 8-2326 76.0%@10.OuM 33.O%@1O.OuM_______ 8-2327 76.0%@10.OuM 23.0%@1O.OuM_______________ B-2328 65.0%@1O.OuM 28.O%@1O.OuM_______ B-2329 72.O%@1O.OuM 53.O%@10.OuM_______ 8-2330 81.0%@1O.OuM 37.0%@10.OuM_______ 8-2331 74.O%@10.OuM 44.0%@10.OuM_______ B-2332 70.0%@1O.OuM 47.O%@1O.OuM _______ ______ B-2333 58.0%@10.OuM 36.O%@10.0uM _______ B-2334 81.0%@1O.OuM 45.O%@1O.OuM _______ 8-2335 82.0%@1O.OuM 50.0%@10.OuM _______ B-2336 48.0% @1 0.OuM 35.0%@ 10.0uM________ 8-2337 46.0%@10.OuM 59.O%@1O.OuM _______ 8-2338 73.0%@10.OuM 50.0%@10.OuM _______________ B-2339 84.0%@10.OuM >1O.OuM B-2340 35.O%@1O.OuM 12.0%@10.OuM 8-2341 75.0%@10.OuM 50.0%@10.OuM B-2342 83.0% @1 O.OuM 46.O%@ 1 .OuM 8-2343 43.0%@1O.OuM 27.0%@1O.OuM_______ 8-2344 71.0%@10.OuM 50.0%@10.OuM _______ ______ B-2345 64.0%@10.OuM 38.0%@1O.OuM _______ B-2346 45.0%@10.0uM 48.0%@10.OuM _______ B-2347 49.0%@10.OuM -50.0%@10.OuM _______ B-2348 76.0%@1O.OuM 48.0%@1O.OuM _______ B-2349 75.0%@10.OuM 27.0%@10.OuM_______________ SUB8TfUMSBHAM(RMOM~ WO 98/52940 PCTIUS98/1-0436 702 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LPS Model % Example# IC50,uM or % or % TNF inhib © inhib @dose inhib@conc. (uM) inhib@conc. (uM) dose @predose time @ predlose time B-2350 138.0%@1O.OuM 56.0%@10.OuM B-2351 77.0%@10.OuM 1.O%@1O.OuM B-2352 37.O%@1O.OuM 19.O%@1O.OuM B-2353 38.O%@1O.OuM 33.O%@1O.OuM B-2354 65.0%@1O.OuM 25.O%@1O.OuM B-2355 84.O%@10.OuM 50.0%@10.OuM B-2356 77.O%@10.OuM 45.O%@1O.OuM B-2357 47.0%@1O.OuM 41.O%@1O.OuM B-2358 17.0%@1O.OuM 52.O%@1O.OuM B-2359 76.O%@1O.OuM 35.O%@10.OuM ________ B-2360 45.O%@1O.OuM >10.OuM ________ B-2361 19.O%@10.OuM 46.0%@10.OuM ________ B-2362 60%@100.OuM 39.O%@1O.OuM ________ B-2363 44.O%@10.OuM 1.O%@1O.OuM _______ B-2364 47.O%@1O.OuM 4.0%@10.OuM _______________ B-2365 82.0%@10.OuM 43.O%@1O.OuM _______________ B-2366 70.O%@ 10.OuM 59.0%@ 10.OuM _______________ B-2367 46.0%@10.OuM 40.O%@1.OuM _______ ______ B-2368 65.O%@1O.OuM 55.O%@1O.OuM _______________ B-2369 32.O%@10.OuM >10.OuM _______ ______ 8-2370 73%@100.OuM 20.0%@10.OuM _______ ______ B-2371 54.O%@10.OuM 36.O%@10.OuM _______________ B-2372 55.O%@100.OuM >10.OuM _______________ 8-2373 50.0%@100.OuM 6%@10.OuM _______ ______ 8-2374 35.0%@1O.OuM 20.0%@10.OuM _______ ______ 8-2375 62.0%@100.OuM >10.OuM 8-2376 32.O%@10.OuM 17.0%@1O.OuM 8-2377 34.O%@10.OuM 17.0%@10.OuM B-2378 48.0%@10.OuM 61.0%@10.OuM _______________ B-2379 73.O%@ 1 0.OuM 45.0%@l1.OuM 8-2380 81%@100.OuM 53.O%@10.OuM 8-2381 68%@100.OuM 2.0%@10.OuM 8-2382 51.0%@10.OuM 24.0%@10.OuM B-2383 63.O%@10.OuM 35.0%@10.OuM 8-2384 49%@100.OuM 1O.O%@10.OuM _______ B-2385 79.O%@10.OuM 19.0%@10.OuM 8-2386 38.0%@10.OuM 19.0%@10.OuM 8-2387 50.0%@100.OUM >10.OuM B-2388 42.0%@10.OuM 24.0%@10.OuM _______ 8-2389 39.0%@10.OuM 29.0%@10.OuM _______ 8UBS1TWEMSWEE(RULE) WO 98/52940 PCTIUS98/1 0436 703 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model % Rat LIDS Model % Example# 1C50,uM or % or % TNF inhib @ inhib @dose inhib@conc. (uM) inhib@conc. (uM) dose @predose time @predose time B-2390 134.O%@1O.OuM 27.O%@1.OuM_______ B-2391 40.O%@1O.OuM 59.O%@10.OuM _______________ B-2392 63.O%@1O.OuM 46.O%@10.OuM _______ B-2393 43.O%@1O.OuM >1 O.OuM_______ B-2394 37.O%@1O.OuM 22.O%@1O.OuM _______ B-2395 32.O%@10.OuM 28.O%@10.OuM _______ B-2396 75.O%@1O.OuM >1O.OuM _______ B-2397 83.O%@1O.OuM 22.O%@1O.OuM_______ B-2398 55%@ 1 O.OuM 1 O.O%@ 10.OuM________ B-2399 69.O%@1O.OuM 18.O%@10.OuM _______ B-2400 60.O%@1O.OuM 40.O%@1O.OuM_______ B-2401 78.O%@1O.OuM 44.O%@1O.OuM_______ B-2402 43.O%@1O.OuM 52.O%@10.OuM _______ B-2403 72% @1 O0.OuM 52.O%@ 1 .OuM ________________ B-2404 58%@ 1 O.OuM 52.O%@ 10.OuM _______________ B-2405 47%@100.OuM >1O.OuM _______________ B-2406 45.O%@1O.OuM 24.O%@1O.OuM _______________ B-2407 47%@ 1 O.OuM 27.O%@ 1 .OuM ________________ B-2408 39.O%@1O.OuM 1O.O%@10.OuM _______________ B-2409 78.O%@1O.OuM 26.O%@10.OuM _______ B-241 0 33.O%@1O.OuM 32.O%@10.OuM _______ B-241 1 26%@ 1OO.OuM 1 3.O%@ 1 .OuM________ B-241 2 40.O%@ 10.OuM 31 .O%@ 10.OuM________ B-2413 75.O%@1O.OuM 37.O%@1O.OuM _______ B-2414 86.O%@1O.OuM 38.O%@1O.OuM________ B-241 5 94.O%@ 1 .OuM 50.O%@ 10.OuM________ B-2416 85.O%@1O.OuM 43.O%@1.OuM _______ B-2417 83.O%@ 1 .OuM 1 8.O%@ 1 .OuM________ B-2418 88.O%@1O.OuM 34.O%@10.OuM ________ _______ B-2419 86.O%@1O.OuM 66.O%@1O.OuM_______ B-2420 70.O%@1O.OuM 34.O%@10.OuM _______ B-2421 89.O%210.OuM 38.O%@10.OuM_______ B-2422 90.O%@1O.OuM 17.O%@1O.OuM_______ B-2423 85.O%@1O.OuM >1O.OuM _______ B-2424 86.O%@1O.OuM 43.O%@1O.OuM _______ ______ B-2425 79.O%@1O.OuM 42.O%@1O.OuM _______ ______ B-2426 88.O%@1O.OuM 53.O%@10.OuM _______ ______ B-2427 87.O%@ 1 .OuM 59.O%@ 1 .OuM _______________ B-2428 182.O%@1O.OuM 50.O%@1O.OuM _______ ______ B-2429 192.O%@ 1 .OuM 32.O%@ 1 .OuM _______________ 8U6BffT=&E8EE(RLUEM WO 98/52940 PCT/US98/10436 704 P38 alpha kinase U937 Cell 1C50,uM Mouse LPS Model % Rat LPS Model % Example# IC50,uM or % or % TNF inhib @ inhib @dose inhib@conc. (uM) inhib@conc. (uM) dose @predose time @predose time B-2430 190.O%@1O.OuM 61.O%@1O.OuM _______ ______ B-2431 85.0%21OuM 68.O%@1O.OuM_______ B-2432 86.0%21 0OuM 40.0% @1 0.OuM _______ B-2433 94.O%@10.OUM 84.O%@1O.OuM________ B-2434 92.0%@10.OuM 63.0%@10.OuM B-2435 84.O%@1O.OuM 4.O%@10.OuM B-2436 80.O%@10.OuM 54.O%@1O.OuM B-2437 82.0%@10.OuM 41.0%@10.OuM _______ B-2438 75.O%@1O.OuM 40.0%@10.OuM _______________ B-2439 81.0%@10.OuM 44.0%@10.OuM _______ ______ B-2440 77.0%@10.OuM 78.O%@10.OuM _______ B-2441 86.0%@10.OuM 46.0%@10.OuM B-2442 86.0%@10.OuM >10.OuM B-2443 84.O%@10.OuM 44.0%@10.OuM _______ B-2444 89.0%@10.OuM 7.0%@10.OuM B-2445 94.0%@1O.OuM 15.0%@10.OuM B-2446 90.0%@10.OuM 28.0%@10.OuM B-2447 94.0%@10.OuM >10O.OuM _______________ B-2448 75.0%@10.OuM 30.0%@10.OuM B-2449 86.0%@10.OuM 42.0%@10.OuM B-2450 87.0%@10.OuM 46.0%@1.OuM B-2451 87.O%@10.OuM 45.0%@1O.OuM B-2452 89.O%@10.OuM 33.0%@10.OuM B-2453 91.0%@10.OuM >10O.OuM B-2454 88.0%@10.OuM 40.0%@10.OuM B-2455 87.0%@10.OuM 54.0%@10.OuM ________ B-2456 86.0%@10.OuM 53.0%@10.OuM _______ B-2457 90.0%@1O.OuM 18.0%@10.OuM ________ B-2458 83.0%@10.OuM 36.0%@10.OuM ________ B-2459 82.0%@10.OuM 81.0%@10.OuM _______ B-2460 80.0%@10.OuM 79.0%@10.OuM _______________ B-2461 67.0%@10.OuM 59.0%@10.OuM _______________ 8TE8HEE(RU WWI

Claims (139)

1. A compound of Formula I R s 2 N 453 5 ZN N S (I) '11 5 wherein R' is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, 10 haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, 15 alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, 20 alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, 25 aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, 30 heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, SUeWMTU(RULEs) WO98/52940 PCT/US98/10436 706 arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or R 1 has the formula R 2 5 O 1 I R 2 6 II I -C-C(CH 2 I - C-N I \ 27 H (II) 35 wherein: i is an integer from 0 to 9; R 2 1 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, 40 alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R 26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and 45 R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, 50 alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, 55 alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, 60 arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene,.alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, suBSnUTES EET(R E) WO98/52940 PCTIUS98/10436 707 alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, 65 heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein 70 said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, 75 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 R 27 is -CHR 28 R 29 wherein R 28 is alkoxycarbonyl, and R 29 80 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one 85 or more radicals independently selected from alkyl and nitro; or R 26 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said heterocycle is optionally substituted with one or more 90 radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and 95 alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; susmMUSTEHEE (RULE 26) WO98/52940 PCT/US98/10436 708 and 100 R 2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, 105 aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, 110 carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl; 115 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, 120 epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or 125 R 2 has the formula: R 3 0 H R 3 2 -C-(CH 2 - C R 31 1 (III) wherein: j is an integer from 0 to 8; and m is 0 or 1; and 130 R 30 and R 31 are independently selected from hydrogen, SUBsmT ESHEET(RULE26) WO98/52940 PCT/US98/10436 709 alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R" 2 is selected from hydrogen, alkyl, aralkyl, 135 heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R 3 " is selected from hydrogen, alkyl, -C(O)R 5 , 140 -C(O)OR 3 s , -SO 2 R 36 , -C(O)NR 7 R 38 , and -S0 2 NR 9 R 40 , wherein R 3s R 36 , R 37 , R 38 , R 39 and R 4 0 are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R 34 is selected from hydrogen, alkyl, aminocarbonyl, 145 alkylaminocarbonyl, and arylaminocarbonyl; or R 2 is -CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy; and R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, / 0 N and 0 R N 0 1 4 3 150 (IV) (V) wherein R 43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and wherein the R 3 pyridinyl, pyrimidinyl, quinolinyl and 155 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, 160 aralkoxy, heterocyclylalkoxy, amino, alkylamino, SUSTUESHEEf(FE WO98/52940 PCT/US98/10436 710 alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, 165 alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, 170 alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR" 44 R 4 " wherein R 44 is alkylcarbonyl or amino, and R" is alkyl or aralkyl; and R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein 175 R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, 180 alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, 185 arylaminoalkylene, aminoalkylamino, and hydroxy; provided R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R' is hydrido; further provided R 2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R 4 is 190 hydrido; and further provided R 4 is not methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof. ssmUSHEE(RULE WO 98/52940 PCT/US98/10436 711

2. A compound of Claim 1 wherein R 1 is selected from hydrido, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower heterocyclyl, lower cycloalkylalkylene, lower haloalkyl, 5 lower hydroxyalkyl, lower aralkyl, lower alkoxyalkyl, lower mercaptoalkyl, lower alkylthioalkylene, amino, lower alkylamino, lower arylamino, lower alkylaminoalkylene, and lower heterocyclylalkylene; or R 1 has the formula R25 O 27 -C- CH2j -N 10 H (II) wherein: i is 0, 1 or 2; and R 2 1 is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower 15 alkoxyalkylene, lower phenoxyalkylene, lower aminoalkyl, lower alkylaminoalkyl, lower phenoxyaminoalkyl, lower alkylcarbonylalkylene, lower phenoxycarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene; and R 26 is selected from hydrogen, lower alkyl, lower 20 alkenyl, lower alkynyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkoxycarbonylalkylene, and lower alkylaminoalkyl; and R 27 is selected from lower alkyl, lower cycloalkyl, lower alkynyl, aryl selected from phenyl, biphenyl and 25 naphthyl, lower heterocyclyl, lower phenylalkyl, lower cycloalkylalkylene, lower cycloalkenylalkylene, lower cycloalkylarylene, lower cycloalkylcycloalkyl, lower heterocyclylalkylene, lower alkylphenylene, lower alkylphenylalkyl, lower phenylalkylphenylene, lower 30 alkylheterocyclyl, lower alkylheterocyclylalkylene, lower alkylheterocyclylphenylene, lower SUBsTUTESHEET(RULE26) WO98/52940 PCTIUS98/10436 712 phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl, lower alkoxyheterocyclyl, lower alkoxyalkoxyphenylene, lower 35 phenoxyphenylene, lower phenylalkoxyphenylene, lower alkoxyheterocyclylalkylene, lower phenoxyalkoxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonylalkylene, lower 40 aminoalkyl, lower alkylaminoalkylene, lower phenylaminocarbonylalkylene, lower alkoxyphenylaminocarbonylalkylene, lower aminocarbonylalkylene, arylaminocarbonylalkylene, lower alkylaminocarbonylalkylene, lower phenylcarbonylalkylene, 45 lower alkoxycarbonylphenylene, lower phenoxycarbonylphenylene, lower alkylphenoxycarbonylphenylene, lower phenylcarbonylphenylene, lower alkylphenylcarbonylphenylene, lower 50 alkoxycarbonylheterocyclylphenylene, lower alkoxycarbonylalkoxylphenylene, lower heterocyclylcarbonylalkylphenylene, lower alkylthioalkylene, cycloalkylthioalkylene, lower alkylthiophenylene, lower phenylalkylthiophenylene, lower 55 heterocyclylthiophenylene, lower phenylthioalklylphenylene, lower phenylsulfonylaminoalkylene, lower alkylsulfonylphenylene,.lower alkylaminosulfonylphenylene; wherein said lower alkyl, 60 lower cycloalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower heterocyclylalkylene, lower alkylheterocyclylphenylene, lower alkoxyphenylene, lower phenoxyphenylene, lower phenylaminocarbonylalkylene, lower 65 phenoxycarbonylphenylene, lower phenylcarbonylphenylene, lower alkylthiophenylene, lower heterocyclylthiophenylene, lower suBsUTEmSHEET (RULE26) WO98/52940 PCT/US98/10436 713 phenylthioalklylphenylene, and lower alkylsulfonylphenylene groups are optionally substituted 70 with one or more radicals independently selected from lower alkyl, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, and cyano; or R 27 is -CHR 46 R 47 wherein R 46 is lower alkoxycarbonyl, and R 47 is selected from lower phenylalkyl, lower 75 phenylalkoxyalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower alkoxycarbonylalkylene, lower alkylthioalkylene, and lower phenylalkylthioalkylene; wherein said phenylalkyl and heterocylcyl groups are optionally substituted with one 80 or more radicals independently selected from lower alkyl and nitro; or R 26 and R 27 together with the nitrogen atom to which they are attached form a 4-8 membered ring heterocycle, wherein said heterocycle is optionally substituted with 85 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 90 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 95 substituted with one or more radicals independently selected from halogen, lower alkyl and lower alkoxy; and R 2 is selected from hydrido, halogen, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, lower haloalkyl, lower hydroxyalkyl, 5- or 6-membered 100 heterocyclyl, lower alkylheterocyclyl, lower heterocyclylalkyl, lower alkylamino, lower alkynylamino, phenylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylamino, lower SUBMUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 714 aminoalkyl, lower aminoalkylamino, lower 105 alkylaminoalkylamino, lower cycloalkyl, lower alkenyl, lower alkoxycarbonylalkyl, lower cycloalkenyl, lower carboxyalkylamino, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonyl, 110 alkoxycarbonylalkyl, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylsulfonyl, lower heterocyclyloxy, and lower heterocyclylthio; wherein the aryl, heterocylyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl groups 115 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 120 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 125 R 2 has the formula: R 30 -H R R 2 - C-( CH - C 31 1 34 33 - m (III) wherein: j is 0, 1 or 2; and m is 0; 130 R 3 1 and R 3 ' are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R 32 is selected from hydrogen, alkyl, aralkyl, 135 heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, 8UBSTTMUTE8H(EE (RLE2) WO98/52940 PCT/US98/10436 715 aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R" 3 is selected from hydrogen, alkyl, -C(O)R", 140 -C(O)OR 35 , -S0 2 R 36 , -C(O)NR 37 R 38 , and -S0 2 NR 9 R; wherein R 35 is selected from alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl, cycloalkenylalkylene, heterocyclylalkylene, alkylarylene, alkylheterocyclyl, 145 arylarylene, arylheterocyclyl, alkoxy, alkenoxy, alkoxyalkylene, alkoxyaralkyl, alkoxyarylene, aryloxyalkylene, aralkoxyalkylene, cycloalkyloxyalkylene, alkoxycarbonyl, heterocyclylcarbonyl, alkylcarbonyloxyalkylene, alkylcarbonyloxyarylene, 150 alkoxycarbonylalkylene, alkoxycarbonylarylene, aralkoxycarbonylheterocyclyl, alkylcarbonylheterocyclyl, arylcarbonyloxyalkylarylene, and alkylthioalkylene; wherein said aryl, heterocyclyl, aralkyl, alkylarylene, arylheterocyclyl, alkoxyarylene, aryloxyalkylene, 155 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 160 R 35 is CHR 4 "R 49 wherein R 48 is arylsulfonylamino or alkylarylsulfonylamino, and R 49 is selected from aralkyl, amino, alkylamino, and aralkylamino; or R 35 is -NR 5 "R 5 1 wherein R 5 1 is alkyl, and R" is aryl; and 165 wherein R 36 is selected from alkyl, haloalkyl, aryl, heterocyclyl, cycloalkylalkylene, alkylarylene, alkenylarylene, arylarylene, aralkyl, aralkenyl, heterocycly1heterocyclyl, carboxyarylene, alkoxyarylene, alkoxycarbonylarylene, alkylcarbonylaminoarylene, 170 alkylcarbonylaminoheterocyclyl, arylcarbonylaminoalkylheterocyclyl, alkylaminoarylene, sues nWESHEET (RULE 2S) WO98/52940 PCTIUS98/10436 716 alkylamino, alkylaminoarylene, alkylsulfonylarylene, alkylsulfonylaralkyl, and arylsulfonylheterocyclyl; wherein said aryl, heterocyclyl, cycloalkylalkylene, 175 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 180 wherein R 7 is selected from hydrogen and alkyl; and wherein R 38 is selected from hydrogen, alkyl, alkenyl, aryl, heterocyclyl, aralkyl, alkylarylene, arylcycloalkyl, arylarylene, cycloalkylalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, 185 aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, aryloxyarylene, arylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylene, alkoxycarbonylarylene, alkylcarbonylcarbonylalkylene, alkylaminoalkylene, alkylaminoaralkyl, alkylcarbonylaminoalkylene, 190 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, 195 haloalkoxy, keto, amino, nitro, and cyano; or R 38 is -CRs 2 R5 3 wherein R" 2 is alkoxycarbonyl, and R 53 is alkylthioalkylene; or R 37 and R 38 together with the nitrogen atom to which they are attached form a heterocycle; and 200 R 39 and R 4 " have the same definition as R 26 and R 27 in claim 1; or R 2 is -CRs 4 Rss wherein R" 4 is phenyl and RS" is hydroxy; or R 2 is selected from the group consisting of ssmTESHEET(RuLEM) WO98/52940 PCT/US98/10436 717 R 5 8 R 5 8 R 58 57 56 R N R N N N ] andN (CH 2 Dk- N 0 (CH 2 ) k 205 CCH 2 Dk (VI) (VII) (VIII) wherein k is an integer from 0 to 3; and R" is hydrogen or lower alkyl; and 210 R" 7 is hydrogen or lower alkyl; or R" 6 and R1 7 form a lower alkylene bridge; and R" 8 is selected from hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, -C(0)R", 215 -S0 2 R 60 , and -C(0)NHR 61 ; wherein R 59 is selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl; wherein 220 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 225 wherein R 60 is selected from alkyl, aryl, heterocyclyl, alkylarylene, alkylheterocyclyl, aralkyl, heterocyclylheterocyclyl, alkoxyarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, and arylsulfonylheterocyclyl; wherein said aryl, 230 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 SUsmUMTE SHEE(RULE26) WO 98/52940 PCT/US98/10436 718 wherein R 61 is selected from alkyl, aryl, 235 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 240 R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, and rN0 N (IV) wherein R 43 is selected from hydrogen, lower alkyl, lower aminoalkyl, lower alkoxyalkyl, lower alkenoxyalkyl 245 and lower aryloxyalkyl; and wherein the R 3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from lower alkylthio, lower alkylsulfonyl, aminosulfonyl, halo, 250 lower alkyl, lower aralkyl, lower phenylalkenyl, lower phenylheterocyclyl, carboxy, lower alkylsulfinyl, cyano, lower alkoxycarbonyl, aminocarbonyl, lower alkylcarbonylamino, lower haloalkyl, hydroxy, lower alkoxy, amino, lower cycloalkylamino, lower alkylamino, 255 lower alkenylamino, lower alkynylamino, lower aminoalkyl, arylamino, lower aralkylamino, nitro, halosulfonyl, lower alkylcarbonyl, lower alkoxycarbonylamino, lower alkoxyphenylalkylamino, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower heterocyclylamino, lower 260 heterocyclylalkylamino, lower phenylalkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyphenylalkylamino, hydrazinyl, lower alkylhydrazinyl, or -NR 62 R 63 wherein R" 2 is lower alkylcarbonyl or amino,.-and R 6 1 is lower alkyl or lower susmuBTTEEET(RAE 28) WO98/52940 PCTIUS98/10436 719 265 phenylalkyl; and R 4 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 5-10 270 membered heterocyclyl groups of R 4 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 275 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 R I is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, 5 dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, 10 piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, 15 methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methylthiomethyl; and 20 R 2 is selected from hydrido, chloro, fluoro, bromo, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, phenyl, biphenyl, fluoromethyl, difluoromethyl, JBSmIUTESHEET (RULE26) WO98/52940 PCT/US98/10436 720 trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, 25 difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, hydroxymethyl, hydroxyethyl, pyridinyl, isothiazolyl, isoxazolyl, thienyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, 30 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, 35 N-phenylamino, piperadinylamino, N-benzylamino, N propargylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, N,N 40 dimethylaminoethylamino, N,N-dimethylaminopropylamino, morpholinylethylamino, morpholinylpropylamino, carboxymethylamino, methoxyethylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1,1 dimethylethoxycarbonyl, 1,1 45 dimethylethoxycarbonylaminoethylamino, 1,1 dimethylethoxycarbonylaminopropylamino, piperazinylcarbonyl, and 1,1 dimethylethoxycarbonylpiperazinylcarbonyl; wherein the aryl, heteroaryl, cycloalkyl and cycloalkenyl groups are 50 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, 55 dimethylamino, methoxycarbonyl, ethoxycarbonyl, and 1,1 dimethylethylcarbonyl; or R 2 is -CR 54 R 55 wherein R 54 is phenyl and R" is hydroxy; and SMIfTUTESHEE(RULEW9 WO98/52940 PCT/US98/10436 721 R 3 is selected from pyridinyl, pyrimidinyl, and 60 purinyl; wherein R 3 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, 65 aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, 70 fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2 methylbutylamino, propargylamino, aminomethyl, 75 aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N 80 dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, 85 fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methyl hydrazinyl, or -NR 62 R 63 wherein R 62 is methylcarbonyl or amino, and R 63 is methyl, ethyl or phenylmethyl; and 90 R 4 is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, MUSBSTMMSUTEHEET (RULE 26) WO98/52940 PCT/US98/10436 722 95 isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein 100 the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R 4 are optionally substituted with one or more radicals independently selected from methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, 105 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 R' is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl; 5 R 2 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 10 optionally substituted with one or more radicals independently selected from fluoro, chloro, bromo, methyl, ethyl, and trifluoromethyl; R 3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R 3 is optionally substituted with one 15 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; 20 R 4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, SUBSTUTESHEET(RULE26) WO98/52940 PCT/US98/10436 723 dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R ' are optionally substituted with one or more radicals 25 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 R I is hydrido or methyl; R 2 is selected from hydrido, methyl or ethyl; R 3 is selected from pyridinyl, pyrimidinyl or 5 quinolinyl; wherein R 3 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, 10 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, 15 trifluoromethyl, nitro, dimethylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer thereof.

6. A compound of Claim 2 wherein R' is selected from hydrido, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, 5 dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, 10 piperazinyl, morpholinyl, benzyl, phenylethyl, 8 SUB5HTUTESELE(RUE2) WO98/52940 PCT/US98/10436 724 morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, 15 methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methylthiomethyl; and 20 R 2 has the formula: R30 H R32 I I _N/ -C-(CH 2 Q. 31 3 'q 33 R m(III) wherein: j is 0, 1 or 2; and m is 0; and 25 R 30 and R 31 are independently selected from hydrogen and lower alkyl; R 32 is selected from hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, aryloxyalkylene, aminoalkyl, lower 30 alkylaminoalkyl, lower phenylaminoalkyl, lower alkylcarbonylalkylene, lower phenylcarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene; R 33 is selected from hydrogen, lower alkyl, -C(O)R 3 1, -C(O)OR 35 , -S0 2 R 3 6 , -C(O)NR 3 7 R 38 , and -S0 2 NR 39 R 40 35 wherein R 35 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 40 alkylphenylene, lower alkylheterocyclyl, phenylphenylene, lower phenylheterocyclyl, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower alkoxyphenylalkyl, lower SUBSTm STEHE (LE) WO98/52940 PCT/US98/10436 725 alkoxyphenylene, lower phenoxyalkylene, lower phenylalkoxyalkylene, lower cycloalkyloxyalkylene, lower 45 alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkylcarbonyloxyalkylene, lower alkylcarbonyloxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower phenylalkoxycarbonylheterocyclyl, lower 50 alkylcarbonylheterocyclyl, lower phenylcarbonyloxyalkylphenylene, and lower alkylthioalkylene; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower 55 phenylheterocyclyl, lower alkoxyphenylene, lower phenoxyalkylene, lower cycloalkoxyalkylene, lower alkoxycarbonylalkylene, and lower alkylcarbonylheterocyclyl groups are optionally substituted with one or more radicals independently 60 selected from lower alkyl, halo, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; or R 3 5 is CHR 48 R 49 wherein R 48 is phenylsulfonylamino or lower alkylphenylsulfonylamino, and R 49 is selected from 65 lower phenylalkyl, amino, lower alkylamino, and lower phenylalkylamino; or R 35 is -NR 50 R 51 wherein R 50 is lower alkyl, and R 51 is aryl selected from phenyl, biphenyl and naphthyl; and wherein R 3 1 is selected from lower alkyl, lower 70 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 75 alkoxyphenylene, lower alkoxycarbonylphenylene, lower alkylcarbonylaminophenylene, lower alkylcarbonylaminoheterocyclyl, lower phenylcarbonylaminoalkylheterocyclyl, lower SUBS3TMUTE, (RUE ) WO98/52940 PCT/US98/10436 726 alkylaminophenylene, lower alkylamino, lower 80 alkylaminophenylene, lower alkylsulfonylphenylene, lower alkylsulfonylphenylalkyl, and lower phenylsulfonylheterocyclyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower phenylalkyl, lower 85 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; 90 and wherein R 37 is selected from hydrogen and lower alkyl; and wherein R 38 is selected from hydrogen, lower alkyl, lower alkenyl, aryl selected from phenyl, biphenyl and 95 naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylcycloalkyl, phenylphenylene, lower cycloalkylalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower 100 alkoxyphenylene, lower phenoxyphenylene, phenylcarbonyl, lower alkoxycarbonyl, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower alkylcarbonylcarbonylalkylene, lower alkylaminoalkylene, lower alkylaminophenylalkyl, lower 105 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 110 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 38 is -CR 52 R 53 wherein R1 2 is lower alkoxycarbonyl, SUBSTUTESHEE (RE26) WO98/52940 PCT/US98/10436 727 115 and R 53 is lower alkylthioalkylene; or R" 7 and R 8 together with the nitrogen atom to which they are attached form a 4-8 membered ring heterocycle; R 39 and R 4 " have the same definition as R 26 and R 27 in claim 2; or 120 R 2 is selected from the group consisting of R 5 8 P 5 8 R58 57 56 R N R N ] a dN and CCH)k- N 0 CCH 2 D)k (CH 2 ) k (VI) (VII) (VIII) wherein k is an integer from 0 to 2; and 125 R 56 is hydrogen or lower alkyl; and R1 7 is hydrogen or lower alkyl; and R" 8 is selected from hydrogen, lower alkyl, lower phenylalkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower heterocyclylalkyl, 130 lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, lower phenylsulfonyl, -C(O)R 59 , -S0 2 R 6 o, and -C(O)NHR 61 ; wherein R 59 is selected from lower alkyl, lower haloalkyl, lower cycloalkyl, aryl selected from phenyl, 135 biphenyl and naphthyl, lower heterocyclyl, lower alkylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower alkoxy, lower alkenoxy, loewr phenylalkoxy, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl; wherein said 140 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 SuBS'lTTE SEET(RU.LE2 ) WO98/52940 PCT/US98/10436 728 haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, 145 nitro, and cyano; and wherein R 6 " is selected from lower alkyl, aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, lower alkylphenylene, lower alkylheterocyclyl, lower phenylalkyl, lower 150 heterocyclylheterocyclyl, lower alkoxyphenylene, lower alkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene, and lower phenylsulfonylheterocyclyl; wherein said aryl selected from phenyl, biphenyl and naphthyl, lower heterocyclyl, 155 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 160 wherein R 61 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, 165 hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and R' is selected from pyridinyl, pyrimidinyl, and purinyl; wherein R 3 is optionally substituted with one or more radicals independently selected from methylthio, 170 methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 175 dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, su rUTEE(RULE M WO98/52940 PCTIUS98/10436 729 180 methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2 methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, 185 cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, 190 morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, 195 methoxyphenylmethylamino, hydrazinyl, 1-methyl hydrazinyl, or -NR 62 R 63 wherein R 62 is methylcarbonyl or amino, and R 63 is methyl, ethyl or phenylmethyl; and R 4 is selected from hydrido, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, 200 cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, 205 pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of R 4 are optionally substituted with one or more 210 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, 215 dimethylamino, and hydroxy; or SBSWMUTESHEET(RULE26) WO98/52940 PCT/US98/10436 730 a pharmaceutically-acceptable salt or tautomer thereof.

7. A compound of Claim 6 wherein R' is hydrido, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl or morpholinylethyl; 5 R 2 has the formula: R 30 H R32 -C-(CH 2 )J - N 31 1 3 m'4 3 m(III) wherein: j is 0, 1 or 2; and m is 0; and 10 R" is hydrogen; and R 31 is selected from hydrogen and lower alkyl; and R 32 is selected from hydrogen and lower alkyl; and R 3 is selected from lower alkyl, -C(O)R, -C(O)ORs, -S0 2 R 36 , -C(O)NRR 37 R 3 , and -S0 2 NR 9 R 4 0 ; 15 wherein R 3 1 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 20 phenoxyalkylene groups are optionally substituted with one or more radicals independently selected from lower alkyl, halo, and lower haloalkyl; and wherein R 3 1 is selected from lower alkyl, phenyl, lower heterocyclyl, lower alkylphenylene, 25 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 30 selected from lower alkyl, halo, hydroxy, lower SUSW UTESHEET(RULE 2 M) WO98/52940 PCT/US98/10436 731 haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and wherein R 37 is hydrogen; and wherein R 3 " is selected from lower alkyl, phenyl, and 35 lower alkylphenylene; wherein R 39 and R 4 " have the same definition as R 26 and R 27 in claim 2; or R 2 is selected from the group consisting of R 5 8 p 5 8 58 57 56 R N N N and (CH 2 D)k- N CCH 2 Dk CCH2)k 40 (VI) (VII) (VIII) wherein k is an integer from 0 or 1; and R" is hydrogen; and R" is hydrogen; and 45 R" 8 is selected from -C(O)R 9 and -S0 2 R 60 wherein R 59 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 50 selected from lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; and wherein R 6 " is selected from lower alkyl; and R 3 is selected from pyridinyl, pyrimidinyl or 55 quinolinyl; wherein R 3 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, BSTUTE8HEET(RULE2S) WO98/52940 PCTIUS98/10436 732 60 amino, hydroxy, and methylcarbonyl; and R 4 is selected from phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein the cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups of 65 R 4 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 70 a pharmaceutically-acceptable salt or tautomer thereof.

8. A compound of Claim 7 wherein R' is hydrido or methyl; and R 3 is selected from pyridinyl, pyrimidinyl or quinolinyl; wherein R 3 is optionally substituted with one 5 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 10 R 4 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 15 a pharmaceutically-acceptable salt or tautomer thereof.

9. A compound of Claim 1 wherein R 1 is hydrido.

10. A compound of Claim 2 wherein R 1 is hydrido.

11. A compound of Claim 3 wherein R' is hydrido.

12. A compound of Claim 6 wherein R' is hydrido. suBsmTSHE (RUSLE) WO 98/52940 PCT/US98/10436 733

13. A compound of Claim 3 wherein R' is methyl or ethyl.

14. A compound of Claim 6 wherein R1 is methyl or ethyl.

15. A compound of Claim 2 wherein R 2 is hydrido.

16. A compound of Claim 3 wherein R 2 is hydrido.

17. A compound of Claim 2 wherein R 4 is optionally substituted phenyl.

18. A compound of Claim 3 wherein R 4 is optionally substituted phenyl.

19. A compound of Claim 6 wherein R 4 is optionally substituted phenyl.

20. A compound of Claim 2 wherein R1 and R 2 are selected independently from hydrido, methyl and ethyl.

21. A compound of Claim 3 wherein R 1 and R 2 are selected independently from hydrido, methyl and ethyl

22. A compound of Claim 2 wherein R 1 and R 2 are selected independently from hydrido, methyl and ethyl; and R 4 is optionally substituted phenyl.

23. A compound of Claim 3 wherein R' and R 2 are selected independently from hydrido, methyl and ethyl; and R 4 is optionally substituted phenyl.

24. A compound of Formula IX SHWEET(RULE 26) WO98/52940 PCT/US98/10436 734 5 NZ z R2 R 4 2 2N N R (IX) wherein Z represents a carbon atom or a nitrogen atom; and 5 R' is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower heterocycyl, lower aralkyl, lower aminoalkyl and lower alkylaminoalkyl; and R 2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6 10 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 15 alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower 20 alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or 25 more radicals independently selected from halo, lower SUBSTITUTESHET(RULE26) WO98/52940 PCT/US98/10436 735 alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or 30 R2 is -CR 54 R 55 wherein R" 4 is phenyl and R" is hydroxy; and R 4 is selected from hydrido, lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl, 5- or 6-membered heterocyclyl, and aryl selected from phenyl, biphenyl, 35 naphthyl; wherein R 4 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 40 R s 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 45 arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower 50 alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR 62 R 63 wherein R 62 is lower alkylcarbonyl or amino, and R1 3 is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof.

25. A compound of Claim 24 wherein R I is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; and R 2 is selected from hydrido, methyl, ethyl, propyl, 5 phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, SUB81TUTESHEET(RULE28) WO 98/52940 PCT/US98/10436 736 N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, 10 benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1 dimethyl)ethylcarbonyl, (1,1 15 dimethyl)ethylcarbonylaminopropylamino, (1,1 dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and 20 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 25 R 4 is selected from cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R 4 is optionally substituted with one or more radicals 30 independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and R s is selected from fluoro, chloro, bromo, methyl, 35 fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, 40 hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, ssMT SHMEE(UM.E) WO98/52940 PCT/US98/10436 737 phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, 45 ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or NR1 2 R 6 R wherein R" 2 is methylcarbonyl or amino, and R 63 is 50 methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof.

26. A compound of Claim 24 wherein R 1 is hydrido.

27. A compound of Claim 25 wherein R' is hydrido.

28. A compound of Claim 24 wherein R' is lower alkyl.

29. A compound of Claim 25 wherein R' is lower alkyl.

30. A compound of Claim 24 wherein R 2 is hydrido.

31. A compound of Claim 25 wherein R 2 is hydrido.

32. A compound of Claim 24 wherein R 1 and R 2 are selected independently from hydrido, methyl and ethyl.

33. A compound of Claim 25 wherein R 1 and R 2 are selected independently from hydrido, methyl and ethyl.

34. A compound of Claim 25 wherein Z represents a carbon atom.

35. A compound of Formula X SUBSTTESHEET (RULEM) WO98/52940 PCT/US98/10436 738 R 5 N R ZP z 5 2 N 2 R N (X) wherein Z represents a carbon atom or a nitrogen atom; and 5 R is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and R 2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6 10 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 15 alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower 20 alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or 25 more radicals independently selected from halo, lower SUB UTMESH (FU.E26) WO98/52940 PCT/US98/10436 739 alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or 30 R 2 is -CR 54 R 55 wherein R1 4 is phenyl and R" is hydroxy; and R 4 is selected from 5- or 6-membered heteroaryl, and aryl selected from phenyl, biphenyl, and naphthyl; wherein R 4 is optionally substituted with one or more 35 radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and R 5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower 40 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 45 alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR 62 R 6 3 wherein R 62 is lower 50 alkylcarbonyl or amino, and R 6 " is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof.

36. A compound of Claim 35 wherein 55 R' is selected from methyl, ethyl, hydroxyethyl and propargyl; and R 2 is selected from methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N 60 ethylamino, N,N-diethylamino, N-propylamino, N phenylamino, aminomethyl, aminoethyl, aminoethylamino, SUBsmumsHEr(FUEM) WO98/52940 PCT/US98/100436 740 aminopropylamino, propargylamino, benzylamino, piperadinylamino, dimethylaminoethylamino, dimethylaminopropylamino, morpholinylpropylamino, 65 morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, N-methylpiperazinyl, carboxymethylamino, methoxyethylamino, (1,1 dimethyl)ethylcarbonyl, (1,1 dimethyl)ethylcarbonylaminopropylamino, (1,1 70 dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, and 1,1-dimethyl ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or 75 more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1 dimethyl)ethoxycarbonyl; and R 4 is selected from phenyl, quinolyl, biphenyl, 80 pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R 4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, 85 benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and R s is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, 90 aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, propargylamino, imidazolylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, 95 piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino; hydroxy, methylcarbonyl, aMM EEE(JLEM WO98/52940 PCT/US98/10436 741 ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, 100 fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and 1-methylhydrazinyl, or NR 62 R 63 wherein R 62 is methylcarbonyl or amino, and R 63 is methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof.

37. A compound of Claim 35 wherein R' is lower alkyl.

38. A compound of Claim 36 wherein R' is lower alkyl.

39. A compound of Claim 35 wherein R 2 is hydrido.

40. A compound of Claim 36 wherein R 2 is hydrido.

41. A compound of Claim 35 wherein R' is methyl or ethyl, and R 2 is selected from hydrido, methyl and ethyl.

42. A compound of Claim 36 wherein R' is methyl or ethyl, and R 2 is selected from hydrido, methyl and ethyl.

43. A compound of Claim 35 wherein Z represents a carbon atom.

44. A compound of Formula XI R 5 N R2 R z 2 2N N R (XI) SUTfIE SHEET (RULE 28) WO98/52940 PCTIUS98/10436 742 wherein Z represents a carbon atom or a nitrogen atom; and 5 R is selected from lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and R 2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6 10 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 15 alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower 20 alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or 25 more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or 30 R 2 is -CR 54 R 55 wherein R" 4 is phenyl and R" is hydroxy; and R 4 is selected from 5- or 6-membered heteroaryl, and aryl selected from phenyl, biphenyl, and naphthyl; wherein R 4 is optionally substituted with one or more 35 radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and R s is selected from halo, amino, cyano, sUBSmumSHEET(FLE26) WO98/52940 PCT/US98/10436 743 aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower 40 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 45 alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR" 2 R 63 wherein R 62 is lower 50 alkylcarbonyl or amino, and R 63 is lower alkyl or lower phenylalkyl; or a pharmaceutically-acceptable salt or tautomer thereof.

45. A compound of Claim 44 wherein R' is selected from methyl, ethyl, hydroxyethyl and propargyl; and R 2 is selected from methyl, ethyl, propyl, phenyl, 5 trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N ethylamino, N,N-diethylamino, N-propylamino, N phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, 10 dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1 dimethyl)ethylcarbonylaminopropylamino, (1,1 15 dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or 20 more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, SUSSTUTESHEET (v Ma WO 98/52940 PCT/US98/10Q436 744 methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1 dimethyl)ethoxycarbonyl; R 4 is selected from phenyl, quinolyl, biphenyl, 25 pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl; wherein R 4 is optionally substituted with one or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, 30 benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and RS is selected from fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, 35 aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, 40 piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, 45 fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and l-methylhydrazinyl, or NR 62 R 63 wherein R 2 is methylcarbonyl or amino, and R 63 is methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof.

46. A compound of Claim 44 wherein R' is lower alkyl.

47. A compound of Claim 45 wherein R 1 is lower alkyl.

48. A compound of Claim 44 wherein R 2 is hydrido.

49. A compound of Claim 45 wherein R 2 is hydrido. SUBSITITESHEEF(RULE26) WO 98/52940 PCT/US98/10436 745

50. A compound of Claim 44 wherein R I is methyl or ethyl, and R 2 is selected from hydrido, methyl and ethyl.

51. A compound of Claim 45 wherein R' is methyl or ethyl, and R 2 is selected from hydrido, methyl and ethyl.

52. A compound of Claim 44 wherein Z represents a carbon atom.

53. A compound of Formula IX R 5 N 4 z R2 4 R 2 2N N (IX) wherein Z represents a carbon atom or a nitrogen atom; and 5 RI is selected from hydrido, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl and lower alkylaminoalkyl; and R 2 is selected from hydrido, lower alkyl, aryl selected from phenyl, biphenyl, and naphthyl, 5- or 6 10 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 15 alkylaminoalkylamino, lower aminoalkyl, lower SUSSTMUMSHE( WO98/52940 PCT/US98/10436 746 aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower 20 alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl; wherein the aryl and heteroaryl groups are optionally substituted with one or 25 more radicals independently selected from halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; or 30 R 2 is -CRs 4 Rs wherein R 4 is phenyl and R" is hydroxy; and R 4 is phenyl that is optionally substituted with one or more radicals independently selected from halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower 35 haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; and R 5 is selected from halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower 40 aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower 45 heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkylcarbonyl, lower alkoxyaralkylamino, hydrazinyl, and lower alkylhydrazinyl, or -NR 2 R 6 3 wherein R1 2 is lower alkylcarbonyl or amino, and R 63 is lower alkyl or lower 50 phenylalkyl; or a pharmaceutically-acceptable salt or tautomer smUSHEET (RULE WO 98/52940 PCT/US98/10436 747 thereof.

54. A compound of Claim 53 wherein R 1 is selected from hydrido, methyl, ethyl, hydroxyethyl and propargyl; R 2 is selected from methyl, ethyl, propyl, phenyl, 5 trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N ethylamino, N,N-diethylamino, N-propylamino, N phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, 10 dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1 dimethyl)ethylcarbonylaminopropylamino, (1,1 15 dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, 1,1-dimethyl ethylpiperazinylcarbonyl; wherein the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl groups are optionally substituted with one or 20 more radicals independently selected from fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl and (1,1 dimethyl)ethoxycarbonyl; R 4 is phenyl that is optionally substituted with one 25 or more radicals independently selected from methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; and R s is selected from fluoro, chloro, bromo, methyl, 30 fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, SUBsmITUMESHEEr(RULE) WO98/52940 PCT/US98/10436 748 35 hydroxyethylamino, imidazolylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, 40 ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, methylcarbonyl, hydrazinyl, and l-methylhydrazinyl, or NR 62 R 63 wherein R 62 is methylcarbonyl or amino, and R 6 is 45 methyl or benzyl; or a pharmaceutically-acceptable salt or tautomer thereof.

55. A compound of Claim 53 wherein R 1 is hydrido or lower alkyl.

56. A compound of Claim 54 wherein R' is hydrido or lower alkyl.

57. A compound of Claim 53 wherein R' is hydrido.

58. A compound of Claim 54 wherein R' is hydrido.

59. A compound of Claim 53 wherein R 2 is hydrido.

60. A compound of Claim 54 wherein R 2 is hydrido.

61. A compound of Claim 53 wherein R 4 is phenyl substituted with one or more fluoro, chloro or bromo.

62. A compound of Claim 54 wherein R 4 is phenyl substituted with one or more fluoro, chloro or bromo.

63. A compound of Claim 53 wherein R' and R 2 are selected independently from hydrido, methyl and ethyl. Wumu SHEET (RLE WO 98/52940 PCT/US98/10436 749

64. A compound of Claim 54 wherein R1 and R 2 are selected independently from hydrido, methyl and ethyl.

65. A compound of Claim 53 wherein Z represents a carbon atom.

66. A compound of Formula IX NY Z2 z R2 4 3 R 4 S 2 N N S (IX) wherein Z represents a carbon atom or a nitrogen atom; and 5 R' is selected from hydrido, lower alkyl, lower hydroxyalkyl and lower alkynyl; and R 2 is selected from hydrido and lower alkyl; and R 4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more halo 10 radicals; and RI 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 R 1 is selected from hydrido, methyl, hydroxyethyl, propargyl; and suBMTnUMESHEET (RME 26) WO98/52940 PCT/US98/10436 750 5 R 2 is hydrido; and R 4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more radicals independently selected from chloro, fluoro and bromo; and 10 R s is selected from hydrido, fluoro, and 1 methylhydrazinyl; or a pharmaceutically-acceptable salt or tautomer thereof.

68. A compound of Claim 67 wherein Z represents a carbon atom; and R1 is selected from hydrido and methyl; and R 2 is hydrido; and 5 R' is selected from phenyl that is optionally substituted with one or more radicals independently selected from chloro, fluoro and bromo; and Ris 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-lH-pyrazol-4 5 yl]pyridine; 4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine; 4- [5-methyl-3-(2-methylphenyl) -1H-pyrazol-4-yl]pyridine; 4-[3-(4-fluorophenyl)-5-methyl-lH-pyrazol-4-yl]pyridine; 4-[5-methyl-3-(4-methylphenyl) -lH-pyrazol-4-yl] pyridine; 10 4-[5-methyl-3- [4-(methylthio)phenyl] -lH-pyrazol-4 yl]pyridine; 4-[3-(4-chlorohpenyl)-5-methyl-liH-pyrazol-4-yl]pyridine; 4-[3-methyl-5-(3-methylphenyl)-lH-pyrazol-4-yl]pyridine; 4-[5-(2,5-dimethylphenyl)-3-methyl-lH-pyrazol-4 15 yl]pyridine; 4-[5-(l,3-benzodioxol-5-yl)-3-methyl-iH-pyrazol-4 ssmUSHEET (RULE WO 98/52940 PCTIUS98/10O436 751 yl] pyridine; 4- [3-methyl-5- (4-phenoxyphenyl) -lH-pyrazol-4--yllpyridine; 4- [5- [(1,1' -biphenyl) - 4 -yl] -3-methyl-1II-pyrazol-4 20 yllpyridine; 4- [3-methyl-5- [3- (phenoxyphenyl) -1I-pyrazol-4 yl] pyridine; 4- [3-methyl-5- [3- (phenylmethoxy)phenyl] -1H-pyrazol-4 yl] pyridine; 25 4- [3-methyl-5- [2- (phenylmethoxy)phenyl] -1H-pyrazol-4 yl] pyridine; 2- [3-methyl-4- (4-pyridinyl) -lH-pyrazol-4-yl] phenol; 3- [3-methyl-4- (4-pyridinyl) -lH-pyrazol-4-yl] phenol; 1-hydroxy-4- (3-methyl-5-phenyl-I--pyrazol-4 30 yllpyridinium; 5- (4-f luorophenyl) -N, N-dimethyl-4- (4-pyridinyl) -iN pyrazol-3 -amine; 5- (4-f luorophenyl) -N-phenyl-4- (4-pyridinyl) -lH-pyrazol-3 amine; 4-Es- (4-f luorophenyl) -3-phenyl-1H-pyrazol-4 35 yllpyridine; 4- [5- (3-methyiphenyl) -3- (trifluoromethyl) -1H-pyrazol-4 yllpyridine;4- [3- (4-f luorophenyl) -4- (4-pyridinyl) -1H pyrazol-5-yl] pyridine; 4- (5-cyciohexyl) -3-methyl-lH-pyrazol-4-yl)pyridine; 40 4-ES- (3-f iuoro-5-methoxyphenyl) -3-methyl-lH-pyrazol-4 yl] pyridine; 4- [5- (3-methylphenyl) -3-propyl-lH-pyrazol-4-yllpyridine; 4- [(3-methyl-5-phenyl-I.-pyrazol-4-yl)methy] pyridine; 4-[13, 5-bis (3-methyiphenyl) -1H-pyrazol-4-yl] pyridine; 45 4-[14-methyl-2- (2-trifluorophenyl) -1H-pyrazol-4 yl] pyridine; 4- [3- (2-chiorophenyl) -5-methyl-1H-pyrazol-4-yl] pyridine; 4- [5-methyl-3- (2,4-dimethylphenyl) -1H-pyrazol-4 yl] pyridine; 50 4-ES- (4-chlorophenyl) -1,3-dimethyl-lH-pyrazol-4 yl] pyridine; 4- [3- (3-f luoro-2-methylphenyl) -5-methyl-1H-pyrazol-4 SUBMMIMTEHEUr(RLU26) WO 98/52940 PCT/US98/10436 752 yl] pyridine; 4- [3- (3,5-dimethyiphenyl) -5-methyl-1H-pyrazol-4 55 yillpyridine; 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 60 yl] benzenamine; 4- [3- (2,3-dihydrobenzofuran-5-yl) -5-methyl-1H-pyrazol-4 yl] pyridine; 4- [3- (4-bromophenyl) -5-methyl-lH-pyrazol-4-yllpyridine; 4- [3- (2-f luorophenyl) -5-methyl-lH-pyrazol-4-yllpyridine; 65 4- [3- (3-f luorophenyl) -5-methyl-1H-pyrazol-4-yllpyridine; 4- [3-methyl-5- [3- (trifluoromethyl)phenyll -1H-pyrazol-4 yl] pyridine; 4- (3-ethyl-4-phenyl-lH-pyrazol-4-yl)pyridine; 4- [5- (3-methoxyphenyl) -3-methyl-1H-pyrazol-4-yllpyridine; 70 4-[13-ethyl-5- (3-methyiphenyl) -lH-pyrazol-4-yllpyridine; 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] -lH-pyrazol-4 75 yllpyridine; 4- [3-methyl-5- (3-thienyl) -1H-pyrazol-4-yllpyridine; 4- [5- (2,4-dichiorophenyl) -3-methyl-1H-pyrazol-4 yl] pyridine; 4-[15- (3-chiorophenyl) -3-methyl-lH-pyrazol-4-yllpyridine; 80 4- [5- (3-chloro-4-methoxyphenyl) -3-methyl-1H-pyrazol-4 yl] pyridine; ethyl 3- (4-chiorophenyl) -4- (4-pyridinyl) -lH-pyrazole-5 propanoate; 4- [3- (4-f luorophenyl) -l-methyl-pyrazol-4-ylllpyridine; 85 5- [5- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin 2-amine; 5- [3-methyl-5- (3-methyiphenyl) -1I-pyrazol-4-yl] pyrimidin 2-amine; suJsnTWrE&LEU(RuLE26) WO98/52940 PCT/US98/10436 753 5-[3-methyl-5-(2-methylphenyl)-IH-pyrazol-4-yl]pyrimidin 90 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; 95 5-[5-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4 yl]pyrimidin-2-amine; 5-[5-(3-chlorophenyl)-3-methyl-1iH-pyrazol-4-yl]pyridin-2 amine; 4-[5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl]pyridin-2 100 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; 105 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 110 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; 115 2-methoxy-5-[5-(4-methoxyphenyl)-3-methyl-1IH-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-4 120 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; SUBSmTESHEET (RULEM) WO 98/52940 PCT/US98/10436 754 125 4-[5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2 methoxypyridine; 2-methoxy-4- [3-methyl-5- (4-methyiphenyl) -1H-pyrazol-4 yll pyridine; 5-Es- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2 130 01; 4- [5- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2 01; 4- [5- (3-methyiphenyl) -3-methyl-1II-pyrazol-4-yllpyridin-2 o1; 135 4- [5- (2-methyiphenyl) -3-methyl-lH-pyrazol-4-yllpyridin-2 01; 4-Es- (4-chiorophenyl) -3-methyl-lH-pyrazol-4-yllpyridin-2 01; 4- [5- (4-f luorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2 140 ol; 4- [5- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yllpyridin 2-ol; 5-ES- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-y1]pyridine 2 -met hanamine; 145 4-ES- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-y1]pyridine 2 -rethanamine; 4- [5- (3-methyiphenyl) -3-methyl-1II-pyrazol-4-yllpyridine 2-me thanamine; 4- [5- (2-methyiphenyl) -3-methyl-1H-pyrazol-4-yllpyridine 150 2 -methanamine; 4- [5- (4-chiorophenyl) -3-methyl-1H-pyrazol-4-yl]pyridine 2 -me thanamine; 4-ES- (4-f luorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine 2-me thanamine; 155 4-ES- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl]pyridine 2-me thanamine; 5- [5- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine 2- carboxamide; 4- [5- (3-chiorophenyl) -3-methyl-2.H-pyrazol-4-yllpyridine 160 2-carboxamide; WSuTmrSH4EU RULEE) WO 98/52940 PCT/US98/11i436 755 4- [5- (3-methyiphenyl) -3-methyl-lH-pyrazol-4-yllpyridine 2 -carboxamide; 4- [5- (2-methyiphenyl) -3-methyl-1H-pyrazol-4-yllpyridine 2 -carboxamide; 165 4- [5- (4-chiorophenyl) -3-methyl-1H-pyrazol-4-ylllpyridine 2 -carboxamide; 4-ES- (4-filuorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine 2-carboxamide; 4- [5- (4-methoxyphenyl) -3-methyl-lH-pyrazol-4-yl] pyridine 170 2-carboxamide; 4-Es- (3-f luoro-4-methoxyphenyl) -3-methyl-1I--pyrazol-4 yll pyridine; 4-Es- (4-f luoro-3-methoxyphenyl) -3-methyl-1H-pyrazol-4 yl] pyridine; 175 4-ES- (4-chloro-3-methoxyphenyl) -3-methyl-1H-pyrazol-4 yl] pyridine; 4- [5-(2, 3-dihydrobenzofuran-6-y1) -3-methyl-lH-pyrazol-4 yl] pyridine; 4- [5- (benzofuran-6-yl) -3-methyl-1H-pyrazol-4-y11 pyridine; 180 4-ES- (3-f luoro-5-methoxyphenyl) -3-methyl-1H-pyrazol-4 yll pyridine; 4-ES- (3-chloro-5-methoxyphenyl) -3-methyl-1H-pyrazol-4 yl] pyridine; 4- [5- (1-cyclohexyen-1-yl) -3-methyl-1H-pyrazol-4 185 y1]pyridine; 4- [5- (1,3-cyclohexadien-1-y1) -3-methyl-111-pyrazol-4 yl] pyridine; 4-Es- (5,6-dihydro-2H-pyran-4-yl) -3-methyl-lH-pyrazol-4 y1] pyridine; 190 4- (5-cyclohexyl-3-methyl-1H-pyrazol-4-yl)pyridine; 4-E5- (4-methoxy-3-methylphenyl) -3-methyl-11--pyrazol-4 yJ-1pyridine; 4-ES- (3-methoxy-4-methylphenyl) -3-methyl-1H-pyrazol-4 yl] pyridine; 195 4-ES- (3-methoxy-S-methylphenyl) -3-methyl-1H-pyrazol-4 yl] pyridine; SU8SMTMM SEET (R)LE 26) WO 98/52940 PCT/US98/10436 756 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; 200 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-lH-pyrazol-4-yl)pyridin-2 205 yl]ethanone; N,N-dimethyl-4-(3-methyl-5-phenyl-lH-pyrazol-2 yl)pyridin-2-amine; 3-methyl-4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine; 3-methoxy-4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine; 210 methyl 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine-3 carboxylate; 4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine-3 carboxamide; 1-[4-(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridin-3 215 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; 220 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyrimidine; 2-methoxy-4-(3-methyl-5-phenyl-lH-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-4 225 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)-lH-pyrazole; 4-(3-furyl)-3-methyl-5-phenyl-lH-pyrazole; 230 3-methyl-5-phenyl-4-(2-thienyl)-lH-pyrazole; 4-(2-furyl)-3-methyl-5-phenyl-1H-pyrazole; 4-(3-isothiazolyl)-3-methyl-5-phenyl-lH-pyrazole SUM~TUTE& t f=9(RLE26) WO 98/52940 PCT/US98/1 0436 757 4- (3-isoxazolyl) -3-methyl-5-phenyl-1H-pyrazole; 4- (5-isothiazolyl) -3-methyl-5-phenyl-1H-pyrazole; 235 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-1I--pyrazole; 4- [3- (4-f luorophenyl) -1H-pyrazol-4-yllpyridine; 2-methyl-4- [3- (3-methyiphenyl) -1H-pyrazolL-4-yllpyridine; 240 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-chiorophenyl) -1-methyl-pyrazol-4-yllpyridine; 4- [3- (4-chiorophenyl) -1-methyl-pyrazol-4-yllpyridine; 245 4- [3- (3-chilorophenyl) -lH-pyrazol-4-yllpyridine; 4- [3- (4-chiorophenyl) -1H-pyrazol-4-yl] pyridine; 4- [3- (3-chiorophenyl) -1H-pyrazol-4-yl] -2-methylpyridine; 4- [3- (3-f luorophenyl) -1-methyl-1H-pyrazol-4-yllpyridine; 4- [3- (3-f luorophenyl) -1H-pyrazol-4-yl] pyridine; 250 4-[3-(3-chlorophenyl)-l-methyl-pyrazol-4-yl]-2 methylpyridine; 5- (4-chiorophenyl) -N-phenyl-4- (4-pyridinyl) -lH-pyrazol-3 amine; 5- (4-chiorophenyl) -N-methyl-4- (4-pyridinyl) -lH-pyrazol-3 255 amine; 5- (4-chiorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -11 pyrazol -3-amine dihydrate; 5- (3-f luorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -lH pyrazol-3 -amine; 260 N,N-dimethyl-5- (3-methyiphenyl) -4- (4-pyridinyl) -1H pyrazol -3-amine; N-methyl-5- (3-methylphenyl) -4- (4-pyridinyl) -lH-pyrazol-3 amine; N-ethyl-5- (3-methyiphenyl) -4- (4-pyridinyl) -1I-pyrazol-3 265 amine; N,N-diethyl-5- (3-methyiphenyl) -4- (4-pyridinyl) -11 pyrazol-3 -amine; 5- (4-chiorophenyl) - N,N-diethyl-4- (4-pyridinyl) -1H qjWM=TUTESETr(RLU2E.) WO 98/52940 PCT/US98/10436 758 pyrazol-3-amine; 270 4-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3 yll]morpholine; 5-(4-chlorophenyl)-N-propyl-4-(4-pyridinyl) -1H-pyrazol-3 amine; 5-(4-chlorophenyl)-N-(phenylmethyl)-4-(4-pyridinyl) -1H 275 pyrazol-3-amine hydrate (2:1); 5-(4-chlorophenyl) -N-(2-methoxyethyl)-4-(4-pyridinyl) -IH pyrazol-3-amine monohydrate; 1,1-dimethylethyl-4-[5-(4-chlorophenyl)-4-(4-pyridinyl) 1H-pyrazol-3-yll] -1-piperazinecarboxylate; 280 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) 285 1H-pyrazol-3-yll -1-piperazinecarboxylate; 1-[5-(4-fluorophenyl)-4-(4-pyridinyl) -1H-pyrazol-3 yl] piperazine trihydrochloride; 1-[5-(4-chlorophenyl)-4-(4-pyridinyl) -1iH-pyrazol-3 yl] piperazine; 290 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; 295 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-yll] 300 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 mmS UTESHEET( RLE WO 98/52940 PCT/US98/10436 759 305 piperazinecarboxylate; 1,1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4 pyrimidinyl) -11-pyrazol-3-yll -l-piperazinecarboxylate; 1,1-dimethylethyl 13-[[5-(4-chlorophenyl)-4-(2-fluoro-4 pyridinyl) -lH-pyrazol-3-yl] amino] propyll carbamate; 310 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yll-4 ethylpiperazine; N- [5- (4-chiorophenyl) -4- (4-pyridiiyl) -lH-pyrazol-3-yl] 1, 2-ethanediamine; 4- [3- (2,6-difluorophenyl) -5-methyl-lH-pyrazol-4 315 yillpyridine; 4- [3- (3-ethyiphenyl) -5-methyl-111-pyrazol-4-yllpyridine; 4-13- (3-chiorophenyl) -5-ethyl-lH-pyrazol-4-yllpyridine; 4- [3-ethyl-5- (3-ethyiphenyl) -1H-pyrazol-4-yllpyridine; 4- [3- (4-chiorophenyl) -5- (1-methylethyl) -1H-pyrazol-4 320 yllpyridine; 4- [3-cyclopropyl-5- (4-f luorophenyl) -1H-pyrazol-4 yl] pyridine; 4- [3- (4-f luorophenyl) -5- (trifluoromethyl) -1H-pyrazol-4 yll pyridine; 325 4-[5-(cyclopropyl-3-(4-(fluorophenyl)-l-methyl-1H pyrazol-4 -yl] pyridine; 5-cyclopropyl-3- (4-f luorophenyl) -4- (4-pyridinyl) -11 pyrazole-1-ethanol; 3- (4-f luorophenyl) -5- (2-methoxy-4--pyridinyl) -4- (4 330 pyridinyl) -1H-pyrazole-1-ethanol; 4- [3- (4-f luorophenyl) -2.-(2-hydroxyethyl) -4- (4-pyridinyl) 1H-pyrazol-5-yl] -2 (211)-pyridinone; 1-acetyl-4- [3- (4-fluorophenyl) -1-(2-hydroxyethyl) -4- (4 pyridinyl) -1H-pyrazol-5-yll -2(11) -pyridinone; 335 Ethyl 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4 pyridinyl) -lH-pyrazol-5-yl] cyclopropanecarboxylate; 2- [3- (4-f luorophenyl) -1-(2-hydroxyethyl) -4- (4-pyridinyl) iH-pyrazol-5-yll cyclopropanecarboxylic acid; 3- (4-f luorophenyl) -5- (4-imidazolyl) -4- (4-pyridinyl) -1H 340 pyrazole-l-ethanol; U 8 S HHEEU(RLE2M WO98/52940 PCT/US98/10436 760 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-3 345 methanol; 1-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-1iH-pyrazol-3 yl]carbonyl]piperazine; 1,1-dimethylethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridinyl) 1H-pyrazol-3-yl]carbonyl]-1-piperazinecarboxylate; 350 4-(1,5-dimethyl-3-phenyl-1iH-pyrazol-4-yl)pyridine; 4-(1,3-dimethyl-5-phenyl-lH-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-4 355 yl]pyridine; 4-[5-ethyl-l-methyl-3-(3-methylphenyl)-1iH-pyrazol-4 yl]pyridine; 4-[3-ethyl-1-methyl-5-(3-methylphenyl)-1H-pyrazol-4 yl]pyridine; 360 4-[3-(4-chlorophenyl)-l-ethyl-5-methyl-lH-pyrazol-4 yl]pyridine; 4-[3-(4-chlorophenyl)-2-ethyl-5-methyl-1H-pyrazol-4 yl]pyridine; 4-[3-(4-fluorophenyl)-lIH-pyrazol-4-yl]pyridine; 365 4-[3-(2-chlorophenyl)-lH-pyrazol-4-yl]pyridine; 3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-1-ethanol; 3-(4-fluorophenyl)-4-(4-pyrimidinyl)-lH-pyrazole-l ethanol; 4-[3-(4-fluorophenyl)-1-methyl-lH-pyrazol-4-yl]pyridine; 370 2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2 pyridinyl]lamino]-1-butanol; 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-IH-pyrazol-4 yl]pyridine; 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]l-2 375 pyridinecarbonitrile; 4-[2-[3-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-l S TM SHEET (RULES WO 98/52940 PCT/US98/1-0436 761 yll ethyl] morpholine; 3- (4-f luorophenyl) -l-methyl-ou-phenyl-4- (4-pyridinyl) -lH pyrazole-5 -methanol; 380 N-[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH--pyrazol-3-yl]-4 morpholineethanamine; 4- [3- (3-chiorophenyl) -1I-pyrazol-4-yl] -2 (lH) -pyridinone hydrazone; 4- [3- (3-chiorophenyl) -lH-pyrazol-4-yll -N- (phenylmethyl) 385 2 -pyridinarnine; 4- [3- (3-chlorophenyl) -lH-pyrazol-4-yl] -N- (phenylethyl) -2 pyridinamine; 4- [3- (3-chlorophenyl) -lH-pyrazol-4-yl] -N-ethyl-2 pyridinamine; 390 4-[3-(4-florophenyl)-lH-pyrazol-4-yl]-2 pyridinecarboxamide; Methyl 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2 pyridinecarboxylate; 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -N-methyl-2 395 pyridinecarboxamide; 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yll -2 pyridinecarboxylic acid; 4- [3- (3-f luorophenyl) -lH-pyrazol-4-yllpyridine; 4- [3- (1,3-benzodioxol-5-yl) -lH-pyrazol-4-yllpyridine; 400 4- [3- (3-f luorophenyl) -l-methyl-lH-pyrazol-4--yllpyridine; 4- [3- (4-chiorophenyl) -lH-pyrazol-4-yllpyridine; 4- [3- (1,3-benzodioxol-5-y) -l-methyl-1H-pyrazol-4-yllpyrid mne; 4- [3- (4-chlorophenyl) -l-methyl-lI--pyrazol-4-yllpyridine; 405 4- [3- (3-chlorophenyl) -l-methyl-l--pyrazol-4-yl] -2-methylp yridine; 4- [5- (3-chlorophenyl) -l-methyl-lH-pyrazol-4 -yll -2 -methylpyridine; 4- [3- (3-chlorophenyl) -l-methyl-lH-pyrazol-4-yllpyridine; 4- [5- (3-chlorophenyl) -l-methyl-lH-pyrazol-4-yl] pyridine; 410 2-methyl-4- [l-methyl-3- (3-methylphenyl) -lH-pyrazol-4 -yll pyridine; 2-methyl-4- [l-methyl-5- (3-methylphenyl) -lH-pyrazol-4 SLBB'TIUE SHET (RULE 2 WO 98/52940 PCTIUS98/10436 762 -yl] pyridine; 4- (3-phenyl-lH-pyrazol-4-yl)pyridine; 415 4- [3- [3- (trifluoromethyl)phenyl] -1H-pyrazol-4-yllpyridine 4- [1-methyl-3- [3- (trifluoromethyl)phenyll -1H-pyrazol-4-yl pyridine; 4- [3- (3,4-difluorophenyl) -1H-pyrazol-4-yllpyridine; 420 4- [3- (4-chiorophenyl) -lH-pyrazol-4-yl] -2-f luoropyridine; 4- [3- (4-bromophenyl) -1H-pyrazol-4yllpyridine; 4- [3- (3,4-difluorophenyl) -1-methyl-JJI-pyrazol-4-yl]pyridi ne; 4- [3- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yl] pyridine; 425 (E)-4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-(2-phenyleth enyl) pyridine; (S) -4- [3- (4-chiorophenyl) -1I-pyrazol-4-yl] -N- (2-methylbut yl) - 2-pyridinamine; 4- [3- (4-chiorophenyl) -1H-pyrazol-4-yl] -N- [(4-methoxy 430 phenyl)methyll - 2-pyridinamine; N- [4- [3- (4-chiorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] 2 -pyridinemethanamine; N- [4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] 2 -pyridinemethanamine; 435 2-filuoro-4- [3- (4-f luorophenyl) -1H-pyrazol-4-yllpyridine; 4- [3- (4-lodophenyl) -lH-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; 440 N- [1-(4-f luorophenyl)ethyl] -4- [3- (4-f luorophenyl) -1H-pyra zol-4-yl] -2-pyridinamine; N- [(3-f luorophenyl)methyrl]-4- [3- (4-f luorophenyl) -1H-pyraz ol-4-yl] -2-pyridinamine; 4- [3- (4-fluorophenyl) -1-methyl-lH-pyrazol-4-yl] -2- (1 445 rethylhydrazino) pyridine; 2-f luoro-4- [3- (4-f luorophenyl) -1-methyl-lH-pyrazol-4-yllp yridine; 4- [3- (3,4-difluorophenyl) -1H-pyrazol-4-yl] -2-f luoro BUBBMJTSHM~(RULE2) WO 98/52940 PCT/US98/1 Q436 763 pyridine; 450 4- [3- (4-f luorophenyl) -lH--pyrazol-4-yl] -3-methylpyridine; 4- [3- (4-f luorophenyl) -l-methyl-lH-pyrazol-4-yll -3-methyl pyridine; 4- [3- (3,4-difluorophenyl) -l-methyl-lH-pyrazol-4-yl] -2-flu oropyridine; 455 3- (4-f luorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -lH-pyrazo le-l-ethanamine; 2- [2- (4-fluorophenyl)ethyl] -4- [3- (4-fluorophenyl) -1 methyl-lH-pyrazol-4-yl] pyridine; 4- [3- (4-fluorophenyl) -1H-pyrazol-4-yl] -N- [1 460 (phenylmethyl) -4-piperidinyl] -2-pyridinamine; N' -[4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] N, N-dimethyl-l, 2-ethanediamine; 2,4-bis [3- (4-f luorophenyl) -lH-pyrazol-4-yllpyridine; N- [4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] -4 465 morpholineethanamine; 3- (4-f luorophenyl) -4- (2-f luoro-4-pyridinyl) -lil-pyrazole 1-ethanol; 4- [3- (4-f luorophenyl) -1H-pyrazol-4-yl] -N- [2- (1H-imidazol l-yl) ethyl] -2-pyridinamine; 470 4-[2-[3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-lH pyrazol-l-yll ethyl] morpholine; (E) -3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethenyll 4-pyridinyl] -lH-pyrazole-1-ethanol; 3- (4-f luorophenyl) -4- (2-f luoro-4-pyridinyl) -N,N-dimethyl 475 lH-pyrazole-l-ethanamine; 3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl) ethyl] -4 pyridinyl] -lH-pyrazole-1-ethanol; 4- [1-[2- (dimethylamino) ethyl] -3- (4-fluorophenyl) -lii pyrazol-4-yl] -N,N-dimethyl-2-pyridinamine; 480 4- [1-[2- (dimethylanino) ethyl] -3- (4-f luorophenyl) -lii pyrazol-4-yl] -N- [(4-f luorophenyl)methyl] -2-pyridinamine; 3- (4-fluorophenyl) -4- [2- [2- (4-fluorophenyl)ethyl] -4 pyridinyl] -N, N-dimethyl-lII-pyrazole-l-ethanamine; N- [(4-fluorophenyl)methyl]-4-[3(or 5)-(4-fluorophenyl)-l- WO 98/52940 PCT/US98/1 0436 764 485 [[2- (4-morpholinyl) ethyl] -lH-pyrazol-4-yl] -2 pyridinamine; 4- [3- (4-f luorophenyl) -lHi-pyrazol-4-yl] -N-4-piperadinyl-2 pyridinamine; N,N-diethyl-3- (4-f luorophenyl) -4- (2-f luoro-4-pyridinyl) 490 lH-pyrazole-l-ethanamine; 4- i- [2- (diethylamino) ethyl] -3- (4-fluorophenyl) -lH pyrazol-4-yll -N- [(4-f luorophenyl)methyl] -2-pyridinamine; 2- [[4- [3- (4- (fluorophenyl) -lH-pyrazol-4-yl] -2 pyridinyl] amino] ethanol; 495 2-[[4-[3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]-2 pyridinyl] amino] ethanol; 3- [[4- [3- (4-f luorophenyl) -lli-pyrazol-4-yl] -2 pyridinyl] amino] -1-propanol; 3- (4-f luorophenyl) -4- [2- [[(4-f luorophenyl)methyl] amino] 500 4-pyridinyl] -lH-pyrazole-l-ethanol; 5- (4-f luorophenyl) -4- [2- [[(4-fluorophenyl)methyl] amino] 4-pyridinyl] -lH-pyrazole-l-ethanol; N,N-diethyl-3- (4-f luorophenyl) -4- (4-pyridinyl) -lH pyrazole-1-ethanamine; 505 N-[(4-fluorophenyl)methyl]-4-[3-(4-fluorophenyl)-l-[2-(4 morpholinyl) ethyl] -lH-pyrazol-4-yl] -2-pyridinamine; N- [5- (4-f luorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4 morphol inepropanamine; N' -[5- (4-fluorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] 510 N,N-dimethyl-l, 3-propanediamine; 5- (4-f luorophenyl) -N-2-propynyl-4- (4-pyridinyl) -lii pyrazol-3 -amine; 3- (4-f luorophenyl) -4- [2- [[(4-f luorophenyl)methyl] amino] 4-pyridinyl] -lI-pyrazole-l-ethanol; 515 5- (4-f luorophenyl) -4- [2- [[(4-fluorophenyl)methyl] amino] 4-pyridinyl] -lH--pyrazole-l-ethanol; 4- [3- [(4-f luorophenyl) -lH-pyrazol-4-yl] quinoline; N- [5- (4-f luorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3 yllglycine methyl ester; 520 N- [5- (4-f luorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3 SUBSfTUTE8HEET(RLEW WO 98/52940 PCTIUS98/1 0436 765 yll glycine; 4- [3- (4-f luorophenyl) -1-(2-propynyl) -lH-pyrazol-4 yl] pyridine; 4- [5- (4-fluorophenyl) -1-(2-propynyl) -lH-pyrazol-4 525 yllpyridine; 4,4 - (lH-pyrazole-3,4-diyl)bis[pyridine]; 4- [3- (3,4-dichlorophenyl) -lH-pyrazol-4-yllpyridine; N- [5- (4-chiorophenyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -4 piperidinamine; 530 2-Chloro-4- [3- (4-f luoropheiyl) -lH-pyrazol-4 yl] pyrimidine; 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yll -2 (lH) -pyrimidinoie hydra zone; 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -N,N-dimethyl-2 535 pyrimidinamine; 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yll -N-methyl-2 pyrimidinamine; 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -N- (phenylmethyl) 2 -pyrimidinamine; 540 N-cyclopropyl-4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2 pyrimidinamine; 4- [3- (4-fluorophenyl) -lH-pyrazol-4-yl] -N- [(4 methoxyphenyl) methyl] -2-pyrimidinamine; 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2-pyrimidinamine; 545 N- [4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2-pyrimidinyll N- (phenylmethyl) acetamide; Ethyl [4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] -2 pyrimidinyl] carbamate; 4- [3- (3-methyiphenyl) -lH-pyrazol-4-yl] pyrimidine; 550 4- [3- (4-chlorophenyl) -1H-pyrazol-4-yllpyrimidine; 4- [3- (3-f luorophenyl) -lI--pyrazol-4-yl] pyrimidine; and 4- [3- (4-f luorophenyl) -lH-pyrazol-4-yl] pyrimidine. suBsTnuTESHM7~(RULEM)" WO 98/52940 PCT/US98/10436 766

70. A compound of Claim 1 selected from compounds, their tautomers and their pharmaceutically acceptable salts, of the group consisting of N F NO N -NH N0 F N ClI N-NH 0 N N -NH NO-CH2 0 SUBSTUTESHEEr(RULEM) WO 98/52940 PCT/US98/10436 767 N F F N O 0 N F N- O-CH2 N-NH o NN NH H O0 CH3 O F( ) N suesmTESHET(uLE WO 98/52940 PCT/US98/10436 768 N-NH N NH F NN N-NH HI N N CH3 O F(R) N N-NH N O1 N F sumistEragiM~s WO 98/52940 PCT/US98/10436 769 H O0 N-N Br - S-N-CH2 0 N) N-NH N H O N-N I1H / s-N-H 2 F 0 Br N SUBTUTES-Er(FuLE26) WO 98/52940 PCT/US98/1 0436 770 F N ~Brz H 0 N-N \ / SN-CH 2 N 0 C I N-N) N F NU~lLEH~~ WO 98/52940 PCT/US98/1 0436 771 c I 0 F SZZ0 0 NF/ 8UslUT81E (RLE26 WO 98/52940 PCTIUS98/10436 772 Fo N U~lUESEE RL 6 WO 98/52940 PCT/US98/10436 773 pI N-NH N CH 3 0 F(R) N N-NH / H CH 3 O F(R) N N-NH / H 0 N SUBSTIUTSHEEr(RULE26) WO 98/52940 PCTIUS98/1 0436 774 CH 3 F-N Np H0 FF SUBTTTENEE(ULH WO98/52940 PCT/US98/10436 775

71. A compound of claim 1 that is 4-[5-(4 fluorophenyl)-1-(2-propynyl)-lH-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)-lH-pyrazole-l-ethanol or a pharmaceutically-acceptable salt or a tautomer thereof.

74. A compound of claim 1 that is 4-[3-(4 fluorophenyl)-l-methyl-lH-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)-lH-pyrazol-3-yl]piperazine or a pharmaceutically-acceptable salt or a tautomer thereof.

76. A compound of claim 1 that is 4-[3-cyclopropyl 5-(4-fluorophenyl)-lH-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)-lH-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)-lH-pyrazol-3-yl]l-4 methylpiperazine or a pharmaceutically-acceptable salt or a tautomer thereof. SUBMIT ESHE (RUMLE) WO98/52940 PCT/US98/10436 776

79. A compound of claim 1 that is 4-[3-(4 fluorophenyl)-lH-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)-lH-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)-l-methyl-lH-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)-lH-pyrazol-4yl]pyridine or a pharmaceutically-acceptable salt or a tautomer thereof.

83. A compound of claim 1 that is 4-[3-(4-chlorophenyl)lH-pyrazol-4-yl]-2-fluoropyridine or a pharmaceutically-acceptable salt or a tautomer thereof.

84. A compound of claim 1 that is 4-[3-(l,3-benzodioxol 5-y)-l-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)l1-methyl-lH-pyrazol-4-yl]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. sUBsTIumSHEET(RULE6) WO98/52940 PCT/US98/10436 777

87. A compound of claim 1 that is 5-(4 fluorophenyl)-N-2-propynyl-4-(4-pyridinyl)-lH-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: R e P R 2 5 2 N 4 N (XII) wherein R' is a hydrocarbyl, heterosubstituted hydrocarbyl or 5 heterocyclyl radical having a molecular weight less than about 360 atomic mass units; and R 2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical that binds with p38 kinase at said ATP binding site of p38 kinase; and 10 R 3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality; and R 4 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than 15 about 360 atomic mass units; provided R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R' is hydrido; further provided R 2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl 20 when R 4 is hydrido; and further provided R 4 is not SUBSTITrESHEET(RULE2) WO98/52940 PCT/US98/10436 778 methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer thereof.

90. A compound of claim 89 wherein R 2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical that binds with Lys 52 , Glu 69 , Leu 73 , Ile 82 , Leu 84 , Leu 101 , and Thr 103 sidechains at said ATP 5 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 R 3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality that hydrogen bonds with the N-H backbone 5 of Met 106 of p38 kinase.

92. A compound of claim 89 wherein R' 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 R 4 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 R 1 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a molecular weight less than about 360 atomic mass units; and 5 R 2 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical wherein said radical binds with Lys 5 2 , Glu 6 9, Leu 73 , Ile82' Leu84, Leu 1 01 , and Thr, 0 3 sidechains suesTrruWTESEr (FULE2) WO98/52940 PCT/US98/10436 779 at said ATP binding site of p38 kinase, said radical being substantially disposed within a hydrophobic cavity 10 formed during said binding by p38 kinase at the ATP binding site; and R 3 is a hydrocarbyl, heterosubstituted hydrocarbyl or heterocyclyl radical having a hydrogen bond acceptor functionality that hydrogen bonds with the N-H backbone 15 of Met 106 of p38 kinase; and R 4 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 R 1 and R 4 are independently selected from hydrocarbyl, heterosubstituted hydrocarbyl and heterocyclyl radicals and have a combined molecular weight less than about 360 5 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 susmUTESEE (RULE2) WO98/52940 PCT/US98/10436 780 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 sueSmUTMSHET(FLUE WO98/52940 PCT/US98/IO436 781 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 R R 2 I ZN N 5 (I) wherein R 1 is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, 10 heterocyclylalkylene, haloalkyl, haloalkenyl, 8USTURESHEET(RULE 26) WO98/52940 PCT/US98/10436 782 haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, 15 heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthicalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, 20 arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, 25 heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, 30 alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or R I has the formula R 2 5 0 R 26 -C-C CH 2 ) i- C-N 27 35 H (II) wherein: i is an integer from 0 to 9; R 2 1 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, 40 aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and WO98/52940 PCT/US98/10436 783 R 2 " is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, 45 alkoxycarbonylalkylene, and alkylaminoalkyl; and R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, 50 alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, 55 alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, 60 arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, 65 alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, 70 alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, 75 alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, SusTIUTESHEET (RULE 26) WO98/52940 PCT/US98/10436 784 alkoxy, keto, amino, nitro, and cyano; or 80 R 27 is -CHR 2 "R 29 wherein R 28 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and 85 heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or R 26 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said 90 heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, 95 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; 100 and R 2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, 105 heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, 110 arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, susmiTESm E uL WO98/52940 PCT/US98/10436 785 115 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, 120 aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, 125 arylsulfonyl, and aralkylsulfonyl; or R 2 has the formula: p 3 0 2H R -- C--(CH 2 .- C -N H 2 -N 3 3 31 3 L m (III) wherein: j is an integer from 0 to 8; and 130 m is 0 or 1; and R" and R 3 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and 135 R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; 140 R 33 is selected from hydrogen, alkyl, -C(O)R, -C (0) ORa 5 , -S0 2 R 6 , -C (0) NR 3 R 38 , and -S0 2 NR 9 R, wherein R 35 , R 36 , R 37 , R 38 , R 39 and R 4° are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and 145 R 34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or UST ESHEET(RULES) WO98/52940 PCT/US98/10436 786 R 2 is -CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy; and R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, , 3 0 N :and ON O I43 150 (IV) (V) wherein R 43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and 155 wherein the R 3 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, 160 alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, 165 alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, 170 alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR 44 R 4 " wherein R 44 is alkylcarbonyl or amino, and R 4 1 is alkyl or aralkyl; and R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, 175 cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals sUBsmTMTESHEE(FULE2) WO98/52940 PCT/US98/10436 787 independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, 180 alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, 185 nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; provided R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R' is hydrido; further provided R 2 is selected from aryl, heterocyclyl, 190 unsubstituted cycloalkyl and cycloalkenyl when R' is hydrido; and further provided R' 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 5 Formula I R 2 4 534 9 2 N (I) where in R' is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, 8UBSTUM MSHEET(RULE 2) WO98/52940 PCTIUS98/10436 788 10 cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, 15 alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, 20 alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, 25 alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, 30 arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or 35 R' has the formula R 2 5 0 926 I R 2 6 -C-C CH 2 C-N I \ 27 H (II) wherein: i is an integer from 0 to 9; R 2 1 is selected from hydrogen, alkyl, aralkyl, 40 heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, SUBMTUMTESHEE(RULE26) WO98/52940 PCT/US98/10436 789 alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R 26 is selected from hydrogen, alkyl, alkenyl, 45 alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, 50 cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, 55 aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, 60 alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, 65 alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, 70 arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, 75 aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups =s 7 IITIT WRMIN-T(ILR M WO98/52940 PCT/US98/10436 790 are optionally substituted with one or more radicals independently selected from alkyl, halo, haloalkyl, 80 alkoxy, keto, amino, nitro, and cyano; or R 27 is -CHR 2 8 R 29 wherein R 28 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and 85 aralkylthioalkylene; wherein said aralkyl and heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or R 26 and R 27 together with the nitrogen atom to which 90 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, 95 alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are optionally substituted with one or more radicals 100 independently selected from halogen, alkyl and alkoxy; and R 2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, 105 alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, 110 cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, BSMM SHEET (RULE2) WO 98/52940 PCT/US98/10436 791 alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, 115 alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally substituted with one or more radicals independently 120 selected from halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, 125 alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or R 2 has the formula: R30 -H R3 -C-( CH 2 D - N 131 1 3 R 3 3 L m (III) wherein: 130 j is an integer from 0 to 8; and m is 0 or 1; and R 3 ' and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, 135 alkoxyalkyl, and alkylcarbonyloxyalkyl; and R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and 140 heterocyclylcarbonylaminoalkylene; R 3 is selected from hydrogen, alkyl, -C(O)R", -C (0) OR 35 , -S0 2 R 36 , -C (0) NR 37 R 3 , and -S0 2 NR 9 R 4 , wherein R 35 , R 36 , R 37 , R 38 , R 39 and R 4 ' are independently selected from hydrocarbon, heterosubstituted hydrocarbon and 145 heterocyclyl; and SUST rESHEE (RULE) WO98/52940 PCTIUS98/10436 792 R 34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or R 2 is -CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy; and R 3 is selected from pyridinyl, pyrimidinyl, 150 quinolinyl, purinyl, 0 N and 0 R N 0 R (IV) (V) wherein R 43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; 155 and wherein the R 3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, 160 carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, 165 aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, 170 aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR 44 R 4 1 wherein R 44 is alkylcarbonyl or amino, and R 4 1 is alkyl or aralkyl; and 175 R' is selected from hydrido, alkyl, alkenyl, alkynyl, SUBSITMUESHEE (RULE26) WO98/52940 PCTIUS98/10Q436 793 cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, 180 alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, 185 alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; provided R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R I is hydrido; 190 further provided R 2 is selected from aryl, heterocyclyl, unsubstituted cycloalkyl and cycloalkenyl when R 4 is hydrido; and further provided R 4 is not methylsulfonylphenyl; or a pharmaceutically-acceptable salt or tautomer 195 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 R R 2 N 5 (I) wherein R' is selected from hydrido, alkyl, cycloalkyl, SUSSWrTE SHlEEr (RULE 26) WO98/52940 PCT/US98/10436 794 alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, 10 heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, 15 heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, 20 arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, 25 heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, 30 alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or R' has the formula R 2 5 O R 2 6 -C--(CH 2 D - C-N I R27 35 H (II) wherein: i is an integer from 0 to 9; R 2 1 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, suM s (RULs) WO98/52940 PCT/US98/10436 795 40 aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R 2 " is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, 45 alkoxycarbonylalkylene, and alkylaminoalkyl; and R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, 50 alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, 55 alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, 60 arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, 65 alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, 70 alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, 75 alkylthioarylene, heterocyclylthioarylene, SUBSTmMUTEMSHEET(RULE28) WO98/52940 PCT/US98/10436 796 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 80 R 27 is -CHR 2 8 R 29 wherein R 2 1 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and 85 heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or R 26 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said 90 heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, 95 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; 100 and R 2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, 105 heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, 110 arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, MsumMTE PsE ( 6) WO 98/52940 PCT/US98/10436 797 carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, 115 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, 120 aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, 125 arylsulfonyl, and aralkylsulfonyl; or R 2 has the formula: R 3 0 H R R --C--(CHQ- C-N 131 CH 2 1J 3 4 m (III) wherein: j is an integer from 0 to 8; and 130 m is 0 or 1; and R 30 and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and 135 R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; 140 R 33 is selected from hydrogen, alkyl, -C(O)R, -C (0) OR, -S0 2 R 36 , -C (0) NR R 8 , and -S0 2 NR 9 R, wherein R 3 , R 36 , R 37 , R 38 , R 39 and R 4 ' are independently selected from hydrocarbon, heterosubstituted hydrocarbon and suBstnUTESHEEr(RULE3) WO98/52940 PCT/US98/10436 798 heterocyclyl; and 145 R 34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or R 2 is -CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy; and R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, 0 N and 0 N 0 143 150 R (IV) (V) wherein R 43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and 155 wherein the R 3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, aralkyl, aralkenyl, aryTheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, 160 alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, 165 alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, 170 alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR 4 R 4 " wherein R 44 is alkylcarbonyl or amino, and R 4 " is alkyl or aralkyl; and SUBSTITUTESHEET(RULE 26 ) WO98/52940 PCT/US98/10436 799 R' is selected from hydrido, alkyl, alkenyl, alkynyl, 175 cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, 180 alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, 185 nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; provided R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R1 is hydrido; further provided R 2 is selected from aryl, heterocyclyl, 190 unsubstituted cycloalkyl and cycloalkenyl when R 4 is hydrido; and further provided R' 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 R 3 R 2 4 N 5 2 N N 5( 5 P sarrruTeffMEU (RULE CO) WO98/52940 PCT/US98/10436 800 wherein R' is selected from hydrido, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, 10 heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, 15 heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, 20 arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, 25 heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, 30 alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene; or R 1 has the formula R 2 5 0 R26 -C- CH 2 ) - C-N I \ 27 35 H (II) wherein: i is an integer from 0 to 9; 8UTUMsEHE (RULE2) WO98/52940 PCTIUS98/10436 801 R 25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, 40 aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and R 26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, 45 alkoxycarbonylalkylene, and alkylaminoalkyl; and R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, 50 alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, 55 alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, 60 arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene,'alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, 65 alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, 70 alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, SUBSMMTUTESHEET(RLE) WO98/52940 PCT/US98/10436 802 aryloxycarbonylarylene, arylcarbonylarylene, 75 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 80 R 27 is -CHR 28 R 29 wherein R 28 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene; wherein said aralkyl and 85 heterocylcyl groups are optionally substituted with one or more radicals independently selected from alkyl and nitro; or R 26 and R 27 together with the nitrogen atom to which they are attached form a heterocycle, wherein said 90 heterocycle is optionally substituted with one or more radicals independently selected from alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, 95 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; 100 and R 2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, 105 heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, WO 98/52940 PCT/US98/10436 803 110 arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, 115 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, 120 aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, 125 arylsulfonyl, and aralkylsulfonyl; or R 2 has the formula: R 30 -H R 3 -- C--CC .- C - 31 CH 2 j 3 32 m (III) wherein: j is an integer from 0 to 8; and 130 m is 0 or 1; and R 30 and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and 135 R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; 140 R 3 is selected from hydrogen, alkyl, -C(O)R, -C (0) OR 3 , -S0 2 R 36 , -C (0) NR 37 R 3 , and -S0 2 NR 3 9 R 40 , wherein R", sugrr3E~ ME(UML~ WO 98/52940 PCT/US98/10436 804 R 36 , R 37 , R 38 , R 39 and R 4 " are independently selected from hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and 145 R 34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or R 2 is -CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy; and R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, N and O 4N 0 143 150 (IV) (V) wherein R 43 is selected from hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and 155 wherein the R 3 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, 160 alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, 165 alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, 170 alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, SUSTmUTESHEET(RULEM) WO98/52940 PCT/US98/10436 805 arylhydrazinyl, or -NR 44 R 4 " wherein R 44 is alkylcarbonyl or amino, and R 45 is alkyl or aralkyl; and R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, 175 cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, 180 alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, 185 nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; provided R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R' is hydrido; further provided R 2 is selected from aryl, heterocyclyl, 190 unsubstituted cycloalkyl and cycloalkenyl when R 4 is hydrido; and further provided R 4 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 5 Formula I SUBMUMSTESHEET(RMLE) WO98/52940 PCT/US98/10436 806 N5 N R 5 (I) wherein Z represents a carbon atom or a nitrogen atom; and R 1 is selected from hydrido, lower alkyl, lower 10 hydroxyalkyl and lower alkynyl; and R 2 is selected from hydrido and lower alkyl; and R 4 is selected from phenyl and benzodioxolyl; wherein phenyl is optionally substituted with one or more halo radicals; and 15 R S 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 5 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, 10 inflammatory bowel disease and cachexia. MSTMUTSHEET (RULE ) WO 98/52940 PCT/US98/10436 807

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)-liH-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)-1iH-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 p38u 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 5 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, 10 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 SUBSMUTESHEET(RULE28) WO98/52940 PCT/US98/10436 808 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 5 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, 10 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 R 3 R 2 R 44 5 2 N N (I) P WO98/52940 PCT/US98/10436 809 wherein R 1 is selected from hydrido, alkyl, cycloalkyl, 5 alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, 10 arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, 15 alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, 20 alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, 25 heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and 30 heterocyclylcarbonyloxyarylene; or R I has the formula R25O R 2 5 0 R26 I I / -C-(CH 2 ) C-N I \ 27 H (II) wherein: i is an integer from 0 to 9; SUBSTUE HEE(RULE 2) WO98/52940 PCT/US98/10436 810 35 R 25 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and 40 R 26 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, 45 cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, 50 alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, 55 alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, 60 arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, 65 aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, 70 alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, SUSSfTRUTESHEET RULE8 WO98/52940 PCT/US98/10436 811 aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals 75 independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or R 27 is -CHR 28 R 29 wherein R 2 1 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, 80 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 85 R 26 and R 27 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, 90 alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are 95 optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and R 2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, 100 aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, 105 alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, 8 uesmUTESHEET(RULE 2 ) WO98/52940 PCT/US98/10436 812 arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, 110 alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally 115 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, 120 alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or R 2 has the formula: R 30 -H R 3 -C-CCH - L -N 3 125 wherein: j is an integer from 0 to 8; and m is 0 or 1; and R 3 " and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, 130 aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R 32 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, 135 alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R 33 is selected from hydrogen, alkyl, -C(O)R, -C(O)OR 5 , -S0 2 R 3 , -C (O)NRR 8 , and -S0 2 NR 9 R 4 0 , wherein R 3 , SUBSTITUTE SHEET(RULE 26) WO 98/52940 PCTIUS98/10436 813 R 36 , R 37 , R 38 , R 39 and R" are independently selected from 140 hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R 34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or R 2 is -CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy; and 145 R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, , 0 N and 0 R N 0 1 4 3 (IV) (V) wherein R 43 is selected from hydrogen, alkyl, 150 aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and wherein the R 3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, 155 aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, 160 cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, 165 aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, SUBSTITUTE SHEET (RULE 26) WO98/52940 PCTIUS98/10436 814 arylhydrazinyl, or -NR 4 R 45 wherein R 44 is alkylcarbonyl or 170 amino, and R 4 1 is alkyl or aralkyl; and R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, 175 alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, 180 aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer 185 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 OC to about 200 oC.

136. A method of preparing pyrazoles of Formula I SmSmUTESHEET(RULE WO98/52940 PCT/US98/10436 815 R 3 R 2 R 5 2 N N (I) wherein R' is selected from hydrido, alkyl, cycloalkyl, 5 alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, 10 arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, 15 alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, 20 alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, 25 heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and SUBSTITUTE SHEET (RULE26) WO98/52940 PCT/US98/10436 816 30 heterocyclylcarbonyloxyarylene; or R1 has the formula R 2 5 0 R26 -C-( CH 2 - C-N 27 H(II) wherein: i is an integer from 0 to 9; 35 R 2 " is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; and 40 R 2 " is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl; and R 27 is selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, 45 cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, 50 alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, 55 alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, 60 arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, sm THEET(RULEM) WO98/52940 PCT/US98/10436 817 alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, 65 aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene; wherein said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, 70 alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene groups are optionally substituted with one or more radicals 75 independently selected from alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano; or R 27 is -CHR 2 'R 29 wherein R 2 1 is alkoxycarbonyl, and R 29 is selected from aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, 80 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 85 R 26 and R 27 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, 90 alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino; wherein said aryl, heterocyclylalkylene and aryloxyalkylene radicals are 95 optionally substituted with one or more radicals independently selected from halogen, alkyl and alkoxy; and SSWESHEE(RUL6) WO 98/52940 PCT/US98/10436 818 R 2 is selected from hydrido, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, 100 aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, 105 alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, 110 alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl; wherein the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl and cycloalkenyl groups are optionally 115 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, 120 alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl; or R 2 has the formula: R30 H R32 -- C--cCH 2 D. 31 1 3 4 m (III) 125 wherein: j is an integer from 0 to 8; and m is 0 or 1; and R 30 and R 31 are independently selected from hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, SUSWTMSHET(RULE26) WO98/52940 PCT/US98/10436 819 130 aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; and R" 2 is selected from hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, 135 alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R" is selected from hydrogen, alkyl, -C(O)R, -C(O)OR , -S0 2 R 6 , -C(O)NRR , and -S0 2 NR 3 9 R 4 , wherein R 3s R 36 , R 37 , R 38 , R 39 and R 4° are independently selected from 140 hydrocarbon, heterosubstituted hydrocarbon and heterocyclyl; and R 34 is selected from hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; or R 2 is -CR 41 R 42 wherein R 41 is aryl, and R 42 is hydroxy; and 145 R 3 is selected from pyridinyl, pyrimidinyl, quinolinyl, purinyl, N and 0 R N 0 R 4 3 (IV) (V) wherein R 43 is selected from hydrogen, alkyl, 150 aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; and wherein the R 3 pyridinyl, pyrimidinyl, quinolinyl and purinyl groups are optionally substituted with one or more radicals independently selected from halo, alkyl, 155 aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, sussmUTESHEE (RULE26) WO98/52940 PCT/US98/10436 820 160 cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, 165 aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, or -NR 44 R 45 wherein R 44 is alkylcarbonyl or 170 amino, and R 4 " is alkyl or aralkyl; and R 4 is selected from hydrido, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein R 4 is optionally substituted with one or more radicals independently selected from halo, alkyl, alkenyl, 175 alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, 180 aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy; or a pharmaceutically-acceptable salt or tautomer 185 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. SUBSTI SHEET(RULE26) WO 98/52940 PCT/US98/10436 821

139. The process of Claim 137 wherein the acidic solvent is an organic solvent containing an acid. SUfEETUTESHEET(RULEM )