AU754830B2 - Substituted pyrazoles as p38 kinase inhibitors - Google Patents

Description

SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS Field of the Invention This invention relates to a novel group of pyrazole compounds, compositions and methods for treating p38 kinase mediated disorders.

o Background of the Invention Mitogen-activated protein kinases (MAP) is a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. The kinases are activated by a variety of signals including nutritional and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines. The p38 MAP kinase group is a MAP family of various isoforms, including p38a, p380 and p387, and is responsible for phosphorylating and activating transcription factors ATF2, CHOP and MEF2C) as well as other kinases MAPKAP-2 and MAPKAP-3). The p38 isoforms are activated by bacterial lipopolysaccharide, physical and chemical stress and by pro-inflammatory cytokines, including tumor necrosis factor (TNF-a) and interleukin-1 The products of the p38 phosphorylation mediate the production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2.

TNF-a is a cytokine produced primarily by activated monocytes and macrophages. Excessive or unregulated TNF production has been implicated in mediating a number of diseases. Recent studies indicate that TNF has a causative role in the pathogenesis of rheumatoid WO 98/52940 PCT/US98/10436 2 arthritis. Additional studies demonstrate that inhibition of TNF has broad application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.

TNF has also been implicated in viral infections, such as HIV, influenza virus, and herpes virus including herpes simplex virus type-i (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitis, among others.

IL-8 is another pro-inflammatory cytokine, which is produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes, and is associated with conditions including inflammation.

IL-1 is produced by activated monocytes and macrophages and is involved in the inflammatory response.

IL-1 plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption.

TNF, IL-1 and IL-8 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines by inhibition of the p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states.

Various pyrazoles have previously been described.

U.S. Patent No. 4,000,281, to Beiler and Binon, describes substituted pyrazoles with antiviral activity against both RNA and DNA viruses such as myxoviruses, adenoviruses, rhinoviruses, and various viruses of the herpes group. WO 92/19615, published November 12, 1992, describes pyrazoles as novel fungicides. U. S. Patent No. 3,984,431, to Cueremy and Renault, describes derivatives of pyrazole-5-acetic acid as having anti-inflammatory activity. Specifically, [1- MsUB TEBMEET(RL)LE2O)' 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 process for the preparation of diphenyl-3,4-methyl-5pyrazole 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 herbicides. EP 515,041 describes pyrimidyl substituted pyrazole derivatives as novel agricultural fungicides.

Japanese Patent 4,145,081 describes pyrazolecarboxylic acid derivatives as herbicides. Japanese Patent 5,345,772 describes novel pyrazole derivatives as inhibiting acetylcholinesterase.

Pyrazoles have been described for use in the treatment of inflammation. Japanese Patent 5,017,470 describes synthesis of pyrazole derivatives as antiinflammatory, anti-rheumatic, anti-bacterial and antiviral drugs. EP 115640, published Dec 30, 1983, describes 4-imidazolyl-pyrazole derivatives as inhibitors of thromboxane synthesis. 3-(4-Isopropyl-lmethylcyclohex-1-yl)-4-(imidazol-l-yl)-1H-pyrazole is specifically described. WO 97/01551, published Jan 16, 1997, describes pyrazole compounds as adenosine antagonists. 4-(3-Oxo-2,3-dihydropyridazin-6-yl)-3phenylpyrazole is specifically described. U.S. Patent No. 5,134,142, to Matsuo et al. describes pyrazoles as having anti-inflammatory activity.

U.S. Patent No. 5,559,137 to Adams et al, describes novel pyrazoles (1,3,4,-substituted) as inhibitors of cytokines used in the treatment of cytokine diseases.

Specifically, 3-(4-fluorophenyl)-1-(4methylsulfinylphenyl)-4-(4-pyridyl)-5H-pyrazole is described. WO 96/03385, published February 8, 1996, describes 3,4-substituted pyrazoles, as having anti- SUBSTmTESHEET(RULE 2 s 4 inflammatory activity. Specifically, 4-[l-ethyl-4-(4pyridyl)-5-trifluoromethyl-lH-pyrazol-3yl]benzenesulfonamide is described.

The invention's pyrazolyl compounds are found to show usefulness as p38 kinase inhibitors.

Description of the Invention In one aspect, the present invention provides a compound, a tautomer of the compound, a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound corresponds in structure to Formula I 3 2 R

R*

4 3j 44 5 N*

N

R as to R 1

R

1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, kenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, and heterocyclylcarbonyloxyalkylene, or

R

1 corresponds in structure to formula (II):

R

25 0 2

H

Si is an integer from zero to 9; R 25 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; as to R 6 and R 2 R 26 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: R 27 is selected from the group consisting of alkyl, cycloalkyl, alkynyl,. aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, ~ST~(aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, 6 alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkyleie, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarboiylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, 00alkeoyycarbonylalkylarylene, alkylthioalkylene, 000 15 cycloalkylthioalkylene, alkylthioarylene, 000 aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: 20 said alkyl, cycloalkyl, aryl, heterocyclyl, o aralkyl, heterocyclylalkylene, :00...alkyiheterocyclylarylene, alkoxyarylene, oooo~oaryloxyarylene, arylaminocarbonylalkylene, 0* aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R 2 is -CHR 2R 2, or 6 and R 27 together with the nitrogen to which they /~T~are attached, f orm a heterocycle, wherein: 7 said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy;

R

28 is alkoxycarbonyl; 2 0:0* R 29 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, 15 alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene, wherein: said aralkyl and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl and nitro; oo.2 as to R 2

R

2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, 'T -alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl, wherein: the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl)carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, hydroxyalkylcarbonyl, alkoxycarbonyl, arylsulfonyl, and aralkylsulfonyl, or

R

2 corresponds in structure to formula (III):

R

30

H

I

R

32 C-(CH2)j-- N R33 R33 R31

R

34 L J m (III), or

R

2 is -CR 41

R

42

R

2 is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl, and cycloalkenyl when R 4 is hydrogen; j is an integer from zero to 8; m is selected from the group consisting of zero and 1;

R

30 and. R 31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, T alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and 307 alkylcarbonyloxyalkyl; 9

R

32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;

R

33 is selected from the group consisting of hydrogen, alkyl, -C(O)R 35

-C(O)OR

35 -S0 2

R

3 6

-C(O)NR

37

R

3 8 and

-SO

2 NR39R 40

R

35

R

36

R

37

R

38

R

39 and R 40 are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon, and heterocyclyl;

R

3 4 is selected from the group consisting of hydrogen, 0 alkyl, aminocarbonyl, alkylaminocarbonyl, and 15 arylaminocarbonyl;

R

41 is aryl;

R

42 is hydroxy;

R

3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, 2O

N

SR43 and 43 wherein: the pyridinyl, pyrimidinyl, quinolinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, salkyl, aralkyl, aralkenyl, 9a aryiheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, aryithia, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, 0 Vto 0* nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, :hydrazinyl, alkyihydrazinyl, aryihydrazinyl, and -NR4445

R

3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R 1 is hydrogen;

R

43 is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and *fee 20 aryloxyalkyl;

R

44 is selected from the group consisting of alkylcarbonyl and amino;

R

4 5 is selected from the group consisting of alkyl and goof aralkyl; and

R

4 is selected from the group consisting of hydrogen, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein: the alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, TZ' arylthioalkylene, 9b alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy.

Compounds of Formula I would be useful for, but not 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 Sproduction by such mammal. Accordingly, the present invention provides a method of treating a cytokinemediated 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 S*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 chronic pulmonary inflammatory disease. The compounds are also useful for the treatment of viral and bacterial infections, including sepsis, septic shock, gram negative sepsis, malaria, meningitis, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS Sf e related complex), pneumonia, and herpesvirus. The WO 98/52940 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 allograft rejections, cardiovascular diseases including atherosclerosis, thrombosis, congestive heart failure, and cardiac reperfusion injury, renal reperfusion injury, liver disease and nephritis, and myalgias due to infection. The compounds are also useful for the treatment of influenza, multiple sclerosis, cancer, diabetes, systemic lupus erthrematosis (SLE), skinrelated conditions such as psoriasis, eczema, burns, dermatitis, keloid formation, scar tissue formation, and angiogenic disorders. Compounds of the invention also would be useful to treat gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds would also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, uveitis, ocular photophobia, and of acute injury to the eye tissue. Compounds of the invention also would be useful for treatment of angiogenesis, including neoplasia; metastasis; ophthalmological conditions such as corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological, but non-malignant, conditions such as hemaginomas, including invantile hemaginomas, angiofibroma of the nasopharynx and avascular necrosis of bone; diabetic nephropathy and cardiomyopathy; and disorders of the female reproductive system such as endometriosis. The compounds of the invention may also be useful for preventing the production of cyclooxygenase-2.

8UBSTTEMSHEET(RULE26) WO 98/52940 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 animals include horses, dogs, and cats.

The present compounds may also be used in cotherapies, partially or completely, in place of other conventional anti-inflammatories, such as together with steroids, cyclooxygenase-2 inhibitors, DMARD's, immunosuppressive agents, NSAIDs, 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 which TNF plays a role, either by control of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disorder mediated by TNF.

As used herein, the term "p38 mediated disorder" refers to any and all disorders and disease states in which p38 plays a role, either by control of p38 itself, or by p38 causing another factor to be released, such as but not limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to p38, would therefore be considered a disorder mediated by p38.

As TNF-/ has close structural homology with TNF-a (also known as cachectin) and since each induces similar biologic responses and binds to the same cellular receptor, the synthesis of both TNF-a and TNF-3 are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF" unless a 1:11RUIESHEET(RULE26)8 13 specifically delineated otherwise.

A preferred class of compounds consists of those compounds of Formula I, wherein: as to R 1

R

1 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower aralkyl, lower alkoxyalkyl, lower mercaptoalkyl, lower alkylthioalkylene, amino, lower alkylamino, lower arylamino, lower alkylaminoalkylene, and lower heterocyclylalkylene, or R corresponds in structure to formula (II): R25 O II R26 -C--(CH2)i-C--N

R

27

H

(II);

i i is selected from the group consisting of zero, 1, and 2;

R

25 is selected from the group consisting of hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, lower phenoxyalkylene, lower aminoalkyl, lower alkylaminoalkyl, lower phenoxyaminoalkyl, lower alkylcarbonylalkylene, lower phenoxycarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene; as to R 26 and R 27

R

26 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower phenylalkyl, lower -<gg alkoxycarbonylalkylene, and lower alkylaminoalkyl, and: 14 R 27 is selected from the group consisting of lower alkyl, lower cycloalkyl, lower alkynyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower phenylalkyl, lower cycloalkylalkylene, lower cycloalkenylalkylene, lower cycloalkylarylene, lower cycloalkylcycloalkyl, lower heterocyclylalkylene, lower alkyiphenylene, lower alkylphenylalkyl, lower phenylalkyiphenylene, lower alkylheterocyclyl, lower alkylheterocyclylalkylene, lower alkylheterocyclylphenylene, lower phenylalkyiheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl, lower alkoxyheterocyclyl, lower *',,alkoxyalkoxyphenylene, lower phenoxyphenylene, lower phenylalkoxyphenylene, lower alkoxyheterocyclylalkylene, lower phenoxyalkoxyphenylene, lower 15 alkoxycarbonylalkylene, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonylalkylene, lower aminoalkyl, lower alkylaminoalkylene, lower phenylaminocarbonylalkylene, lower alkoxyphenylaminocarbonylalkylene, lower aminocarbonylalkylene, arylaminocarbonylalkylene, lower alkylaminocarbonylalkylene, lower phenylcarbonylalkylene, lower alkoxycarbonylphenylene, lower phenoxycarbonylphenylene, lower alypeoyaboypeyee loe lower phenylcarbonylphenylene, lower alkoyphenylrbon cylphenylene, lower alkoxycarbonylheteocyylphenylene, lower alkeoyycarbonylalkylphenylene, lower alkylthioalkylene, cycloalkylthioalkylene, lower alkylthiophenylene, lower phenylalkylthiophenylene, lower heterocyclylthiophenylene, lower /Th'ienylthioalklyphenylene, lower phenylsulfonylaminoalkylene, lower alkylsulfonylphenylene, lower alkylaminosulfonylphenylene, wherein: said lower alkyl, lower cycloalkyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower phenylalkyl, lower heterocyclylalkylene, lower alkylheterocyclylphenylene, lower alkoxyphenylene, lower phenoxyphenylene, lower phenylaminocarbonylalkylene, lower phenoxycarbonylphenylene, lower phenylcarbonylphenylene, lower alkylthiophenylene, lower heterocyclylthiophenylene, lower phenylthioalklylphenylene, and lower alkylsulfonylphenylene are optionally substituted with 1 one or more radicals independently selected from the group consisting of lower alkyl, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, and cyano, or

R

27 is -CHR 6

R

47 or

R

26 and R 27 together with the nitrogen 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 the group consisting of lower alkyl, phenyl, biphenyl, naphthyl, heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenoxyalkylene, lower alkoxyphenylene, lower alkylphenoxyalkylene, lower alkylcarbonyl, lower alkoxycarbonyl, lower phenylalkoxycarbonyl, lower alkylamino, and lower alkoxycarbonylamino, wherein: said phenyl, biphenyl, naphthyl, lower heterocyclylalkylene, and lower phenoxyalkylene are i optionally substituted with one or more radicals 16 independently selected from the group consisting of halogen, lower alkyl, and lower alkoxy;

R

46 is lower alkoxycarbonyl;

R

47 is selected from the group consisting of lower phenylalkyl, lower phenylalkoxyalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower alkoxycarbonylalkylene, lower alkylthioalkylene, and lower phenylalkylthioalkylene, wherein: the phenylalkyl and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl and nitro; *2 as to R 2

R

2 is selected from the group consisting of hydrogen, halogen, lower alkyl, phenyl, biphenyl, naphthyl, lower haloalkyl, lower hydroxyalkyl, 5- to 6-membered heterocyclyl, lower alkylheterocyclyl, lower heterocyclylalkyl, lower alkylamino, lower alkynylamino, phenylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkylaminoalkylamino, lower cycloalkyl, lower alkenyl, lower alkoxycarbonylalkyl, lower cycloalkenyl, lower carboxyalkylamino, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonyl, alkoxycarbonylalkyl, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylsulfonyl, lower heterocyclyloxy, and lower heterocyclylthio, wherein: the phenyl, biphenyl, naphthyl, heterocylyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl are foptionally substituted with one or more radicals 17 independently selected from the group consisting of halo, keto, lower alkyl, lower alkynyl, phenyl, 5- to 6-membered heterocyclyl, lower phenylalkyl, lower heterocyclylalkyl, lower epoxyalkyl, carboxy, lower alkoxy, lower aryloxy, lower phenylalkoxy, lower haloalkyl, lower alkylamino, lower alkylaminoalkylamino, lower alkynylamino, lower amino(hydroxyalkyl), lower heterocyclylalkylamino, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, and phenylsulfonyl, or

R

2 is -CRR 42 or

R

2 corresponds in structure to a formula selected from the group consisting of:

SS

S.

R

3 0

I

R31

R

S

.55.

55.55

S

R

5 7

(III),

R

58 R58 R58 N R 56 N N

(CH

2 N 0 (VI) (CHI (VIII (VII), and j is selected from the group consisting of zero, 1, (CH)kand 2; m is zero;

R

30 and R 31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, 18 alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; R32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene;

R

33 is selected from the group consisting of hydrogen, alkyl, -C(O)R 35 -C(O)0R 3 5 -S0 2

R

3 6

C(O)NR

3 7

R

3 8 and -S0 2

NR

3 9

R

4 0 as to R 3 R is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl, cycloalkenylalkylene, heterocyclylalkylene, alkylarylene, alkyiheterocyclyl, arylarylene, aryiheterocyclyl, alkoxy, alkenoxy, alkoxyalkylene, alkoxyaralkyl, alkoxyarylene, aryloxyalkylene, aralkoxyalkylene, cycloalkyloxyalkylene, alkoxycarbonyl, heterocyclylcarbonyl, alkylcarbonyloxyalkylene, alkylcarbonyloxyarylene, alkoxycarbonylalkylene, alkoxycarbonylarylene, aralkoxycarbonyiheterocyclyl, alkylcarbonyiheterocyclyl, arylcarbonyloxyalkylarylene, and alkylthioalkylene, wherein: said aryl, heterocyclyl, aralkyl, alkylarylene, aryiheterocyclyl, alkoxyarylene, aryloxyalkylene, cycloalkoxyalkylene, alkoxycarbonylalkylene, and alkylcarbonyiheterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano, or R 31 is CHR 48

R

4 9 or -A Z

R

35 is -NR 50

R

5 1

R

36 is selected from the group consisting of alkyl, haloalkyl, aryl, heterocyclyl, cycloalkylalkylene, alkylarylene, alkenylarylene, arylarylene, aralkyl, aralkenyl, heterocyclylheterocyclyl, carboxyarylene, alkoxyarylene, alkoxycarbonylarylene, alkylcarbonylaminoarylene, alkylcarbonylaminoheterocyclyl, arylcarbonylaminoalkylheterocyclyl, alkylaminoarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, alkylsulfonylaralkyl, and arylsulfonylheterocyclyl, wherein: said aryl, heterocyclyl, cycloalkylalkylene, aralkyl, alkylcarbonylaminoheterocyclyl, and alkylsulfonylarylene groups are optionally 15 substituted with one or more radicals independently selected from the group consisting of alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano;

R

48 is selected from the group consisting of arylsulfonylamino, and alkylarylsulfonylamino;

R

50 is alkyl; R51 is aryl; as to R and R38:

R

3 7 is selected from the group consisting of hydrogen and alkyl, and: R38 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heterocyclyl, aralkyl, alkylarylene, arylcycloalkyl, arylarylene, cycloalkylalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, aryloxyarylene, arylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylene, alkoxycarbonylarylene, ,Ny b o ylcrbonylcarbonylalkylene, alkylaminoalkylene, alkylaminoaralkyl, alkylcarbonylaminoalkylene, alkylthioarylene, alkylsulfonylaralkyl, and aminosulfonylaralkyl, wherein: said aryl, heterocyclyl, aralkyl, and heterocyclylalkylene are optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano, or R38 i C52 53 O R" is or

R

37 and R 38 together with the nitrogen to which they are attached, form a heterocycle;

R

52 is alkoxycarbonyl;

R

53 is alkylthioalkylene; as to R 3 9 and R 40 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkyiheterocyclylalkylene, alkylheterocyclylarylene, aralkyiheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, Lsarylaminocarbonylalkylene, alkylaminocarbonylalkylene, 0 0 0

S

*0 @0

S

S

*0 *5

S

S S 0@ 5*

S

0

S.

S**

*5 0

SO

S

0* *S S S 0 arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, 15 aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals 20 independently selected from the group consisiting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or

R"

9 is -CHR 'R 29 or

R

3 and R 40 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy;

R

28 is alkoxycarbonyl;

R

29 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene, wherein: said aralkyl and heterocyclyl are optionally substituted with one or more radicals independently Sselected from the group consisting of alkyl and nitro;

R

41 is phenyl; 15 R 42 is hydroxy; k is an integer from zero to 3; as to R 56 and R 57

SR

56 is selected from the group consisting of hydrogen and lower alkyl, and R 57 is selected from the group consisting of hydrogen and lower alkyl, or

R

56 and R 5 form a lower alkylene bridge;

R

5 8 is selected from the group consisting of hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, -C(O)R 59

-SO

2

R

60 and -C(0)NHR 61

R

59 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, wherein: said aryl, heterocyclyl, and aralkyl are optionally substituted with one or more radicals independently selected from the group consisting of

I

C

alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and

R

60 is selected from the group consisting of alkyl, aryl, heterocyclyl, alkylarylene, alkylheterocyclyl, aralkyl, heterocyclylheterocyclyl, alkoxyarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, and arylsulfonylheterocyclyl, wherein: said aryl, heterocyclyl, and aralkyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano;

R

61 is selected from the group consisting of alkyl, aryl, alkylarylene, and alkoxyarylene, wherein: said aryl group is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano;

R

3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, and r o

N

SR43 wherein: the pyridinyl, pyrimidinyl, quinolinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of lower alkylthio, halo, lower alkyl, lower aralkyl, lower phenylalkenyl, lower phenylheterocyclyl, carboxy, cyano, lower alkoxycarbonyl, aminocarbonyl, lower u alkylcarbonylamino, lower haloalkyl, hydroxy, lower 5 alkoxy, amino, lower cycloalkylamino, lower O'1O alkylamino, lower alkenylamino, lower alkynylamino, lower aminoalkyl, arylamino, lower aralkylamino, nitro, halosulfonyl, lower alkylcarbonyl, lower alkoxycarbonylamino, lower alkoxyphenylalkylamino, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyphenylalkylamino, hydrazinyl, lower alkylhydrazinyl, and -NRR 45

R

43 is selected from the group consisting of hydrogen, lower alkyl, lower aminoalkyl, lower alkoxyalkyl, lower alkenoxyalkyl, and lower aryloxyalkyl;

R

44 is selected from the group consisting of lower alkylcarbonyl and amino;

R

45 is selected from the group consisting of lower alkyl and lower phenylalkyl; and R is selected from the group consisting of hydrogen, lower cycloalkyl, lower cycloalkenyl, phenyl, biphenyl, 20 naphthyl, and 5- to 10- membered heterocyclyl, wherein: the lower cycloalkyl, lower cycloalkenyl, phenyl, biphenyl, naphthyl, and 5-10 membered heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of lower alkylthio, halo, lower alkyl, lower alkynyl, lower alkoxy, lower aryloxy, lower aralkoxy, lower heterocyclyl, lower haloalkyl, amino, cyano, nitro, lower alkylamino, and hydroxy; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

0c- A class of compounds of particular interest consists of these compounds of Formula I, wherein:

R

1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chioromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichioroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, 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 methyithiomethyl; 2 as to R

R

2 is selected from the group consisting of hydrogen, chloro, fluoro, bromo, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, phenyl, biphenyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichioromethyl, trichioromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichiorofluoromethyl, difluoroethyl, difluoropropyl, dichioroethyl, dichloropropyl, hydroxymethyl, hydroxyethyl, pyridinyl, isothiazolyl, isoxazolyl, thienyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, 22 N-methylpiperazinyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N, N-dimethylamino, N-ethylamino, N,N-diethylamino, N-N-propylamino, N,N-dimethylamino, N-methyl-N-phenylamino, N-phenylamino, piperadinylamino, N-benzylamino, N-propargylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, N, N-dimethylaminoethylamino, N,N-dimethylaminopropylamino, morpholinylethylamino, morpholinyipropylamino, carboxymethylamino, methoxyethylamino, methoxycarbonyl, ethoxycarbonyl, 00 0propoxycarbonyl, 1, 1-dimethylethoxycarbonyl, 1, l-iehltoyaboyaio.yaio ,l-dimethylethoxycarbonylaminopropylamino, 1..pipraineylexcarbonyl ndoylmio 1,ldmtyehxcroypiperazinylcarbonyl, wheein .00.:the aryl, heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or 20 more radicals independently selected from the group consisting of fluoro, chloro, bromo, keto, methyl, ethyl, isopropyl, tert-butyl, isobutyl, benzyl, carboxy, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, dimethylamino, methoxycarbonyl, ethoxycarbonyl, and 1, 1-dimethylethylcarbonyl, or *2 is-R41 R42

*R

41 is phenyl; 42 is hydroxy; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, and purinyl, wherein: 23 the pyridinyl, pyrimidinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chlorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (l-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methyl-hydrazinyl, and -NR 44

R

45

R

4 4 is selected from the group consisting of __-methylcarbonyl and amino; 24

R

45 is selected from the group consisting of methyl, ethyl, and phenylmethyl; and

R

4 is selected from the group consisting of hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl, wherein: the cycloalkyl, cycloalkenyl, aryl, and 15 heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, and hydroxy; or a tautomer of the compound, or a pharmaceutically 0* acceptable salt of the compound or tautomer.

Another class of compounds of particular interest consists of these compounds of Formula I, wherein:

R

1 is selected from the group consisting of hydrogen, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl, and morpholinylethyl;

R

2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, trifluoromethyl, ko rmethoxycarbonylethyl, N,N-dimethylamino, N-phenylamino, piperidinyl, piperazinyl, pyridinyl, N-methylpiperazinyl, and piperazinylamino, wherein: the phenyl, piperidinyl, and pyridinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, and trifluoromethyl;

R

3 is selected from the group consisting of pyridinyl, pyrimidinyl, and quinolinyl, wherein: pyridinyl, pyrimidinyl, and quinolinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, bromo, methyl, cyano, methoxycarbonyl, 15 aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, -methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; S. R 4 is selected from the group consisting of phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl, wherein: the phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

26 A class of compounds of specific interest consists of those compounds of Formula I, wherein:

R

1 is selected from the group consisting of hydrogen and methyl;

R

2 is selected from the group consisting of hydrogen, methyl, and ethyl;

R

3 is selected from the group consisting of pyridinyl, pyrimidinyl, and quinolinyl, wherein: pyridinyl, pyrimidinyl, and quinolinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, bromo, methyl, cyano, methoxycarbonyl, 9 *S aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, 9 5 methoxy, dimethylamino, benzylamino, phenethylamino, 15 aminomethyl, amino, hydroxy, and methylcarbonyl; *4

R

4 is phenyl optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, S 20 nitro, dimethylamino, and hydroxy; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

Still another class of compounds of particular interest consists of those compounds of Formula I, wherein:

R

1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, S dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, 27 propargyl, 1-propynyl, 2-propyyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methyithiomethyl; R2 corresponds in structure to a formula selected from the group consisting of: e r c r r I

(CH

2 1 131

(III)

R

58 R57

R

58 N R 561 (CH2)k N 0 (VI) (C2)k (VIII (VII), and j is selected from the group consisting of zero, 1, (CH2)kand 2; m is zero;

R

30 and R 3 1 are independently selected from the group consisting of hydrogen and lower alkyl; R32 is selected from the group consisting of hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, ower alkoxyalkylene, aryloxyalkylene, aminoalkyl, lower a:lvylaminoalkyl, lower phenylaminoalkyl, lower 28 alkylcarbonylalkylene, lower phenylcarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene;

R

33 is selected from the group consisting of hydrogen, lower alkyl, -C(O)R 35 -C(O)OR 35, -SO 2 R C(O)NR R 3, and

-SO

2 NR39 as to R 3

R

35 is selected from the group consisting of lower alkyl, lower cycloalkyl, lower haloalkyl, lower alkenyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower phenylalkyl, lower phenylcycloalkyl, lower cycloalkenylalkylene, lower heterocyclylalkylene, lower alkylphenylene, lower alkyiheterocyclyl, phenylphenylene, lower phenylheterocyclyl, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower alkoxyphenylalkyl, lower alkoxyphenylene, lower phenoxyalkylene, lower phenylalkoxyalkylene, lower cycloalkyloxyalkylene, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkylcarbonyloxyalkylene, lower alkylcarbonyloxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower phenylalkoxycarbonylheterocyclyl, lower alkylcarbonylheterocyclyl, lower phenylcarbonyloxyalkylphenylene, and lower alkylthioalkylene, wherein: said phenyl, biphenyl, naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylheterocyclyl, lower alkoxyphenylene, lower phenoxyalkylene, lower cycloalkoxyalkylene, lower alkoxycarbonylalkylene, and lower alkylcarbonylheterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, lower j

LS,

A

Y

C I

O

I

29 haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano,

R

35 is CHR 4

R

49 or

R

35 is -NR 0

R

51

R

48 is selected from the group consisting of phenylsulfonylamino and lower alkylphenylsulfonylamino;

R

49 is selected from the group consisting of lower phenylalkyl, amino, lower alkylamino, and lower phenylalkylamino;

R

50 is lower alkyl;

R

51 is selected from the group consisting of phenyl, biphenyl, and naphthyl;

R

36 is selected from the group consisting of lower alkyl, lower haloalkyl, phenyl, biphenyl, naphthyl, lower 15 heterocyclyl, lower cycloalkylalkylene, lower alkylphenylene, lower alkenylphenylene, phenylphenylene, lower phenylalkyl, lower phenylalkenyl, lower heterocyclylheterocyclyl, carboxyphenylene, lower alkoxyphenylene, lower alkoxycarbonylphenylene, lower alkylcarbonylaminophenylene, lower alkylcarbonylaminoheterocyclyl, lower phenylcarbonylaminoalkylheterocyclyl, lower alkylaminophenylene, lower alkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene, lower alkylsulfonylphenylalkyl, and lower phenylsulfonylheterocyclyl, wherein: said phenyl, biphenyl, naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkylcarbonylaminoheterocyclyl, and lower alkylsulfonylphenylene are optionally substituted with one or more radicals independently s selected from the group consisting of lower alkyl,

C-^

*-9 halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; as to R 37 and R 38

R

37 is selected from the group consisting of hydrogen and lower alkyl, and:

R

38 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylcycloalkyl, phenylphenylene, lower cycloalkylalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower Salkoxyphenylene, lower phenoxyphenylene, phenylcarbonyl, lower alkoxycarbonyl, lower alkoxycarbonylalkylene, lower S 15 alkoxycarbonylphenylene, lower alkylcarbonylcarbonylalkylene, lower alkylaminoalkylene, lower alkylaminophenylalkyl, lower alkylcarbonylaminoalkylene, lower alkylthiophenylene, lower alkylsulfonylphenylalkyl, and lower 20 aminosulfonylphenylalkyl, wherein: said phenyl, biphenyl, naphthyl, lower S• heterocyclyl, lower phenylalkyl, and lower heterocyclylalkylene are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano, or

R

38 is -CR2R 53 or

R

37 and R 38 together with the nitrogen to which they are attached, form a 4-to 8- membered ring heterocycle; as to R 39 and R 40 31- R 39 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: R 40is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkyiheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkyiheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonyiheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, **oyrlmncabnllyee *mncroyllyee axarylaminocarbonylalkylene, aminocarbonylalkylene, arylamcarbonylalkylene, alk ylancarbonyla lkylene, arylcarbonylaylene, alkyloxycarbonylarylene, ~arylocarbonylarylene, alkylarylxcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfohylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, r~rx alkylheterocyclylarylene, alkoxyarylene, 32 aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or

R

3 is -CHR R 29 or

R

39 and R 40 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: ooo 9 said aryl, heterocyclylalkylene, and 20 aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group

S

consisting of halogen, alkyl, and alkoxy; k is an integer from zero to 2;

R

56 is selected from the group consisting of hydrogen and lower alkyl;

R

57 is selected from the group consisting of hydrogen and lower alkyl;

R

58 is selected from the group consisting of hydrogen, lower alkyl, lower phenylalkyl, aryl selected from the group consisting of phenyl, biphenyl and naphthyl, lower heterocyclyl, lower heterocyclylalkyl, lower -alkoxycarbonyl, lower alkylsulfonyl, lower pu

S

4 4 i^3 iPr

I-

33 phenylalkylsulfonyl, lower phenylsulfonyl, -C(O)R 59 -SO2R 60 and -C(O)NHR 61

R

59 is selected from the group consisting of lower alkyl, lower haloalkyl, lower cycloalkyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower alkylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower alkoxy, lower alkenoxy, lower phenylalkoxy, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl, wherein: said phenyl, biphenyl, naphthyl, lower heterocyclyl, and lower phenylalkyl groups are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano;

R

60 is selected from the group consisting of lower alkyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, ooo* lower alkylphenylene, lower alkylheterocyclyl, lower 20 phenylalkyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene, lower alkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene, and lower phenylsulfonylheterocyclyl, wherein: said phenyl, biphenyl, naphthyl, lower heterocyclyl, and lower phenylalkyl groups are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano;

R

61 is selected from the group consisting of lower a alkyl, phenyl, biphenyl, naphthyl, lower alkylphenylene, '-and lower alkoxyphenylene, wherein: 34 said phenyl, biphenyl, and naphthyl are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano;

R

3 is selected from the group consisting of pyridinyl, pyrimidinyl, and purinyl, wherein: the pyridinyl, pyrimidinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichioromethyl, dichloromethyl, chioromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chiorophenylmethyl, chiorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chlorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N,N-direthylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morphol inylethylamino, C (l-ethyl-2-hydroxy)ethylamino,

A

VI.,'

34a piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methyl-hydrazinyl, and -NR 44

R

45 R44 is selected from the group consisting of methylcarbonyl and amino

R

4 5 is selected from the group consisting of methyl, ethyl, and phenylmethyl; and V0%. R 4 is selected from the group consisting of hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, :0 15 morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, 00 20 tetrahydropyranyl, tetrahydrofuryl, benzofuryl, 0: dihydrobenzofuryl, and benzodioxolyl, wherein: *00* the cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, methylsulfinyl, methylsulfonyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, and hydroxy; or a tautomer of the compound, or a pharmaceutically 13 r ceptable salt of the compound or tautomer.

34b Still another class of compounds of particular interest consists of those compounds of Formula I, wherein:

R

1 is selected from the group consisting of hydrogen, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl, and morpholinylethyl;

R

2 corresponds in structure to a formula selected from the group consisting of: 9

R

3 0 -C-(CH2)j--

R

3 1

R

SH

SC

134

R

R

32

\R

33 m

(III)

R

58 57

R

58 f o oo ft t f f ft ft f ft f ft ft ftftf N R56 N N

(CH

2 )k 0

(CH

2

(VIII

(VII), and j is selected from the group consisting of zero, 1, CH2)kand 2; m is zero;

R

30 is hydrogen;

R

31 is selected from the group consisting of hydrogen and lower alkyl;

R

32 is selected from the group consisting of hydrogen and lower alkyl;

R

33 is selected from the group consisting of lower alkyl, -C(O)R 3 5

-C(O)OR

3 -S0 2

R

36

C(O)NRR

3 8 and

-SO

2 NR9R 4 0

X

<in 34c

R

35 is selected from the group consisting of lower alkyl, lower cycloalkyl, phenyl, lower heterocyclyl, lower alkylphenylene, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower phenoxyalkylene, and lower phenylalkoxyalkylene, wherein: said phenyl and lower phenoxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, and lower haloalkyl;

R

36 is selected from the group consisting of lower alkyl, phenyl, lower heterocyclyl, lower alkylphenylene, phenylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene, and lower alkylamino, wherein: said phenyl and lower heterocyclyl groups are optionally substituted with one or more radicals independently selected from the group consisting of lower *e alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; 20 R 3 7 is hydrogen;

R

38 is selected from the group consisting of lower alkyl, phenyl, and lower alkylphenylene; as to R 3 9 and R 40

R

39 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and:

R

40 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, -alkylheterocyclylalkylene, alkylheterocyclylarylene, Q6 K> 34d aralkyiheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkyleie, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, 0 SS alkoxycarbonylheterocyclylarylene, S alkoxycarbonylalkoxylarylene, 15 heterocyclylcarbonylalkylarylene, alkylthioalkylene, to cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsul fonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, too.

wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R 39is -CHR 28R 2, or 34e

R

39 and R 40 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy; k is selected from the group consisting of zero 15 and 1;

R

56 is hydrogen;

R

57 is hydrogen;

R

5 is selected from the group consisting of -C(O)R 5 9 and -SOzR 6 0 20 R 9 is selected from the group consisting of lower alkyl, lower cycloalkyl, phenyl, lower alkylphenylene, and lower alkoxyalkylene, wherein: said phenyl is optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano;

R

60 is lower alkyl;

R

3 is selected from the group consisting of pyridinyl, pyrimidinyl, and quinolinyl, wherein: the pyridinyl, pyrimidinyl, an quinolinyl are optionally substituted with one or more radicals Sr pindependently selected from the group consisting of

N,

oo oo o o oo o oooo oo o *o *o *o 34f fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl;

R

4 is selected from the group consisting of phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl, wherein: the phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio,fluoro, chloro, bromo, methyl, ethyl, 15 methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

Still another class of compounds of specific interest consists of those compounds of Formula I, wherein:

R

1 is selected from the group consisting of hydrogen and methyl;

R

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

-A

x- 34g

R

4 is phenyl optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

o

I

In one embodiment of the present invention, the compounds of Formula I satisfy one or more of the following conditions:

R

1 is hydrogen or lower alkyl; more preferably, R 1 is hydrogen or methyl; and still more preferably, R 1 is hydrogen; 1c R 2 is hydrogen or lower alkyl; more preferably, R 2 is hydrogen or methyl; and still more preferably, R 2 is hydrogen; s R' is substituted or unsubstituted pyridinyl; and preferably, the pyridinyl is a 4-pyridinyl; or R' 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' substitutent is attached to the carbon atom positioned between two nitrogen atoms of the pyrimidinyl ring.

SA family of specific compounds of particular interest within Formula I consists of compounds, tautomers and pharmaceutically-acceptable salts thereof as follows: 4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazol-4yl]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-1H-pyrazol-4-yl]pyridine; 4-[5-methyl-3-(4-metheylphenyl)-H-pyrazol-4-ylpyridine; 4-[5-methyl-3-[4-(methylthio)phenyll-lH-pyrazol-4yl]pyridine; (4-chlorohpenyl) methyl-1H-pyrazol-4-yl pyridine; 2ns tatmr ndpamcutclyacetbeslt hro as folos WO 98/52940 WO 9852940PCTIUS98/1 0436 36 4- [3-methyl-5- (3-methyiphenyl) -1H-pyrazol-4-ylilpyridine; 4- (2,5-dimethyiphenyl) -3-methyl-1H-pyrazol-4 yl] pyridine; 4-Es- (1,3-benzodioxol-5-yl) -3-methyl-lH-pyrazol-4yllpyridine; 4- [3-methyl-5- (4-phenoxyphenyl) -2H-pyrazol-4-yllpyridine; 4- -biphenyl) -4-ylj -3-methyl-lH-pyrazol-4yl] pyridine; 4- [3-rethyl-5- (phenoxyphenyl) -1H-pyrazol-4yl Ipyridine; 4- [3-methyl-5- (phenylmethoxy)phenyl] -lH-pyrazol-4yl]I pyridine; 4- [3-methyl-5- (phenylmethoxy)phenyl] -lH-pyrazol-4yl] pyridine; 2- [3-methyl-4- (4-pyridinyl) -lH-pyrazol-4-yl]phenol; 3- [3-methyl-4- (4-pyridinyl) -lH-pyrazol-4-yllphenol; 1-hydroxy-4- (3-methyl-5-phenyl-1H-pyrazol-4yl] pyridinium; (4-f luorophenyl) N-dimethyl-4- (4-pyridinyl) -1Hpyrazol-3-amine; (4-f luorophenyl) -N-phenyl-4- (4-pyridinyl) -lH-pyrazol-3amine; 4- (4-f luorophenyl) -3-phenyl-1H-pyrazol-4yl] pyridine; 4- (3-methyiphenyl) (trifluoromethyl) -lH-pyrazol-4yllpyridine;4- (4-fluorophenyl) (4-pyridinyl) -lHpyrazol -5 -yl] pyridine; 4- (5-cyclohexyl) -3-methyl-lH-pyrazol-4-yl)pyridine; 4- (3-f luoro-5-methoxyphenyl) -3-methyl-lH-pyrazol-4yl] pyridine; 4- (3-methyiphenyl) -3-propyl-lH-pyrazol-4-yl]pyridine; 4- [(3-methyl-5-phenyl-1H-pyrazol-4-yl)methyllpyridine; 4- [3,5-bis(3-methylphenyl) -1H-pyrazol-4-yllpyridine; 4- [4-methyl-2- (2-trifluorophenyl) -lH-pyrazol-4yl) pyridine; 4- (2-chiorophenyl) -5-methyl-1H-pyrazol-4-yllpyridine; 4- [5-methyl-3- (2,4-dimethyiphenyl) -lH-pyrazol-4- SUBBMSHEET(RULE26) WO 98/52940 WO 9852940PCT/US98/1 0436 37 yl] pyridine; 4- (4-chiorophenyl) -1,3-dimethyl-1H-pyrazol-4yl] pyridine; 4- (3-f luoro-2-methylphenyl) -5-methyl-1H-pyrazol-4yl]pyridine; 4- (3,5-ditnethyiphenyl) -S-tethyl-1H-pyrazol-4yl] pyridine; 4- (3,5-dimethoxypheiyl) -5-methyl-1H-pyrazol-4yl]I pyridine; 4- [5-methyl-3- (3-nitrophenyl) -1H-pyrazol-4-yllpyridine; N,N-dirnethyl-4- [5-methlyl-4- (4-pyridinyl) -lH-pyrazol-3 yl] benzenamine; 4- (2,3-dihydrobenzofuran-5-yl) -5-methyl-lH-pyrazol-4yl] pyridine; 4- (4-bromophenyl) -5-rethyl-1H-pyrazol-4-yl] pyridine; 4- (2-f luorophenyl) -5-methyl-1H-pyrazol-4-y1]pyridine; 4- (3-f luorophenyl) -5-methyl-lH-pyrazol-4-yllpyridine; 4- [3-methyl-5- (trifluoromethyl)phenyl] -1H-pyrazol-4yl] pyridine; 4- (3-ethyl-4-phenyl-lH-pyrazol-4-yl)pyridine; 4- (3-methoxyphenyl) -3-methyl-1H-pyrazol-4-yllpyridine; 4- [3-ethyl-S- (3-methylphenyl) -1H-pyrazoJ.-4-yl] pyridine; 4- (3,4-difluorophenyl) -3-methyl-1H-pyrazol-4yl] pyridine; 4- (3-ethoxyphenyl) -3-methyl-lH-pyrazol-4-yl)pyridine; 4- [3-methyl-5- (trifluoromethyl)phenyl] -1H-pyrazol-4yl] pyridine; 4- [3-methyl-5- (3-thienyl) -lH-pyrazol-4-yllpyridine; 4- (2,4-dichiorophenyl) -3-methyl-1H-pyrazol-4yllpyridine; 4- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine; 4- (3-chloro-4-methoxyphenyl) -3-methyl-1H-pyrazol-4yl Ipyridine; ethyl 3- (4-chiorophenyl) (4-pyridinyl) propanoate; 4- (4-f luorophenyl) -l-methyl-pyrazol-4-yllpyridine; SU6S1ThTSHEET(RUE8) WO 98/52940 WO 9852940PCTIUS98/1 0436 38 (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yl]pyrimidin- 2 -amine; [3-methyl-5- (3-methyiphenyl) -1H-pyrazol-4-yl] pyrimidin- 2-amine; 5- [3-methyl-5- (2-rethylphenyl) -lH-pyrazol-4-yllpyrimidin- 2-amine; (4-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyrimidin- 2-amine; (4-f luorophenyl) -3-methyl-lH-pyrazol-4-yllpyrimidin- 2-amine; (4-methoxyphenyl) -3-methyl-lH-pyrazol-4yl] pyrimidin- 2-amine; (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2amine; 4- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2amine; 4- (3-methyiphenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2amine; 4- (2-methyiphenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2amine; 4- (4-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2amine; 4- (4-f luorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2amine; 4- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yllpyridin- 2-amine; [5-(3-chiorophenyl) -3-methyl-lH-pyrazol-4-yl) -2methoxypyridine; [3-methyl-5- (3-methylphenyl) -lH-pyrazol-4ylllpyridine; (4-methoxyphenyl) -3-methyl-1H-pyrazol-4yl] pyridine; 4- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yl] -2methoxypyridine; 2-methoxy-4- [3-methyl-5- (3-methyiphenyl) -lH-pyrazol-4yl] pyridine; 13LJEIS'rrr= FHEU (FAJM =00 WO 98/52940 WO 9852940PCT/US98/10436 39 2-methoxy-4- [3-methyl-5- (2-methyiphenyl) -1H-pyrazol-4yl] pyridine; 4- (4-chiorophenyl) -3-methyl-1N-pyrazol-4-yl] -2methoxypyridine; (4-fluoropheny1)-3-methyl-2lH-pyrazo1-4-y1]-2methoxypyridine; 2-methoxy-4- [3-methyl-5- (4-iethylphenyl) -1H--pyrazol-4yl] pyridine; (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2- 01; 4-15- (3-chlorophenyl) -3-methyl-1H-pyrazol-4-yilpyridil-2oi; 4- (3-methylphenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2oi; 4- (2-methyiphenyl) -3-methyl-1H-pyrazol-4-yilpyridin-2ol; 4- (4-chiorophenyl) -3-methyi-1H-pyrazol-4-yllpyridin-2oi; 4- (4-f luorophenyl) -3-methyl-lH-pyrazol-4-yllpyridil-2- 01; 4- (4-methoxypheny.) -3-methyl-1H-pyrazol-4-yllpyridin- 2-ol; [5-(3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridile- 2-me thanamine; 4- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine- 2 -methanamine; 4- [5-(3-methyiphenyl) -3-methyl-1H-pyrazol-4-yllpyridine- 2 -methanamine; 4- (2-methylphenyl) -3-methyl-1H-pyrazoi-4-yl]pyridile- 2-methanamine; 4- (4-chiorophenyl) -3-methyi-lH-pyrazol-4-yllpyridile- 2 -methanamine; 4- (4-f luorophenyl) -3-methyl-1H-pyrazol-4-yllpyridile- 2 -me thanamine; 4- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yllpyridile- 2-me thanamine; SUB ESHE-T(WuE26) WO 98/52940 WO 9852940PCTIUS98/I 0436 (3-chiorophenyl) -3-rethyl-lH-pyrazol-4-yllpyridine- 2 -carboxamide; 4- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-ylllpyridine- 2- carboxamide; 4- (3-methyiphenyl) -3-methyl-lH-pyrazol-4-yljpyridine- 2 -carboxamide; 4- [5-(2-methyiphenyl) -3-methyl-lH-pyrazol-4-yllpyridine- 2- carboxamide; 4- (4-chloropheiyl) -3-methyl-1H-pyrazol-4-yllpyridine- 2-carboxamide; 4- (4-f luorophenyl) -3-rethyl-1H-pyrazol-4-yllpyridine- 2 -carboxamide; 4- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yllpyridine- 2 -carboxamide; 4- (3-f luoro-4-methoxyphenyl) -3-methyl-lH-pyrazol-4yll pyridine; 4-Es- (4-f luoro-3-methoxyphenyl) -3-methyl-lH-pyrazol-4yl] pyridine; (4-chloro-3-methoxyphenyl) -3-methyl-lH-pyrazol-4ylllpyridine; 4- (2,3-dihydrobenzofuran-6-yl) -3-rethyl-lH-pyrazol-4yllpyridine; 4-Es- (benzofuran-6-yl) -3-methyl-lH-pyrazol-4-yllpyridine; 4- (3-f luoro-5-methoxyphenyl) -3-methyl-lH-pyrazol-4yllpyridine; 4- (3-chloro-5-methoxyphenyl) -3-methyl-1H-pyrazol-4yl] pyridine; 4- (1-cyclohexyen-1-yl) -3-methyl-lH-pyrazol-4yl]I pyr idine; (1,3-cyclohexadien-1-yl) -3-methylL-1H-pyrazol-4yl] pyridine; (5,6-dihydro-2H-pyran-4-yl) -3-methyl-lH-pyrazol-4yl] pyridine; 4- (5-cyclohexyl-3-methyl-1H-pyrazol-4-yl)pyridine; 4- (4-methoxy-3-methylphenyl) -3-methyl-lH-pyrazol-4yll pyridine; SUBST9SHEUT(RULE2 WO 98/52940 WO 9852940PCT/US98/10436 41 4-15- (3-methoxy-4-methylphenyl) -3-methyl-lH-pyrazol-4yl] pyridine; 4- (3-methoxy-5-methylphenyl) -3-methyl-1H-pyrazol-4yl] pyridine; 4- (3-furyl) -3-methyl-1H-pyrazol-4-yllpyridine; 2-methyl-4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine; 2-methoxy-4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine; methyl 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyri-dine-2carboxylate; 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine-2carboxamide; 1- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridin-2yl] ethanone; N,N-dimethyl-4- (3-methyl-5-phenyl-I--pyrazol-2yl)pyridin-2-amiie; 3-methyl-4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine; 3-methoxy-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine; methyl 4- (3-methyl-5-phenyl-1H-pyrazol-4y1)pyridine-3carboxyl ate; 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine-3carboxamide; 1- (3-methyl-5-phenyl-lH-pyrazol-4-yl) pyridin-3yl]I ethanone; 3-bromo-4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine; N,N-dimethyl-4- (3-methyl-5-phenyl-1H-pyrazol-2yl) pyridin-3-amine; 2-methyl-4- (3-methyl-5-phenyl-lH-pyrazol-4-yl) pyrimidine; 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyrimidine; 2-methoxy-4- (3-methyl-5-phenyl-lH-pyrazol-4yl)pyrimidine; 4- (3-rethyl-5-phenyl-ll-pyrazol-4-yl)pyrimidin-2-amine; N,N-dimethyl-4- (3-methyl-5-phenyl-lH-pyrazol-4yl) pyrimidin-2 -amine; 4- (5,6-dihydro-2H-pyran-4-yl) pyrazole; 3-methyl-5-phenyl-4- (3-thienyl) -2H-pyrazole; 81 USHEErUE2 WO 98/52940 WO 9852940PCTIUS98/1 0436 42 4- (3-furyl) -3-methyl-5-phenyl-1H-pyrazole; 3-methyl-5-phenyl-4- (2-thienyl) -1H-pyrazole; 4- (2-furyl) 4- (3-isothiazolyl) -3-methyl-5-phenyl-1H-pyrazole 4- (3-isoxazolyl) -3-methyl-5-phenyl-1H-pyrazole; 4- (5-isothiazolyl) -3-methyl-S-phenyl-lH-pyrazole; 4- (5-isoxazolyl) 3-methyl-5-phenyl-4- (5-thiazolyl) -lH-pyrazole; 3-methyl-4- (5-oxazolyl) 4- (4-fluorophenyl) -lH-pyrazol-4-yllpyridine; 2-methyl-4- (3-methyiphenyl) -1H-pyrazol-4-yllpyridine; 4- (l-methyl-3-phenyl-lH-pyrazol-4-yl)pyridine; 4- (3-phenyl-lH-pyrazol-4-yl)pyridine; 2-methyl-4- (3-phenyl-lH-pyrazol-4-yl)pyridine; 4- (3-chiorophenyl) -l-methyl-pyrazol-4-yllpyridine; 4- (4-chiorophenyl) -1-methyl-pyrazol-4-yllpyridine; 4- (3-chiorophenyl) -1H-pyrazol-4-yl]pyridine; 4- (4-chiorophenyl) -lH-pyrazol-4-yllpyridine; 4- (3-chiorophenyl) -1H-pyrazol-4-yl] -2-methylpyridine; 4-13- (3-f luorophenyl) -1-methyl-lH-pyrazol-4-yllpyridine; 4- (3-f luorophenyl) -lH-pyrazol-4-yl]pyridine; 4- (3-chilorophenyl) -1-methyl-pyrazol-4-yl] -2methylpyridine; (4-chiorophenyl) -N-phenyl-4- (4-pyridinyl) -lH-pyrazol-3amine; (4-chiorophenyl) -N-methyl-4- (4-pyridinyl) -1H-pyrazol-3amine; (4-chiorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -1Hpyrazol -3-amine dihydrate; 5- (3-f luorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -1Hpyrazol -3-amine; (3-methyiphenyl) (4-pyridinyl) -iNpyrazol -3-amine; (3-methyiphenyl) (4-pyridinyl) -lH-pyrazol-3amine; (3-methyiphenyl) (4-pyridinyl) -1H-pyrazol-3- SLMSTMMMmT(RuLF-26) WO 98/52940 WO 9852940PCT/US98/I 0436 43 amine; (3-methyiphenyl) (4-pyridinyl) -1Hpyrazol -3-amine; (4-chiorophenyl) N,N-diethyl-4- (4-pyridinyl) -lHpyrazol-3-amine; 4- (4-chiorophenyl) (4-pyridinyl) -lH-pyrazol-3yl] morpholine; (4-chiorophenyl) -N-propyl-4- (4-pyridinyl) -lH-pyrazol-3amine; 5- (4-chiorophenyl) (phenylmethyl) (4-pyridinyl) -1Hpyrazol-3-amine hydrate (4-chiorophenyl) (2-methoxyethyl) (4-pyridinyl) -lHpyrazol -3-amine monohydrate; 1,1-dimethylethyl 4- (4-chiorophenyl) (4-pyridinyl) 1H-pyrazol-3-yl] -1-piperazinecarboxylate; 1- (4-chiorophenyl) (4-pyridinyl) -1H-pyrazol-3yl] piperazine trihydrochioride; 1- (4-chiorophenyl) (4-pyridinyl) -lH-pyrazol-3-yl] -4methylpiperazine; 1,1-dimethylethyl 4- [5-(4-fluorophenyl) (4-pyridinyl) 1H-pyrazol-3-yl] -1-piperazinecarboxylate; 1- (4-f luorophenyl) (4-pyridinyl) -1H-pyrazol-3yl] piperazine trihydrochioride; 1- (4-chiorophenyl) (4-pyridinyl) -lH-pyrazol-3yllpiperazine; N- (4-chiorophenyl) (phenylmethyl) amino] -4pyridinyl] -1H-pyrazol-3-yl] 3-propanediamine, trihydrochioride; 1- [5-(4-chiorophenyl) (4-pyridinyl) -1H-pyrazol-3-y1] -4- (phenylmethyl) piperazine; 4- (4-f luorophenyl) (1-piperazinyl) -1H-pyrazol-4yl] pyrimidine, dihydrochioride; 1,1-dimethylethyl [3-[[5-(4-chlorophenyl)-4-(4pyridinyl) -1H-pyrazol-3-yl] amino] propyl] carbamate; N- [4-chiorophenyl) (4-pyridinyl) -1H-pyrazol-3-yl] 1, 3-propanediamine, trihydrochioride monohydrate; S~qSMME9tiEE2u) WO 98/52940 WO 9852940PCT/US98/1 0436 44 i,i-dimethylethyl [[5-(4-chlorophenyl)-4-(4pyridinyl) -1H-pyrazol-3-yl] amino] ethyl] carbamate; 1,i-dimethylethyl 4-[5-(4-chlorophenyl)-1-(2hydroxyethyl) (4-pyridinyl) -lH-pyrazol-3-yl] -1piperazinecarboxylate; 1,1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4pyrimidinyl) -lH-pyrazol-3-yl] -1-piperazinecarboxylate; 1,1-dimethylethyl [3-[[5-(4-chlorophenyl)-4-(2-fluoro-4pyridinyl) -lH-pyrazol-3-yl] amino] propyl] carbamate; 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4ethylpiperazine; N- (4-chiorophenyl) (4-pyridinyl) -lH-pyrazol-3-yl] 1,2 -ethanediamine; 4- (2,6-difluorophenyl) -5-methyl-1H-pyrazol-4yllpyridine; 4- (3-ethyiphenyl) -5-methyl-lH-pyrazol-4-yl]pyridine; 4- (3-chiorophenyl) -5-ethyl-lH-pyrazol-4-yllpyridine; 4- [3-ethyl-5- (3-ethyiphenyl) -lH-pyrazol-4-yllpyridine; 4- (4-chiorophenyl) (1-methylethyl) -lH-pyrazol-4yllpyridine; 4- [3-cyclopropyl-5- (4-f luorophenyl) -1H-pyrazol-4yl] pyridine; 4- (4-f luorophenyl) (trifluoromethyl) -lH-pyrazol-4yl] pyridine; 4-[5-(cyclopropyl-3-(4-(fluorophenyl)-l-methyl-1Hpyrazol-4-yl] pyridine; 5-cyclopropyl-3- (4-f luorophenyl) (4-pyridinyl) -lHpyrazole-l- ethanol; 3- (4-fluorophenyl) (2-methoxy-4-pyridinyl) (4pyridinyl) -lH-pyrazole-l-ethanol; 4- (4-f luorophenyl) -1-(2-hydroxyethyl) (4-pyridinyl) -2 (lH) -pyridinone; 1-acetyl-4- (4-fluorophenyl) -1-(2-hydroxyethyl) (4pyridinyl) -lH-pyrazol-5-yl] -2 (lH) -pyridinone; Ethyl 2- [3-(4-fluorophenyl)-l-(2-hydroxyethyl)-4-(4pyridinyl) -lH-pyrazol-5-yl] cyclopropanecarboxylate; "USMfUMEE(RA1EM) WO 98/52940 WO 9852940PCTIUS98/10Q436 2- (4-f luorophenyl) -1-(2-hydroxyethyl) (4-pyridinyl) cyclopropanecarboxylic acid; 3- (4-f luorophenyl) (4-imidazolyl) (4-pyridinyl) -lHpyrazole- 1-ethanol; 4- (4-chloro-3-methylphenyl) -lH-pyrazol-4-yllpyridine (4-f luorophenyl) (4-pyridinyl) -1H-pyrazole-3carboxylic acid; (4-f luorophenyl) (4-pyridinyl) -1H-pyrazole-3methanol; l-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3yl Icarbonyl] piperazine; 1,1-dirnethylethyl 4- (4-f luorophenyl) (4-pyridinyl) lH-pyrazol-3-ylI carbonyl] -1-piperazinecarboxylate; 4- 5-dimethyl-3-phenyl-lH-pyrazol-4-yl)pyridine; 4- (l,3-dimethyl-5-phenyl-lH-pyrazol-4-yllpyridine; 4- (4-chlorophenyl) 5-dimethyl-lH--pyrazol-4yl] pyridine; 4- (4-chlorophexyl) -l,3-dimethyl-lH-pyrazol-4yl] pyridine; 4- [5-ethyl-1-methyl-3- (3-methylphenyl) -lH-pyrazol-4yl] pyridine; 4- [3-ethyl-1-methyl-5- (3-methylphenyl) -lH-pyrazol-4yl I pyridine; 4- (4-chlorophenyl) -l-ethyl-5-methyl-lH-pyrazol-4yllpyridine; 4- (4-chlorophenyl) -2-ethyl-5-methyl-lH-pyrazol-4yl] pyridine; 4- (4-f luorophenyl) -lH--pyrazol-4-yllpyridine; 4- (2-chlorophenyl) -lH-pyrazol-4-yllpyridine; 3- (4-f luorophenyl) (4-pyridinyl) -lH-pyrazole-l-ethanol; 3- (4-f luorophenyl) (4-pyrimidinyl) -lH-pyrazole-lethanol; 4- (4-f luoropheiyl) -1-methyl-lH-pyrazol-4-yllpyridine; 2- (4-fluorophenyl) -1H-pyrazol-4-yl] -2pyridinyl] amino] -1-butanol; 4- [5-bromo-3- (4-f luorophenyl) -l-methyl-lH-pyrazol-4- SuBB1TW~EET(RULE26) yl.]pyridine; 4- (4-fluorophenyl) -1H-pyrazol-4-yl] -2pyridinec arbonitrile; 4- (4-fluorophenyl) (4-pyridinyl) -lH-pyrazol-.yl] ethyllmorpholine; 3- (4-fluorophenyl) -1-rethyl-a-phenyl-4- (4-pyridinyl) -lH- -methanol; N- (4-fluorophenyl) (4-pyridinyl) -lH-pyrazo.-3-yl] -4morphol ineethanamine; 4- (3-chiorophenyl) -lH-pyrazol-4-yl] -2 (1H)-pyridinone hydrazone; 4- (3-chiorophenyl) -1H-pyrazol-4-yl] (phenylmethyl) 2 -pyridinamine; 4-[3-(3-chiorophenyl) -11-pyrazol-4-yl] (phenylethyl) -2pyridinamine; 4- (3-chiorophenyl) -1H-pyrazol-4-yl] -N-ethyl-2pyridinamine; (4-fluorophenyl) -1H-pyrazol-4-yl] -2pyridinecarboxamide; Methyl (4-fluorophenyl)-1H-pyrazol-4-yl] -2pyridinecarboxylate; 4-13- (4-fluorophenyl) -lH-pyrazol-4-yl] -N-methyl-2pyridinecarboxanide; 4- (4-flu'rophenyl) -lH-pyrazol-4- ylI pyridinecarboxylic acid; 4-13- (3-f luorophenyl) -lH-pyrazol-4-yllpyridine; 4-13- (1,3-benzodioxol-5-yl) -1H-pyrazol-4-yllpyridine; 4-13- (3-f luorophenyl) -1-methyl-lH-pyrazol-4-yllpyridine; 4- (4-chiorophenyl) -1H-pyrazol-4-yllpyridine; 30 4-13- (1,3-benzodioxol-5-y) -l-methyl-lH-pyraz-ol'-4-yllpyrid mne; 4-13- (4-chiorophenyl) -1-methyl-lH-pyrazol-4-yllpyridine; 4-13- (3-chiorophenyl) -l-methyl-1H-pyrazol-4-yl] -2-methyip yridine; 4- (3-chiorophenyl) -l-methyl-1H-pyrazol-4 -yl] -2-methylpyridine; STl,, 4- (3-chiorophenyl) -1-methyl-lH-pyrazol-4-yllpyridine; WO 98/52940PCIS/103 PCTIUS98/10436 47 4- (3-chiorophenyl) -1-methyl-lH-pyrazol-4-yl]pyridine; 2-methyl-4- [1-methyl-3- (3-methyiphenyl) -lH-pyrazol-4 -yl] pyridine; 2-methyl-4- [1-methyl-5- (3-methyiphenyl) -1H-pyrazol-4 yl Ipyri dine; 4- (3-phenyl-1H-pyrazol-4-yl) pyridine; 4- (trifluoromethyl)phenyl] -lH-pyrazol-4-yllpyridine 4- [1-methyl-3- (trifluoromethyl)phenyl] -1H-pyrazol-4-yl ]pyridine; 4- (3,4-difluorophenyl) -lH-pyrazoil-4-yllpyridine; 4- (4-chiorophenyl) -lH-pyrazol-4-yl] -2-f luoropyridine; 4- (4-bromophenyl) -1H-pyrazol-4y11 pyridine; 4- (3,4-difluorophenyl) -1-methyl-1FI-pyrazol-4-yllpyridi ne; 4- (4-bromophenyl) -1-methyl-lH-pyrazol-4-y1)pyridine; (4-f luorophenyl) -lH-pyrazol-4-yl] (2-phenyleth enyl) pyridine; (4-chiorophenyl) -lH-pyrazol-4-yl] (2-methylbut yl)- 2-pyridinamine; 4- (4-chiorophenyl) -lH-pyrazol-4-yl] [(4-methoxyphenyl)methyl] 2-pyridinamine; N- (4-chiorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] 2 -pyridinemethanamine; N- (4-f luorophenyl) -1H-pyrazol-4-ylI -2-pyridinyl] 2 -pyridinemethanamine; 2-f luoro-4- (4-f luorophenyl) -1H-pyrazol-4-yllpyridine; 4- (4-iodophenyl) -lH-pyrazol-4-yl]pyridine; 4- (4-iodophenyl) -l-methyl-1H-pyrazol-4-yl]pyridine; 4- [1-methyl-3- (trifluoromethyl)phenyl] -1H-pyrazol-4-y1 pyridine; N- luorophenyl)ethyl] (4-f luorophenyl) -1H-pyra zol-4-yl] -2-pyridinamine; N- luorophenyl)methyl] (4-f luorophenyl) -1H-pyraz ol-4-yl] -2-pyridinamine; 4- (4-fluorophenyl) -1-methyl-lH-pyrazol-4-y1] (1- SUBMMMUTSHEEM(RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 48 methyihydrazino) pyridine; 2-f luoro-4- (4-fluoropheiyl) -1-methyl-lH-pyrazol-4-yllp yridine; 4- (3,4-difluorophelyl) -1H-pyrazol-4-yl] -2-f luoropyridine; 4- (4-f luorophenyl) -1H-pyrazol-4-yl] -3-methylpyridine; 4- (4-f luorophenyl) -1-rethyl-lH-pyrazol-4-yl] -3-methylpyridine; 4- (3,4-difluorophenyl) -l-methyl-1H-pyrazol-4-yl] -2-flu oropyridine; 3- (4-f luorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -lH-pyrazo le-1-ethanamine; 2- (4-fluorophenyl) ethyl] (4-fluorophenyl) -1methyl-lH-pyrazol-4-yl] pyridine; 4- [3-(4-fluorophenyl)-lH--pyrazol-4-yl]-N-[l- (phenylmethyl) -4-piperidinyl] -2-pyridinamine; N' (4-fluorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] N, N-dimethyl -l,2-ethanedianine; 2,4-bis (4-f luorophenyl) -lH-pyrazol-4-yl]pyridine; N- (4-f luorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] -4morphol ineethanamine; 3- (4-f luorophenyl) (2-f luoro-4-pyridinyl) -1H-pyrazole- 1-ethanol; 4- (4-f luorophenyl) -lH-pyrazol-4-yl] (iN-imidazoll-yl) ethyl] -2-pyridinamine; 4- (4-fluorophenyl) (2-fluoro-4-pyridinyl) -1Hpyrazol-1-yl] ethyl] morpholine; (4-fluorophenyl) (4-fluorophenyl) ethenyl] 4-pyridinyl] -lH-pyrazole-1-ethanol; 3- (4-f luorophenyl) (2-fluoro-4-pyridinyl) -N,N-dimethyl- 1H-pyrazole-1-ethanamine; 3- (4-fluorophenyl) (4-fluorophenyl) ethyl) -4pyridinyl] -lH-pyrazole-1-ethanol; 4- (dimethylamino)ethyl] (4-fluorophenyl) -lHpyrazol-4-yl] -N,N-dimethyl-2-pyridinamine; 4- (dimethylamino)ethyl] (4-fluorophenyl) -lH- SU6BnTUTESEET(RULE26) WO 98/52940 WO 9852940PCTIUS98/1 0436 49 pyrazol-4-yl] luorophenyl) methyl] -2-pyridinamine; 3- (4-fluorophelyl) (4-fluoropheriyl)ethyl] -4pyridinyl] -N,N-dimethyl-lH-pyrazole-1-ethananine; N-[(4-fluorophenyl)methyl] [3(or (4-fluorophenyl) -1- (4-morpholinyl)ethyl] -lH-pyrazol-4-yl] -2pyridinamine; 4- (4-f luorophenyl) -1H-pyrazol-4-yl] -N-4-piperadinyl-2pyridinamine; N,N-diethyl-3- (4-f luorophenyl) (2-f luoro-4-pyridinyl) lH-pyrazole-l-ethanamine; 4- (diethylamino) ethyl] (4-fluorophenyl) -lHpyrazol-4-yl] luorophenyl) methyl] -2-pyridinamine; 2- (fluorophenyl) -lH-pyrazol-4-yl] -2pyridinyl] amino] ethanol; [3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]-2pyridinyl] amino] ethanol; 3- (4-fluorophenyl) -lH-pyrazol-4-yl] -2pyridinyl] amino] -1-propanol; 3- (4-f luorophenyl) [[(4-fluorophenyl)methyl] amino] 4-pyridinyl] -lH-pyrazole-1-ethanol; (4-f luorophenyl) [[(4-fluorophenyl)methyl] amino] 4-pyridinyl] -lH-pyrazole-1-ethanol; N,N-diethyl-3- (4-fluorophenyl) (4-pyridinyl) -lHpyrazole- 1-ethanamine; N-[(4-fluorophenyl)methyl]-4-[3-(4-fluorophenyl)-l-[2-(4morpholinyl) ethyl] -lH-pyrazol-4-yl] -2-pyridinamine; N- (4-f luorophenyl) (4-pyridinyl) -1H-pyrazol-3-yl] -4morphol inepropanamine; N' (4-fluorophenyl) (4-pyridinyl) -lH-pyrazol-3-yl] N,N-dimethyl-l, 3-propanediamine; (4-f luorophenyl) -N-2-propynyl-4- (4-pyridinyl) -1Wpyrazol-3-amine; 3- (4-fluorophenyl) [[(4-fluorophenyl)methyl] amino] 4-pyridinyl] -1H-pyrazole-l-ethanol; 5- (4-f luorophenyl) [[(4-fluorophenyl)methyl] amino] 4-pyridinyl] -1H-pyrazole-l-ethanol; VUBBTfrLmrSHEM(RU=E) WO 98/52940 WO 9852940PCT/US98/1 0436 4- [(4-fluorophenyl) -1H-pyrazol-4-ylllquinoline; N- (4-f luorophenyl) (4-pyridinyl) -lH-pyrazol-3yllglycine methyl ester; N- luorophenyl) (4-pyridinyl) -lH-pyrazol-3yllglycine; 4- (4-fluorophenyl) -1-(2-propynyl) -lH-pyrazol-4yl] pyridine; 4- (4-fluorophenyl) -1-(2-propynyl) -lH-pyrazol-4yl] pyridine; 4,4'-(2.H-pyrazole-3,4-diyl)bis[pyridine]; 4- (3,4-dichiorophenyl) -lH-pyrazol-4-yllpyridine; N- (4-chiorophenyl) (4-pyridinyl) -1H-pyrazol-3-yl] -4piperidinamine; 2-Chloro-4- (4-filuorophenyl) -lH-pyrazol-4yllpyrimidine; 4- (4-f luorophenyl) -lH--pyrazol-4-yl] -2 (1H)-pyrirnidinone hydrazone; 4- (4-f luorophenyl) -lH-pyrazol-4-yl] -N,N-dimethyl-2pyrimidinamine; 4- (4-f luorophenyl)-1H-pyrazol-4-yl] -N-methyl-2pyrimidinamine; 4- (4-f luorophenyl) -lH-pyrazol-4-ylI (phenylmethyl) 2 -pyrimidinamine; N-cyclopropyl-4- (4-f luorophenyl) -1H-pyrazol-4-yl] -2pyrimidinamine; 4- (4-f luorophenyl) -1H-pyrazol-4-yll methoxyphenyl) methyl] -2-pyrimidinanine; 4- (4-f luorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinamine; N- (4-f luorophenyl) -lH--pyrazol-4-yl] -2-pyrimidinyl] N- (phenylmethyl)acetamide; Ethyl (4-f luorophenyl) -lH-pyrazol-4-yl] -2pyrimidinyl] carbainate; 4- (3-methyiphenyl) -lH-pyrazol-4-yllpyrimidine; 4- (4-chiorophenyl) -lH-pyrazol-4-yllpyrinidine; 4- (3-f luorophenyl) -lH-pyrazol-4-yllpyrimidine; and 4- (4-f luorophenyl) -lH-pyrazol-4-ylllpyrimidine.

SuesTMRrEHE(RE2 51 Within Formula I there is another subclass of compounds of high interest represented by Formula IX:

N

R2 R4 4 1 1N

N

R (IX); 5 Z is selected from the group consisting of and

R

1 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower heterocycyl, lower aralkyl, lower aminoalkyl, and lower alkylaminoalkyl; as to R2:

R

2 is selected from the group consisting of hydrogen, lower alkyl, phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, morpholinyl, lower 0 15 haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl, wherein: 52 the phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, and morpholinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl, and lower alkoxycarbonyl, or

R

2 is -CR4R 42

R

41 is phenyl;

R

42 is hydroxy;

R

4 is selected from the group consisting of hydrogen, 0 0 t lower cycloalkyl, lower cycloalkenyl, lower ;cycloalkyldienyl, 5- to 10- membered heterocyclyl, phenyl, biphenyl, and naphthyl, wherein: the lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl, 5- to 10- membered heterocyclyl, phenyl, biphenyl, and naphthyl are optionally substituted with one or more radicals independently 20 selected from the group consisting of halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, and hydroxy;

R

s is selected from the group consisting of hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyaralkylamino, hydrazinyl, lower alkylhydrazinyl, and

-NR

44

R

45

R

44 is selected from the group consisting of lower alkylcarbonyl and amino; and

R

45 is selected from the group consisting of lower alkyl and lower phenylalkyl; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

A preferred class of compounds consists of those compounds of Formula IX, wherein:

R

1 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxyethyl, and propargyl;

R

2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, 20 aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, S dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, and 1,1-dimethyl-ethylpiperazinylcarbonyl, wherein: the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl are optionally substituted with one or more radicals independently Sselected from the group consisting of fluoro, chloro, 54 bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, and (1,1-dimethyl)ethoxycarbonyl;

R

4 is selected from the group consisting of cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl, wherein: the cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chioro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy;

R

5 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (l-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, l-methylhydrazinyl, and

-NR

44

R

45

R

44 is selected from the group consisting of methylcarbonyl and amino; and

R

45 is selected from the group consisting of methyl and benzyl; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

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

R

s

I

4 3 5 N

SR

R Z is selected from the group consisting of and R is selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkynyl, lower *.e 15 aminoalkyl, and lower alkylaminoalkyl; as to R 2

R

2 is selected from the group consisting of hydrogen, lower alkyl, phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower A-TSTF2 alkylheterocyclyl, lower carboxycycloalkyl, lower 56 carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl, wherein: the phenyl, biphenyl, and naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, and morpholinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl, and lower alkoxycarbonyl, or

SR

2 is -CR R 42

R

4 is phenyl;

R

42 is hydroxy;

R

4 is selected from the group consisting of 5- to membered heteroaryl, phenyl, biphenyl, and naphthyl, wherein: i* the heteroaryl, phenyl, biphenyl, and naphthyl S 20 are optionally substituted with one or more radicals independently selected from the group consisting of halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, and hydroxy;

R

5 is selected from the group consisting of hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower T--e t heterocyclylalkylamino, lower aralkylheterocyclylamino, 57 lower alkylaminocarbonyl, lower alkoxyaralkylamino, hydrazinyl, lower alkylhydrazinyl, and -NR44R45

R

44 is selected from the group consisting of lower alkylcarbonyl and amino; and

R

45 is selected from the group consisting of lower alkyl and lower phenylalkyl; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

A preferred class of compounds consists of those compounds of Formula X, wherein: SR1R is selected from the group consisting of methyl, ethyl, hydroxyethyl, and propargyl; R is selected from the group consisting of methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, 20 aminoethylamino, aminopropylamino, propargylamino, benzylamino, piperadinylamino, dimethylaminoethylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, N-methylpiperazinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, and 1,1-dimethyl-ethylpiperazinylcarbonyl, wherein: the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl are optionally Ssubstituted with one or more radicals independently selected from the group consisting of fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, and (1,1-dimethyl)ethoxycarbonyl;

R

4 is selected from the group consisting of phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl, wherein: the phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chioro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy;

R

5 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, propargylamino, imidazolylamino, morpholinylethylamino, (l-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, l-methylhydrazinyl, and -NR 44

R

45 R44 is selected from the group consisting of Ar\Y-ST,§methylcarbonyl and amino; and

R

45 is selected from the group consisting of methyl and benzyl; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

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

R

5 4

RZ

:4 3

N

R

N

R (XI) Z is selected from the group consisting of and

R

1 is selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl, and lower alkylaminoalkyl; 0 0* as to R2: 2 15 R is selected from the group consisting of hydrogen, lower alkyl, phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl, wherein: the phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, and morpholinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl, and lower alkoxycarbonyl, or

R

2 is -CRR42; R'4 is phenyl; *4

R

2 is hydroxy;

R

4 is selected from the group consisting of 5- to membered heteroaryl, phenyl, biphenyl, and naphthyl, wherein: the heteroaryl, phenyl, biphenyl, and naphthyl are optionally substituted with one or more radicals **independently selected from the group consisting of 20 halo, lower alkyl, lower alkoxy, aryloxy, lower *"aralkoxy, lower haloalkyl, lower alkylthio, lower S: alkylamino, nitro, hydroxy;

R

5 is selected from the group consisting of hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyaralkylamino, S ydrazinyl, lower alkylhydrazinyl, and

-D

-NR

44

R

4 5

R

44 is selected from the group consisting of lower alkylcarbonyl and amino; and

R

45 is selected from the group consisting of lower alkyl and lower phenylalkyl; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

A preferred class of compounds consists of those compounds of Formula XI, wherein:

R

1 is selected from the group consisting of methyl, i ethyl, hydroxyethyl, and propargyl;

R

2 is selected from the group consisting of methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, 20 morpholinylpropylamino, morpholinylethylamino, S•piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, and 1,1-dimethyl-ethylpiperazinylcarbonyl, wherein: the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, and (1,1-dimethyl)ethoxycarbonyl;

R

4 is selected from the group consisting of phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl, wherein: the phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chioro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy;

R

5 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, norpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, l-methylhydrazinyl, and -NR 44R 4 5

R

44 is selected from the group consisting of methylcarbonyl and amino; and

R

4 5 is selected from the group consisting of methyl benzyl; or 63 a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

A preferred class of compounds consists of those compounds of Formula IX, wherein: Z is selected from the group consisting of and

R

1 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl, and lower alkylaminoalkyl; as to R 2 2

R

2 is selected from the group consisting of hydrogen, lower alkyl, phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, morpholinyl, lower S 15 haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower S* 20 heterocyclylalkyl, lower heterocyclylalkylamino, lower S* alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower 0oo0 alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl, wherein: the phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, and morpholinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl, lower hydroxyalkylcarbonyl, and lower alkoxycarbonyl, or 64

R

2 is -CR4R42;

R

41 is phenyl;

R

42 is hydroxy;

R

4 is phenyl optionally substituted with one or more radicals independently selected from the group consisting of halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, and hydroxy;

R

5 is selected from the group consisting of hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, S 15 lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyaralkylamino, .hydrazinyl, lower alkylhydrazinyl, and

-NR

4 R4

R

44 is selected from the group consisting of lower alkylcarbonyl and amino; and

R

45 is selected from the group consisting of lower alkyl and lower phenylalkyl; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

A class of compounds of specific interest consists of those compounds of Formula IX, wherein:

R

1 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxyethyl, and propargyl;

R

2 is selected from the group consisting of methyl, yI ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, 64a methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, 1-dimethyl) ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, and 1,1-dimethyl-ethylpiperazinylcarbonyl, wherein: the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, chioro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, and (1,1-dimethyl)ethoxycarbonyl;

R

4 is phenyl optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy;

R

5 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-rethylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (1-ethyl-2-hydroxy)ethylamino, piperidinylamino, P pyridinylmethyl amino, phenylmethylpiperidinyl amino, 64b aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, 1-methylhydrazinyl, and

-NR

44

R

4

R

44 is selected from the group consisting of methylcarbonyl and amino; and

R

45 is selected from the group consisting of methyl and benzyl; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

Another class of compounds of specific interest 15 consists of those compounds of Formula IX, wherein: Z is selected from the group consisting of and R' is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, and lower alkynyl; 20 R 2 is selected from the group consisting of hydrogen and lower alkyl;

R

4 is selected from the group consisting of phenyl and benzodioxolyl, wherein: the phenyl is optionally substituted with one or more halo radicals;

R

5 is selected from the group consisting of hydrogen, halo, and alkylhydrazinyl; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

Still another class of compounds of specific interest consists of those compounds of Formula IX, wherein: 64c Z is

R

1 is selected from the group consisting of hydrogen, methyl, hydroxyethyl, and propargyl;

R

2 is hydrogen;

R

4 is selected from the group consisting of phenyl and benzodioxolyl, wherein: the phenyl is optionally substituted with one or more radicals independently selected from the group consisting of chloro, fluoro, and bromo;

R

5 is selected from the group consisting of hydrogen, fluoro, and l-methylhydrazinyl; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

i 15 A preferred class of compounds of specific interest consists of those compounds of Formula IX, wherein: Z is

R

1 is selected from the group consisting of hydrogen and methyl;

R

2 is hydrogen;

R

4 is phenyl optionally substituted with one or more radicals independently selected from the group consisting of chloro, fluoro, and bromo; and

R

5 is selected from the group consisting of hydrogen and fluoro; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

The term "hydrido" denotes a single hydrogen atom This hydrido radical may be attached, for example, to an oxygen atom to form a hydroxyl radical or two Shydrido radicals may be attached to a carbon atom to form a methylene radical. Where used, either alone or S*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, tertbutyl, pentyl, iso-amyl, hexyl and the like. The term "alkenyl" embraces linear or branched radicals having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about six carbon atoms.

Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, and orientations. The term "alkynyl" embraces linear or WO 98/52940 PCT/US98/10436 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 having two to about six carbon atoms. Examples of alkynyl radicals include propargyl, 1-propynyl, 2propynyl, 1-butyne, 2-butenyl and l-pentynyl. The term "cycloalkyl" embraces saturated carbocyclic radicals having three to about twelve carbon atoms. The term "cycloalkyl" embraces saturated carbocyclic radicals having three to about twelve carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to about eight carbon atoms.

Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "cycloalkylalkylene" embraces alkyl radicals substituted with a cycloalkyl radical. More preferred cycloalkylalkylene radicals are "lower cycloalkylalkylene" which embrace lower alkyl radicals substituted with a lower cycloalkyl radical as defined above. Examples of such radicals include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl. The term "cycloalkenyl" embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. Cycloalkenyl radicals that are partially unsaturated carbocyclic radicals that contain two double bonds (that may or may not be conjugated) can be called "cycloalkyldienyl". More preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl. The term "halo" means halogens such as fluorine, chlorine, bromine or iodine. The term "haloalkyl" embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, umSmUTEHEET(RULE) WO 98/52940 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 halo atoms or a combination of different halo radicals.

"Lower haloalkyl" embraces radicals having one to six carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term "hydroxyalkyl" embraces linear or branched alkyl radicals having one to about ten carbon atoms any one of which may be substituted with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals.

Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms "alkoxy" and "alkyloxy" embrace linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and 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 radicals. The "alkoxy" radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkoxy radicals. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces 8U6MtUTESHEMT(RLUEff) WO 98/52940 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 halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkylene, acyl, carboxy, and aralkoxycarbonyl. The term "heterocyclyl" embraces saturated, partially unsaturated and unsaturated heteroatom-containing ring-shaped radicals, which can also be called "heterocyclyl", "heterocycloalkenyl" and "heteroaryl" correspondingly, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocyclic group containing 1.to 4 nitrogen atoms pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.

Heterocyclyl radicals may include a pentavalent nitrogen, such as in tetrazolium and pyridinium radicals. The term "heteroaryl" embraces unsaturated heterocyclyl radicals.

Examples of heteroaryl radicals include unsaturated 3 to susmuMMtE EE(ULE2 WO 98/52940 PCT/US98/10436 69 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl 4H-1,2,4-triazolyl, 1H- 1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclyl group containing 1 to nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl etc.), etc.; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for example, thienyl, etc.; unsaturated 3- to 6membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl 1,2,4-oxadiazolyl, 1,3,4oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl 1,2,4- thiadiazolyl, 1,3,4thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms benzothiazolyl, benzothiadiazolyl, etc.) and the like. The term "heterocycle" also embraces radicals where heterocyclyl radicals are fused with aryl or cycloalkyl radicals.

Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said "heterocyclyl group" may have 1 to 3 substituents such as alkyl, hydroxyl, halo, alkoxy, oxo, amino, alkylthio and alkylamino. The term "heterocyclylalkylene" embraces subs11T rES!EEr(RULE 26) WO 98/52940 PCT/US98/10436 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" 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 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 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 radical, of one to about ten carbon atoms, attached to a divalent 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, 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 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 further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide haloalkylsulfonyl smSiTUTEHEEr (RULE 26) WO 98/52940 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 "sulfonamidyl" denote NH 2 0 2 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 arpyl radicals. Examples of such alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and radicals formed from succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, mandelic, pantothenic, ?-hydroxybutyric, galactaric and galacturonic acids. The term "carbonyl", whether used alone or with other terms, such as "alkoxycarbonyl", denotes The terms "carboxy" or "carboxyl", whether used alone or with other terms, such as "carboxyalkyl", denotes -C02H. The term "carboxyalkyl" embraces alkyl radicals substituted with a carboxy radical. More preferred are "lower carboxyalkyl" which embrace lower alkyl radicals as defined above, and may be additionally substituted on the alkyl radical with halo.

Examples of such lower carboxyalkyl radicals include carboxymethyl, carboxyethyl and carboxypropyl. The term "alkoxycarbonyl" means a radical containing an alkoxy radical, as defined above, attached via an oxygen atom to a carbonyl radical. More preferred are "lower alkoxycarbonyl" radicals with alkyl portions having one to six carbons. Examples of such lower alkoxycarbonyl (ester) radicals include substituted or unsubstituted methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxycarbonyl. The term "alkoxycarbonylalkyl" embraces alkyl radicals substituted with a alkoxycarbonyl radical as defined above. More preferred are "lower alkoxycarbonylalkyl" radicals with s8mfSTUTEHEET(RULE26) WO 98/52940 PCT/US98/10436 72 alkyl portions having one to six carbons. Examples of such lower alkoxycarbonylalkyl radicals include substituted or unsubstituted methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonyl-ethyl and ethoxycarbonylethyl. The term "alkylcarbonyl", includes radicals having alkyl, hydroxylalkyl, radicals, as defined herein, attached to a carbonyl radical. Examples of such radicals include substituted or unsubstituted methylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, hydroxymethylcarbonyl, hydroxyethylcarbonyl. The term "aralkyl" embraces arylsubstituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The aryl in said aralkyl may be additionally substituted with one or more substituents selected independently from halo, alkyl, alkoxy, halkoalkyl, haloalkoxy, amino and nitro. The terms benzyl and phenylmethyl are interchangeable. The term "heterocyclylalkylene" embraces saturated and partially unsaturated heterocyclyl-substituted alkyl radicals (also can be called heterocycloalkylalkylene and heterocycloalkenylalkylene correspondingly), such as pyrrolidinylmethyl, and heteroaryl-substituted alkyl radicals (also can be called heteroarylalkylene), such as pyridylmethyl, quinolylmethyl, thienylmethyl, furylethyl, and quinolylethyl. The heteroaryl in said heteroaralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term "aryloxy" embraces aryl radicals attached through an oxygen atom to other radicals. The term "aralkoxy" embraces aralkyl radicals attached through an oxygen atom to other radicals. The term "aminoalkyl" embraces alkyl radicals substituted with amino radicals. More preferred are "lower aminoalkyl" radicals. Examples of such radicals include aminomethyl, aminoethyl, and the like. The term "alkylamino" denotes amino groups which are substituted S1UTErmr~SHE~r (RULE2) WO 98/52940 PCT/US98/1 0436 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,Nalkylamino, such as N-methylamino, N-ethylamino, N,Ndimethylamino, N,N-diethylamino or the like. The term "arylamino" denotes amino groups which are substituted with one or two aryl radicals, such as N-phenylamino.

The "arylamino" radicals may be further substituted on the aryl ring portion of the radical. The term "aminocarbonyl" denotes an amide group of the formula

C(=O)NH

2 The term "alkylaminocarbonyl" denotes an aminocarbonyl group which has been substituted with one or two alkyl radicals on the amino nitrogen atom.

Preferred are "N-alkylaminocarbonyl" and "N,Ndialkylaminocarbonyl" radicals. More preferred are "lower N-alkylaminocarbonyl" and "lower N,Ndialkylaminocarbonyl" radicals with lower alkyl portions as defined above. The term "alkylcarbonylamino" embraces amino groups which are substituted with one alkylcarbonyl radicals. More preferred alkylcarbonylamino radicals are "lower alkylcarbonylamino" having lower alkylcarbonyl radicals as defined above attached to amino radicals.

The term "alkylaminoalkylene" embraces radicals having one or more alkyl radicals attached to an aminoalkyl radical.

The "hydrocarbon" moieties described herein are organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Preferably, these moieties comprise 1 to carbon atoms.

The heterosubstituted hydrocarbon moieties described SUeBSlUTEMHEET (RE 26) WO 98/52940 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 halogen atom. These substituents include lower alkoxy such as methoxy, ethoxy, butoxy; halogen such as chloro or fluoro; ethers; acetals; ketals; esters; heterocyclyl such as furyl or thienyl; alkanoxy; hydroxy; protected hydroxy; acyl; acyloxy; nitro; cyano; amino; and amido.

The additional terms used to describe the substituents of the pyrazole ring and not specifically defined herein are defined in a similar manner to that illustrated in the above definitions. As above, more preferred substituents are those containing "lower" radicals. Unless otherwise defined to contrary, the term "lower" as used in this application means that each alkyl radical of a pyrazole ring substituent comprising one or more alkyl radicals has one to about six carbon atoms; each alkenyl radical of a pyrazole ring substituent comprising one or more alkenyl radicals has two to about six carbon atoms; each alkynyl radical of a pyrazole ring substituent comprising one or more alkynyl radicals has two to about six carbon atoms; each cycloalkyl or cycloalkenyl radical of a pyrazole ring substituent comprising one or more cycloalkyl and/or cycloalkenyl radicals is a 3 to 8 membered ring cycloalkyl or cycloalkenyl radical, respectively; each aryl radical of a pyrazole ring substituent comprising one or more aryl radicals is a monocyclic aryl radical; and each heterocyclyl radical of a pyrazole ring substituent comprising one or more heterocyclyl radicals is a 4-8 membered ring heterocyclyl.

The present invention comprises the tautomeric forms of compounds of Formulas I and IX. As illustrated below, the pyrazoles of Formula I and I' are magnetically and structurally equivalent because of the prototropic Is;ITESHEE(RULESM WO 98/52940 PCT/US98/10436 tautomeric nature of the hydrogen:

R

3

R

2

R

3

R

2 2 N -4 Nn N N

H

C

I

C

The present invention also comprises compounds of Formula I, IX, X and XI having one or more asymmetric 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.

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, a P38 kinase mediated disorder, inflammation, and/or arthritis, comprising a therapeutically-effective amount of a compound of Formula I, or a therapeuticallyacceptable salt or tautomer thereof, in association with at least one pharmaceutically-acceptable carrier, 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 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 UBSrn MTESHEET(RULE26) WO 98/52940 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 3position substituent binds to a specific peptide sequence of the enzyme. In particular, it is believed to bind to the sidechains of Lys 52 Glu 69 Leu 73 Ile 82 Leu 84 Leu 101 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 for ERK-2). Where the 3-position substituent is aryl or heteroaryl, such aryl or heteroaryl may be further substituted. It is hypothesized that such ring substituents may be beneficial in preventing hydroxylation or further metabolism of the ring.

The substituent at the 4-position of the pyrazole ring is one that is a partial mimic of the adenine ring of ATP, although it may be further elaborated.

Preferably, it is a planar substituent terminated by a suitable hydrogen bond acceptor functionality. It is hypothesized that this acceptor hydrogen bonds to the backbone N-H of the Met 106 residue while one edge of this substituent is in contact with bulk solvent.

Substitution at the 5-position of the pyrazole ring is well tolerated and can provide increased potency and selectivity. It is hypothesized that such substituents extend out in the direction of the bulk solvent and that suitable polar functionality placed at its terminus can interact with the sidechain of Asp" 09 leading to increased potency and selectivity.

Similarly, substitution on the nitrogen atom at the 1- or 2-position of the pyrazole ring is well tolerated and can provide increased potency. It is hypothesized that a hydrogen substituent attached to one of the ring nitrogen atoms is hydrogen bonded to Asp 6 Preferably, the nitrogen atom at the 2-position is double bonded to the carbon atom at the 3-position of the pyrazole while 8UgeS ESHEET(RULE26) the nitrogen atom at the 1-position of the pyrazole is available for substitution with hydrogen or other substituents.

The 5-position substituent and the 1- or 2- position substituent of the pyrazole can be selected so as to improve the physical characteristics, especially aqueous solubility and drug delivery performance, of the substituted pyrazole. Preferably, however, these substituents each have a molecular weight less than about 360 atomic mass units. More preferably, these substituents each have a molecular weight less than about 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

3

R

2 4 /4 3 R4 N

N

R

I (XII); 20 R 1 is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl have a molecular weight of less than about 360 atomic mass units;

R

2 is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl bind with p38 kinase at an ATP binding site of p38 kinase;

R

3 is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl have a hydrogen bond acceptor functionality;

R

4 is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl have a molecular weight of less than S* 15 about 360 atomic mass units;

R

3 is not 2-pyridinyl when R 4 is 2-hydroxyphenyl and when R 1 is hydrogen;

R

2 is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl, and cycloalkenyl 20 when R 4 is hydrogen;

R

4 is not methylsulfonylphenyl; and the substituted pyrazole specifically binds to an ATP binding site of p38 kinase; or a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer.

A class of substituted pyrazoles of particular interest consists of those compounds of Formula XII, wherein:

R

1 is selected from the group consisting of a hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl have a molecular weight of less than about 360 atomic mass units;

R

2 is selected from the group consisting of a hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl radical, wherein: said hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl radical binds with Lys 5 2 Glu 69 Leu 73 Ile 82 Leu 84 Leu 1 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; R is selected from the group consisting of a hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl have a hydrogen bond acceptor functionality that hydrogen bonds with the N-H backbone of Mets 06 of p38 kinase; and R is selected from the group consisting of a hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl have a molecular weight of less than about 360 atomic mass units.

The present invention also provides a method of treating a TNF mediated disorder, a p38 kinase mediated disorder, inflammation and/or arthritis in a subject, the method comprising treating a subject having or susceptible to such disorder or condition with a therapeuticallyeffective amount of a compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the k r i compound or tautomer, wherein: the compound corresponds in structure to Formula I: R32 Re1

N

R as to Rl: R' is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, 10 hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, aryiheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene,.acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, and heterocyclylcarbonyloxyalkylene, or R' corresponds in structure to formula (II): R 25 0 1 H 2 1 1 R 2 6 C H2)i C- Nw R 27 i is an integer from zero to 9; R 25 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; 10 as to R 2 and R 27 26 *R is selected from the group consisting of hydrogen, .alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: 15 R 2 7 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkyiheterocyclyl, alkylheterocyclylalkylene, alk--ylheterocyclylarylene, aralkyiheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, TF-,-,arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: are said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R" is -CHR 2R'R, or

R

2 6 and R 27 together with the nitrogen to which they attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently s~lected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: 83 said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy;

R

28 is alkoxycarbonyl; R29 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene, wherein: said aralkyl and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl and nitro, or 2 as to R: 15 R 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl, wherein: the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl)carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl,

R

2 corresponds in structure to formula (III): R3 0

H

C-(CH2)j C N I R 33 R31

R

34 J m (III), or

R

2 is -CR41R42

R

2 is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl, and cycloalkenyl 15 when R 4 is hydrogen; j is an integer from zero to 8; m is selected from the group consisting of zero and 1; 9*o

R

30 and R 31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl;

R

32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; 84a

R

33 is selected from the group consisting of hydrogen, alkyl, -C(O)R 35

-C(O)OR

35

-SO

2

R

36

NR

3

R

38 and

-SO

2 NR 9

R

40

R

35

R

36

R

3 7

R

3 8

R

3 9 and R 40 are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon, and heterocyclyl;

R

34 is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl;

R

4 1 is aryl;

R

42 is hydroxy;

R

3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl,

R

4 3

N

R

I

and R43 wherein: the pyridinyl, pyrimidinyl, quinolinyl, and 15 purinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, ksr, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, alkylaminoalkylamino, 84b hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, and -NR44R 4

R

3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R 1 is hydrogen;

R

43 is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl;

R

4 is selected from the group consisting of alkylcarbonyl and amino;

R

4 is selected from the group consisting of alkyl and S. 15 aralkyl; and

R

4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, cycloalkyl, S. 20 cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxyl.

OFFN

0'c~ WO 98/52940 PCT/US98/10436 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 addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceuticallyacceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic 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 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, phydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, 3hydroxybutyric, galactaric and galacturonic acid.

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 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, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- WWu=%anTUTtESr(RULE)26) WO 98/52940 PCT/US98/10436 k 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-

III.

General Synthetic Procedures The compounds of the invention can be prepared according to the following procedures of Schemes I-XVIII wherein R 1

R

2

R

3

R

4

R

5 and Ar 1 are as previously defined for the compounds of Formula I, IX, X and XI except where expressly noted.

SCHEME I N 0

R

0 RA H base or base/ac1d base/ IH22

STSNRNH

2 N R

NHRPNH

2 acid or 4 l 2 heat R N base N NNR Ts

R

6 Scheme I shows the synthesis of pyrazole 5 by two qJBSfff~SH"EEF (AJLV6) WO 98/52940 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, provides the a,3-unsaturated ketone 3. In route 1, ketone 3 is first converted to epoxide 4, such as by treatment with hydrogen peroxide solution at room temperature, in the presence of base such as sodium hydroxide. Treatment of epoxide 4 with hydrazine in ethanol or other suitable solvent at a temperature ranging up to 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 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.

UBSmUTESHEME(RULE26) WO 98/52940 PCT/US98/10436 88 SCHEME II halogenation base

CH

3

RO

OEt

S

R6 N NHNH 2

R

11 Scheme II shows the synthesis of pyrazole 12 of the 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 agent, such as bromine, N-bromosuccinimide or Nchlorosuccinimide, in suitable solvents, such as acetic acid, methylene chloride, methanol, or combinations thereof, forms the a-halogenated ketone 10 (wherein X is halo). Examples of suitable hydrohalide salts include the hydrochloride and hydrobromide salts. Reaction of haloketone 10 with thiosemicarbazide 11 (where R 6 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 pyrazole 12. Examples of suitable solvents for this UmsmiHSERUa) 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 OC.

Thiosemicarbazides which are not commercially available may be conveniently prepared by one skilled in the art by first reacting an appropriate amine with carbon disulfide in the presence of a base, followed by treatment with an alkylating agent such as methyl iodide.

Treatment of the resultant alkyl dithiocarbamate with hydrazine results in the desired thiosemicarbazide. This chemistry is further described in E. Lieber and R.C.

Orlowski, J. Orq. Chem., Vol. 22, p. 88 (1957). An alternative approach is to add hydrazine to appropriately substituted thiocyanates as described by Y. Nomoto et al., Chem. Pharm. Bull., Vol. 39, p.86 (1991). The Lieber and Nomoto publications are incorporated herein by reference.

SCHEME III S 0I

R

1 N NH 2

N-N

N 14 R3T route 1 17 0H 16 H 1 3 1\ R X 0 H 5 2

R

n 0°C u 15 R N-N 0 route 2 Y 2 R 3 18 0 heat C180 -200 C)

P

2

N-NH

2

SR

3

R

2 25°-200°C 54 N N route 3 19 uBSmmj rEs CET(RULE26) WO 98/52940 PCT/US98/10436 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 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 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 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 S+4 21 22 0 route 1 route 2 base/ H 2 ,0 e/z I TsNR'NH2

R

3

R

3 R2 R 3 19 8UmMUTE8HEET(ULE26) WO 98/52940 PCT/US98/10436 91 Synthetic Scheme IV describes the preparation of pyrazole 19.

SCHEME V x x R NHNH NHR 1 So Ivent N N 31 32 x

N

NaHMDS/THF 1 R4COOMe N R p or P 4 R COOEt 33 X haly alkyl R Me, CH 2

CH

2

OH

R

4 cyclopropyl, 4-pyridyl, 4- imidazoly Scheme V shows the two step synthesis of the 3substituted 4-pyridyl-5-arylpyrazoles 33 of the present invention by cyclization of hydrazone dianions with carboxylates. In step 1, the reaction of substituted pyridylmethyl ketones 31 (prepared, for example, as later described in Scheme IX) with hydrazines in the presence of solvents such as ethanol gives ketohydrazones 32.

Examples of suitable hydrazines include, but are not limited to, phenylhydrazine and p-methoxyphenylhydrazine.

In step 2, the hydrazones 32 are treated with two equivalents of a base such as sodium bis(trimethylsilyl)amide in a suitable solvent such as tetrahydrofuran to generate dianions. This reaction may be carried out at temperatures of about 0 °C or lower.

SUBSiuT MsHEFT (RULE 28) WO 98/52940 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 step with a dehydrating agent, such as a mineral acid, to produce the target pyrazole in some instances.

"S=MrmmEU (RURLE 2 SCHEME VI p /CH 3

R'CO

2 x bas -e 3 R 4 0 R N H NH a.

NNHR1 37 Rj heteroaryl

R

4 ubstituted or unsubst ituted pheny X =lower alkyl, lower alIkenylI or arylI N N2H p 3) \N H

DOME

d i met hy I aceta I Me2 0

DMF

d dimet hylI aceta I tNP' WO 98/52940 PCT/US98/10436 94 Scheme VI shows an alternative method for synthesizing pyrazoles which are unsubstituted at the position of the ring. In accordance with this method, a heteroarylmethyl ketone 34 is synthesized by first treating a heteroarylmethane with a strong base such as lithium hexamethyldisilazide or lithium diisopropylamide.

Examples of suitable heteroarylmethanes are 4methylpyridine, 4-methylpyrimidine, 2,4-dimethylpyridine, 2-chloro-4-methylpyrimidine, 2-chloro-4-methylpyridine and 2-fluoro-4-methylpyridine. The resulting heteroarylmethyl lithium species is then reacted with a substituted benzoate ester to produce ketone 34.

Examples of suitable benzoate esters are methyl and ethyl p-fluorobenzoate and ethyl and methyl p-chlorobenzoate.

Ketone 34 is converted to the aminomethylene derivative by reaction with an aminomethylenating agent such as dimethylformamide dimethyl acetal or tertbutoxybis(dimethylamino)methane. Ketone 35 is converted to pyrazole 36 by treatment with hydrazine.

A modification of this synthetic route serves to regioselectively synthesize pyrazole 38 which contains a substituted nitrogen at position 1 of the ring. Ketone 34 is first converted to hydrazone 37 by reaction with the appropriate substituted hydrazine. Examples of suitable hydrazines are N-methylhydrazine and N-(2hydroxyethyl)hydrazine. Reaction of hydrazone 37 with an aminomethylenating agent produces pyrazole 38. Examples of suitable aminomethylenating agents include dimethylformamide dimethyl acetal and tertbutoxybis(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 aminosubstituted heteroaromatic derivative. Examples of such amines include benzylamine, cyclopropylamine and ammonia.

81 3'(i7=8EE(F ULEs%) WO 98/52940 PCT/US98/10436 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.

8u1 11ESHEM (MRLE2) SCHEME VII KMnOA

R]I_.

I

2

CH

3 E D C/~T NHR~u 1 N P 1 P lo N1 1 N P 10 p 1 1 WO 98/52940 PCT/US98/10.436 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 40, or coupled with amine NR"R 1 (wherein R" 1 and R" are independently selected, for example, from hydrogen, alkyl and aryl, or together with the nitrogen atom to which they are attached form a 4-8 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur) to form amide 41 followed by reduction to generate amine derivative 42.

SCHEME VIII 4 N NH N 43 1 Base 2. R 1

-X

R

2

R

3

R

2 R R 1

N

R

4

XR

1 N\ N 44 Scheme VIII illustrates the synthesis of pyrazoles 44 and 45 from pyrazole 43. The alkylation of the ring nitrogen atoms of pyrazole 43 can be accomplished using conventional techniques. Treatment of pyrazole 43 with an appropriate base (for example, sodium hydride) followed by treatment with an alkyl halide (for example,

CH

3 I) yields a mixture of isomers 44 and 8U9B111UTE8HEEr(RULE20 WO 98/52940 WO 9852940PCT/US98/1 0436 98 SCHEME IX

CO

2 Et 46 R 12 C H 3 pl

N

4 7 ilithium hexamethyldisilazide tetrahydrofuran, RI 0 desoxybenzo in dimethylformamide dimethyl acetal C4 fold excess) tetrahydrofuran C1 volume)

RT

hydrazine hydrate ethanol N- H

H

Sj~eerrMHEE (FOXESIR) WO 98/52940 PCT/US98/10436 99 Scheme IX illustrates the synthesis of 3-aryl-4pyridyl-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 (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 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 12 is hydrogen, alkyl, halo, trifluoromethyl, methoxy or cyano, or represents methylenedioxy.

The 3-aryl-4-pyrimidinyl-pyrazoles of the present invention can be synthesized in the manner of Scheme IX by replacing pyridine 47 with the corresponding pyrimidine. In a similar manner, Schemes X through XVII can be employed to synthesize 3-aryl-4-pyrimidinylpyrimidines corresponding to the 3-aryl-4-pyrimidinylpyrazoles shown in those schemes.

SUBsmuTTEMSHE(RULE26) WO 98/52940 PCT/US98/10436 100 SCHEME X

NH

2 NH- R 1

N

H

N

R

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

Schemes XI through XVIII illustrate further modifications that can be made to Scheme IX to synthesize other 3-aryl-4-pyridyl-pyrazoles having alternative substituents.

8LfleM8HWwRULEn6) WO 98/52940 WO 9852940PCT/US98/I 0436 SCHEME X1

NH

2 NHR 1 ethanol major product

N

N'l

N

minor product SCHEME XII

N

N-P

1 A 1 3 NH- R 2 0 210OC H 1hr 56 In Scheme XII, X is chioro, if luoro or bromo; R 13 is, for example, hydrogen, alkyl, phenyl, aralkyl, heteroarylalkyl, amino or alkylamino; and R 2 0 is, for example, hydrogen or alkyl.

SUBS1TrM8HW(RULE26) WO 98/52940 WO 9852940PCT/US98/1 0436 102 SCHEME XIII brom ine

OMF

acet ic ac idc p 1 2 N N

N-

'N Br

N

57 SCHEME XIV mCPBA p 1 N-P 1

H

58 tr imethy I aiIy I cyan idce N-P 1 l-lTMEET(RL)LEgS) WO 98/52940 WO 9852940PCT/US98/10436 103 SCHEME XV O H N 11~-' m~eth~ane silronyl cniorloe

H

R 12 P 1 N II b7 N LJN P 1

OMS

N H In Scheme XV, n is 1, 2, 3, 4 or 5; and R 1 4 and R 1 are independently selected from, for example, hydrogen, alkyl or aryl, or together with the nitrogen atom to which they are attached form a 4-7 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur.

SCHEME XVI R 12 N 1 Mg 2. P1 Br

N

TESHEEr(RL1E2~ WO 98/52940 WO 9852940PCT/US98/1 0436 104 In Scheme XVI, R 1 6 is selected, for example, from hydrogen, alkyl and phenyl.

SCHEME XVII 0 N-chlorosuccinimide di methy Ifor mainide N P I H HN N N- P 1l7 HN- R 17 In Scheme XVII, R' 7 is selected, for example, from alkyl, phenylalkyl and heterocyclylalkyl.

SUBSTITLJE SHE (RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 105 SCHEME XVIII x

NH

N

N R 1. [03 2 TMSCN Me 2 NCOC I H 2 0 2

K

2

CO

3 DMF dimetnyl acetal MeOH x

NH

7

N

N n.2

CO

2 Me

P

18

P

1 9

NH

2 saponi1fy '0H Compounds wherein the 2-position of the pyridine ring is substituted by a carboxyl group or a carboxyl.

derivative may be synthesized according to the procedures outline in Scheme XVIII. The starting pyridyl pyrazole 67 is converted to the 2-cyano derivative 68 by first SUBMMMTE TULE 26) WO 98/52940 PCT/US98/10436 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 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 reaction with dimethylformamide dimethyl acetal in methanol. The ester 70 is converted to its carboxylic acid 71 by saponification. Typical saponification conditions include reaction with a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as ethanol or ethanol and water or methanol and water or the like. Ester 70 is also convertible to substituted amide 72 by treatment with a desired amine, such as methylamine at a suitable temperature.

Temperatures may range from room temperature to 180 0

C.

In Scheme XVIII, R 18 and R 19 are independently selected, for example, from hydrogen, alkyl and aryl, or together with the nitrogen atom to which they are attached form a 4-8 membered ring that may contain one or more additional heteroatoms selected from oxygen, nitrogen or sulfur.

The following examples contain detailed descriptions of the methods of preparation of compounds of Formulas I, XI, X and XI. These detailed descriptions fall within the scope, and serve to exemplify, the above described General Synthetic Procedures which form part of the invention. These detailed descriptions are presented for illustrative purposes only and are not intended as a restriction on the scope of the invention. All parts are by weight and temperatures are in Degrees centigrade unless otherwise indicated. All compounds showed NMR spectra consistent with their assigned structures. In some cases, the assigned structures were confirmed by 9uerB1TUE8HEEiM(RULU2) WO 98/52940 PCT/US98/1436 107 nuclear Overhauser effect (NOE) experiments.

The following abbreviations are used: HC1 hydrochloric acid MgSO4 magnesium sulfate Na2SO4 sodium sulfate NaI04 sodium periodate NaHS03 sodium bisulfite NaOH sodium hydroxide KOH potassium hydroxide

P

2 05 phosphorus pentoxide Me methyl Et ethyl MeOH methanol EtOH ethanol HOAc (or AcOH) acetic acid EtOAc ethyl acetate

H

2 0 water H202 hydrogen peroxide

CH

2 C1 2 methylene chloride

K

2

,C

3 potassium carbonate KMnO 4 potassium permanganate NaHMDS sodium hexamethyldisilazide DMF dimethylformamide EDC 1-(3-dimethylaminopropyl)3-ethylcarbodiiminde hydrochloride HOBT l-hydroxybenzotriazole mCPBA 3-chloroperoxybenzoic acid Ts tosyl TMSCN trimethylsilyl cyanide Me 2 NCOCl N,N-dimethylcarbamoyl chloride SEM-C1 2-(trimethylsilyl)ethoxymethyl chloride h hour hr hour min minutes THF tetrahydrofuran TLC thin layer chromatography msmTESHEEu(RuLEM6) WO 98/52940 PCT/US98/10436 108 DSC differential scanning calorimetry b.p. boiling point m.p. melting point eq equivalent RT room temperature Example A-i N CH3 F

N

0H 4-[5-C3-fluoro-4-methoxyphenyl)-3methyl-1H-pyrazol-4-yl]pyridine Step 1: Preparation of 4-(3-fluoro-4-methoxvlphenyl)-3pyridvl-3-butene-2-one A solution of 4-pyridylacetone (1.0 g, 7.4 mmol), 3fluoro-p-anisaldehyde (1.25 g, 8.1 mmol), and piperidine (0.13 g, 1.5 mmol) in toluene (50 ml) was heated to reflux. After 18 hours, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The crude product (3.0 g) was purified by column chromatography (silica gel, 65:35 ethyl acetate/hexane) to give 4-(3-fluoro-4-methoxylphenyl)-3pyridyl-3-butene-2-one as a pale yellow solid (1.60 g, Step 2: Preparation of 4-[5-(3-fluoro-4-methoxvphenyl)-3methvl-1H-Dprazol-4-vl]pyridine To a solution of 3-pyridyl-4-(3-fluoro-4methoxylphenyl)-3-butene-2-one (step 1) (0.99 g, 3.65 mmol) in acetic acid (25 ml), p-toluenesulfonyl hydrazide (0.68 g, 3.65 mol) was added. The reaction solution was heated to reflux for 6 hours. Acetic acid was removed by distillation from the reaction solution. The resulting residue was diluted with CH2C12 (150 ml), washed with 8UBST UTESEET(RULE26) WO 98/52940 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-4methoxyphenyl)-3-methyl-lH-pyrazol-4-yl]pyridine as a pale yellow solid (213 mg, Anal. Calc'd for

C

16

H

14 N30F.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

C H 3

N

N

H

4-C3-methyl-5-phenyl-1H-pyrazol-4-yl) pyridine Step 1: Preparation of 4-pyridylacetone 4-Pyridylacetone was prepared according to the method of Ippolito et al, U.S. Patent 4,681,944.

Step 2: Preparation of 4-phenvl-3-(4-pyridvl)-3-butene- 2-one Using the procedure of Example A-l, step 1, 4pyridylacetone (step 1) (1 g, 7.4 mmol) was condensed with benzaldehyde (790 mg, 7.4 mmol) in benzene (15 mL) containing piperidine (50 mg) at reflux. The desired 4phenyl-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 1 5

H

13 NO (223.28): C, 80.69; H, 5.87; N, 6.27. Found: C, 80.59; H, 5.79; N, 6.18.

Step 3: Preparation of 4-phenvl-3-(4-pyridyl)-3,4epoxy-2-butanone Using the procedure of Example A-l, step 2, a solution of 4-phenyl-3-(4-pyridyl)- 3-butene-2-one (step 2) (1.25 g, 5.6 mmol) in methanol (20 ml) was treated 6uSnnJTEBHEE(RUL)E2 WO 98/52940 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)-3,4epoxy-2-butanone (270 mg, Step 4: Preparation of 4-(3-methyl-5-phenyl-lH-pyrazol- 4-vl)pyridine Using the procedure of Example A-1, step 3, a solution of 4-phenyl-3-(4-pyridyl)-3,4-epoxy-2-butanone (step 3) (250 mg, 1 mmol) in ethanol (15 ml) was treated with anhydrous hydrazine (50 mg, 1.5 mmol) and heated to reflux for 4 hours. The crude product was purified by chromatography (silica gel, 1:1 acetone/hexane). The product was recrystallized from ethyl acetate and hexane to give 4-(3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine (81 mg, 35%) as a crystalline solid: m. p. 212-214 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.

Example A-3

CH

3 N N/

H

4-[5-methyl-3-C2-methylphenyl)-1Hpyrazol-4-yl]pyridine Step 1: Preparation of 4-(2-methylphenyl)-3-(4-pyridyl)- 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 was removed by a Dean-Stark trap. After heating at SUBMUMWEW8HEEr (RULEM WO 98/52940 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-(2methylphenyl)-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-methylphenyl)-3-(4-pyridyl)- 3,4-epoxy-2-butanone To a solution of 4-(2-methylphenyl)-3-(4-pyridyl)-3butene-2-one (step 1) (1.0g, 4.2 mmol) in methyl alcohol (18 ml), a solution of H202 (30% by wt.) (0.95 g, 8.4 mmol) and sodium hydroxide (0.18 g 4.6 mmol) in water (4 ml) was added. The reaction was stirred at room temperature for 70 hours. After methyl alcohol was removed, water (25 ml) and ethyl acetate (100 ml) were added and the two phase mixture was stirred for minutes. The layers were separated, and the aqueous layer was washed with ethyl acetate (100 ml). The combined organic layer was dried with Na2S04, filtered and concentrated to give an oil. 4-(2-Methylphenyl)-3- (4-pyridyl)-3,4-epoxy-2-butanone was isolated from the oil residue by chromatography.

Step 3: Preparation of 4-[5-methyl-3-(2-methylphenyl)lHpvrazol-4-yl]pyridine A solution of 4-(2-methylphenyl)-3-(4-pyridyl)-3,4epoxy-2-butanone (step 2) (0.11 g, 0.434 mmol) and hydrazine hydrate (0.043 g, 0.868 mmol) in ethyl alcohol 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)-1Hpyrazol-4-yl]pyridine: Anal. Calc'd for C16H15N 3 (249.32): C, 77.08; H, 6.06; N, 16.85. Found: C, 76.66; H, 5.91; N, 16.84.

SUsrmnTEBHEEr(RULE26) WO 98/52940PCIS8I03 PCTIUS98/10436 112 Example A-4 CH3

N

H

-3-C4-f I uoropheny I IHpyrazol-4-yI]pyridirie By following the method of Example A-3 and substituting p-f luorobenzaldehyde for o-tolualdehyde, the titled compound was prepared: Anal. Calc'd for Cj5H1 2

N

3

F

0.1 H 2 0: (249.32): C, 70.63; H, 4.82; N, 16.47. Found: C, 70.63; H, 4.78; N, 16.40.

Example

CH

3

/NN

IIH

4-E5-methyl-3-C4-methylphenyl)-lHpyrazo I-4-y ljpyridine By following the method of Example A-3 (with one minor modification: in Step 2, the preparation of the intermediate epoxide was accomplished at 0-10 0 C for 1 hour, and the reaction was quenched by being partitioned SU9BTWUTEKEE(RULEXD) WO 98/52940 WO 9852940PCTIUS98/1 0436 113 between water, containing 2 eq. sodium bisulfite, and ethyl acetate) Lnd substituting p-tolualdehyde for otolualdehyde, the titled product was isolated: Anal.

Calc'd for C 16

H

15

N

3 (249.32) C, 77.08; H, 6.06; N, 16.85. Found: C, 76.97; H, 6.09; N, 16.90.

Example A-6 fCH 3

N

N

SH

4-[5-methyI-3-[4-(methylthio~phenyI]- IH-pyrazol-4-y1]pyridine By following the method of Example A-5 and substituting 4-(methylthio)benzaldehyde for ptolualdehyde, 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.

SuBS7WMUEErULE26) WO 98/52940 WO 9852940PCTJUS98/1 0436 114 Example A-7 1-U 3-C1-chloroohenytD-5-methy)-1HpyrazoI-4-yl]pyridine By following the method of Example A-5 and substituting p-chlorobenzaldehyde for p-tolualdehyde, the titled product was obtained. Anal. Calc'd for Cj 5

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.

Example A-8

CH

3

/N

H

4-[3-methyI-5-C3-methylphenyl)-lHpyrazol-4-yl]pyridine By following the method of Example A-5 and substituting m-tolualdehyde for p-tolualdehyde, the titled product was obtained: Anal. Calc'd for C 1 6

H

15 N3 0.2H 2 0: C, 75.98; H, 6.14; N, 16.61. Found: C, 76.06; H, SHEET RLJLEI WO 98/52940 WO 9852940PCTIUS98/1 0436 115 6.05; N, 16.38.

Example A-9

N

4-E5-C2,5-dimethylphenylD-3-methyl- 1l-pyrazol-4-ylpyridine 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 Cl7Hl7N3 0.1H20: C, 77.01; H, 6.54; N, 15.85. Found: C, 76.96; H, 6.81; N, 15.51.

Example 1,3-benzodioxol-5-ylD-3-methyl- 1H-pyrazoI-4-yljpyridine 4-Pyridylacetone (1.5 g, 12 mmol) piperonal (1.6 g, 10.6 mmol), acetic acid (110 mg, 1.8 mrnol), and piperidine (110 mg, 1.3 mmol) were dissolved in toluene rVFMMFEHEMr(RULE 2 WO 98/52940 PCT/US98/10436 116 mL) and heated for 2 hours at reflux in a flask equipped with a Dean-Stark trap. The solution was cooled to room temperature, and ethyl acetate was added to precipitate a solid, which was collected on a filter plate (1.25 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 evaporated. The residue was dissolved in ethyl acetate, washed with 5% aqueous potassium carbonate, and water.

The organic layer was dried (MgS04), filtered and evaporated to obtain a yellow solid. This solid was triturated with methylene chloride, yielding benzodioxol-5-yl)-3-methyl-1H-pyrazol-4-yl]pyridine which was collected on a filter plate (220 mg, 42% yield).

Anal. Calc'd for C16H13N 3 02: C, 68.81; H, 4.69; N, 15.04.

Found: C, 68.02; H, 4.54; N, 14.76. MS 280 (base peak).

Example A-11

N

CH

3

N

Ph

H

4-[3-methyl-5-C4-phenoxypheny 1H-pyrazol-4-yl]pyridine 4-Pyridylacetone (1.5 g, 12 mmol), 4phenoxybenzoldehyde 92.1 g, 10.6 mmol), acetic acid (110 mg, 1.8 mmol), and piperidine (110 mg, 1.3 mmol) were dissolved in toluene (30 mL) and heated for 2 hours at $9gT11uTEWHU(RULE2) 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 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-(4phenoxyphenyl)-lH-pyrazol-4-yl]pyridine was obtained (100 mg, 66% yield): Anal. Calc'd for C 2 1

H

17

N

3 0 0.1 H 2 0: C, 76.62; H, 5.27; N, 12.76. Found: C, 76.37; H, 5.19; N, 12.64. MS 328 (base peak).

Example A-12

CH

3

N

Ph H 1,1 -biphenyl]-4-y1]-3-methyl 1H-pyrazol-4-yl]pyridine The same procedure as for the preparation of Example was used, substituting 4-formylbiphenyl in place of piperonal, to give 4-[5-[(l,l'-biphenyl)-4-yl]-3-methyl- 1H-pyrazol-4-yl]pyridine as a white solid: MS 312 (base peak).

Example A-13 N0N

CH

3 Ph

N

H

4-[3-methyl-5-[3-(phenoxypheny

I)-

1H-pyrazol-4-yl]pyridine s sLmUTEHEEsT(RULEO) WO 98/52940 PCT/US98/1 0436 118 The same procedure for the preparation of Example Awas used, substituting 3-phenoxybenzaldehyde in place of piperonal, to give 4- E3-methyl-5-[13- (phenoxyphenyl) 1H-pyrazol-4-yllpyridine as a white solid.

Example A-14 IC H3

N

H

4-[3-methyI-5-[3-Cphenylmethoxy~phenyl]> 1H-pyrazoI-4-ylJpyridine The same procedure for the preparation of Example Awas used, substituting 3-benzyloxybenzaldehyde in place of piperonal, to give 4-[3-methyl-5-[3- (phenylmethoxy)phenyl] -lH-pyrazol-4-yl] pyridine as a white solid: MS 342 (base peak).

Example

N

K-H

4 -[3-methyI-5-[2-CphenylmethoxyDphenyl]-lH-pyrazol-4-yljpyridine The same procedure for the preparation of Example Awas used, substituting 2-benzyloxybenzaldehyde in place of piperonal, to give 4-[3-methyl-5-[2- SuLsM MWEU (RULEs) WO 98/52940 WO 9852940PCTIUS98/1 0436 119 (phenylmethyloxy)phenyl] -lH-pyrazol-4-yl] pyridine. MS 342 (base peak).

Example A-16

NN

H

OH

pyrazol-4-yljplenol The same procedure for the preparation of Example Awas used, substituting 2-hydroxybenzaldehyde in place of piperonal, to give 2- [3-rethyl-4- (4-pyridinyl) -1Hpyrazol-4-yllphenol: MS 252 (base peak).

Example A-17

N\

N 3-[3-methyl-4-C4-pyridinyID-IHpyrazol-'1-yljphenol The same procedure for the preparation of Example A- 10 was used, substituting 3-hydroxybenzaldehyde in place of piperonal, to give 3- [3-rethyl-4- (4-pyridinyl) -111pyrazol-4-yllphenol: MS 252 (base peak).

WO 98/52940 WO 9852940PCT[US98/I 0436 120 Example A-l8 CH3

N

H

1-hydroxy-4I-[3-methyI-5-phenyl-lHpyrazol-'1-yl]pyridinlum To a solution of 4- (3-methyl-5-phenyl-lH-pyrazol-4yl)pyridine (Example A-2) (2.06 g, 8.76 mrnol) in a mixture of CH2C12 (10 mL) and MeOH (20 mL), was added 3chloroperoxybenzoic acid (57-86%) (2.65 g, 8.76 mmol).

The reaction was stirred at room temperature for 2h, quenched with K2C03 solution 15 mL), and concentrated. The resulting residue was partitioned between EtOAc (2.0 L) and H20 (500 mL) The organic layer was separated, washed with H120 (500 mL), dried over MgSO4, filtered and concentrated to give l-hydroxy-4- [3methyl-5-phenyl-lH-pyrazol-4-yllpyridiniun (1.12 g, MS 252 (base peak).

Example A-19 N I

IN

N

F H 5-C'4-fluorophenyi)-NN-dimethy--4-C4pyrid infl 1H-pyrazolI- 3-amIne 8HEE~ (RILE WO 98/52940 PCT/US98/10436 121 Step 1: Preparation of 1-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 4picoline (18.6 g, 0.20 mol) in dry THF (200 mL) over 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 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 magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 1-fluoro-4-(4'pyridylacetyl)benzene (19.9 g, 92 as an oil which solidified upon standing: 90-91 oC; Anal. Calc'd for C 13

H

10 FNO: C, 72.55; H, 4.68; N, 6.51. Found: C, 72.07; H, 4.66; N, 6.62.

Step 2: Preparation of 1-fluoro-4-(4'pyridvlbromoacetvl)benzene To a solution of l-fluoro-4-(4'pyridylacetyl)benzene (step 1) (10.0 g, 0.046 mol) in acetic acid (200 mL) was added a solution of bromine (8.2 g, 0.052 mol) in acetic acid (20 mL) dropwise. The reaction mixture was stirred at room temperature overnight. After the solvent was removed, the residue was triturated with ethyl acetate. A yellow solid formed, which was filtered and air-dried to give 1fluoro-4-(4'-pyridylbromoacetyl)benzene (14.5 The compound was used in next step without further purification.

uBmmut8HEET(RULE) WO 98/52940 PCT/US98/10436 122 Step 3: Preparation of 5-(4-fluorophenvl)-N, N-dimethyl- 4-(4-pyridinyl)-1H-pyrazol-3-amine A mixture of 1-fluoro-4-(4'-pyridylbromoacetyl)benzene (step 2) (3.8 g, 0.01 mol) and 4,4-dimethylamino- 3-thiosemicarbazide (1.2 g, 0.01 mol) in ethanol (10 mL) was heated at reflux for 30 minutes. The dark 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, dried over magnesium sulfate, filtered, and concentrated.

The resulting residue was purified by chromatography (silica gel, ethyl acetate) to give 0.3 g 5-(4fluorophenyl)-N, N-dimethyl-4-(4-pyridinyl)-1H-pyrazol-3amine (0.3 g, 11 as a light yellow solid: 245- 247 oC. Anal. Calc'd for C 1 6

H

1 5

FN

4 C, 68.07; H, 5.36; N, 19.84. Found: C, 68.00; H, 5.37; N, 19.61.

Example N

H

N-Ph

N

F H 5-(4-fluorophenyl)-N-phenyl-4- C4-pyridiny I)-1H-pyrazo -3-amine 5-(4-Fluorophenyl)-N-phenyl-4-(4-pyridinyl)-lHpyrazol-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 0

H

1 5FN4 0.1 H20: C, 72.33; H, 4.61; N, 16.87. Found: C, 72.16; H, 4.56; N, 16.77.

SUBSITrM SHMEET(RULEM) WO 98/52940 WO 9852940PCTIUS98/1 0436 123 Example A-21 P h

N

H

,4-E5-C4-fluoropheny ID- 3-phenylI- 1HpyrazoI-,q-yI]pyridine Stelp 1: Preparation of 1-f luoro-4- (40- pyridylacetyl) benzene N-benzovlhydrazone To a solution of benzoic hydrazide (1.36 g, 0.01 mol) in THF (20 mL) was added 1-fluoro-4- pyridylacetyl)benzene (2.15 g, 0.011 mol) in one portion followed by a drop of conc. HCl. The reaction mixture was stirred at room temperature overnight. There was white precipitate formed, which was filtered, washed with ether and air-dried to give 1-f luoro-4- pyridyJlacetyl)benzene N-benzoylhydrazone (2.90 g, 79 as a mixture of cis and trans (ratio, 1:9) isomers.

Sten 2: Preparation of 4-[5-(4-fluorolphenyl)-3-phenvl- 1H-pyrazol-4-vll pyridine 1-Fluoro-4- -pyridylacetyl) benzene Nbenzoylhydrazone (step 1) (0.50 g, 1.5 mmol) was heated at 180 OC under N 2 for 15 minutes, then cooled. The resulting solid was purified by chromatography (silica gel, 1:1 ethyl acetate/hexane) to give fluorophenyl) -3-phenyl-1H-pyrazol-4-yllpyridine (0.25 g, 53 as a pale yellow solid: m.p. 265-267 OC. Anal.

Calc'd for C20H 14 FN3 0.25 H20: C, 75.10; H, 4.57; N, 13.14. Found: C, 74.98; H, 4.49; N, 12.87.

&uJWM)TEU~(RuLEM~ WO 98/52940 PCT/US98/10436 124 Example A-22 N

-FF

F

N

H

4-[5-(3-methylphenylID-3-CtrifluoromethyI- 1H-pyrazol-4-yl]pyridine Step 1: Preparation of 3-(4'-pvridylacetvl)toluene 3-(4'-Pyridylacetyl)toluene was prepared by the same method as described for Example A-19, step 1 in yield.

Step 2: Preparation of trifluoroacetyl hvdrazide A mixture of ethyl trifluoroacetate (14.2 g, 0.10 mol) and hydrazine hydrate (5.54 g, 0.11 mol) in ethanol mL) was heated at reflux for 6 hours. Solvent was removed and the resulting residue was dried in vacuum to give trifluoroacetyl hydrazide (12.3 g, 96 as a clear oil which solidified upon standing.

Step 3: Preparation of 4-[5-(3-methvlphenyl)-3- (trifluoromethyl)-1H-Dpyrazol-4-vl]pyridine A mixture of 3-(4'-pyridylacetyl)toluene (2.11 g, 0.01 mol) and trifluoroacetyl hydrazide (step 2) (1.0 g, 0.01 mol) was heated at 200 OC under N 2 for 15 minutes.

The crude residue was purified by chromatography (silica gel, 35:65 ethyl acetate/hexane) to give methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4yl]pyridine (0.56 g) as a white solid: m.p. 237-239 oC.

Anal. Calc'd for C 16

H

12

F

3

N

3 C, 63.36; H, 3.99; N, 13.85.

WW=E. r (MF-ELEM WO 98/52940 PCT/US98/10436 125 Found: C, 63.6; H, 4.00; N, 13.70.

Example A-23 N

N

N

F

4-[3-(4-fluorophenyl)-4-(4-pyridinyi)- A mixture of 1-fluoro-4-(4'-pyridylacetyl)benzene g, 4.6 mmol) and isonicotinic hydrazide (0.63 g, 4.6 mmol) in THF (25 mL) was heated to dissolution and then evaporated to dryness. The resulting solid was heated first to 140 oC, which caused a phase change, and subsequently melted on further heating until 180 °C whereupon a solid crystallized out. The reaction was immediately cooled, diluted with 10 HC1 (50 mL) and washed with chloroform. The aqueous layer was neutralized with bicarbonate and a tan colored solid was precipitated out. The solid was purified by treatment with activated carbon (Darco) in boiling MeOH (100 mL), followed by filtration and concentration, to give 4-[3- (4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl]pyridine (1.05 g, 69 as a shiny tan solid: m.p. 304 oC (DSC).

Mass (MH 137 Anal. Calc'd for CI 9 Hl3N 4 F.1/4H20: C, 71.13; H, 4.24; N, 17.46. Found: C, 70.88; H, 3.87; N, 17.38.

sBsmurtUTEHEr RUE 26 WO 98/52940PCUS/143 PCT/US98/10436 126 Example A-24 4-C5-cyclohexyl)-3-rnethyl-lH-pyrazol-A4-yl~pyridine Step 1: Preparation of 4-cyclohexyl-3-pyridyl-3-butene- 2-one 4-Cyclohexyl-3-pyridyl-3-butene-2-one was prepared by the method of Example A-i, step 1 by replacing of 3fluoro-p-anisaldehyde with cyclohexanecarboxaldehyde.

Step 2: Preparation of 4- (5-cvclohexvl) -3-methyl-1Hpyrazol-4-yl)-pyridine 4- (5-Cyclohexyl) -3-methyl-1H-pyrazol-4-yl)pyridine was prepared by the method for Example A-i, step 2, by replacing 4- (3-f luoro-4-methoxylphenyl) -3-pyridyl-3butene-2-one with 4-cyclohexyl-3-pyridyl-3-butene-2-one (step Anal. Calc'd for C15H1 9

N

3 C, 73.56; H, 7.98; N, 17.16. Found: C, 73.72; H, 7.91; N, 19.98.

Example 0 A1-[5-C3-ftuoro-5-methoxyphenyl)-3methyl -1H-pyrazo I-4.-y Ilpyr idine q"VMSK-rT(RUL.E26) WO 98/52940 WO 9852940PCTIUS98/1 0436 127 (3-Fluoro-5-methoxyphenyl) -3-methyl-3-methyllH-pyrazol-4-yl~pyridine was prepared by the method of Example A-i, steps 1 and 2 by replacing 3-f luoro-panisaldehyde with 3-fluoro-rn-anisaldehyde: Anal. Calc'd for C 16

H

1 zjN 3 OF: 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: 8U~8HE~(RUek) WO 98/52940 PCTIUS98/1 0436 No R R 2 m.p. or Anal.Calc'd Anal. Calc'd (calcd/found)

_DSC(

0 C Formula C H N 4, CH 77.95/ 6903 15.151 26 H 185-186 C 18

H

1 9

N

3 77.95/ 6.90/ tc, N 77.51 6.93 14.73 27 H CH 3 7571/ 6.16/ 16.55/ 271 H 1fji -1C 142-144 C 16

HISN

3 759 6164 I tZ_ N75.69 6.11 16A99 28 H 1-1 13 240-2 C 2 2

H

1 9

N

3 80.09/ 5.96/ 12.74/ N.0.25H 0 79.74 5.90 13.01

H

3 228.8 C 6 1 N F 3 63.36/ 3.99/ 13.85/ 291 H I I63.28 3.73 13.69 301 H 1 -1c 3 1 189.6 C 1 5

H

1 2

N

3 66.13/ 4.55/ 15.42/ N_ ci .0.15HO 65.98 4.31 15.74 311 H 1- CH3 171.6 C 17 H N 3 76.49/ 6.57/ 15.74/ 321 76.69 6.53 15.61 CN 67.35 5.29 15.02 9/ H '1 CH3 *t188.8 C 1 6

H

1 4

N

3 F 71.89/ 5.28/ 15.72/ 3N 71.72 5.45 15.77 I 215.7 C N 77.54/ 6.51/ 15.96/ 1 41 H 1 1CH 3

.NC

17 H1 17

N

3 77.24 6.80 15.71 H I CH 3 f 1 N I 201.4 C 17

H

17

N

3 0 68.10/ 5.88/ 14.01/ .0.25H120 67.92 5.65 13.65 361 I H1210.7 C 15

H

12

N

4 0, 63.26/ 4.42/ 19.67/ T4N NO 2 .0.251120 63.59 4.39 19.31 1 H Cl1 3

C!

4 ~252.5 C 1 7

H

1 8

N

4 73.35/ 6.52/ 20.13/ N _72.61 6.79 19.59 38 C 73.63/ 5.45/ 15.15/ 38 H 0, I2CJ N CH 3 196.3 C17H15N 73.43 5.46 15.19 391 H I CH 3 252.8 C 15

H

12 N 57.34/ 3.85/ 13.37/ Br 57.09 3.79 13.06 401 H 1 N 1 H I 198.5 C 15

H

1 2

N

3 F 71.13/ 4.78/ 16.59/ F 71.23 5.01 16.76 -1 H CH3 -225.6 C 1 N 71.13/ 4.78/ 16.59/ L HH 1 N70.74 4.66 16.44 142 Ht-H I 219.5 C 1 6

H

1 2

F

3 N 63.36/ 3.99/ 13.85/ 63.19 4.07 13.38 H227.7 C16HN3 76.53/ 6.10/ 16.73/ 1- HC I I_ 2 1H,O 76.53 6.20 16.49 a III I I MiM(RULE26)~E WO 98/52940 PCTIUS98/1 0436 -1I- I I -I No R R 2 44 H CH3 4* CH 2 CHi 4 CH 3 481H I 4tCH3 R N

I

1'N

CN

't Ofi,

CN

R4 CF3 yCI -r -cI M.P. or

DSC('C

175.6

C

17

H

19

N

3 412.1 168.5 211.2 49 H Anal.Cale'd Formula

C

16 Hl 5

N

3 0 15H 2 0

C

15 HllN 3

F

2

C

17 Hl 7

N

3 0 151120

C

16 Hl 2

N

3

F

3 .0.2H-,0

C

13

,H

1

N

3

S

C

15

HIN

3 C12

C

15

H

12

N

3 C1 15H 2 0

C

16

H

1 4

N

3 C1

C

19

H

17

N

3 0 2 C1 71.70/ 71.92 77.54/ 77.13 66.42/ 66.12 72.40/ 72.39 62.62/ 62.64 64.71/ 64.44 59 23/ 59.22 66.13/ 66.33 64.11/ 63.85 64.32/ 63.98 5.75/ 5.76 6.51/ 6.28 4.09/ 3.86 6.18/ 5.87 4.7/4.0 4.06 4.59/ 4.58 3.65/ 3.24 4.55/ 4.62 4.71/ 4.69 4.83/ 5.08 Aml. C I H IN 15.68/ 15.29 15.96/ 15.69 15.49/ 15.25 14.90/ 14.50 13.69/ 13.35 17.41/ 17.27 13.81/ 13.81 15.42/ 15.05 14.02/ 13.93 11.84/ 11.80 H 4 1-CH 3 H 4

-CH

3 189.2 211.7 219.8 163.4 0 IhN

O'

I I I 5.8 118 gF

N

H C15Hl2N3F .0.21120 H C 14

H

10

N

3

F

70.15/ 70.18 70.28/ 69.97 4.86/ 4.60 4.21/ 3.84 16.35/ 16.47 17.56/ 17.53

H

s%%lWM=T1HET(RLE96) WO 98/52940 WO 9852940PCT/US98/1 0436 130 The following pyrazoles could be prepared by the procedures described above: Example A-56 5- (3-chlorophenyl) -3-methyl-lH-pyrazol- 4-yllpyrimidin-2-amine; Example A-57 5- [3-methyl-5- (3-methyiphenyl) -lH-pyrazol- 4-yl] pyrimidin-2-amine; Example A-58 5- [3-methyl-5- (2-methyiphenyl) -lH--pyrazol- 4-yl] pyrimidin-2-amine; Example A-59 5- (4-chlorophenyl) -3-methyl-iN-pyrazol- 4 -yll pyrimidin-2-amine; Example A-60 5- (4-fluorophenyl) -3-methyl-lH-pyrazol- 4 -yll pyrimidin-2 -amine; Example A-61 5- (4-methoxyphenyl) -3-methyl-lH-pyrazol- 4-yll pyrimidin-2-amine; Example A-62 5- (3-chiorophenyl) -3-methyl-1H-pyrazol- 4-yl] pyridin-2-amine; Example A-63 4- (3-chiorophenyl) -3-methyl-lH-pyrazol- 4-yllpyridin-2-amine; Example A-64 4- (3-methylphenyl) -3-methyl-lH-pyrazol- 4-yl] pyridin-2-amine; Example A-65 4- (2-methylphenyl) -3-methyl-lH--pyrazol- 4-yl] pyridin-2 -amine; Example A-66 4- (4-chlorophenyl) -3-methyl-lH-pyrazol- 4-yllpyridin-2-amine; Example A-67 4- (4-f luorophenyl) -3-methyl-lH-pyrazol-4yl] pyridin-2-amine; Example A-68 4- [5-(4-methoxyphenyl) -3-methyl-iN-pyrazol- 4-yl] pyridin-2-amine; Example A-69 5- (3-chlorophenyl) -3-methyl-lH-pyrazol- 4 -yl] -2 -me thoxypyridine; Example A-70 2-methoxy-5- [3-methyl-5- (3-methylphenyl) 1H-pyrazol-4-yl] pyridine; Example A-71 2-methoxy-5- (4-methoxyphenyl) -3-methyllH-pyrazol-4-yl] pyridine; Example A-72 4- (3-chiorophenyl) -3-methyl-lH-pyrazol- URN -111 U I ESHM(RULE26) WO 98/52940 WO 9852940PCTIUS98/1 0436 131 4-yl] -2-methoxypyridine; Example A-73 2-methoxy-4- [3-methyl-5- (3-methyiphenyl) 1H--pyrazol-4-yl] pyridine; Example A-74 2-methoxy-4- [3-methyl-5- (2-methyiphenyl) 1H-pyrazol-4-yl] pyridine; Example A-75 4- (4-chiorophenyl) -3-methyl-lH-pyrazol- 4-yl] -2-methoxypyridine; Example A-76 4- (4-f luorophenyl) -3-methyl-lH-pyrazol- 4-yll -2-methoxypyridine; Example A-77 2-methoxy-4- [3-methyl-5- (4-methyiphenyl) lH-pyrazol-4-yllpyridine; Example A-78 (3-chiorophenyl) -3-methyl-iN-pyrazol- 4-yllpyridin-2-ol; Example A-79 4-Es- (3-chlorophenyl) -3-methyl-lH-pyrazol- 4-yllpyridin-2-ol; Example A-80 4- (3-methylphenyl) -3-methyl-ilH-pyrazol- 4-yl] pyridin-2 -ol; Example A-81 4- (2-methylphenyl) -3-methyl-lH-pyrazol- 4-yl] pyridin-2 -ol; Example A-82 4- (4-chlorophenyl) -3-methyl-lH-pyrazol- 4-yl] pyridin-2 -ol; Example A-83 4- (4-f luorophenyl) -3-methyl-lH-pyrazol- 4-yl)pyridin-2-ol; Example A-84 4- (4-methoxyphenyl) -3-methyl-lH-pyrazol- 4-yllpyridin-2-ol; Example A-85 5- (3-chlorophenyl) -3-methyl-lH-pyrazol- 4-yl] pyridine-2 -methanamine; Example A-86 4- (3-chlorophenyl) -3-methyl-lH-pyrazol- 4-yl) pyridine-2 -methanamine; Example A-87 4- (3-methylphenyl) -3-methyl-1H-pyrazol- 4-yl] pyridine -2 -methanamine; Example A-88 4- (2-methylphenyl) -3-methyl-lH-pyrazol- 4-yl] pyridine -2 -methanamine; Example A-89 4- (4-chlorophenyl) -3-methyl-lI{-pyrazol- 4-yl] pyridine-2-methanamine; Example A-90 4- (4-f luorophenyl) -3-methyl-lH-pyrazol- .1mJrEBHEErRULEZS) WO 98/52940 WO 9852940PCTIUS98/1 0436 132 4-yl] pyridine-2 -methanamine; Example A-91 4- (4-methoxyphenyl) -3-methyl-lH-pyrazol- 4-yl] pyridine-2-methanamine; Example A-92 5- (3-chiorophenyl) -3-methyl-lH-pyrazol- 4-yl] pyridine-2 -carboxamide; Example A-93 4- (3-chiorophenyl) -3-methyl-lH-pyrazol- 4-yl] pyridine- 2- carboxamide; Example A-94 4- (3-methylphenyl) -3-methyl-lH-pyrazol- 4-yl] pyridine-2-carboxamide; Example A-95 4- (2-methylphenyl) -3-methyl-lH-pyrazol- 4-yl] pyridine-2-carboxamide; Example A-96 4- (4-chiorophenyl) -3-methyl-1H-pyrazol- 4-yl] pyridine-2 -carboxamide; Example A-97 (4-f luorophenyl) -3-methyl-lH-pyrazol- 4 -yl] pyridine-2 -carboxamide; Example A-98 4- (4-methoxyphenyl) -3-methyl-lH-pyrazol- 4-yl] pyridine -2 -carboxamide; Example A-99 4- (3-f luoro-4-methoxyphenyl) -3-methyllH-pyrazol-4-yl) pyridine; Example A-100 4- (4-fluoro-3-methoxyphenyl) -3-methyl- 1H-pyrazol-4-yl] pyridine; Example A-101 4- (4-chloro-3-methoxyphenyl) -3-methyl- 1H-pyrazol-4-yl] pyridine; Example A-102 4- (2,3-dihydrobenzofuran-6-yl) -3methyl-lH-pyrazol-4-yl] pyridine; Example A-103 4- (benzofuran-6-yl) -3-methyl-lHpyrazol-4-yl] pyridine; Example A-104 4- (3-f luoro-5-methoxyphenyl) -3-methyl- 1H-pyrazol-4-yll pyridine; Example A-l05 4- (3-chloro-5-methoxyphenyl) -3-methyllH-pyrazol-4-yl] pyridine; Example A-lO6 4-[5-(l-cyclohexyen-l-yl)-3-methyl-lHpyrazol-4-yl] pyridine; Example A-107 4- [5-(l,3-cyclohexadien-l-yl)-3-methyl-1Hpyrazol-4-yllpyridine; Example A-108 4- [5-(5,6-dihydro-2H-pyran-4-yl) -3-methyl- 8 UBSTTUrESHEErTMLE 21) WO 98/52940 WO 9852940PCT/US98/1 0436 133 lH-pyrazol-4-yl] pyridine; Example A-109 4- (5-cyclohexyl-3-methyl-lH-pyrazol-4yl) pyridine; Example A-l10 4- (4-methoxy-3-methylphenyl) -3-methyllH-pyrazol-4-yl] pyridine; Example A-ill 4- (3-methoxy-4-methylphenyl) -3-methyllH-pyrazol-4-yl] pyridine; Example A-112 4- (3-methoxy-5-methylpheiyl) -3-methyllH-pyrazol-4-yl] pyridine; Example A-113 4-[5-(3-furanyl)-3-methyl-1H-pyrazol-4yl] pyridine; Example A-114 2-methyl-4- (3-methyl-5-phenyl-1H-pyrazol- 4 -yl) pyridine; Example A-115 2-methoxy-4- 4-yl)pyridine; Example A-116 methyl 4- (3-methyl-5-phenyl-lHi-pyrazol-4yl) pyridine-2 -carboxylate; Example A-117 4- (3-methyl-5-phenyl-lH-pyrazol-4yl) pyridine-2 -carboxamide; Example A-118 1- (3-methyl-5-phenyl-lH-pyrazol-4yl) pyridin-2-yl] ethanone; Example A-119 N,N-dimethyl-4- pyrazol -2 -yl) pyridin-2 -amine; Example A-120 3-methyl-4- 4-yl)pyridine; Example A-121 3-methoxy-4- 4-yl) pyridine; Example A-122 methyl 4- (3-methyl-5-phenyl-lH-pyrazol-4yl) pyridine carboxylate; Example A-123 4- (3-methyl-5-phenyl-lH-pyrazol-4yl) pyridine carboxamide; Example A-124 1- (3-methyl-5-phenyl-lH-pyrazol-4yl) pyridin- 3-yl] ethanone; Example A-125 3-bromo-4- (3-methyl-5-phenyl-lH-pyrazol-4yl)pyridine; Example A-126 N,N-dimethyl-4- 6USFLOSMMHEEr (PULE 06% WO 98/52940 WO 9852940PCTIUS98/1 0436 134 pyrazol-2-yl) pyridin-3-amine; Example A-127 2-methyl-4- 4 -yl) pyrimidine; Example A-128 4- (3-methyl-5-phenyl-lH-pyrazol-4yl)pyrimidine; Example A-129 2-methoxy-4- 4-yl) pyrimidine; Example A-130 4- (3-methyl-5-phenyl-lH-pyrazol-4yl) pyrirnidin-2-amine; Example A-131 N,N-dimethyl-4- pyrazol -4-yl) pyrimidin-2-amine; Example A-132 4- (5,6-dihydro-2H-pyran-4-yl) phenyl H-pyrazole; Example A-133 pyrazole; Example A-134 pyrazole; Example A-135 pyrazole; Example A-136 pyrazole; Example A-137 pyrazole; Example A-138 pyrazole; Example A-139 pyrazole; Example A-140 pyrazole; Example A-141 pyrazole; Example A-142 pyrazole; Example A-143 4-yllpyridine; Example A-144 3 -methyl-5-phenyl-4 -thienyl) -lH- 4- (3-furanyl) 3-methyl-5-phenyl-4- (2-thienyl) -lH- 4- (2-furanyl) 4- (3-isothiazolyl) 4- (3-isoxazolyl) 4- (5-isothiazolyl) 4- (5-isoxazolyl) 3-methyl-5-phenyl-4- (5-thiazolyl) -1H- 3-methyl (5 -oxazolyl) -5-phenyl H- 2-methyl-4- (3-methyiphenyl) -lH-pyrazol- 4- (l-methyl-3-phenyl-lH-pyrazol-4-yl) pyridine; SUBTMSHEEU(RULE26) WO 98/52940 WO 9852940PCTIUS98/10436 135 Example A-145 Example A-146 yl) pyridine; Example A-147 yllpyridine; Example A-148 yl] pyridine; Example A-149 yl] pyridine; Example A-150 yl]I pyridine; Example A-151 4- (3-phenyl-lH-pyrazol-4-yl)pyridine; 2-methyl-4- (3-phenyl-lH-pyrazol-4- 4- (3-chiorophenyl) -l-methyl-pyrazol-4- 4- (4-chiorophenyl) -l-methyl-pyrazol-4- 4- (3-chiorophenyl) -lH-pyrazol-4- 4- (4-chlorophenyl) -lH-pyrazol-4- 4- (3-chlorophenyl) -lH-pyrazol-4-ylj -2methylpyridine; Example A-152 4- (3-f luorophenyl) -l-methyl-lH-pyrazol- 4-yllpyridine; Example A-153 4- (3-f luorophenyl) -lH-pyrazol-4ylllpyridine; and Example A-154 4- (3-chiorophenyl) -i-methyl-pyrazol-4yl] -2-methylpyridine.

The compounds of Examples A-155 through A-172 were synthesized in accordance with the chemistry described above (particularly Scheme II) and illustrated by many of the previously disclosed Examples by selection of the corresponding starting reagents: Example A-155

P

(4-chlorophenyl) -N-phenyl-4- (4-pyridinyl) -lH- SUBBM M)TSWET (RULE 2) WO 98/52940 WO 9852940PCT/US98/10436 136 pyrazol-3-amine: DSC 261 OC. Anal. Calc'd for C 2

,H

15 C1N, 0.25 H 2 0 (MW 351.32) C, 68.38, 4.30, N, 15.95.

Found: C, 68.25, H, 4.41, N, 15.74.

Example A-156

CI

H

N

(4-chiorophenyl) -N-methyl-4- (4-pyridinyl) -1H-pyrazol-3amine: DSC 260 OC. Anal. Calc'd for C 15 ,Hl 3 C1N, 0.125 H 2 0 (MW 287.00): C, 62.77, H, 4.57, N, 19.52. Found: C, 62.78, H, 4.33, N, 19.22.

Example A-157 ci

N.

IN

N /N- (4-chiorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -1Hpyrazol-3-amine dihydrate: DSC 230 OC. Anal. Calc'd for

C

16

H

15 C1N, 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.

SUBS1TUTESWHEE (RULE 2) WO 98/52940 WO 9852940PCTIUS98/I 0436 137 Example A-158

*F

H

N

'N

N (3-f luorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -1Hpyrazol-3-amine: DSC 227 OC. Anal. Calc'd for C 1 6 H,,FN, 0.125 H 2 0 (MW 284.57) 67.53, H, 5.31, N, 19.69.

Found: C, 67.60, H, 5.20, N, 19.84.

Example A-159 N,N-dimethyl-5- (3-methyiphenyl) (4-pyridinyl) -lHpyrazol-3-amine: DSC 222 OC. Anal. Calc'd for C 17

H

18 N, 0.25 H~2O (MW 282.86) 72.19, H, 6.41, N, 19.81. Found: C, 71.99, H, 6.46, N, 19.90.

SLMM=E(RLE2M WO 98/52940 WO 9852940PCTIUS98/10436 138 Example A-160

H

N

N I N N

HN-

(3-methyiphenyl) (4-pyridinyl) -1H-pyrazol-3amine: DSC 226 IC. Anal. Calc'd for C 16 0.125 H 2 0 (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 N-ethyl-5- (3-methyiphenyl) (4-pyridinyl) -1H-pyrazol-3amine: DSC 227 OC. Anal. Calc'd for C,,HlN 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.

9JBS~fUSHEEF(RULE26) WO 98/52940 WO 9852940PCTIUS98/1 0436 139 Example A-162 (3-methyiphenyl) (4-pyridinyl) -iNpyrazol-3-amine: DSC 234 OC. Anal. Calc'd for Cl 9

H

2 2

N*

4 (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

CI

H

N

N

N I N E t Et 5- (4-chiorophenyl) N,N-diethyl-4- (4-pyridinyl) -1Hpyrazol-3-amine: m.p. 260-261 0 C. Anal. Calc'd for

C

18

H

19 C1N, (MW 326.83): C, 66.15, H, 5.86, N, 17.14.

Found: C, 66.03, H, 5.72, N, 17.23.A[ WO 98/52940 WO 9852940PCT/US98/1 0436 140 Example A-164

IN

0 4- (4-chiorophenyl) (4-pyridinyl) -lH-pyrazol-3y1]morpholine: DSC 279 OC. Anal. Calc'd for C,,Hl 7 C1N,0 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 5- (4-chiorophenyl) -N-propyl-4- (4-pyridinyl) -1H-pyrazol-3amine: DSC 244 0 C. Anal. Calc'd for C 17

H

17 C1N, 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.

B~E~tRU26) WO 98/52940 WO 9852940PCT/US98/1 0436 141 Example A-166 Isolated as 5- (4-chiorophenyl) (phenylmethyl) (4pyridinyl)-1H-pyrazol-3-amine hydrate DSC 237 1C.

Anal. Calc'd for C 21

H

17 C1N, 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 ci

N

HN

N

100 Isolated as 5- (4-chiorophenyl) (2-methoxyethyl) (4pyridinyl) -lH-pyrazol-3-amine monohydrate: DSC 223 OC.

Anal. Calc'd for C 17

H

17 ClN,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.

MMST=EB=%t(RuLE2Q WO 98/52940 WO 9852940PCT/US98/I 0436 142 Example A-168

NH

N

0 0 1,1-dirnethylethyl 4- (4-chiorophenyl) (4-pyridinyl) 1H-pyrazol--3-yl] -1-piperazinecarboxylate: DSC 251 OC.

Anal. Calc'd for C 2 3

H

2 ,C1N 5 0 (MW 439.95) C, 62.79, H, 5.96, N, 15.92. Found: C, 62.40, H, 5.82, N, 15.82.

Example A-169

CI

NH

N

;N

N

C)

H

Isolated as 1- (4-chiorophenyl) (4-pyridinyl) -lHpyrazol-3-yllpiperazine trihydrochioride: DSC 99 *C.

SU6SflUE8HEUV.LE WO 98/52940 WO 9852940PCTIUS98/1 0436 143 Anal. Calc'd for C 18

H

18 C1N, 3 HCl (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

N H N N N N 1- (4-chiorophenyl) (4-pyridinyl) -1H-pyrazol-3-yl] -4methylpiperazine: m.p. 247-249 OC. Anal. Calc'd for

C

19

H

20 ClN 5 0.75 H 2 0 (MW 367.33) C, 62.12, H, 5.49, N, 19.06. Found: C, 62.45, H, 5.86, N, 19.32.

Example A-171

F

NH

-N

N

N

0 1, 1-dimethylethyl 4- (4-f luorophenyl) (4-pyridinyl) 1H-pyrazol-3-y1] -1-piperazinecarboxylate: m.p. 243-244 SuBSfTUTBHE(RULE26) WO 98/52940 PCT/US98/10436 144 Anal. Calc'd for C 2 3

H

2 6

FN

5 0 2 0.5 CH 3

CH

2

CO

2

CHCH

3

(MW

467.55): C, 64.22, H, 6.47, N, 14.98. Found: C, 63.90, H, 6.61, N, 14.88.

Example A-172 3HCI 1-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3yl]piperazine trihydrochloride: m.p. 204-206 oC. Anal.

Calc'd for CeHiFn 5 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)-lH-pyrazol-3yl]piperazine: m.p. 264-265 OC. Anal. Calc'd for

C

18 HiC1Ns 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 accordance with the chemistry described in Scheme II by selection of the corresponding starting reagents further include the compounds disclosed in Table 2.

WWMMWEU(RA.EW(wwnr~ TABLE 2 Example General Microanalysis

DSC

Procedure Formula C caic C found H caic H found N caic N found deg C A- 173 Sch. 11 C24H125C1N63H14-.5H-20 50.63 50.58 4.96 5.03 14.76 14.68 182 A-174 Sch. II C25H24C1N5-0.125H20 69.47 69.33 5.60 5.56 16.20 16.11 259 A-175 Sch. II C17H17FN6-1.25H20 48.64 48.45 4.56 4.86 20.02 20.24 82 A-176 Sch. II C22H-26C1N502 61.75 61.57 6.12 6.04 16.37 16.34 217 A-177 Sch. Il C17H18C1N5-3HCIPH2O 44.85 44.96 4.65 4.87 15.38 15.17 220 A-178 Sch. II C21H-24C1N502-0.125H20 60.61 60.51 5.81 5.81 16.83 16.64 232 A-179 Sch. II C25H30 CIN503 62.04 61.76 6.25 6.25 14.47 14.37 220 A-180 Sch. II C22H-25 1zN602.0.5H-20 60.96 60.86 5.81 6.21 19.39 19.47 N.D.

A-181 Sch. II C22H25 CIFN502 59.26 58.98 5.65 5.55 15.71 15.36 210 A-182 Sch. II C20H22CIN50.75H20 62.98 62.97 5.81 5.64 18.36 17.83 271 A-183 Sch. II C16H19Cl4NS53HC1 45.41 45.37 4.53 4.7412 WO 98/52940 WO 9852940PCTUS98/1 0436 146 Example A-173 3HC I N- (4-chiorophenyl) (phenylmethyl)amino] -4pyridinylll H-pyrazol-3-yl] -1,3-propanediamine, trihydrochioride Example A-174 c I

NH

N

N

Bn LO 1- (4-chiorophenyl) (4-pyridinyl) -iH-pyrazol-3yl] (phenylmethyl)piperazine SJBMnUTESH (t XE) WO 98/52940 WO 9852940PCTIUS98/10436 147 Example A-175

*F

N NH

N

N~N

H

Isolated as 4- (4-f luorophenyl) (1-piperazinyl) -lHpyrazol-4-yl] pyrimidine, dihydrochioride Example A-176 HBoc 1,1-dimethylethy. [3-[[5-(4-chlorophenyl)-4-(4pyridinyl) -1H-pyrazol-3-yl] amino] propyl] carbamate BUBSITUTSWEET (RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 148 Example A-177 Isolated as N- [4-chiorophenyl) (4-pyridinyl) -1Hpyrazol-3-yl] 3-propanediamine, trihydrochioride monohydrat e Example A-178 1,1-dimethylethyl [[5-(4-chlorophenyl)-4-(4pyridinyl) -lH-pyrazol-3-yll amino] ethyl] carbamate SLW~nSHEUr(RULE26) WO 98/52940 WO 9852940PCTIUS98/1 0436 149 Example A-179

N

Boc 1,1-dimethylethy. 4-[5-(4-chlorophenyl)-1-(2hydroxyethyl) (4-pyridinyl) -1H-pyrazol-3-yl] -1piperazinecarboxylate Example A-180

F

NH

N

N

Boc 1,1-dimethylethyl 4-[5-(4-fluorophenyl)-4-(4pyrimidinyl) H-pyrazol -3 -yl] -1-piperazinecarboxylate Surflt7EBMHM(RULE2M WO 98/52940 WO 9852940PCT/US98I1 0436 150 Example A-181 HBoc 1,1-dimethylethyl (4-chiorophenyl) (2-fluoro-4pyridinyl) -1H-pyrazol-3-yl] amino] propyl] carbamate Example A-182 c I

NH

N

NN

CN)

Et 1- (4-chiorophenyl) (4-pyridinyl) -lH-pyrazol-3-yl] -4ethylpiperazine SLSUBSITU ETE(FrULEM6 WO 98/52940 WO 9852940PCT/US598/10436 151 Ex ample A-183 N- (4-chiorophenyl) (4-pyridinyl) -1H-pyrazol-3-yl] 1, 2-ethanediamine The compounds of Examples A-184 through A-189 were synthesized in accordance with the chemistry described above (particularly in Schemes I and IV) and illustrated by the previously disclosed Examples by selection of the corresponding starting reagents: Example A-184

F

N

/N

H

F

N

4-[3-(2,6-difluorophenyl)-5-methyl-lH-pyrazol-4yllpyridine: Anal. Calc'd for C 1511

F

2 N1 3 C, 66.42; H, 4.09; N, 15.49. Found: C, 66.20; H, 3.94; N, 15.16; M.P.

BUBjj36TEB=hiEE (ROULE fb=) WO 98/52940 WO 9852940PCTIUS98/1 0436 152 236.67 OC.

Example A-185 4- (3-ethyiphenyl) -5-methyl-1H-pyrazol-4-yllpyridine: Anal. Calc'd for C 17

H

17

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.

Example A-186 Cl

NH

4- (3-chiorophenyl) -5-ethyl-1H-pyrazol-4-yllpyridine: Anal Calc'd for ClH 14 ClN 3 O. mole H20: C, 67.15; H, 4.91; N, 14.33. Found: C, 66.95; H, 5.00; N, 14.36. DSC: 176.18 OC.

SU6MflUTESHEgET E2 WO 98/52940 WO 9852940PCT/US98/1 0436 1-53 Example A-187 4- [3-ethyl-5- (3-ethyiphenyl) -lH-pyrazol-4-yl~pyridine: Anal. Calc'd for C,,H, 9

N

3 *00. 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 4- (4-chiorophenyl) (1-methylethyl) -lH-pyrazol-4yllpyridine: Anal. Calc'd for C 17 Hl 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.

WO 98/52940 PCT/US98/10436 154 Example A-189

F

NH

N

4-[3-cyclopropyl-5-(4-fluorophenyl)-1H-pyrazol-4yl]pyridine: Anal. Calc'd for C 17

H,

4

FN

3 C, 73.1; H, N, 15.04. Found: C, 73.23; H, 4.89; N, 14.63; m.p.: 240 oC.

5.05; 239- The compound of Example A-190 was synthesized in accordance with the chemistry described above (particularly in Scheme III) and illustrated by the previously disclosed Examples by selection of the corresponding starting reagents: Example A-190 4-[3-(4-fluorophenyl)-5-(trifluoromethyl)-lH-pyrazol-4yl]pyridine This compound was prepared by the same procedure as 8U MSHEEr(RU&-E WO 98/52940 WO 9852940PCTIUS98/1 0436 155 described for Example A-22 by replacing pyridylacetyl) toluene with 1-f luoro-4- -pyridylacetyl) benzene (prepared as set forth in Example A-19).

Anal. Calc'd for C,,HF 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 synthesized in accordance with the chemistry described above (particularly in Scheme V) by selection of the corresponding starting reagents: Example A-191

F

'NN

N

N

4- (cyclopropyl-3- (fluorophenyl) -l-methyl-lHpyrazol -4 -yl Ipyridine Step 1: Preparation of 1- (4-f luorophenyl) (4- Pyridinyl) ethanone methylhydrazone NNHMe l-C4-fIuorophenyI)-2--C4-pyr idinyI)ethanone methy~hydr-azone SUfLMMTE SHEET(RUE WO 98/52940 PCT/US98/10436 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 stirred at room temperature overnight. After the removal of solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium carbonate solution, washed with brine, and dried over magnesium sulfate. The filtrate was concentrated and the crude product was recrystallized from diethyl ether and hexane to afford 7.5 g of a yellow solid product (77% yield), 1-(4-fluorophenyl)-2-(4pyridinyl)ethanone methylhydrazone.

Step 2: Preparation of 4-[5-(cyclopropvl-3-(4- (fluorophenyl)-l-methyl-lH-pvrazol-4-vl]pvridine To a solution of sodium hexamethyldisilazide 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 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 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 3 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane/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 yield), mp: 129-130 OC; IH NMR (CDCL) 6 8.53 2H), 7.32 2H), 7.14 2H), 6.97 2H), 4.00 3H), 1.83 1H), 0.95 2H), 0.36 2H); Anal. Calc'd For C 18 HiFN 3 C, 73.70; H, 5.50; N, 14.32. Found: C, asTfUTEfsHEE(RULE26) WO 98/52940 WO 9852940PCTIUS98/1 0436 157 73.63; H, 5.57; N, 14.08.

Example A-192

F

__N

N -H 5-cyclopropyl-3- (4-f luorophenyl) (4-pyridinyl) -1Hpyrazole- 1-ethanol Step 1: Preparation of 1- (4-f luorophenyl) (4- Pyridinvi) ethanone (2 -hvdroxyethvl) hvdrazone 1-C 4-flIuorophenylI)- 2-C4-pyr id iny I)etha none C 2- hydrox yet hyI) hydr azone To a flask containing hydroxyethyl hydrazine (3.4 g, 0.04 mol) at 80 OC was added 4-f luorobenzoyl-4'-pyridinyl methane (8.6 g, 0.04 moi) portionwise. The yellow oil was stirred at this temperature overnight. The cooled reaction mixture was dissolved with hot ethyl acetate and then triturated with hexane to give 8.9 g of product, 1- (4-f luorophenyl) (4-pyridinyl)ethanone (2hydroxyethyl)hydrazone, as a yellow crystal mp: 122-123 OC.

WO 98/52940 WO 9852940PCTIUS98/I 0436 158 Step 2: -Preparation of 1- (4-f luorophenvi) (4pyridinvl)ethanone f2- [f(l,1dimethylethvl) dimethylsilyl] oxvl ethvll hydrazone

F

NNHCH

2

CH

2 O5 i- t- BuMe 2

N

1-C4-fluorophenyI)-2-C4-pyridInyI)ethanone t2-[ECCl1-dimethylethyl~dimethylsiy]oxy~ethyjjhydrazone To a solution of the 1-(4-fluorophenyl)-2-(4pyridinyl) ethanone (2 -hydroxyethyl) hydrazone prepared in step 1 (2.73 g, 0.01 mol) and (1,1dimethylethyl)dimethylsilyl chloride (1.5 g, 0.01 mol) in mL of DMF was added imidazole portionwise. The reaction mixture was stirred at room temperature overnight. Water was added and extracted with ethyl acetate, the organic layer was washed with water, washed with brine, dried over magnesium sulfate and filtered.

The filtrate was concentrated to give 3.8 g of crude product, 1- (4-f luorophenyl) (4-pyridinyl) ethanone [2- 1-dimethylethyl) dimethylsilyl] oxy] ethyl] hydrazone, as a yellow oil that was used in the next step without further purification.

&Uffn=%iU-T(R&E'W WO 98/52940 PCT/US98/10436 159 Step 3: 5-cyclopropyl-1- [2-[[(1,1-dimethylethyl) dimethylsilvloxy]ethyl]-3,4-diphenvl-1H-pyrazole

NCH

2 CHOSI -t-BuMe 2 5-cyclopropyl-1-[2-[[C1,1-dimethylethyI) dimethylsilyl]oxy]ethyl]-3,4-dlphenyl-1H-pyrazole To a solution of sodium hexamethyldisilazide (4.2 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 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 3 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 0.30 g of product, 5-cyclopropyl-l-[2-[[(l,ldimethylethyl) dimethylsilyl]oxy]ethyl]-3,4-diphenyl-lHpyrazole, as a light yellow oil (35% yield), 1H NMR

(CDCL

3 6 8.53 2H), 7.32 2H), 7.14 J 5.6 Hz, 2H), 6.97 2H), 4.47 J 4.8 Hz, 2H), 4.14 (t, J 4.8 Hz, 2H), 1.93 1H), 0.95 2H), 0.87 (s, 9H), 0.41(m, 2H); Anal. Calc'd For C 25

H

32

FN

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

SUB8111UTsHEET(MU=LEO WO 98/52940 PCT/US98/10436 160 Step 4: Preparation of 5-cyclopropvl-3-(4-fluorophenyl)- 4-(4-pyridinyl)-H-pyrazole-l-ethanol To a solution of the compound prepared in step 3 (0.27 g, 0.00062 mol) in 5 mL of THF was added tetrabutylammonium fluoride (1.9 mL of 1.0 M THF solution) at room temperature. After 1 hour, water was added and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 9:1) to give 0.16 g of product, 5-cyclopropyl-3-(4fluorophenyl)-4-(4-pyridinyl)-IH-pyrazole-l-ethanol, as a pale yellow solid, mp: 155-157 OC; IH NMR (CDCL 3 6 8.53 (br s, 2H), 7.32 2H), 7.14 J 5.6 Hz, 2H), 6.97 2H), 4.42 J 4.8 Hz, 2H), 4.14 J 4.8 Hz, 2H), 1.83 1H), 0.93 2H), 0.35(m, 2H); Anal.

Calc'd For C, 9 H,3FN 3 0: C, 70.57; H, 5.61; N, 12.99. Found: C, 70.46; H, 5.87; N, 12.84.

Example A-193

F

N N

OH

N OMe 3-(4-fluorophenyl)-5-(2-methoxy-4-pyridinyl)-4-(4pyridinyl)-iH-pyrazole-l-ethanol To a solution of sodium hexamethyldisilazide (7.4 mL, 1.0 M in THF) at 0 oC was added a solution of the sufsmserrrms"RaE~ WO 98/52940 PCT/US98/10436 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-(2methoxy)pyridinecarboxylate (0.0.59 g, 0.0035 mol) in mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 3 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 0.28 g of product, 3-(4-fluorophenyl)-5-(2methoxy-4-pyridinyl)-4-(4-pyridinyl)-1H-pyrazole-lethanol, as a yellow solid, mp: 168-169 1H NMR (CDCL3) 6 8.42 2H), 8.20 (dd, J 0.7, 5.2 Hz, 1H), 7.37 2H), 7.02 2H), 6.95 2H), 6.71 (dd, J 1.4, 5.2 Hz, 1H), 6.66 J 0.7 Hz, 1H), 4.20 2H), 4.14 2H), 3.95 3H); Anal. Calc'd for C 22 Hz 9

FN

4 0 2

C,

67.86; H, 4.91; N, 14.35. Found: C, 67.46; H, 5.08; N, 14.03.

F

N

N OSi Ct-Bu)Me, N OMe 4-[1-[2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-3-(4-fluorophenyl-4-(4-pyridinyl) -H-pyrazol- 5-yl]-2-methoxypyridine IJBBSafl1UESE (RULE 28) WO 98/52940 PCT/US98/10436 162 A second compound, 4-[1-[2-[[(1,1-dimethylethyl) dimethylsilyl]oxy]ethyl]-3-(4-fluorophenyl-4-(4pyridinyl)-lH-pyrazol-5-yl]-2-methoxypyridine also was isolated from the above reaction as a yellow oil by chromatography. 1 H NMR (CDCL 3 6 8.45 2H), 8.20 (m, 1H), 7.40 2H), 7.04 2H), 6.93 2H), 6.81 (m, 2H), 4.24 2H), 4.14 2H), 3.98 3H), 0.83 (s, 9H), 0.02 6H).

Example A-194

F

N

/OH

NNO

H

4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)- 1H-pyrazol-5-yl]-2(1H)-pyridinone To a solution of 3-(4-fluorophenyl)-5-(2-methoxy-4pyridinyl)-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 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 C1 2 /NH40H, 5:94:1) to give 0.07 g of product, 4-[3-(4-fluorophenyl)-1-(2hydroxyethyl)-4-(4-pyridinyl)-1H-pyrazol-5-yl]-2(1H)- STmgUTESHEET(RLE28) WO 98/52940 PCT/US98/1 0436 163 pyridinone, as a yellow solid (32% yield), mp: 250-251 0 C; 1 H NMR (DMSO-d): 6 11.74 1H), 8.45 J Hz, 2H), 7.35 3H), 7.16 2H), 7.03 d, J Hz, 2H), 6.37 1H), 6.05 J 5.2 Hz, 1H), 5.0 (m, 1H), 4.13 2H), 3.81 2H); Anal. Calc'd for

C

21

H,,FN

4 0 2 *0.2 HO 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

SN

OH

N N 0 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- (4-pyridinyl)-1H-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 oC; 1H NMR (CDC1 3 6 8.50 2H), 7.39 3H), 7.02 (m, 4H), 6.59 1H) 6.08 (dd, J 1.4, 5.2 Hz, 1H), 4.52 J 6.0 Hz, 2H), 4.43 J 6.0 Hz, 2H), 2.04 Anal. Calc'd for C 23

H,FN

4 0 3 *0.3 H,20: C, 65.46; H, 4.63; N, 13.28. Found: C, 65.09; H, 4.64; N, 12.99.

U6BSTUnESHEET(RULE28) WO 98/52940 PCT/US98/10436 164 Example A-196

F

OH

I-

N

N

O

0 Ethyl 2-[3-(4-fluorophenyl)-l-(2-hydroxyethyl)-4-(4- 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 solution was stirred at this temperature for 30 minutes.

Then a solution of diethyl 1,2-cyclopropanedicarboxylate (1.12 g, 0.006 mol) in 10 mL of dry THF was added. The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. Water was added and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on silica gel (ethyl acetate/hexane, 8:2) to give 0.18 g of product, ethyl 2- [3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)as a light yellow oil (35% yield), 1 H NMR (CDCL) 6 8.55 2H), 7.32 2H), 7.11 2H), 6.97 2H), 4.38 (m,2H), 4.16 4H), 2.47 1H), 1.53 2H), 1.26 Hz, 3H), 2H), 0.90 2H); Anal. Calc'd for

C

22

H

22

FN

3 0 3 *0.25 H 2 0: C, 66.07; H, 5.67; N, 10.51 Found: C, gmUTESHEEr(RULE26) WO 98/52940 PCT/US98/10436 165 65.89; H, 5.80; N, 9.95.

Example A-197

F

NH

N

N

CO

2

H

2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridinyl)acid To a solution of ethyl 2-[3-(4-fluorophenyl)-1-(2hydroxyethyl)-4-(4-pyridinyl)-lH-pyrazol-5-yl] cyclopropanecarboxylate prepared in accordance with Example A-196 (0.21 g, 0.00045 mol) in 10 mL of methanol was added a solution of sodium hydroxide (0.09 g, 0.0022 mol) in 2 mL of water. The reaction mixture was stirred at reflux for 6 hours. After the solvent was removed, the residue was dissolved with 10 mL of 1N HC1 and stirred for 30 minutes. The pH was then adjusted to 5-6 by addition of IN sodium hydroxide solution and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium and filtered.

The filtrate was concentrated and the crude was purified by recrystallization from ethanol and ether to give 0.1 g of product, 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4- (4-pyridinyl)-1H-pyrazol-5-yl]cyclopropanecarboxylic acid, as a white solid (60% yield), mp: 253-255 oC; H NMR

(CD

3 OD): 6 8.46 2H), 7.32 2H), 7.25 2H), 7.04 2H), 4.39 J 5.0 Hz, 2H), 4.03 2H), 2.60 (m, 1H), 1.51 2H), 0.97 2H); Anal. Calc'd For suq&lUESHR'EElE 8) WO 98/52940 PCT/US98/10436 166

C

20

H,,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

I IOH N 7 NH

N

3-(4-fluorophenyl)-5-(4-imidazolyl)-4-(4-pyridinyl)-1Hpyrazole-1-ethanol Step 1: Preparation of methyl 1-[[2-(trimethylsilvl) ethoxy]methyl]-1H-pyrrole-3-carboxvlate

CO

2 Me TM S 0 N N methyl 1- [[2-(trimethylsilyl)ethoxy]methyl] -1H-pyrrole-3carboxylate To a suspension of sodium hydride (1.0 g, 0.025 mol) in 50 mL of DMF was added methyl 4-imidazolecarboxylate (2.95 g, 0.023 mol) portionwise at room temperature. The mixture was stirred at room temperature for 0.5 hours.

Then SEM-C1 (4.17 g, 0.025 mol) was added dropwise over minutes. The reaction mixture was stirred for 4 hours and quenched by adding water. The aqueous phase was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude aLmESHUEE T(RULE26) WO 98/52940 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.

Step 2: Preparation of 4-l1-[2-[[(1,1-dimethylethyl) dimethylsilylloxy]ethyl]-3-(4-fluorophenvl-5-[1- trimethysilyl)ethoxy]methyl-1H-imidizol-4-yl] -H-pyrazol- 4-yllpyridine

F

N

N 05i (t-Bu)Me 2 N

N

0-/

TMS

[(1,1-dimethylethyl)dimethylsilyl] oxy]ethyl]-3-(4-fluorophenyl)-5-[1-[[2trimethylsilyl)ethoxy]methyl]-lH-imidazol-4-yl]-1Hpyrazol-4-yl]pyridine To a solution of sodium hexamethyldisilazide 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 8 g, 0.002 mol) in 10 mL of dry THF dropwise. The dark brown solution was stirred at this temperature for minutes. Then a solution of the compound prepared in step 1 of the present Example (0.54 g, 0.0021 mol) in 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 SLeMnuMtEBHME(RuECO 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 solidified upon standing (91% yield), mp: 79-80 OC; 1H NMR

(CDCL

3 6 8.48 J 6.0 Hz, 2H), 7.68 J 1.3 Hz, 1H), 7.38 J 6.0 Hz, 2H), 7.10 2H), 7.00 (m, 2H), 6.93 J 1.3 Hz 1H), 5.25 2H), 4.53 J 6.0 Hz, 2H), 4.12 J 6.0 Hz, 2H), 3.84 J Hz 2H), 0.92 J 8.0 Hz, 2H), 0.84 9H), 0.021 18H); Anal. Calc'd For C 3

H,

44 FN02Si 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-fluorophenvl)-5-(4imidazolyl)-4-(4-pyridinyl)-1H-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 M in THF). After the mixture was heated at reflux for 3 hours, the solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified on silica gel (methylene chloride/methanol, 95:5) to give 0.22 g of the product, 3-(4-fluorophenyl)-5-(4-imidazolyl)-4-(4-pyridinyl)-lHpyrazole-l-ethanol, as a white solid (63% yield), mp: 227-228 OC; 'H NMR (DMSO-d 6 6 8.45 2H), 7.83 (s, 1H), 7.35 2H), 7.15 4H), 7.09 1H), 5.20 (br s, 1H), 4.32 2H), 3.81 2H); Anal. Calc'd For

C,

9 Hi 6 FNsO: C, 65.32; H, 4.62; N, 20.05. Found: C, 64.98; H, 4.55; N, 19.79.

The compound of Example A-199 was synthesized in accordance with the chemistry described above (particularly in Scheme VI) by selection of the 8LnT6flrESEE(REU L WO 98/52940 WO 9852940PCTIUS98/1 Q436 169 corresponding starting reagents: Example A-199

ZNH

N

C I 4- (4-chloro-3-methylphenyl) -lH-pyrazol-4-yl]pyridine Anal. Calc'd for C.

1 5 H3.

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.

.0 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: Example A-200 (4-f luorophenyl) (4-pyridinyl) -1H-pyrazole-3carboxylic acid euMTrrE6Ejr(RULE 26) WO 98/52940 PCT/US98/10436 170 A mixture of 4-[3-(4-fluorophenyl)-5-methyl-lHpyrazol-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 tertbutanol (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 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-(4fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-3-carboxylic acid (isolated as the monohydrate salt) (2.9777 g, 43.7 Anal. Calc'd for C,,HoN 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).

Example A-201

N<

OH

N

N

5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-methanol To a suspension of 5-(4-fluorophenyl)-4-(4pyridinyl)-lH-pyrazole-3-carboxylic acid, monohydrate prepared in accordance with Example A-200 (0.526 g, mmol) in dry THF (15 ml) at reflux under nitrogen, a solution of 1N lithium aluminum hydride in THF (4.0 ml, SUB UTE EET (RULE 26) WO 98/52940 PCT/US98/10436 171 mmol) was added dropwise over 15 minutes. A precipitate formed. The mixture was boiled for an additional hour. Excess lithium aluminum hydride was then decomposed by cautiously adding a solution of 4N potassium hydroxide in water (0.5 ml). Upon hydrolysis, a white salt precipitated. After the addition was complete, the mixture was heated at reflux for minutes. The hot solution was filtered by suction through a Buchner funnel, and remaining product was extracted from the precipitate by refluxing with THF 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 give a crude product (0.45 Recrystallization of the crude product from methanol gave 5-(4-fluorophenyl)-4-(4pyridinyl)-lH-pyrazole-3-methanol (0.2808 g, DSC: 260.26 oC; Anal. Calc'd for C 1

,HI

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 (MH) 270 (base peak).

Example A-202 N 0 N NH S NN

H

F

l-[[5-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3yl]carbonyl]piperazine 8UtSTmUTES HEE(RULE 26) WO 98/52940 PCT/US98/10436 172 Step 1: Preparation of 1,1-dimethylethyl fluorophenvl)-4-(4-pyridinyl)-1H-pyrazol-3-vl]carbonyl 1-piperazinecarboxylate N NBoc

N/N

H

F

To a solution of 5-(4-fluorophenyl)-4-(4-pyridinyl)- 1H-pyrazole-3-carboxylic acid, monohydrate prepared in accordance with Example A-200 (0.9905 g, 3.5 mmol) and 1hydroxybenzotriazole (0.4824 g, 3.57 mmol) in DMF (20 ml) at 0 oC under nitrogen, 1-(3-dimethylaminopropyl)3ethylcarbodiiminde 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 1butoxycarbonylpiperazine (0.6585 g, 3.5 mmol) was added followed by N-methylmorpholine (0.40 ml, 3.6 mmol). The 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, the solvent was removed under reduced pressure to give a crude product (1.7595 1,1-Dimethylethyl fluorophenyl)-4-(4-pyridinyl)-lH-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, 63.85; H, 5.80; N, 15.51; Found: C, 63.75; H, 5.71; N, 15.16. MS (MH) 452 (base peak).

DAMUMMEU( 261(3~bEE6 WO 98/52940 PCT/US98/10436 173 Step 2: Preparation of 1-[[5-(4-fluorophenvl)-4-(4pyridinyl)-1H-vprazol-3-yl]carbonyl]piperazine bis(trifluoroacetate), monohydrate A solution of the compound prepared in step 1 (0.1804 g, 0.4 mmol) in methylene chloride (1.0 ml) and TFA 0.3 ml) was stirred at room temperature under nitrogen for 2 hours. The solvent was removed under reduced pressure and TFA was chased by methylene chloride and methanol. The resulting colorless oily residue was dried in a vacuum oven overnight to give fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3yl]carbonyl]piperazine (isolated as the bis(trifluoroacetate), monohydrate salt) (0.2400g, 100%) as a white solid. Anal. Calc'd for

C

19 HiNsOF.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 synthesized in accordance with the chemistry described above (particularly in Scheme VIII) by selection of the corresponding starting reagents: Example A-203 4-(1,5-dimethyl-3-phenyl-

N-

N

4-(1,5-dimethyl-3-phenyl-lH-pyrazol-4-yl)pyridine SuasmnlUEHEET(RULE26) WO 98/52940 PCT/US98/10436 174

N

4-(1,3-dimethyl-5-phenyl-lH-pyrazol-4-yl]pyridine A 60% dispersion of sodium hydride (41 mg, 0.00172 moles) (prewashed with hexane) in mineral oil (69 mg) was added with 5 ml of dioxane to a stirred solution of 4-(3methyl-5-phenyl-lH-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 CH 3 I (122 mg, 0.00086 mole) in 10 ml dioxane was added and the mixture was stirred at room temperature for 20 hours. The mixture was concentrated to a solid. The products were partitioned between water (15 ml) and ethyl acetate ml). The organic layer was dried over Na 2

SO

4 filtered and concentrated to a solid. The products were purified and separated by radial chromatography. NMR (NOE experiments) showed that the first component off the column (the minor component) was 4-(1,3-dimethyl-5phenyl-lH-pyrazol-4-yl]pyridine, and the second material off the column was 4-(1,5-dimethyl-3-phenyl-lH-pyrazol-4yl)pyridine.

Major isomer (4-(1,5-dimethyl-3-phenyl-lH-pyrazol-4yl)pyridine): 94-99 oC. Anal. calc'd for

C

16

HI

1

N

3 *0.1MHO2: C, 77.08; H, 6.06; N, 16.85. Found: C, 76.59; H, 5.70; N, 16.62 81 11IMESHE(~br(RULEM WO 98/52940 WO 9852940PCTJUS98/1 0436 175 Example A-204

NN

N

C I 4- (4-chiorophenyl) -1,5-dimethyl-lH-pyrazol-4yl] pyridine

N

4- (4-chiorophenyl) -1,3-dimethyl-1H-pyrazol-4yllpyridine (the compound of Example A-32) 4- (4-chiorophenyl) -l,5-dimethyl-lH-pyrazol-4ylllpyridirie and 4- (4-chiorophenyl) -1,3-dimethyl-lHpyrazol-4-yllpyridine were prepared by the same procedure as described for Example A-203 by replacing 4- (3-methyl- 5-phenyl-lH-pyrazol-4-yl)pyridine with 4- (4chlorophenyl) -5-methyl-lH-pyrazol-4-yl) pyridine (prepared as set forth in Example A-7).

Major Isomer (4-[3-(4-chlorophenyl)-1,5-dimethyl-lHpyrazol-4-yllpyridine): Anal. calc'd for C 1 6

H

1 4

N

3 C1 (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.

SUBn11UTE 8HEEr (RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 176 Minor Isomer 15- (4-chiorophenyl) -1,3-dimethyl-llpyrazol-4-yllpyridine): 82-88 0 C. Anal. calc'd for C 1 6

H,,N

3 C1: C, 67.72; H, 4.97; N, 14.81; Found: C, 67.56; H, 4.96; N, 14.73.

Example A-205 4- [5-ethyl-l-methyl-3- (3-methyiphenyl) -1H-pyrazol-4yll pyridine 4- [3-ethyl-l-methyl-5- (3-methyiphenyl) -lH-pyrazol-4yl] pyridine 4- [5-ethyl-l-methyl-3- (3-methyiphenyl) -1H-pyrazol-4ylllpyridine and 4- [3-ethyl-l-methyl-5- (3-methyiphenyl) 1H-pyrazol-4-yllpyridine were prepared by the same procedure as described for Example A-203 by replacing 4- (3-methyl-5-phenyl-lH-pyrazol--4-yl)pyridine with 4- (4methyiphenyl) -5-ethyl-1H-pyrazol-4-yl) pyridine (prepared SUBSW MSWEET (RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 177 as set forth in Example Major Isomer [5-ethyl-1-methyl-3- (3-methyiphenyl) -21pyrazol-4-yllpyridine) Anal. Calc'd for C1 8

H

1 9

NO

3 *0.45

MH

2 O: C, 75.73; 7.03; N, 14.77. Found: C, 76.03; H, 6.87 N, 14.28.

Minor Isomer [3-ethyl-1-methyl-5- (3-methyiphenyl) -1Hpyrazol-4-yllpyridine): Anal. Calc'd for

C

1 eH 1 N0 3 00.30MH,0: C, 76.46; H, 6.99; N, 14.86. Found: C, 76.58; H, 6.98; N, 14.63.

Example A-206 4- (4-chiorophenyl) -1-ethyl-5-methyl-1H-pyrazol-4yllpyridine: Anal. Calc'd for C1 7

H

1

,N

3 Cl (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 0

C.

Example A-207

N

N

Et GLIS1UrESIEr (RULE co) WO 98/52940 PCT/US98/10436 178 4-[3-(4-chlorophenyl)-2-ethyl-5-methyl-lH-pyrazol-4yl]pyridine: Anal. Calc'd for C 1

,H,

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 0

C.

The compounds of Examples A-208 and A-209 were prepared in accordance with the chemistry described above (particularly in Scheme IX): Example A-208

F

N

SN--H

N I H 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine Step 1: Preparation of 4-fluorobenzovl-4'-pyridyl methane To a mixture of 4-picoline (32.6 g, 0.35 moles) and ethyl-4-fluorobenzoate (50.45g, 0.3 moles), maintained at was added lithium bis(trimethylsilylamide) (600 mL in a steady but rapid stream so as to maintain 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 HC1 at 0 oC to lower the pH to about 7. The organic layer was separated and the aqueous layer re-extracted with of toluene (100 mL). The organic layer was dried (sodium sulfate) and concentrated, to furnish a yellow solid which on trituration with hexanes (200 mL) provided the pure desoxybenzoin, 4anlMMMSKEV(RTRUM~ WO 98/52940 PCT/US98/10436 179 fluorobenzoyl-4'-pyridyl methane, in 90% yield (58g). 1H NMR was consistent with the proposed structure.

Step 2: To a suspension of the desoxybenzoin prepared in step 1 (30g, 0.14 moles) in tetrahydrofuran (50 mL) was added dimethylformamide dimethyl acetal (50 mL) and the mixture stirred at ambient temperature for two days. The solution was then concentrated to dryness and the solid paste obtained was triturated with hexanes (150 mL) to furnish a yellow solid which was of sufficient purity (as determined by NMR) and was used for the next step without additional purification. Yield: 33.9 g 'H NMR was consistent with the proposed structure.

Step 3: The vinyl amine prepared in step 2 (33.9g, 0.1255 moles) was dissolved in 125 mL of ethanol and cooled to 0 oC. Hydrazine hydrate (8.0g of anhydrous or 16.0g. of 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 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 fine off-white precipitate was filtered and dried to give 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine. Yield: 27.3g. Mass spectrum: m/z 240. 1H NMR was consistent with the proposed structure. Anal. calc'd for

C,

4 HoFN 3 C, 70.28; H, 4.21; N, 17.56. Found: C, 70.11; H, 4.33; N, 17.61.

s8UmSUTEHEEr( RJlE2) WO 98/52940 PCT/US98/10436 180 Example A-209 Cl

NH

N

N

4-[3-(2-chlorophenyl)-1H-pyrazol-4-yl]pyridine This compound was prepared by the same procedure described for Example A-208 using the corresponding starting reagents.

Anal. Calc'd for C 1

,H,

1 C1N 3 C, 65.76; H, 3.94; N, 16.43.

Found: C, 65.22; H, 3.91; N, 16.50. m.p. (DSC): 208.46

OC.

The compounds of Examples A-l0 and A-211 illustrate were prepared in accordance with the chemistry described above (particularly in Scheme X): Example A-210

F

N

N OH

N

N H 3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-l-ethanol SUBS1TUTESHEET(RULE26) WO 98/52940 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 acetic acid in a 500 mL Erlenmeyer flask. After gentle boiling (1 hour), a small sample was evacuated at high vacuum and examined by 1H NMR to confirm completion of hydrazone formation. On cooling to ambient temperature, the reaction mass solidified to a yellow cake. DMF dimethylacetal (36 mL, 0.27 moles) was then added and the mixture heated to 80C for 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 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 process) results in a copious formation of crystals.

Suction filtration followed by washing with 10% ethanolwater (50 mL), followed by drying, furnishes 3-(4fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-l-ethanol as a light yellow crystalline solid. Re-heating the filtrate to clarity as before, followed by cooling, yields additional product. The third and fourth recovery from the mother liquor on standing overnight furnishes the remaining 3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole- 1-ethanol. Total yield: (12.3 3.3 0.4 0.4} 16.4g. Mass spectrum, m/z 284. 'H NMR was consistent with the proposed structure. Anal. calc'd for

C,

6

H,

4 FN30 H 2 0: C, 63.78; H, 5.35; N, 13.95. Found: C, 63.55; H, 5.07; N, 13.69.

IsWTn1uTEHEErM (RUE AS) WO 98/52940 PCT/US98/10436 182 Example A-211

F

N

N

N^N

3-(4-fluorophenyl)-4-(4-pyrimidinyl)-1H-pyrazole-lethanol 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 4methyl-pyrimidine.

The compound of Example A-212 was prepared in accordance with the chemistry of Scheme XI: Example A-212

F

N

N--CH

3 4-[3-(4-fluorophenyl)-l-methyl-lH-pyrazol-4-yl]pyridine The vinyl amine prepared in Step 2 of Example A-208 (5.0g, 0.0185 moles) was taken up in ethanol (75mL) and cooled to 0 oC. Methyl hydrazine (1.7g, 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 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 10% HC1 (100 mL) and washed with methylene chloride (100 SLMSTMMSHERr(R LE26 WO 98/52940 PCT/US98/10436 183 mL) and the water layer treated with activated charcoal After filtration through Celite, the solution was neutralized with sodium hydroxide to pH 8 with good stirring and cooling. The cream colored precipitate was filtered, washed with water and dried. The solid 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, the solids formed were filtered, washed with cold toluene/heptane (25 mL) followed by hexane (25 mL) and dried to yield the pure title compound. 1 H NMR confirmed the structure (including regiochemistry using NOE experiments). Yield: 2.1g. Mass spectrum, m/z 254 (base peak). Anal. calc'd for C 15

H,

1

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 accordance with the chemistry of Scheme XII: Example A-213

F

N

N N--H

HN

H

OH

2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2pyridinyl]amino]-1-butanol BWS =ESHEE r(RULE 26) 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- 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 obtained, 2-[[4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2pyridinyl]amino]-1-butanol, was suction-filtered and washed with an additional 5 mL of water followed by toluene and dried. Yield: 190mg. Mass spectrum, m/z 343. 1H NMR was consistent with the proposed structure.

The compound of Example A-214 was prepared in accordance with the chemistry of Scheme XIII: Example A-214

F

N

N-CH

3 N I Br 4-[5-bromo-3-(4-fluorophenyl)-1-methyl-lH-pyrazol-4yl]pyridine To a solution of 4-[3-(4-fluorophenyl)-1-methyl-lHpyrazol-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 S UDSWUMSHMR( RUE 26j 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)-1methyl-lH-pyrazol-4-yl]pyridine (1.24g, mp 174.38 0

C;

Mass spectrum m/z 332, 334; 1 H NMR was consistent with the proposed structure. Anal. Calc'd for C, 15

HN

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.

The compound of Example A-215 was prepared in accordance with the chemistry of Scheme XIV: Example A-215

F

N

/\N-CH

3

N

CN

4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2pyridinecarbonitrile Step 1: To a solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4yl]pyridine (4.3g, 17.97 mmol) (prepared in accordance with Example A-208) in methanol (100 mL) was added 3chloroperoxybenzoic acid (5.44 g in 57 purity, 17.97 mmol). The solution was stirred at 25 OC for overnight.

The mixture was concentrated. KCO0 100 mL) was added to the residue. A precipitate was formed, filtered and washed with water (30 mL x 3) to give the suesfl1UtEBHEE ULE2) 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 (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 starting materials were gone. The mixture was partitioned into ethyl acetate:water (100 mL:20 mL). The organic layer was washed with K 2 CO 20 mL), water mL), brine (50 mL), dried over MgSO 4 filtered and concentrated to give 4-[3-(4-fluorophenyl)-lH-pyrazol-4yl]-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 CisHgN 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.

The compound of Example A-216 was prepared in accordance with the chemistry of Scheme XV: Example A-216

F

N

N

4-[2-[3-(4-fluorophenyl)-4-(4-pyridinyl) -H-pyrazol-lyl]ethyl]morpholine GL~sffWE&Effa(RULu;Eas WO 98/52940 PCT/US98/10436 187 Step 1: 3-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-lethanol (prepared in accordance with Example A-210) (10.0 g, 0.0353 moles) was suspended in pyridine (100 mL) and 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 chilled water (100 mL) and methylene chloride (150 mL) was added and the two layers separated. The water layer was reextracted 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 79% yield (10.1g). 1H NMR was consistent with the proposed structure. The compound was used as such for step 2.

Step 2: The mesylate prepared in step 1 (5.0 g, 0.0138 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 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. Recrystallization from toluene/hexane provided fluorophenyl)-4-(4-pyridinyl)-IH-pyrazol-lyl]ethyl]morpholine as a solid. Yield: 4.5g Mass spectrum, m/z 353. 1H NMR was consistent with the proposed structure. Anal. calc'd for C 20

H

21

FN

4 0: C, 68.16; H, 6.01; N, 15.90. Found: C, 68.20; H, 6.21; N, 15.80.

81 W=flUTE8HEE (RULE 26) WO 98/52940 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

HO

3-(4-fluorophenyl)-l-methyl-a-phenyl-4-(4-pyridinyl)-1H- To solid magnesium (60 mg, 5 mmol) under nitrogen was added a solution of 4-[5-bromo-3-(4-fluorophenyl)-lmethyl-1H-pyrazol-4-yl]pyridine (450 mg, 1.35 mmol) (prepared in accordance with Example A-214) in tetrahydrofuran (7 mL). The mixture was heated at 40 °C for 2 hours. Benzaldehyde (1 mL) was added. The mixture was heated to 45 oC for 2 hours. It was quenched with HC1 mL, IN) 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.

The residue was purified with a silica gel column to give the title compound (59 mg, 12% yield). MS: m/z 360 1H NMR was consistent with the proposed structure.

Anal. Calc'd for C 22 H3,N 2 0F.0.6EtOAC: C, 71.1; H, 5.6; N, 10.2; Found: C, 70.9; H, 5.47; N, 10.2.

SU1JsUTESHEEr(RULE 26) 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): Example A-218

F

N

N- H N 0 (4-fluorophenyl)-4-(4-pyridinyl) -1H-pyrazol-3-yl]-4morpholineethanamine The starting desoxybenzoin prepared in step 1 of Example A-208, 4-fluorobenzoyl-4'-pyridyl methane, g, 0.0046 moles) was dissolved in 10 mL of DMF and cooled to -10 oC (dry ice-aqueous isopropanol). Nchlorosuccinimide (0.62 g, 0.0046 moles) was added in one 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 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 mL) furnished an off white solid, fluorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4morpholineethanamine, which was re-filtered and dried.

S9BBMl1TE8EE(RULE WO 98/52940 PCT/US98/10436 190 Yield: 0.95g. Mass Spec. m/z: 368 (base peak).

Anal. Calc'd for C 20

H

22 FNsO. C, 65.38; H, 6.04; N, 19.06.

Found: C, 64.90; H, 5.92; N, 18.67.

Example A-219

H

2

NHN'

4-[3-(3-chlorophenyl)-1H-pyrazol-4-yl]-2(1H)-pyridinone hydrazone Step 1: Preparation of (E)-2-(2-bromo-4-pyridinvl)-N,Ndimethylethenamine 4-Methyl-2-bromopyridine (1.0 g, 5.8 mmol) and tbutoxybis(dimethylamino)methane (5 ml) were heated to 150 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 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 SUBMMOHM(RA126)4~'R~ l~~ WO 98/52940 PCT/US98/1 0436 191 oil suitable for use in step 2.

Step 2: Preparation of (Z)-2-(2-bromo-4-pyridinyl)-l-(3chlorophenyl)-3-(dimethylamino)-2-propen-1-one 0 NMe 2

CI

N Br The product from step 1 (1.0 g, 4.4 mmol) was dissolved in methylene chloride (15 ml). Triethylamine (900 mg, 8.8 mmol) was added at 0 oC, followed by the addition of 3-chlorobenzoyl chloride (350 mg, 4.5 mmol).

The mixture was stirred under nitrogen for 16 hours.

Solvent was evaporated in vacuo and the residue was dissolved in ether (25 ml), stirred with magnesium sulfate (500 mg) and silica gel (500mg), and filtered.

Ether was evaporated and the residue was chromatographed on silica gel using mixtures of acetone and methylene chloride as eluents to give 670 mg of the product, (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.

Step 3: Preparation of 2-bromo-4-[3-(3-chlorophenyl)-1Hpyrazol-4-yl]pyridine

F\

sUSBfmTEsHaE (RLE2) WO 98/52940 PCT/US98/10436 192 A solution of the product from step 2 (650 mg, 1.8 mmol) and hydrazine monohydrate (100 mg) in ethanol ml) was refluxed for 24 hours. Solvent was evaporated and the residue was chromatographed on silica gel using mixtures of ethyl acetate and toluene as eluents to give 2-bromo-4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]pyridine (190 mg, 31%) as an oil: Anal. Calc'd for C, 1 HgBrClN 3

C,

50.25; H, 2.71; N, 12.56. Found: C, 50.10; H, 2.60; N, 12.40.

Continued elution with mixtures of ethyl acetate and methanol gave 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]- 2(1H)-pyridinone hydrazone (190 mg, 36%) as a crystalline solid: m.p. 163-164 OC.; MS 286. Anal. Calc'd for C 14

H

12

N

5 C1: C, 58.85; H, 4.23; N, 24.51. Found: C, 58.53; H, 4.28; N, 24.87.

Example A-220 N

CI

PhH2CHN

N

H

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 (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 8u1 nTUESHEEr(RMLE2) WO 98/52940 PCT/US98/10436 193 and the residue chromatographed on silica gel using mixtures of ethyl acetate and toluene to give chlorophenyl)-lH-pyrazol-4-yl]-N-(phenylmethyl)-2pyridinamine (110 mg, 61%) as a solid, m.p. 179-180 OC.

Anal. Calc'd For C 21

H

1 ,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 PhH2CHCHN

N

I

H

4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]-N-(phenylethyl)-2pyridinamine A solution of the bromopyridine compound prepared in step 3 of Example A-219 (250 mg, 0.75 mmol) in phenethylamine (5 ml) was heated at 175 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 drying over magnesium sulfate and removal of solvent, the residue was chromatographed on silica gel with mixtures of ethyl acetate and toluene to give chlorophenyl)-lH-pyrazol-4-yl]-N-(phenylethyl)-2pyridinamine (230 mg, 81%) as a solid, m.p. 185-186 OC.

Anal. Calc'd For C 22 HgCIN 4 C, 70.49; H, 5.11; N, 14.95. Found: C, 70.29; H, 5.15; N, 14.66.

SUMtE8HMEE(RULEM) WO 98/52940 PCT/US98/10436 194 Example A-222 EtHN 4-[3-(3-chlorophenyl)-lH-pyrazol-4-yl]-N-ethyl-2pyridinamine A solution of the bromopyridine compound prepared in step 3 of Example A-219 (300 mg, 0.9 mmol) in ethylamine ml) and ethanol (5 ml) as heated at 150 oC in a sealed tube for 9 hours. The solvent was removed in vacuo and the residue chromatographed on silica gel with ethyl acetate/30 toluene to give chlorophenyl)-lH-pyrazol-4-yl]-N-ethyl-2-pyridinamine (125 mg, 46%) as a solid, m.p. 186-187 oC.

Anal. Calc'd For C 16 HlC1N 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 above (particularly in Scheme XVIII) by selection of the corresponding starting reagents: UBsTIUESHEEr(RULEW WO 98/52940 PCT/US98/10436 195 Example A-223

F

NH

N N

N

0 NH 2 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2pyridinecarboxamide 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 mchloroperoxybenzoic 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, airdried to give 8.2 g of a product as a white solid mp: 207-209 0

C.

Step 2: Preparation of 4-[3-(4-fluorophenyl)-IH-pyrazol- 4-vl]-2-pyridinecarbonitrile To a solution of the product of step 1 (5.1 g, 0.02 mol) in 20 mL of DMF was added trimethylsilyl cyanide g, 0.025 mol), followed by a solution of N, Ndimethylcarbamoyl chloride (2.7 g, 0.025 mol) in 5 mL of DMF at room temperature. After stirring overnight, the "uBsmr=%BHEERuE28% WO 98/52940 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 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]-2pyridinecarbonitrile as a pale yellow solid, mp: 238-2390C.

Step 3: Preparation of 4-[3-(4-fluorophenyl)-IH-pyrazol- 4-vl]-2-pyridinecarboxamide: To a solution of 4-[3-(4-fluorophenyl)-lH-pyrazol-4yl]-2-pyridinecarbonitrile from step 2 (0.45 g, 0.0017 mol) in 10 mL of DMSO was added hydrogen peroxide (0.24 mL of 30% aqueous solution, 1.7 mmol) and potassium carbonate (0.04 g, 0.4 mmol) at 0°C. The mixture was stirred for 1 hour while allowing it to warm to room temperature. Water was added and the precipitate was collected by filtration and air-dried to give 0.32 g of 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2pyridinecarboxamide as a white solid (67% yield), mp: 230-231 OC. Anal. Calc'd for CHnFN40: C, 63.83; H, 3.93; N, 19.85. Found C, 63.42; H, 3.66; N, 19.58.

Example A-224

F

8UmOTUTESHEEf(RULE26) WO 98/52940 PCT/US98/10436 197 Methyl 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2pyridinecarboxylate To a suspension of 4-[3-(4-fluorophenyl)-lH-pyrazol- 4-yl]-2-pyridinecarboxamide prepared as set forth in Example A-223 (2.9 g, 0.01 mol) in 50 mL of methanol was added N,N-dimethylformamide dimethyl acetal (3.67 g, 0.03 mol) dropwise. The reaction mixture was stirred at room temperature overnight and heated at reflux for 4hours.

After cooling, the precipitate was collected by filtration and air-dried to give 2.0 g of methyl fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinecarboxylate as a white solid (69% yield), mp: 239-241 0 C. Anal. Calc'd for

C

16

HFN

3 0 2 C, 64.64; H, 4.07; N, 14.13. Found: C, 64.36; H, 4.10; N, 14.27.

Example A-225

F

NH

NN

0 N

H

4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N-methyl-2pyridinecarboxamide A mixture of methyl 4-[3-(4-fluorophenyl)-1Hpyrazol-4-yl]-2-pyridinecarboxylate prepared as set forth in Example A-224 (0.45 g, 1.5 mmol) and 20 mL of methylamine (40% aqueous solution) was heated at 120 0 C in a sealed tube for 16 hours. After cooling, water was UBUE8EEr(RuLEG) WO 98/52940 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)-1Hpyrazol-4-yl]-N-methyl-2-pyridinecarboxamide as a white solid, mp: 88-890C. 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.

Example A-226

F

NH

NK N 0 OH 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2pyridinecarboxylic acid To a solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4yl]-2-pyridinecarboxylate prepared as set forth in Example A-224 (0.90 g, 0.003 mol) in 10 mL of ethanol was added a solution of sodium hydroxide (0.24 g, 0.006 mol) in 5 mL of water. The reaction mixture was heated at reflux for 10 hours. After the removal of solvent, the residue was dissolved in water and acidified with citric acid solution to pH 5. Then the aqueous phase was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate and concentrated. The crude was purified by treating with ether to give 0.62 g of 4- [3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-pyridinecarboxylic SLNZMMS~E=-[ (RI ILE WO 98/52940 PCT/US98/10436 199 acid as a white solid (73% yield), mp: 245°C(dec). Anal Calc'd for C 1 sHIoFN 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.

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 analysis results for each compound also are disclosed in Table 3.

SUBsmlsUTEHEE (RUL E) TABLE Example General Microanalysis Procedure M+l C caic C found H caic H found N caic N found water BtOAc added A-227 IX 240. 69 69 4.3 4.6 17.2 16.8 0.25 A-228 IX 266 65.69 65.69 4.41 4.33 15.32 14.98___ A-229 XI 254 70.6 70.6 4.8 4.5 16.5 16.3 0.1 A-230 IX 256 65.76 65.48 3.94 3.78 16.43 16.52 A-231 XI 280 64.18 63.95 4.39 4.31 13.86 13.90 A-232 XI 271 66.79 66.79 4.48 4.24 15.58 15.32 A-233 XI 284 66.9 66.8 5 5 14.6 14.9 0.2 A-234 XI 270 65.9 65.6 4.6 4.6 15.4 15.4 0.2 A-235 XI -264 77 76.7 6.5 6.5 15.8 15.7 0.1 A-236 IX 221 75.38 75.44 5.06 5.1 18.84 19 0.1 A-237 IX 290 61.52 61.67 3.58 3.51 14.35 14.32 A-238 XI 304 63.36 63.28 3.99 3.91 13.85 13.83 A-239 IX 258 65.37 65.39 3.53 3.52 16.33 16.31___ A-240 IX 274 61.44 61.14 3.31 3.01 15.35 114.95 A-241 IX 300 56.02 55.99 3.36 3.26 14.00 14.01 A-242 XI 272 66.42 66.41 4.09 4.04 15.49 15.32___ A-243 XI 314 57.34 57.22 3.85 3.68 13.37 13.27 A-244 IX 342 76.39 76.16 4.81 4.51 12.31 12.05 0.25___ A-245 XII 341 64.89 64.65 6.36 6.17 15.93 15.82 0.6 A-246 XII 1391 66.08 66.18 5.04 5.56 14.01 12.26 A-247 XII 1362 164.46 64.16 4.65 4.34 18.79 18.65 0.6 A-249 XII 12581 64.91 64.84 3.58 3.63 16.22 115.98 0.1

I

U

A-250 Ix 348 48.44 48.07 2.9 2.82 12.1 12.01___ A-251 xi 362 49.88 49.89 3.35 3.51 11.63 11.54___ A-252 xi 304 63.36 63.34 3.99 3.96 13.85 13.81___ A-253 XII 377 68.24 68.17 5 4.71 14.47 14.34 0.6 A-254 XII 363 66.31 66.12 4.77 4.31 14.73 14.6 1 A-215 XIV 265 67.3 67.4 3.5 3.4 20.9 20.7 0.2 A-255 XII 298 64.63 64.64 5.42 5.41 23.55 23.32___ A-256 XI 272 66.42 66.58 4.09 4.26 15.49 14.78___ A-257 IX 276 60.11 60.4 3.06 3.18 15.02 14.73 0.25 A-258 IX 254 A-259 XI 268 71.89 71.63 5.28 5.24 15.72 15.84 A-260 X 290 62.28 62.41 3.48 3.48 14.53 14.51 A-261 X, XV 311 69.26 69.2 6.2 6.25 17.95 17.89 0.1 A-262 XI 376 72.71 72.5 5.17 4.98 11.06 10.99 0.25 A-263 XII 428 70.81 70.59 6.28 6.45 15.88 15.08 0.75 A-264 XII 326 63.79 63.76 6.39 6.09 20.66 20.45 0.75 A-265 IX 400 66.18 66.77 4.1 4.23 16.78 15.83 1 A-266 XII 368 62.32 62.38 6.28 6.5 18.17 17.56 1 A-267 XI 302 62.66 62.85 4.47 4.34 13.7 13.53 0.4 A-268 XII 349 62.9 63.2 5.2 4.8 22.7 22.5 0.75 0.1 A-269 XI, XV 371 61.85 61.84 5.71 5.24 14.42 14.17 1 A-270 XI, XV 404 70.66 70.7 4.82 4.61 10.3 10.15 0.25 A-271 XI, XV 329 65.8 65.3 5.5 5.6 17.1 16.8 A-272 XI 406 69.95 70.13 5.35 5.28 10.14 9.89 A-273 XI 354 66.9 67.2 6.9 6.6 19.1 18.7 0.2 0.1 XI, XII, A-274 XV 1434 63.6 63.1 6.3 5.8 14.4 14 2 0.2

I

U

A-275 XI, XV 433 70.44 70.74 6.18 6.3 12.64 12.05 0.6 XI, XII, A-276 XV 476 65.9 66.2 6.1 6.1 13.3 13.6 0.5 A-277 XII 338 61.11 63.02 6.48 6.39 18.75 16.61 A-278 XI, XV 357 64.2 63.8 6.5 6 15 14.8 1 XI, XII, A-279 XV 462 67.4 67.1 6.7 6.2 13.6 13.7 0.6 A-280 XII 299 61.27 61.47 5.37 5.11 17.86 17.21 0.9 A-281 XII 313 64.63 64.94 5.55 5.63 17.73 17.48 0.2 A-282 XII 313 64.63 64.81 5.55 5.43 17.73 17.38 0.3 A-283 XI, XII 407 67.2 67 5 5.2 13.6 13.2 0.25 A-284 XI, XV 339 70 70.3 6.9 6.9 16.3 16.2 0.25 XI, XII, A-285 XV 476 68.2 68.5 5.7 6.2 14.7 13.6 A-286 XVII 382 59.77 59.69 6.81 6.56 16.6 16.65 2.25 A-287 XVII 340 56.07 56.26 7.31 7.1 17.21 17.27 3.75 A-288 XVII 293 69.42 69.4 4.52 4.6 19.05 19.09 0.1 A-289 XI, XII 407 68 67.5 5 4.5 13.8 13.5 A-290 XI, XII 407 64 64.5 5.3 4.9 13 12.4 1.4 A-291 IX 290 74.7 74.9 4.2 4.2 14.5 14.5 A-292 XVII 326 61.22 61.46 4.77 4.53 16.8 16.97 0.4 A-293 XVII 313 55.75 55.98 4.85 4.02 16.25 16.37 1.8 A-294 XI 278 73.6 73.2 4.4 4.2 15.2 A-295 XI 278 67.9 67.7 4.9 4.3 14 13.7 1.3 A-296 IX 70.3 70.4 4.5 4.7 25.2 25.4 A-297 IX 57.9 57.7 3.1 2.9 14.5 14.5 WO 98/52940 WO 9852940PCTIUS98/1 0436 203 Example A-227

F

N\

N- H N

H

4- (3-f luorophenyl) -1H-pyrazol-4-ylllpyridine Example A-228 /-0 0 N 4- (1,3-benzodioxol-5-yl) -lH-pyrazol-4-yllpyridine Example A-229 SUeBTffSHWI V8EE (RU2 6) WO 98/52940 WO 9852940PCTIUS98/1 0436 204 4- (3-f luorophenyl) -l-methyl-lH-pyrazol-4-yllpyridine Example A-230 c I

N

H-

4- (4-chiorophenyl) -1H-pyrazol-4-yllpyridine Example A-231 4- (1,3-benzodioxol-5-y) -1-methyl-lH-pyrazol-4-ylllpyrid ine Example A-232 c I

N

N-CH

3

N

a~ffEW(PELE26) WO 98/52940 WO 9852940PCTIUS98/I 0436 205 4- (4-chiorophenyl) -l-rethyl-lH-pyrazol-4-yllpyridine Example A-233 i somer 4- (3-chiorophenyl) -1-methyl-1H-pyrazol-4-yl] -2-methylp yridine and 4- (3-chiorophenyl) -1-methyl-1H--pyrazol-4 -ylI-2-methylpyridine .0 Example A-234 c I

N

N-CH

3 N z i somer 4- (3-chiorophenyl) -1-methyl-1H-pyrazol-4-yllpyridine and 4- (3-chiorophenyl) -1-tethyl-1H-pyrazol-4-yllpyridine JWnTUE=MW~ (MUE M WO 98/52940 WO 9852940PCTIUS98/I 0436 206 Example A-235 CH3 N-C

H

3

CH

3 2-methyl-4- [1-methyl-3 (or (3-methyiphenyl) -lH-pyrazol-4 -yllpyridine Example A-236 N N N- H

NN

4- (3-phenyl-1H-pyrazol-4-yl) pyridine Example A-237

CF

3 N N N- H

NN

4- (trifluoromethyl)phenyl) -lH-pyrazol-4-yllpyridine SUBBTFIUEMSHEEU WO 98/52940 WO 9852940PCTIUS98/1 0436 207 Example A-238

CF

3

N

N- CH 3 N 4- [l-methyl-3- (trifluoromethyl)phenyl] -1H-pyrazol-4yl] pyridine Example A-239

F

FN

N- H N "Z- 4- (3,4-difluorophenyl) -lH-pyrazol-4-yl]pyridine OUBMEET (MRULE U)t WO 98/52940 WO 9852940PCTIUS98/I 0436 208 Example A-240 4- (4-chiorophenyl) -1H-pyrazol-4-yl] -2-f luoropyridine Example A-241 4- (4-bromophenyl) -lH-pyrazol-4y1]pyridine Example A-242 4- (3,4-difluorophenyl) -l-methyl-lH-pyrazol-4-yllpyridi &Wf$WEiEff(RLEM WO 98/52940 WO 9852940PCTIUS98/1 0436 209 Example A-243 N-C H 4- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yllpyridine Example A-244 (4-f luorophenyl) -lH-pyrazol-4-yl] (2-phenyleth enyl)pyridine eue&WTE=SHEUr 1(PUM.E 2 WO 98/52940 WO 9852940PCTIUS98/1 0436 210 Example A-245 (4-chiorophenyl) -1H-pyrazol-4-yl] (2-methylbut yl) 2-pyridiriamine Example A-246

~OCH

3 4- (4-chiorophenyl) -1H-pyrazol-4-yl] [(4-methoxyphenyl)methyl] 2-pyridinamine DJWff MSW.E7 (ME 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 211 Example A-247 (4-chiorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] 2 -pyridinemethanamine Example A-248 N- (4-f luorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] 2 -pyridinemethanamine Anal Calc'd: C, 41.12; H, 3.58; N, 9.22. Found: C, 41.74; H, 5.05; N, 11.11.

8JBUflTTE SHEET (RULE 28) WO 98/52940 PCTIUS98/1 0436 212 Example A-249

F

N

NH

N -H

F

2-f luoro-4- (4-f luorophenyl) -lH-pyrazol-4-yllpyridiie Example A-250 4- (4-iodophenyl) -lH-pyrazol-4-ylllpyridine Example A-251 N) N N-CH 3

N

4- (4-iodophenyl) -l-methyl-lH-pyrazol-4-yllpyridine SUBSTMESHEff(RULE26) WO 98/52940 WO 9852940PCTIUS98/1 0436 213 Example A-252

F

3

C

N N N-OH 3

N

4- [l-rethyl-3- (trifluoromethyl)phenyl] -1H-pyrazol-4-yl I pyridine Example A-253 N- luorophenyl)ethyl] (4-f luorophenyl) -11--pyra zol-4-ylI 2-pyridinamine g"M =.TESEET(RLs WO 98/52940 WO 9852940PCT/US98/I 0436 214 Example A-254

F*

N

NH

N H N

F.

N- luorophenyl)methyl]1 (4-f luorophenyl) -1H-pyraz ol-4-yl] 2-pyridinamine Example A-255 4- (4-fluorophenyl) -1-methyl-lH-pyrazol-4-yl] (1rethylhydrazino) pyridine MSMM&iMT(RLLE26) WO 98/52940 WO 9852940PCT/US98/I 0436 215 Example A-256 2-f luoro-4- (4-f luorophenyl) -1-methyl-1H-pyrazol-4-yllp yridine Example A-257 4- (3,4-difluorophenyl) -lH-pyrazol-4-yl] -2-f luoropyridine 8UB9WMMKEff(RULE2M WO 98/52940 WO 9852940PCTIUS98/1 0436 216 Example A-258 'CH3 4- (4-f luorophenyl) -1H-pyrazol-4-yl] -3-methylpyridine Example A-259 4- (4-f luorophenyl) -1-methyl-1H--pyrazol-4-yl] -3-methyip yridine Example A-260

SLISUMSHEE(RUCM

WO 98/52940 WO 9852940PCTIUS98/1 0436 217 4- (3,4-difluorophenyl) -l-methyl-1H-pyrazol-4-yl] -2-flu oropyridine Example A-261

N

1 C H 3- (4-f luorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -iN-pyrazo le-1-ethanamine Example A-262 N- CH 3 2- (4-fluorophenyl)ethyll-4- (4-fluorophenyl) -1methyl-1H-pyrazol-4 -yl) pyridine SUSBTTUTSHEUT(RUE26 WO 98/52940 WO 9852940PCTIUS98/1 0436 218 Example A-263 N H N~

HN

4- (4-fluorophenyl) -1H-pyrazol-4-yl] [1- (phenylmethyl) -4-piperidinyll -2 -pyridinamine Example A-264 N (4-f luorophenyl) -lH-pyrazol-4-ylI -2-pyridinyl] N, N-dimethyl -1,2 -ethanediamine vMMUMfEEU (RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 219 Example A-265 2,4-bis (4-f luorophenyl) -lH-pyrazol-4-yllpyridine Example A-266

F

N- (4-f luorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] -4morphol ineethanamine su6qmnrE8HEffr(RuLE"I0 WO 98/52940 WO 9852940PCTIUS98/1 0436 220 Example A-267 3- (4-f luorophenyl) (2-f luoro-4-pyridinyl) -lH-pyrazole- 1-ethanol Example A-268

F

N H N N HN-

N

4- (4-fluorophenyl) -lH-pyrazol-4-yl] (lH-imidazol- 1-yl) ethyl] -2-pyridinamine SUBSHEET

(RULES

WO 98/52940 WO 9852940PCTIUS98/1 0436 221 Example A-269 r 0 N

N

4-[2-[3-(4-fluorophenyl)-4-(2-fluoro-4-pyridinyl)-Hpyrazol-1-yl] ethyl] morpholine Example A-270

F

N

N

F

luorophenyl) (4-fluorophenyl)ethenyl] 4-pyridilyl] -1H-pyrazole-1-ethanol WO 98/52940 WO 9852940PCTIUS98/I Q436 222 Example A-271 0H3 3- (4-f luorophenyl) (2-f luoro-4-pyridinyl) -N,N-dimethyl- JA--pyrazole-l1-ethanamine Example A-272 3- (4-f luorophenyl) (4-f luorophenyl)ethyl] -4pyridinyl] -lH-pyrazole-l-ethanol m=n11UTESHET WO 98/52940 WO 9852940PCTIUS98/1 0436 223 Example A-273 4- (dimethylamino) ethyl] (4-f luorophenyl) -lHpyrazol-4-yll -N,N-dimethyl-2-pyridinamine Example A-274 4- (dimethylamino) ethyl] (4-fluorophenyl) -lHpyrazol-4-yl] luorophenyl)rnethyl] -2-pyridinamine MUMMMTETU(RLE26) WO 98/52940 WO 9852940PCTIUS98/1 0436 224 Example A-275 3- (4-fluorophenyl) (4-fluorophenyl) ethyl] -4pyridinyl] N-dimethyl-lH-pyrazole-l-ethanamine Example A-276

F

I-I

N

N

H N

F

N-[(4-fluorophenyljmethyl]-4-[3(or 5)-(4-fluorophenyl)-l- (4-morpholinyl) ethyl] -1H-pyrazol-4-yl] -2-pyridinamine

SLMITRMSHEU(RMEM)

WO 98/52940 WO 9852940PCT/US98/1 0436 225 Example A-277

F

N

NH

N-

HN

'CN H 4- (4-f luorophenyl) -lH-pyrazol-4-yl) -N-4-piperadinyl-2pyridinarnine Example A-278 N,N-diethyl-3- (4-fluorophenyl) (2-f luoro-4-pyridinyl) 1H-pyrazole- 1-ethanamine 8U9B1TffMTEUE(RULE2M WO 98/52940 WO 9852940PCT/US98/10436 226 Example A-279 4- (diethylamino)ethyl] (4-flJuorophenyl) -1Hpyrazol-4-yl] [(4-fluorophenyl)methyl] -2-pyridinamine MMMMSHEU(MA.E26) WO 98/52940 WO 9852940PCT/US98/I 0436 227 Example A-280

HN

0 H 2- (fluorophenyl) -lH-pyrazol-4-yl] -2pyridinyl] amino] ethanol Example A-281 2- (4-fluorophenyl) -l-methyl-lH-pyrazol-4-yl] -2pyridinyl] amino] ethanol MJUI11jTMSHME(RULE26) WO 98/52940 WO 9852940PCT/US98/1 0436 228 Example A-282 3- II[4- (4-fluorophenyl) -lH-pyrazol-4-Yl] -2pyridinyl] amino] -l-propanol Example A-283 3 (or 5)-(4-fluorophenyl)-4-[2-U[(4fluorophenyl)methyl] amino] -4-pyridinyl] -1H-pyrazole-lethanol SUqSTff=%JM(RULE2M WO 98/52940 PCT/US98/1 0436 229 Example A-284

F

rCH3

N

N

N'

N,N-diethyl-3- (4-fluorophenyl) (4-pyridinyl) -lHpyrazole-l-ethanamine Example A-285

F

0

N

N

NJ

N N HN aN N- [(4-fluorophenyl)methyl]-4-[3-(4-fluorophenyl)-1-[2-(4morpholinyl) ethyl] -lH-pyrazol-4-yl] -2-pyridinarnine Example A-286

F

NN

N-H 0 H'N

N

N H N- (4-f luorophenyl) (4-pyridinyl) -lH-pyrazol-3-yl] -4morphol inepropanamine SB~nTTE8HET(RLE2B WO 98/52940 WO 9852940PCT/US98/10Q436 230 Example A-287

F

N

N- H CH3 N -CH 3 N (4-f luorophenyl) (4-pyridinyl) -1H-pyrazol-3-ylI N, N-dimethyl -1,3 -propanediamine Example A-288

F

N

N- H

HN

N (4-f luorophenyl) -N-2-propynyl-4- (4-pyridinyl) -1Hpyrazol -3-amine Example A-289 ammmUEBHEE(RiLE26) WO 98/52940 WO 9852940PCT/US98/1 0436 231 3- (4-f luorophenyl) luorophenyl)methyll amino] 4-pyridinyl] -1H-pyrazole-1-ethanol Example A-290 (4-f luorophenyl) luorophenyl)methyl] amino] 4-pyridinyl] -lH-pyrazole-1-ethanol Example A-291 4- luorophenyl) -lH-pyrazol-4-yllquinoline awnw8m&-E(RULE 26 WO 98/52940 WO 9852940PCT/US98/1 0436 232 Example A-292

CO

2 Me N- (4-f luorophenyl) (4-pyridinyl) -lH-pyrazol-3yllglycine methyl ester Example A-293

F

N

NH

N M HN C0 2

H

N- (4-f luorophenyl) (4-pyridinyl) -lH-pyrazol-3yllglycine Example A-294 S&UMEEET (RULE2s) WO 98/52940 WO 9852940PCTIUS98/10436 233 4- (4-fluorophenyl) -1-(2-propynyl) -1H-pyrazol-4yl] pyridine Example A-295

N

N

N

4- (4-f luoropheiyl) -1-(2-propyiyl) -1H-pyrazol-4yl] pyridine Example A-296 4,4 (1H-pyrazole-3,4-diyl)bis [pyridine] Example A-297

CL-

SJBB1111E8KEE(RU.E26) WO 98/52940 WO 9852940PCT/US98/1 0436 234 4- (3,4-dichiorophenyl) -lH-pyrazol-4-yl]pyridine Example A-298 HN CNH N-[5-C4-chlorophenyl)-4- CA-pyridinyl)-1H-pyrazol-3-yl] 4-p iper idi nam ine The pyrimidine-substituted compounds of Examples A- 299 through A-312 were synthesized in accordance with the chemistry described in Schemes I-XVIII by selection of the corresponding starting reagents: Example A-299 2-Chloro-4- (4-f luorophenyl) -lH-pyrazol--4-ylljpyrimidine Step 1: e~wnSHEET (RULE 26) WO 98/52940 PCT/US98/10436 235 SNMe, N N NMe 2 A mixture of 2,6-dichloro-4-methylpyrimidine (5.0 g, 0.031 mol), triethylamine (6.23 g, 0.062 mol) and catalytic amount of 5% Pd/C in 100 mL of THF was hydrogenated on a Parr apparatus under 40 psi at room temperature. After 0.5 hour, the catalyst was filtered and the filtrate was concentrated. The crude was purified by chromatography on silica gel (ethyl acetate/hexane, 3:7) to give 2.36 g of product as a pale yellow crystal (50% yield); mp: 47-49 oC.

Step 2: Preparation of 2-(2-chloro-4-pyrimidinyl)-1-(4fluorophenvl)ethanone

F

o

CI

2-(2-chloro-4-pyrlmldlnyl)-1-(4-fluorophenyl)ethanone 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 minutes. After 1 hour, a solution of ethyl 4fluorobenzoate (7.62 g, 0,045 mol) in THF was added and SU6S1TUfEKEET (RULEs6) WO 98/52940 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 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.

Step 3: Preparation of (E)-2-(2-chloro-4-pyrimidinyl)-3- (dimethylamino)-1-(4-fluorophenvl)-2-propen-l-one

F

0 N ~N NMe 2

CI

CE)-2-C2-chloro-4-pyr imidinyl)-3-(dimethylamino)-1-4-f luorophenyl)-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 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.

Step 4: Preparation of 2-chloro-4-[3-(4-fluorophenyl)- 1H-pyrazol-4-vllprimidine 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 was collected by filtration and air-dried to give 1.85 g of 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4- SUBSP~ ff SHEk~r(RLU2B)i~ WO 98/52940 PCT/US98/10436 237 yl]pyrimidine as a yellow solid, mp: 204-205 oC; Anal.

Calc'd for C 13

H

8 ClFN 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.

Example A-300

F

NH

/N

N N

NHNH

2 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2(1H)-pyrimidinone hydrazone A solution of the compound prepared in step 3 of Example A-299 (1.5 g) and hydrazine hydrate (5mL) in ethanol was heated at reflux overnight. After the reaction mixture was cooled, the solvent was removed.

The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude product was purified by recrystallization from ethyl acetate and hexane to give 0.5 g of product, 4-[3-(4-fluorophenyl)-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

HFN

6

C,

57.77; H, 4.10; N, 31.10. Found: C, 57.70; H, 4.31; N, 30.73.

SMnUTESHEEUR(RLE26) WO 98/52940 PCT/US98/10436 238 Example A-301

F

NH

NN

N\

4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-N,N-dimethyl- 2-pyrimidinamine Step 1: Preparation of NMe 2 N N NMe 2 A solution of the compound prepared in step 2 of Example A-299 (3.0 g, 0.02 mol) and tertbutylbis(dimethylamino)methane (10.45 g, 0.06 mol) in 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 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 OC; 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.

VjBsffMSHEE (FJLME2B) WO 98/52940 PCT/US98/10436 239 Step 2: Preparation of 4-[3-(4-fluorophenyl)-IH-Dyrazol- 4-vl]-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 (0.65 g, 0.0064 mol) in 10 mL of toluene was added 4fluorobenzoyl chloride dropwise. The mixture was heated at reflux for 10 hours and the solvent was removed. The residue was partitioned between ethyl acetate and water.

The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude (1.6 g) was then dissolved in mL of ethanol. The solution was treated with hydrazine hydrate (0.36 g, 0.006 mol) and the mixture was heated at reflux for 2 hours. After ethanol was removed, the residue was partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 1:1) to give 0.6 g of product, 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-N,Ndimethyl-2-pyrimidinamine, as a yellow solid (33% yield), mp: 155-156 oC; Anal. Calc'd for CisH 4 ,FNs: C, 63.59; H, 4.98; N, 24.72. Found: C, 63.32; H, 4.92; N, 24.31.

Example A-302

F.

sBmUTfIE8HEET(RULE WO 98/52940 WO 9852940PCT/US981 0436 240 4-13- (4-f luorophenyl) -lH-pyrazol-4-yl] -N-methyl-2pyrimidinamine A suspension of 2-chloro-4- (4-f luorophenyl) -lHpyrazol-4-yllpyrimidine prepared in accordance with Example A-299 (0.3 g, 0.0011 mci) in 10 rnL of methylamine water solution) was heated in a sealed tube at 100 0 C overnight. The mixture was then cooled to room temperature and the precipitate was filtered, air-dried to give 0.2 g of product, 4-[3-(4-fluorophenyl) -iNpyrazol-4-yl]-N-methyl-2-pyrinidinamine, as a white solid (68% yield), mp: 217-218 OC; Anal Calc'd for C,,Hl 2

FN

5

C,

62.45; H, 4.49; N, 26.01. Found: C, 62.58; H, 4.36; N, Example A-303

F

N.N

NH

N.

HN N 4- (4-f luorophenyl) -1H-pyrazol-4-yl] (phenylmethyl) 2 -pyrimidinamine This compound was synthesize by refluxing 2-chloro- 4- (4-f luorophenyl) -1H-pyrazol-4-yl)pyrimidine prepared in accordance with Example A-299 in benzylamine overnight. The product, 4- (4-f luorophenyl) -lHpyrazol-4-yl] (phenylmethyl) -2-pyrimidinamine, was obtained as a white solid in 95% yield; mp: 216-217 OC; B E (RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 241 Anal. Calc'd for C 20

H,

6

FN_

5 C, 69.55; H, 4.67; N, 20.28.

Found: C, 69.73; H, 4.69; N, 19.90.

Example A-304

F

N H N N -N

HN

N-cyclopropyl-4-[3- (4-f luorophenyl) -lH-pyrazol-4-ylI -2pyrimidinamine This compound was synthesized by stirring 2-chioro- 4- (4-f luorophenyl) -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- (4-f luorophenyl) -lil-pyrazol- 4-yl]-2-pyrimidinamine, was obtained as a white solid in 26% yield, mp: 203-204 OC; Anal. Calc'd for C 16

C,

65.07; H, 4.78; N, 23.71. Found: C, 64.42; H, 4.82; N, 23 .58.

5JftfWUE88E(RUC~) WO 98/52940 WO 9852940PCT/US98/1 0436 242 Example A-305

F

NH

HNN

4- (4-fluorophenyl) -lH--pyrazol-4-yl] methoxyphenyl) methyl] -2-pyrimidinarnine This compound was synthesized by ref luxing 2-chioro- 4- (4-f luorophenyl) -lH-pyrazol-4-yl] pyrimidine prepared in accordance with Example A-299 in 4-methoxybenzylamine overnight. The product, 4- (4-f luorophenyl) -lHpyrazol-4-yl] [(4-methoxyphenyl)rnethyl] -2pyrimidinamine, was obtained as a off-white solid in yield, mp: 183-185 OC; Anal. Calc'd for C 2

,H

18 FN,0: C, 67.19; H, 4.83, N, 18.66. Found: C, 67.01; H, 5.11; N, 18.93.

Example A-306

F

NH

N

N N

NH

2 1,10,IEISf)I=rgimpUMA0% WO 98/52940 PCT/US98/10436 243 4- [3-(4-fluorophenyl) -1H-pyrazol-4-yl]l-2-pyrimidinamine A solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4yl]-N-[(4-methoxyphenyl)methyl]l-2-pyrimidinamine prepared in accordance with Example A-305 (0.35 g, 0.00093 mol) in mL of trifluoroacetic acid was heated at reflux for 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 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, fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine, as a pale yellow solid (59% yield), mp: 273-274 oC; Anal.

Calc'd for C 13

H,FN

5 0.25 HO 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

I -I

=N

N N O N N-[4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl] N-(phenylmethyl)acetamide To a mixture of 4-[3-(4-fluorophenyl)-1H-pyrazol-4yl]-N-(phenylmethyl)-2-pyrimidinamine prepared in accordance with Example A-303 (0.15 g, 0.00043 mol), DMAP mWUTESHEEr(RULE 26) WO 98/52940 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 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, (4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]-N- (phenylmethyl)acetamide, as a white solid (60% yield), mp: 176-178 oC; Anal. Calc'd for C 22 Hs 1

FN

5 C, 68.21; H, 4.68; N, 18.08. Found: C, 67.67; H, 4.85; N, 17.79.

Example A-308

F

NH

,N

N N HN o 0 Ethyl [4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2pyrimidinyl]carbamate 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 MnTUTff4ESET(RLE6) 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 was trituated with ether to give 0.15 g of product, ethyl [3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2pyrimidinyl]carbamate, as a white solid (46% yield), mp: 163-165 OC; Anal. Calc'd for C 1 6

H,

4 FNsO 2 C, 58.71; H, 4.31; N, 21.04. Found: C, 59.22; H, 4.51; N, 21.66.

Example A-309

NH

NiN 4-[3-(3-methylphenyl)-1H-pyrazol-4-yl]pyrimidine This compound was prepared by the same procedure as described for Example A-208 except that 1-methyl-3-(4'pyrimidinylacetyl) benzene (prepared as set forth in Step 1 of Example A-19 from 4-methyl-pyrimidine and methyl 3methylbenzoate) was used in place of 4-fluorobenzoyl-4pyridinyl 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.

GUBsmTMUEE (RULE 26) WO 98/52940 PCT/US98/10436 246 Example A-310

N

N 7 NH

N

CI

4-[3-(4-chlorophenyl)-1H-pyrazol-4-yl]pyrimidine This compound was prepared according to the chemistry described in Schemes VI and IX by selection of the corresponding pyrimidine starting material in place of the pyridine starting material.

Anal. Calc'd for C 13 HgN 4 C1*0.25MH 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 I NH -NH

F

4-[3-(3-fluorophenyl)-lH-pyrazol-4-yl]pyrimidine This compound was prepared according to the chemistry described in Schemes VI and IX by selection of ~ouas~,m~~~HEI~(F~L~kEes) 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, 23.22. Found: C, 64.78; H, 3.75; N, 23.31. m.p. (DSC): 168.58 oC.

Example A-312 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine This compound was prepared according to the chemistry described in Schemes VI and IX by selection of the corresponding pyrimidine starting material in place of the pyridine starting material.

Anal. Calc'd for C, 3

H

9 gNF (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.

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: qjBS1TIUTE8HEUT(MLU2 WO 98/52940 WO 9852940PCTIUS98/1 0436 248

N/

4-[3-C 4- chlIor op he ny C1-piperazinyl)-lH-pyrazol- 4-yljpyr imidine C4-pyridinyI)-1H-pyrazoI-3-yl~piperazine WO 98/52940 WO 9852940PCTIUS98/10436 249 1-[A-C4-pyridinyl)-5- 4-CtriflIuoromethylI pheny I]- IH-pyrazol-3-yI]piperazine

N

N

H

-IH-pyrazol-3-yI]benzonitrile Jf1UFESEff 26~E).

WO 98/52940 WO 9852940PCT/US98/I 0436 250

N

N

H

5-C(l-ethynylIphenylI -A-C'I-pyr Idifl -1 H- pyrazolI-3- yI] p iperaz ine 5-C4-fluorophenyl>-4- C I-pyr id inylI)- N- 3-pyrro Iid i nylI- IH-pyrazolI- 3-amine N H HN

-O

5-CA-chlorophenyl)-4- C4-pyridinyl)-N-3-pyrrolidinyl- 1H-pyrazo 1-3-amine

RLEAW

WO 98/52940 WO 9852940PCTIUS98/1 0436 251 N-[5-C4-fluorophenyl)-4- C 4- pyr idinfl H-pyraZo I-3- yI -4-piper idinamine 3-C4-fluorophenyl)-5- C 1--p iperaz infl C4-pyr idinfl 1H-pyrazo I- 1-ethanol MJBBflTUrESHEEr (RULE 26) WO 98/52940 WO 9852940PCTIUS98/I 0436 252

N

N

H

4-c hioropheny I C 1--pi per az i fly 1) -4- (4-pyr idinfl H-pyrazo le- 1-ethanol 4-[2-aminoethyl)-2-C4-fluoro phe-nyl)-4,5,6,7-tetrahydro- 3-C4-pyridinyl)pyrazoto 5-a]pyr imid in- 6-o1 VWBTffM&Er(IPALE 2" WO 98/52940 WO 9852940PCTIUS98/10Q436 253 c I

N

SN

OH

NH 2 4- E2- am inoet hy C4- ch Ior o phe-nyl)-,1,5,6.-tetrahydro- 3-(4-pyridinyl~pyrazolo E1,5-a]pyrimidin-6-ol cI

N\

N

OH

3-C4-chlorophenyIJ--i-C,4-pyrimidinyl)- 1H-pyrazole-1-ethanol WO 98/52940 WO 9852940PCTIUS98/1 0436 254

N

5-C4-fluorophenylD-4--(4-pyrimidinyl)- 1H-pyrazole-3-ethanamine

N

N H N N ch loropheny 1)-4-C 4-pyr imid iny IH-pyrazole-3-ethanamine

N

,4-[3-(4-fluorophenyi)-5-C4-piperidinyl)- IH-pyrazol-4-yI]pyrimidine WO 98/52940 WO 9852940PCTIUS98/1 0436 255 N >N A-[3-C4-chlarophenyID-5-C4-piper-idinyl)> IH-pyrazol-4-ylJpyrimidine N 'fN NH COMe 3-C4-flIuorophenylI IH-pyrazo I-4-yl]I 2-pyrimidinyljacetamide

NH

4-E 3-C4-ch Ioropheny 1H-pyrazo -1-y I- 2-pyrimidinyljacetamide W-U1M8HEE(ULF-2M WO 98/52940 WO 9852940PCT/US98/I 0436 256

F

N

NH

N -N NHCOEt 3-C4-flIuoropheny I D- H-pyrazolI-4-yl] 2-pyrimidinyipropanamide N -N NHCOEt N-C4-[3-C4-fluorophenyID-1H-pyrazol-4-y I]- 2-pyr imid infl propanami de

F

N

NH

N

NH-L

6-L3-CA4-fluorophenyl)-1H-pyrazol-4-yIJ-lH-purine WO 98/52940 WO 9852940PCTIUS98/10436 257 c I

N

NH

N_

N

N

6-E3-('-chlorophenyID-1H-pyrazol-A-yi]-1H-purine

N

NH

N-E4-[3-C4-chlorophenyl)-lH-pyrazol-A-yIJ- 2- pyr 1m idinfl pheny met hy Jacetam ide 6 n 1 N-[-1-3-C-fluorophenyID-1H-pyrazoI-4-yIj- 2-pyrimidinylj-N-Cphenylmethyl~propanamide SUBSMMUTSHMTr(RULE 2) WO 98/52940 PCT/US98/10436 258 ci

N.

N H B NCOEt Bn" N-[4-[3-C4-chlorophenyl)-1H-pyrazol-4-yl]- 2-pyrimidinyl]-N-(phenylmethyl)propanamide BIOLOGICAL EVALUATION p38 Kinase Assay 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 synthesized from total RNA as follows: 2 pg of RNA was annealed to 100 ng of random hexamer primers in a 10 1 l 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 1l of 50 mM dNTP's, 4 p 1 of 5X buffer, 2 p1 of 100 mM DTT and 1 p1 (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.

Amplification of p38 cDNA was performed by aliquoting pl of the reverse transcriptase reaction into a 100 pl PCR reaction containing the following: 80 pl dH 2 0, 2 pl mM dNTP's, 1 1 l each of forward and reverse primers VJ=UTEn~~iEL7(RAIE28) WO 98/52940 PCT/US98/10436 259 pmol/il), 10 pl 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 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 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 ligated into BamHI digested pGEX 2T plasmid DNA (PharmaciaBiotech) using T-4 DNA ligase (New England Biolabs) as described by T. Maniatis, Molecular Cloning: A Laboratory Manual, 2nd ed. (1989). The ligation reaction was transformed into chemically competent E.

coli DH10B cells purchased from Life-Technologies following the manufacturer's instructions. Plasmid DNA was isolated from the resulting bacterial colonies using a Promega WizardTM miniprep kit. Plasmids containing the appropriate Bam HI fragment were sequenced in a DNA Thermal Cycler (Perkin Elmer) with PrismTM (Applied Biosystems Inc.). cDNA clones were identified that coded for both human p38a isoforms (Lee et al. Nature 372, 739). One of the clones which contained the cDNA for p38a-2 (CSBP-2) inserted in the cloning site of pGEX 2T, 3' of the GST coding region was designated pMON 35802.

The sequence obtained for this clone is an exact match of the cDNA clone reported by Lee et al. This expression plasmid allows for the production of a GST-p38a fusion protein.

$UBBOnUE8HETE I(RLE2M WO 98/52940 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 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 °C with constant shaking until the culture reached an absorbance of 0.8 at 600 nm. Expression of the fusion protein was induced by addition of isopropyl b-Dthiogalactosidse (IPTG) to a final concentration of 0.05 mM. The cultures were shaken for three hours at room temperature, and the cells were harvested by centrifugation. The cell pellets were stored frozen until protein purification.

Purification of p38 Kinase-a: All chemicals were from Sigma Chemical Co. unless noted. Twenty grams of E. coli cell pellet collected from five 1 L shake flask fermentations was resuspended in a volume of PBS (140 mM NaC1, 2.7 mM KC1, 10 mM Na 2 HP0 4 1.8 mM KH 2 PO4, pH 7.3) up to 200 ml. The cell suspension was adjusted to 5 mM DTT with 2 M DTT and then split equally into five 50 ml Falcon conical tubes. The cells were sonnicated (Ultrasonics model W375) with a 1 cm probe for 3 X 1 minutes (pulsed) on ice. Lysed cell material was removed by centrifugation (12,000 x g, minutes) and the clarified supernatant applied to glutathione-sepharose resin (Pharmacia).

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.

The resin was collected by centrifugation (600 x g, min) and washed with 2 x 150 ml PBS/1% Triton X-100, SAMM&Hc~ ~F:~ET(RULE26)i WO 98/52940 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 units/mg) and mixed gently for 4 hours at room temperature. The glutathione-sepharose resin was removed by centrifugation (600 x g, 5 min) and washed 2 x 6 ml with PBS. The PBS wash fractions and digest supernatant containing p38 kinase protein were pooled and adjusted to 0.3 mM PMSF.

Mono 0 Anion Exchange Chromatography: The thrombin-cleaved p38 kinase was further purified by FPLC-anion exchange chromatography. Thrombin-cleaved sample was diluted 2-fold with Buffer A (25 mM HEPES, pH 25 mM beta-glycerophosphate, 2 mM DTT, 5% glycerol) and injected onto a Mono Q HR 10/10 (Pharmacia) anion exchange column equilibrated with Buffer A. The column was eluted with a 160 ml 0.1 M-0.6 M NaCl/Buffer A gradient (2 ml/minute flowrate). The p38 kinase peak eluting at 200 mM NaCl was collected and concentrated to 3-4 ml with a Filtron 10 concentrator (Filtron Corp.).

Sephacryl S100 Gel Filtration Chromatography: 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 NaC1, 2 mM DTT, glycerol)). Protein was eluted from the column with Buffer B at a 0.5 ml/minute flowrate and protein was detected by absorbance at 280 nm. Fractions containing p38 kinase (detected by SDS-polyacrylamide gel electrophoresis) were pooled and frozen at -80 oC.

Typical purified protein yields from 5 L E. coli shake flasks fermentations were 35 mg p38 kinase.

SUSmUTESHEETr(RULE26) WO 98/52940 PCT/US98/10436 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 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 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 polypropylene plates. Each reaction well contained 25 mM HEPES pH 7.5, 10 mM magnesium acetate and 50 jM unlabeled ATP. Activation of p38 was required to achieve sufficient signal in the assay. Biotinylated PHAS-I was used at 1-2 ig per 50 il reaction volume, with a final concentration of 1.5 AM. Activated human p38 kinase alpha was used at 1 jg per 50 1l reaction volume representing a final concentration of 0.3 pM. 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 used at 1.2 pCi per 50 pl reaction volume. The reaction proceeded either for one hour or overnight at 30 oC.

Following incubation, 20 pl of reaction mixture was transferred to a high capacity streptavidin coated filter plate (SAM-streptavidin-matrix, Promega) prewetted with phosphate buffered saline. The transferred reaction mix was allowed to contact the streptavidin membrane of the Promega plate for 1-2 minutes. Following capture of biotinylated PHAS-I with 32 P incorporated, each well was washed to remove unincorporated 32 P-ATP three times with 2M NaC1, three washes of 2M NaCI with 1% phosphoric, three washes of distilled water and finally a single wash 8I111iFEls HEEr(RLUL2S) WO 98/52940 PCT/US98/10436 263 of 95% ethanol. Filter plates were air dried and 20 Al of scintillant was added. The plates were sealed and counted. Results are shown in Table 4.

A second assay format was also employed that is based on p38 kinase alpha induced phosphorylation of EGFRP (epidermal growth factor receptor peptide, a 21 mer) in the presence of 33 P-ATP. Compounds were tested in fold serial dilutions over the range of 100yM to 0.001AM in 1% DMSO. Each concentration of inhibitor was tested in triplicate. Compounds were evaluated in reaction volumes in the presence of 25 mM Hepes pH mM magnesium acetate, 4% glycerol, 0.4% bovine serum albumin, 0.4mM DTT, 50AM unlabeled ATP, 25 Ag EGFRP (200AM), and 0.05 uCi gamma 33 P-ATP. Reactions were 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 minutes at room temperature, the reaction was stopped by addition of 1501l 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 50A1 of clarified solution head volume was transferred from the.reaction wells to Microlite-2 plates. 150g1 of Microscint 40 was then added to each well of the Microlite plate, and the plate was sealed, mixed, and counted.

SUBWESHET(RLES6) WO 98/52940 PCT/US98/10436 264 TABLE 4 Example p38 kinase (uM) 1 4.6 2 8 <0.1 16 3.8 23 2.6 26 0.7 28 0.3 33 34 36 12.1 38 0.8 39 1.1 1.3 42 0.3 43 <0.1 44 <0.1 <0.1 46 <0.1 47 3.2 48 1.8 50 2.3 51 <0.1 52 0.1 53 0.9 54 0.7 55 6.4 143 <0.1 TNF Cell Assays Method of Isolation of Human Peripheral Blood Mononuclear Cells: Human whole blood was collected in Vacutainer tubes containing EDTA as an anticoagulant. A blood sample (7 ml) was carefully layered over 5 ml PMN Cell Isolation Medium (Robbins Scientific) in a 15 ml round bottom centrifuge tube. The sample was centrifuged at 450-500 x g for 30-35 minutes in a swing out rotor at room temperature. After centrifugation, the top band of cells were removed and washed 3 times with PBS w/o calcium or magnesium. The cells were centrifuged at 400 x g for minutes at room temperature. The cells were resuspended sUBTsmUTEHEE(RULE26) WO 98/52940 PCT/US98/10436 265 in Macrophage Serum Free Medium (Gibco BRL) at a concentration of 2 million cells/ml.

LPS Stimulation of Human PBMs: 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 (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 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 Histiocytic Lymphoma Cell Line: U937 cells (ATCC) were propagated in RPMI 1640 containing 10% fetal bovine serum, 100 IU/ml penicillin, 100 pg/ml streptomycin, and 2 mM glutamine (Gibco).

Fifty million cells in 100 ml media were induced to terminal monocytic differentiation by 24 hour incubation with 20 ng/ml phorbol 12-myristate 13-acetate (Sigma).

The cells were washed by centrifugation (200 x g for min) and resuspended in 100 ml fresh medium. After 24-48 hours, the cells were harvested, centrifuged, and resuspended in culture medium at 2 million cells/ml.

LPS Stimulation of TNF production by U937 Cells: U937 cells (0.1 ml, 2 million/ml) were incubated with 0.1 ml compound (0.004-50 iM, final concentration) for 1 hour in 96 well microtiter plates. Compounds were prepared as 10 mM stock solutions in DMSO and diluted in SUme UTESHEEr(RULE26) WO 98/52940 PCT/US98/10436 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 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 9jBamBWEET (RULEs) WO 98/52940 WO 9852940PCTIUS98/1 Q436 267 TABLE Example. Human PBM Assay U937 Cell Assay (am) 1C50 HAWM 1 2 1.6 0.578 4 0.1 0.222 0.274 7 0.2 0.201 8 <0.1 9 0.4 0.7 1.687 12 13 4.8 14 1.2 17 1.1 19 0.3 0.484 1.089 21 0.077 22 3.2 24 8.2 26 <0.1 0.029 27 2.7 28 0.1 29 2.2 30 2.6 31 0.8 1.053 32 2.696 33 0.4 34 35 0.7 36 1.4 37 1.5 0.099 38 0.2 0.208 39 0.7 0.244 40 0.4 41 42 0.7 43 <0.1 0.243 44 0.4 0.477 45 <0.1 0.04 46 0.329 47 2.359 48 2.2 0.522 49 6.8 50 0.9 51 0.074 54 0.2 0.13 <0.1 0.228 143 0.301 SLWMTUTSHETKU26) WO 98/52940 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 [Sprague Dawley Co.] were used in this model. Each rat weighed approximately 300 g and was fasted overnight prior to testing. Compound administration was typically by oral gavage (although intraperitoneal, subcutaneous and intravenous administration were also used in a few instances) 1 to 24 hours prior to the LPS challenge.

Rats were administered 30 yg/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 quantitative analysis of TNF-a by Enzyme Linked-Immuno- Sorbent Assay ("ELISA") [Biosource]. Additional details of the assay are set forth in Perretti, et al., Br.

J. Pharmacol. (1993), 110, 868-874, which is incorporated by reference in this application.

Mouse Assay Mouse Model Of LPS-Induced TNF Alpha Production: TNF alpha was induced in 10-12 week old BALB/c female mice by tail vein injection with 100 ng lipopolysaccharide (from S. Typhosa) in 0.2 ml saline.

One hour later mice were bled from the retroorbital sinus and TNF concentrations in serum from clotted blood were quantified by ELISA. Typically, peak levels of serum TNF ranged from 2-6 ng/ml one hour after LPS injection.

The compounds tested were administered to fasted mace by oral gavage as a suspension in 0.2 ml of methylcellulose and 0.025% Tween 20 in water at 1 hour or 6 hours prior to LPS injection. The 1 hour protocol allowed evaluation of compound potency at Cmax plasma levels whereas the 6 hour protocol allowed estimation of 8UsmTUTHEET(RULE26) WO 98/52940 PCT/US98/10436 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.

Additional results obtained using the abovedescribed assays are set forth in Table 6 below. p38 assay and U937 cell assay results are expressed as ICs Mouse-LPS assay results are expressed as percent inhibition.

SUsmWTTSHEBUEr(LU W6) WO 98/52940 WO 9852940PCTIUS98/1 0436 270 TABLE 6 Example p38 1 p38 2 U937 xnLPS !DLPS mLPS 8h 6h dose 1h, 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 A-231 0.174 0.3225 86 30 94 A-232 0.048 96 A-233 0.044 A-234 0.103 A-235 0.104 A-236 0.237 A-237 0.093 0.087 A-238 10.177 0.4016 A-239 0.034 51 30 87 A-240 0.961 78 30 A-241. 0.338 79 30 87 A-242 ___0.047 95 30 87 A-243 10.729 82 A-244 0.099 A-245 <.001 0.0337 A-246 0.403 0.592 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 A-253 1<.001 0.0044 61 A-254 0.081 0.1411 A-215 2.34 0.2976 38 30 A-256 0.813 0.4562 A-257 1.081 <.01 0.5167_____ A-213 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 A-261 ___0.008 0.2542 48 30 92 A-216 0.018 1.8287 27 30 91 1A-262 <0.1 1A-263 1<0.011 <0.1 0.54341 49 MSMMiEEr(RLJLE26) WO 98/52940 PCT/US98/ 10436 271

I

Example p381 p382 U937 mLPS mLPS nLP iLPS MLPS nmLP S~ 8h 6h dose lh, A-264 0.2594 61 A-265 <0.1 0.6016 32 A-266 0.5393 0 A-267 0.43 2.6681 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 0.583 -8 A-273 6.98 >10 43 A-274 <0.1 0.92 21 10.14 A-275 2 A-276 0.176 0.45 -24 A-277 0.026 33 A-278 0.285 2.3 62 A-279 0.005 0.7 64 A-280 0.134 15 A-281 0.053 22 A-218 0.044 18 A-282 0.045 0.0973 30 A-283 <0.1 0.7998 -20 A-284 0.98 0.5088 -1 A-285 <0.1 0.1795 11 A-286 0.057 0.09 29 A-287 0.041 0.27 -24 A-288 0.017 0.3 40 A-289 <0.1 0.14 44 A-290 6.0191 4 A-291 0.388 1.1309 36 A-292 1.15 A-293 0.73 A-294 0.015 0.5 61 A-295 7.66 >10 94 A-296 26 A-297 0.52 0.17 89 'p38ac in vitro assay results based on PHAS-I assay procedure 2 p38oc in vitro assay results based on EGFRP assay procedure SUB TUTESHEET -(RULE26) WO 98/52940 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 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 Lake City, UT) in complete Freund's adjuvant (Sigma) on day 0 at the base of the tail. Injection volume was 100 pl. Animals were boosted on day 21 with 50 pg of CII in incomplete Freund's adjuvant (100 p1 volume). Animals were evaluated several times each week for signs of arthritis. Any animal with paw redness or swelling was counted as arthritic. Scoring of arthritic paws was conducted in accordance with the procedure set forth in Wooley et al., Genetic Control of Type II Collagen Induced Arthritis in Mice: Factors Influencing Disease Suspectibility and Evidence for Multiple MHC Associated Gene Control., Trans. Proc., 15:180 (1983). Scoring of severity was carried out using a score of 1-3 for each paw (maximal score of 12/mouse). Animals displaying any redness or swelling of digits or the paw were scored as 1. Gross swelling of the whole paw or deformity was scored as 2. Ankylosis of joints was scored as 3.

Animals were evaluated for 8 weeks. 8-10 animals per group were used.

Preparation And Administration Of Compounds: The compounds tested on mice having collagen-induced arthritis were prepared as a suspension in methylcelluose (Sigma, St. Louis, MO), 0.025% Tween (Sigma). The compound suspensions were administered by oral gavage in a volume of 0.1 ml b.i.d. Administration began on day 20 post collagen injection and continued SU031BTfUTE88E(RULE0B WO 98/52940 PCT/US98/10436 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.

TABLE 7 Compound Inhibition of Arthritis A-210 58.5 15 mpk A-172 49.3 100 mpk A-189 51.6 30 mpk 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 compounds of this invention in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carrier" materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and composition may, for example, be administered orally, intravascularly intraperitoneally, subcutaneously, intramuscularly (IM) or topically. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, hard or soft capsule, lozenges, dispensable powders, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection (IV, IM, subcutaneous or jet) as a composition wherein, for example, saline, dextrose, or water may be used as a suitable carrier. The pH of su1 ULe3 WO 98/52940 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 composition. A suitable parenteral composition can also include a compound formulated as a sterile solid substance, including lyophilized powder, in injection vials. Aqueous solution can be added to dissolve the compound prior to injection. The amount of therapeutically active compounds that are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the inflammation or inflammation related disorder, the route and frequency of administration, and the particular compound employed, and thus may vary widely. The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 1000 mg, preferably in the range of about 7.0 to 350 mg. A daily dose of about 0.01 to 100 mg/kg body weight, preferably between about 0.1 and about 50 mg/kg body weight and most preferably between about 0.5 to 30 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day. In the case of skin conditions, it may be preferable to apply a topical preparation of compounds of this invention to the affected area two to four times a day. For disorders of the eye or other external tissues, mouth and skin, the formulations are preferably applied as a topical gel, spray, ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base.

sLr SSHMET (RULE 26) WO 98/52940 3 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 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.

Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane. The transdermal patch may include the compound in a suitable solvent system with an adhesive system, such as an acrylic emulsion, and a polyester patch. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and SUBSlUFE SHEE(RULE 28) WO 98/52940 PCT/US98/10436 276 the wax together with the oil and fat make up the socalled emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 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, 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 nongreasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used. Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The anti-inflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to and particularly about 1.5% w/w. For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, smm aiE (RUL[ WO 98/52940 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, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.

Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

All patent documents listed herein are incorporated by reference.

Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations.

SUB mUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 278 Description of parallel array synthesis methodology utilized to prepare compounds of Examples B-i, B-ii, and B-iii.

Scheme B-I describes the parallel array reaction blocks that were utilized to prepare compounds of Examples B- 0001 through B-1574, and by analogy could also be used to prepare compounds of Examples B-1575 through B-2269.

Parallel reactions were performed in multi-chamber reaction blocks. A typical reaction block is capable of performing 48 parallel reactions, wherein a unique compound is optionally prepared in each reaction vessel B1. Each reaction vessel B1 is made of either 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 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 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.

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 1111rM WO 98/52940 PCT/US98/10436 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.

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 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 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.

SU smwsEHET(RLEPB) WO 98/52940 PCT/US98/10436 280 Scheme B-1

BI

BI

B3 B7 BI0 B2: f r i t B6: i nert gas inlet valve.

S BS: vacuum valve.

Bll B4 -B9 is anoptional insert to allow collection vial racks Bl 1 to be mounted within the lower reaction block chamber Scheme B-2 illustrates the various utilizations of functionalized resins to purify reaction vessel products B22 prior to filtration from the fritted vessels B1 into collection vials B9. Said functionalized resins perform as 1) resin-bound reagents B12, which give rise to resinbound reagent byproducts B13; 2) sequestrants B14 or of excess solution-phase reactants B16 or B17, respectively. Solution-phase reactants B16 and B17 contain inherent reactive functionality -rfl and -rf 2 SUssmuTESHEET(RULEa) WO 98/52940 PCT/US98/10436 281 which enable their chemoselective sequestration by the complementary reactive functionality -Crfl and -Crf 2 attached to resins B14 and B15; 3) sequestrants B18 of solution-phase byproducts B19. Byproduct B19 contains molecular recognition functionality -mr 2 which enables its chemoselective sequestration by the complementary functionality -Cmr 2 attached to resin B18; 4) reactionquenching resins B20 which give rise to quenched resins B21. Resin B20 contains functionality -Q which mediates 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 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 postreaction sequestration of B24 by the complementary 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 B16, particularly 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 their reaction with sequestration-enabling-reagents B26.

B26 contain highly reactive, complementary functionality Crfl which reacts with B16 to form B27 in situ. The SJ.BU1UTESHEERLE) WO 98/52940 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 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.

Similar use of the bifunttional sequestration-enablingreagent 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, 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 complementary functionalized solution phase reactants, reagents, or byproducts from solution phase faster than resin cross-neutralization. Similarly, resins containing mutually reactive or neutralizing reaction-quenching functionality are able to quench solution phase reactants, products, or byproducts faster than resin cross-neutralization.

SJLmMTE8HEET (RULE 26 WO 98/52940 PCT/US98/10436 283 Scheme B-2 A-Ser-mr -a Cmr-O Cmr-O-*- BPSer-mr B27 B28 B31 CrfSer-mr Cmr 2 Ser-mr SB26 R CRbp B29 B12 B13 A-rfi B-rf 2 P PB-mr 2 B16 B17 B22 B 19 1 4 R-tag Rbp-tag Crfj Crf 2 -O B24 B25 Cmr 2 B14 B15 0- B B18 B21 Ctag-Q 0 Denotes insoluble resin B23 Scheme B3 describes the modular robotics laboratory 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 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.

Reactions are initiated at the modular Stations #2 and #2 DUP. Station #2DUP is defined as a duplicate of Station #2 and is used to increase capacity within the robotics laboratory. A reaction block is mounted at Station #2 or #2 DUP. Also, racks containing reactants, reagents, solvents, and resin slurries are also mounted at Station #2 or #2 DUP. Under the control of a chemical UBmTWm HEE(RULE26) WO 98/52940 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 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 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 reaction block may occur while the reaction block is mounted at the robot station. Preferably, however, the reaction block is removed after all volume transfers are complete and the reaction block is brought to ambient temperature. The reaction block is transferred off-line to either a vertical- or lateral shaking Incubator Station The Automated weighing/archival Station #3 performs the functions of weighing empty collection vials (to obtain tare weights of collection vials) and also performs the functions of weighing collection vials containing filtered, purified products (to obtain gross weights of collection vials). After product-containing collection vials have been weighed (gross weight determinations) at workstation the collection vial products are optionally redissolved into an organic solvent at workstation Transfer of solvents is accomplished with syringes which control a mounted one-up septumpiercing/argon purging cannula. Each product-containing 8LMWMMT(E(ULE= WO 98/52940 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 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 collection racks at Savant Automated Solvent Evaporation Stations #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 removal stations were purchased from the Savant Company (model SC210A speedvac unit equipped with model RVT4104 vapor trap and model VN100 vapornet cryopump).

Stations #7 and #7DUP perform analytical processing functions. Station #7DUP is defined as a duplicate of Station #7 to increase capacity within the robotics laboratory. Product-containing collection racks are mounted at either of these stations. Each productcontaining collection vial is then prepared as a solution of known molarity as directed and recorded by the chemical informatics mapping file. Optionally, this dissolution function is performed by prior processing of the collection vial rack at Station #3 as described above. Station#7 or #7DUP, under the control of the chemical informatics mapping file, transfers aliquots of each product vial into unique and identifable microtiter plate wells that are utilized to perform analytical determinations.

8UBSmTUTESHEET(RULE26) WO 98/52940 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 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 degasser, model G1312A binary pump, a model G1316A column heater, and a model G1315A diode array detector.

The HP unit has been interfaced with a commercially available autosampler rack (Gilson Company 215 autosampler). Station #8 or #8DUP is utilized for the determination of product purity and identity by performing high performance liquid chromatography (HPLC) and companion atmospheric pressure chemi-ionization (APCI) or electrospray mass spectrometry for molecular weight determination.

Another microtiter plate is prepared at Station #7 or #7DUP for subsequent utilization at a commercially available flow-probe Varian NMR spectrometer Station (Varian Instruments flow probe NMR, 300 MHz, interfaced with a commercially available Gilson 215 autosampler).

Proton, 13 -Carbon, and/or 1-Fluorine NMR spectra are determined at this Station Other microtiter plates are optionally mounted at Station #7 or #7DUP for the purpose of preparing productcontaining plates for biological assays. Aliquots of 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 SuLsmnUE8HEE(RUL£26) WO 98/52940 PCT/US98/10436 287 recorded by the chemical informatics system for retrieval by biologists who perform the biological assaying of products.

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, 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 MagnaIR 560 interfaced with an InspectIR microscope for resin mounting and positioning).

Scheme B-3 The lines interconnecting the modular Stations denote the transfer of chemical racks, reaction blocks, and/or collection vial racks from one modular Station to another.

s~gllJTElFSHEET (RULE 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 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 server.

The ChemLib IT system is a client/server software application developed to support and document the data handling flow in the robotics laboratory described above.

This IT system integrates the chemist with the robotics synthesis laboratory and manages the data generated by this processes.

The software running on the server warehouses all the electronic data for the robotics chemistry unit. This SUBSI38rr1UE;HETUE 4" WO 98/52940 PCT/US98/10436 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 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 v3.5 and Microsoft Visual 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 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 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).

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 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 9jeWmSTESEat(KULE'=) WO 98/52940 PCT/US98/10436 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 Therefore a well in the Electronic 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 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 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 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 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 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 GMM:SHEU (RULE 2) WO 98/52940 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 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 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 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 (microtiter plate) to be sent for analysis and/or biological assaying. The mass spectrometric and HPLC results for each well are recorded and scored into the ChemLib system.

The 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.

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 UnmzTWESHEor (RULE I WO 98/52940 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 robotics hardware by Bohdan Automation, Inc. Mundelein, Illinois, and a PC currently running Microsoft Windows for Workgroup v3.11 and Ethernet software. The robotics workstation PC is logged into the network for one-way communication that allows the workstation to access the server for file access only.

General Scheme B4 Scaffold C-i with a primary amine functionality contained within the R 4 substituent is reacted in spatially addressed, parallel array reaction block vessels with excess of electrophiles RJ-Q wherein Q is chloro, bromo, or an acid activating group including but not limited to N-hydroxysuccinimide. RJ-Q includes acid chlorides, alkyl chloroformates, sulfonyl chlorides, activated esters of carboxylic acids, activated carbamates, and isocyanates. Reaction of scaffold C-i with R 3 -Q'is effected in the presence of a tertiary amine base at room temperature in a mixture of a polar aprotic solvent and/or a halogenated solvent. As illustrated in Scheme B-4 the products of the general formulae B-i are isolated in purified form by addition of a carbonylfunctionalized resin B32 which covalently sequesters any unreacted primary amine scaffold C-i as resin-bound adduct B35, and also by the addition of a primary aminefunctionalized resin B33 which covalently sequesters any remaining electrophile Ra-Q from each reaction mixture as ~uesr~aa~dE~~sW~00%i 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 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

R2 R 4

R

3 C-i R contains a primary amine function -NH, N- NH RJ-Q R2-R 4 rR3 Base Base-HQ

CHO

B32

NH

2 B33 B-i R contains a derivatized

-NH-R

J function 0--NH 2 B33 O-NH 2

HQ

B36

N-NH

SR4' R 2

R

3

Q-NH-RU

B34 Scheme B-5 specifically illustrates the derivatization of the primary amine-containing scaffold C1 to afford the desired products B-i in a parallel 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 8U9Bfl1U~E88EE3 (rUlBs WO 98/52940 PCT/US98/10436 294 addressed format. A solution of the desired primary amine-containing scaffold Cl (limiting amount,) in dimethylformamide (DMF) is added to the reaction vessels followed by a 4.0 fold stoichiometric excess solution of N-methylmorpholine in DMF. To each reaction vessel is then added the electrophiles: either a 2.0 fold stoichiometric excess when RJ-Q is an acid chloride or alkyl chloroformate, or a 1.5 fold stoichiometric excess when R -Q is a sulfonyl chloride, or a 1.25 fold stoichiometric excess when 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 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 resin-charged reaction block is shaken vertically for 14-20 h on an orbital shaker at ambient temperature to allow optimum agitation of the resin-containing vessel mixtures. The excess electrophiles RJ-Q and any unreacted scaffold amine C1 are removed from the reaction medium as insoluble adducts 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 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.

SnLrESKEE(RLE2) WO 98/52940 PCT/US98/10436 295 Scheme

R.Q

F

NH- RJ

Q--CHO

B32

CH

3 O NH 2 B33

NH-RJ

B34

N

S-HO

CH

3 3NH 2 B33

NH

2

HQ

B36 Scheme B-6 illustrates a general synthetic method involving the parallel array reaction of a scaffold C-ii containing a secondary amine functionality within the definition of the R 4 substituent. Each reaction vessel is charged with the secondary amine-containing scaffold Cii, followed by the introduction of a stoichiometric 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, seBmUTESHEEa(RU WO 98/52940 PCT/US98/10436 296 sulfonyl chlorides, activated esters of carboxylic acids, activated carbamates, and isocyanates. Reaction of scaffold C-ii with R -Q is effected in the presence of tertiary amine base at room temperature or elevated temperature in a mixture of a polar aprotics solvent and/or a halogenated solvent. After solution-phase reactions have progressed to afford crude product mixtures in each vessel, the products B-ii are isolated in purified form by the addition of the isocyanate-functionalized resin B38 which covalently sequesters remaining secondary amine scaffold C-ii as resin-bound adduct B39, and also by the addition of the primary amine-functionalized resin B33 which covalently sequesters remaining electrophile RL-Q from each reaction 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 concentration of the filtrates affords purified products B-ii filtered away from resin-adducts B33, B36, B38, B39, and SMITUIESHE~ (r(RULE e" WO 98/52940 PCT/US98/10436 297 Scheme B-6 N-NH

N-NH

R2R4 R'-Q R2 R 4

R

3

R

3 Base Base-HQ C-ii B-ii R contains a secondary R contains a derivatized amine function -NH -N-RL amine function N=C=0 NH 2

-NH

2 B38 B33 B33

N-NH

o R4 R 2 O' NH-RL -NH 2

.HO

3-NH B36 B39 B40 B36 Scheme B-7 illustrates the conversion of the secondaryamine containing scaffold C-2 to the desired products Bii. In a parallel array synthesis reaction block, individual reaction products are prepared in each of 48 multiple reaction block vessels. A solution of the scaffold C-2 (limiting amount) in dimethylformamide (DMF) is added to the reaction vessels followed by a 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 R -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 isocyanate. The reaction mixtures are incubated at USBMImUTESHEET(RULE26) WO 98/52940 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 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 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, affords purified product solutions in collection vials filtered away from resin-adducts B33, B36, B38, B39, and Concentration of filtrates affords purified products B-ii.

III sHET(~EET(UL26 WO 98/52940 PCT/US98/10436 299 Scheme B-7 N-NH

N-NH

F N H R F N CH3

HO

C-2 CH 3

CH

3 -NH2 Q--CHO B33 B38 H2 SNH-RL B33 O N -NH HN N (-NH2. HO B39 B36 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 Cii, followed by the introduction of a stoichiometric excess of an optionally unique electrophile RL-Q into each vessel. Reaction of scaffold C-ii with R_-Q is effected in the presence of tertiary amine base at room temperature or elevated temperature in a mixture of a polar aprotic solvent and/or a halogenated solvent.

9 rr!ESHEEr(BUl26) WO 98/52940 PCT/US98/10436 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 and N-methylmorpholine. The reaction mixtures are incubated at ambient temperature for 2-8 h. Each reaction vessel is then charged with the sequestrationenabling reagent phenylsulfonylisocyanate B41. This reagent B41 reacts with remaining secondary amine 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 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 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.

SiU9nnEiSHEET(RULE2)U WO 98/52940 WO 9852940PCTIUS98/10436 Scheme B-8

N-NH

R

2 R4

R

3 C-ii R 4 contains a secondary amine function -NH.

0 -SO 2 N=C=0 B41

I

RLQ

N-NH

2 -I/X

R

4 Base

O-NH

2 B33 Base-HQ B-ii R" contains a derivatized -N-R'1 amine function QO- NH 2 B33

(Z)-NHH

B36 00

N-NH

N N 1RR H 1 4, R A 3

Q-NH-AL

Q- NH 2 B33 tQA-NH 3 OWip-NH 2 B33 0 0

S

N H

NH

Scheme B-9 illustrates the method of Scheme B-8 using scaffold C-2. A solution of the scaffold C-2 (limiting Ufl1UFEHEU (RLU26) WO 98/52940 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 dichloroethane (DCE) solution: either a 2.0 fold stoichiometric excess is used when R -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 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 reagent phenylsulfonylisocyanate B41. This reagent B41 reacts with remaining secondary amine scaffold C-2, converting C-2 to the in situ-derivatized compound Subsequent incubation of these vessel mixtures with a large excess (15-20 fold stoichiometric excess) of the amine-functionalized resin B33 sequesters the solutionphase species RL-Q, HQ, B41, and B45 as the resin-bound adducts B40, B36, B44, and B46, respectively. The resincharged reaction block is shaken vertically for 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 B33, B36, B44, and B46 and subsequent rinsing of the vessel resinbed with DCE affords filtrates containing the purified products B-ii. Concentration of the filtrates affords the purified products B-ii.

III &HE f (RULE 26) WO 98/52940 WO 9852940PCTIUS98/I 0436 Scheme B-9

RL-Q

C-2 R otisa secondary amine function -NH.

0 -SO 2

N=C=O

B41

I

6H 3 B33 6H 3 B-ii R4contains a derivatized -N-R L amine function 0-NH 2 B33 0O_NH-RL

O-NH

2

HO

e 0-NH 3 O- _NH 2 B33

XNH

QJ-NH

Another general method for the parallel array reaction block synthesis is illustrated in Scheme B-l0 for the derivatization of the carboxylic acid-containing scaffold KMMTTI=%et

(RUL=)

WO 98/52940 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 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 with the sequestration-enabling-reagent B50 (tetrafluorophthalic anhydride). The reagent B50 reacts with remaining excess amine B47 to afford the in situderivatized intermediates B51 which contain carboxylic acid molecular recognition functionality. Subsequent 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 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.

mfHEETM(ULE26) WO 98/52940 WO 9852940PCTIUS98/1 0436 305 8UBB1ITU1ESEEE(RUE2B) WO 98/52940 PCT/US98/10436 306 Scheme B-ll illustrates the conversion of the acid containing scaffold C-49 to the desired amide products Biii in a parallel synthesis format. A limiting amount of the scaffold C-49 is added as a solution in 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 a dimethylformamide solution of a unique amine B47 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 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 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 aminefunctionalized resin B33 and dichloromethane solvent are added to each reaction vessel. The amine-containing resin B33 converts B51, any remaining B50, and any remaining C-49 to their resin-bound adducts B52, B53, and 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 resin-containing vessel mixtures. Filtration of the insoluble resin- adducts B33, B52, B53, and B55 and subsequent rinsing of the vessel resin-bed with UBSMUIESHEET(RULEs) 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.

WUSsmTEHEE (RULE 2) WO 98/52940 PCT/US98/I 0436 Scheme B-1l

OH

OH

3 'N N Bs F R NH cP

DMF/DCM

excess B48 N' B47 C-49 NRB N- RC 0 7

H

3 +CfD B49 B-iii

F

B47 (remaining)

X

F 0 F a FN I3 OH F N- BC

RB

B51 0-NH 2 B33 G0

H

3

N--

B33 F 0

F

FOH

F 0 B52

OH

'N 1/ H 3

F

N

B33 E) G

H

3 N-Qw (remaining) 8H~Er (RULE~) WO 98/52940 PCT/US98/10436 309 Although Schemes B-1 through B-1 describe the use of parallel array chemical library technology to prepare 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 purified by conventional means such as chromatography and/or crystallization).

A general synthesis of pyridylpyrazole scaffolds C-i, Cii, and C-iii is depicted in Scheme C-1.

Step A: Picoline is treated with a base chosen from but not limited to n-butyllithium (n-BuLi), lithium di-isopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), potassium t-butoxide (tBuOK), or sodium hydride (NaH) in 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 from 30 minutes to 48 hours during which time the temperature may range from -20 °C to 120 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 purified by crystallization and/or chromatography.

UBSmUTE HEET(RLE26) WO 98/52940 PCT/US98/10436 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 methyl ether, or t-BuOH from -78 °C to 50 °C 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 the temperature is maintained between -50 °C and 50 oC.

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.

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 HN0 3 The temperature during this step is maintained between -20 °C 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 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 alkylated with Q-C(RA)- (CH2) nC0 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 1111UIIESHMMLU" h~eB WO 98/52940 PCT/US98/10436 311 between -20 oC and 150 OC and reaction times between 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 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 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.

awmm wEBE (RU L-E WO 98/52940 WO 9852940PCTIUS98/10436 312 N\ Scheme C-i Step A 1)Base 2) 0 R 2-JOR B56 Step B 1) Base 4 2) XCOR

N-NH

R

2

N'

Ci or Cii Step D Step C

NH

2

NH

2 O 0

N

B58 1) QCH(R A)_(CH2)nCO 2 alky (1359) 2) saponification or acid hydrolysis 3) neutralization R A C0 2 H

H,

~2 R R 4

R

N

C-iii C-iv A synthesis of pyridylpyrazole scaffold C-1 is depicted in Scheme C-2.

Step A: $HEE~ (FULEM) WO 98/52940 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.

This solution is then added to neat ethyl pfluorobenzoate 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 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.

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 1-3 h. After this time, N-Cbz-protected glycine Nhydroxysuccinimide 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.

Step 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 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 WBIm1UTESHEET(RULE26) WO 98/52940 PCT/US98/10436 314 silica gel chromatography, giving rise to purified C- ICbz.

Step: D The Cbz protecting group contained in compound C-1Cbz is cleaved using hydrogen gas under pressure and Pd-C in methanol solvent. The resulting amine C-i is obtained by filtration and concentration.

111111 TESHEUMME26)s WO 98/52940 WO 9852940PCT/US98/1 0436 Scheme C-2 Step A 1) L-iHMDSITHF N\ 0 F BeE60O Step B 1) t-BuOK/t-BuOH 2) 0 NH-Cbz N-a B62 0 N-HStepOC 0 0 N-HNH-Cbz 1) MeCO 2 H, pH 6.5 NHCb

NH

2

NH

2 -hydrateF F N 1

N

C-1 Cbz B63

H

2 Pd-C, MeOH Step

D

N-NH

NH

2

F

8U6B1TUT8HEET(RLUE2) WO 98/52940 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 organic solvent such as THF, ether, t-BuOH or dioxane from -78 OC to 50 OC 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 nCRF(RG)-CO 2 H or BocNRH- (CH 2 nCRF (RG) -C 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 OC. The mixture is then poured into water and extracted with an organic 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 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 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 The resulting mixture is allowed to stir at 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.

8"7fIsk4EET (RULE0 WO 98/52940 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 from HOAc, H 2

SO

4 HC1, 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 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 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.

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 (R H is hydrogen) or a free secondary amine (RH not equal to hydrogen). The Boc protecting 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 amines C-v are then optionally crystallized or purified by chromatography.

8uW1TuTE8HEE(RLE WO 98/52940 WO 9852940PCTIUS98/1 0436 318 Scheme C-3 Step A 1) Base 2) Boc or Cbz.

Boc or Cbz 0 0H Step B 1) Base 2) 0 LjN-0 R 0 B66 Boc or

'RNH

2

NH

2 Boc or Cbz, N( StepOC RH Cv-Boc or Cv-Cbz

H

2 Pd-C, MeGH or TEA, CH 2

CI

2 Step

D\

nN-NH V8STU1MEE~T(RLU20~ WO 98/52940 PCT/US98/10436 319 The synthesis of scaffolds C-vi is accomplished as shown in Scheme C-4.

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 ranging from 1-24 h. Solvent is then evaporated and the resulting imine B69 is used in step B without further purification.

Step B: The pyridylpyrazole imine B69 is dissolved in THF and stirred under nitrogen at temperatures ranging from -78 to -20 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 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 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.

aUBIUTEEHtEET(UE) WO 98/52940 PCT/US98/10436 320 Scheme C-4 N-NBoc N-NHBoc Ph

R

2

NH

2 HCOPh RN R_ R 2 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

R2

NH

2 1 3 aF "RF R3 R C-vi The synthesis of maleimide-containing scaffolds C-vii is accomplished as shown in Scheme The maleimide pyrazole scaffolds C-vii are synthesized as depicted in scheme C-5. Condensation reaction of a primary amine H 2 N-R with a maleic anhydride 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 acetophenone derivative B72 in the presence of a Pd(0) V =161111 W 8 H M (R LUR i 06 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 hydrazine to afford the desired maleimide pyrazole scaffold C-vii.

Scheme

H

2

N-R

X 1. acid 0 2. acid anhydride (X is chloro, bromo, or triflate) X.

N-R

0 B71 0 A r k 0 B72 0 N-R Pd /base Ar

ON

73 B73 0 0 R4 O R4 B74 0 O or R4 O-N

O

NH

2

NH

2

N-NH

Ar R 4

O

N

0 R C-vii 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 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 SmBImUTE8HEET(RULE26) WO 98/52940 WO 9852940PCT/US98/1 Q436 322 Pd 2 (dba) 3 and sodium t-butoxide to f orm the f luoroacetophenone substituted maleimide B79. The B79 is treated with tert-butoxybis (dimethylamino)methane to yield the a-ketoenamine B80. The a-ketoenamine B80 is condensed with hydrazine to f orm the maleimide pyrazole skeleton B81. The 2, 4 -dime thoxybenzyl group protecting group is optionally removed with ceric ammonium nitrate (CAN) to give compound C-63.

Scheme C-6 OMe o OMe N OMe

H

2 Nz Br, 1. AcOH B 0 2. AC 2 0 0 OMe B77 B78

(CH

3 3 00CH[N(CH 3 2 2 OMe

NH

-ro

CAN

N

I

MeC 0

F

Pd 2 (dba) 3 NaOBu-t 0 OMe 0 o OMe N-

N-NH

F 0

NH

0 C-63

NH

2

NH

2 Scheme C-7 illustrates the synthesis of maleimidecontaining scaffolds C-64 and C-65. These scaffolds C-49 and C-50 are synthesized according to the general methods WO 98/52940 WO 9852940PCTIUS98/1 0436 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 2,4dime thoxylbenzyl groups with CAN and subsequent removal of the Boc-protecting groups with trifluoroacetic acid (TFA) affords the scaffolds C-64 and Scheme C-7 0 0 CMe 0 ~t-BocHN1)oN- I 0 N OMe 882 F 0 0 WOe or F 87 OMe B84 NHBC F B79 0 or N-o No" 0-Nj We t-Boc o 0 0 N 883 F 0 WOe

N.

885 Boc N-NH

N-NH

NH-BOG C NH 2 F0 1) CAN F /0 N TFA NH

N

N

H B86 0 OMe C-64 o MeO

N-NH

N-NH NH S N-BOC F 0 0 F 0NH N -NH 887 0 N\ OMe C-650 MeO &WFBTE8HEU(RULE2) WO 98/52940 PCT/US98/10436 324 The various functionalized resins and sequestrationenabling-reagents utilized to prepare and purify parallel reaction mixtures are more fully described below, including their commercial source or literature reference to their preparation.

B32 B33 B38 B48 B41 4-bel \/CHO Nova N H 2 Prep, N J. An

NH

2 Methy

N=C=O

cl O c\ 3 H3C CH3

CH

3 2N=C=enze

SO

2 N=C=O Aldrich nzyloxybenzaldehyde functionalized polystyrene.

tbiochem cat. #01-64-0182 ared as reported in D. L. Flynn et al, merican Chemical Society (1997) 119, 4874-4881.

ylisocyanate functionalized polystyrene.

biochem cat. 01-64-0169 Polymer bound EDC, prepared as reported by M. C. Desai et al, Tetrahedron Letters (1993) 34, 7685.

nesulfonylisocyanate, purchased from Chemical Company. Cat# 23,229-7 luorophthalic anhydride, purchased Idrich Chemical Company. Cat 33,901-6 8$HEE(RXE2) WO 98/52940 PCT/US98/10436 325 Experimental procedure for the parallel synthesis of a series of amides, carbamates, ureas and sulfonamides B- 0001 through B-0048 from scaffold C-1.

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 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 200 uL). A stock solution of each of the electrophiles was then added to the appropriate reaction 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 sulfonyl chlorides in dichloroethane. The parallel reaction apparatus was then orbitally shaken (Labline Benchtop orbital shaker) at 200 RPM at ambient 8sBrmE8HSEEr(Rua6) WO 98/52940 PCT/US98/10436 326 temperature (23-30 OC) 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 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 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 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.

The yields and analytical data for the products obtained using this method are shown below.

fiSm HET(RUL

E

WO 98/52940 PCT/US98/10436 Example# Calcd Observed %Yield Mass Spec Mass Spec Mass Spec (M+H) 8Stmt1ESHEET(LE-A WO 98/52940 WO 9852940PCT/US98/10436 328 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) B-0008 F 86 448 449 B-0009 F-Qi-ro 83 368 369 B-001 0 FQ 86 338 339 0 B-001 1 FJ I92 402 403 B-0012 IF 74 442 43 0 B-001 3 IF j 91 446 447 B-001 4 FQ~ ~84 352 353 B-001 5 F 94 380 381 B-0016 F- F 89 440 441 B-0017 F-Q 1 83 498 499 0 8=11MEMEET(PILLEN) WO 98/52940 PCT/US98/10436 Example# Observed %Yield MasSe Mass Spec Mass Spec(M+H) I\ I /NH 1 B-0018 F 24 439 440 B-0019 F/c 89 474 475 0c B-0020 IF c 90 440 441 B-0021 F 85 386 387 B-0022 FQ35 417 418

N

B-0023 F 94 397 398

OO

B-0024 IF 87 417 418 B-0025 F- o 5-354 0 B-0026 FoF 87 426 427 B-0027 F 89 350 351 0 a6mUTESfEt(FMA.E2) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) B-0028 FQ1 92 456 0 B-0029 IF 89 428 429 B-0030 IF 37 498 499 B-0031 F Q 18 407 408 0 B-0034 92Jt 4 646 463 o0 B-0036 F-0 0 92 446 447 00 -1-T=8HEU(RME2M WO 98/52940 PCT/US98/I 0436 Example# Calcd Observed %Yield Mass Spec Mass Spec MassSpec

(M+H)

i~ 00r- 96 3 B-0038 F 84 390 393 B-0039 I F 87 402 403 00 B-0040 F9! 92 416 417 0 B-0041 i-fy'^V 75 444 445 0 B-0042 F 1 54 390 391 0 B-0043 F ll)K. 80 396 397 I 0 o B-0044 Q 81 310 311 0

F

-F

B-0045 N" 91 408 409 CF 3 B-0046 F- CF 2 25 464 465 B-0047 F J) 88 430 431 o0 ME8NEErgRUlE) WO 98/52940 WO 9852940PCT/US98/1 Q436 Example# Calcd. Observed %Yied Mss pecMass Spec %Yie~ MassSpec (M+H) B-0048 95 414 415 u~wf=$W(VPJL2) WO 98/52940 WO 9852940PCT/US98/1 0436 By analogy to the procedure identified above for the preparation of Examples B0001-B0048, the following examples B-0049 through B-1573 were prepared.

s~Wn~rEFri

V

WO 98/52940 PCT/US98/I 0436 334

N-NH

I NHRJ

N

Example#

R

2 %Yed Calcd. Observed R Rj YieldMass Spec Mass Spec

(M+H)

GWMWMWW(RJLE2M WO 98/52940 WO 9852940PCTIUS98/1 0436 335 Example#t 2 Calcd.Observed R j%Yield MasSc Mass Spec MassSpec(M+H) sI Ffu2E8Hwqr(RLEf%9A WO 98/52940 PTU9/03 PCT[US98/10436 336 Example# %Yild Calcd. Observed %YedMass Spec Mass Spec

(M+H)

I T E8-0066 F 0 89 351 8-06 F- 92 386 387 0 6-008 F'"6 89 432 433 0 B-0069 F i 1K1 37 390 391 B-0070 F18 432 433 B-0071 F 0 64414 B-0072 IF0 13 432 433 0 6-07 FQ00~B 92 450 451

F

8-07 Foj 28 390 391 B-0075 o 0\I 93 402 403 Vj3STff=%fEr(RULE26) WO 98/52940 WO 9852940PCT/US98/10Q436 337 Example# 2Yel Calcd. Observed R R %ield Mass Spec Mass Spec

(M+H)

SWnUFESNEET (RuLEs) WO 98/52940 PCTIUS98/1 0436 Example# %Yild Catcd. Observed %Yed Mass Spec Mass Spec

(M+H)

GI WO 98/52940 WO 9852940PCTIUS98/1 0436 339 Example# %Yild Calcd. Observed %Yed Mass Spec Mass Spec

(M+H)

.11,,EEV13LEm WO 98/52940 PCT/US98/10436 340 Example# Cac.Observed %Yield asSpe Mass Spec %Yiel MassSpec (M+H) 'IPA I-E 26) sionmew V WO 98/52940 WO 9852940PCT/US98/1 9436 Example# 2 Calcd. Observed R R %Yield MascSpe Mass Spec MassSpec (M+H) B-01 04 F- 59 426 427 0 B-01 05 F- IS- 79 360 361 0 -0 0 B-01 07 F S 33 346 347 B-01 013 1 6 467 B-01 09 IF-Q 65 450 451 L 0 B-01 11 F i I 41 458 459 8-01 12 F 19 467 468 0 N? B-01 13 F 78 453 454 $=Ill SHMT~(RLU26) WO 98/52940 WO 9852940PCT/US98/10436 342 Example# 2 Calcd. Observed R Rj%Yield MascSpe Mass Spec MassSpec (M+H) IHE RI8), WO 98/52940 WO 9852940PCTIUS98/10436 Example# 2 Calcd.Observed R Rj%Yield MascSpe Mass Spec MassSpec(Mi-H) B-0124 IF-Q-- 11\ 87 456 457 B-01 25 F- -,45 472 473 B-0126 F. 100 476 477 B-01 27 \-SN 100 433 434

CN

B-01 28 IF10 48- 0

C

0 B-01329 F- 93 48 469 00 B-01 30 IF-Q-- D 90 468 469 0- B-0l 32 JF-, 78 436 437 B-01 33 :Fo I- 76 426 427 11 &WUBTESEE(RULE26) WO 98/52940 WO 9852940PCT[US98/1 0436 Example#

R

2 Yi~d Calcd. Observed R RjYild Mss pecMass Spec MassSpec(M.H) B-0134 IF-Q- 87 444 445 0 B-0137 IF 35 480 481 B-01 38 IF-y- i 60 500 B-01 39 F 73 585 586

I\%

-0 0 B-0141 F-o 100 483 484 B-0142 F0 10 90 444 445 B-0143 F~ 61 492 49 0~ 0 SUDSMUTSHEET (RULE6) WO 98/52940 WO 9852940PCT/US98/I 0436 345 Example# 2 Calcd.Observed R Rj%Yield Mas Spe Mass Spec MassSpec (M+H) JBflhJ1ESEU (RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 346 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) B-0145 48 433 434 6-14 ~\XNH32 415 416 B-0147 T 67 471 472 B-1879 465- B-1 9 F65 353 354 B-0 50 53 465 466 6-11 F68 401 402 &,EU(F:ULE26) WO 98/52940 PCT/US98/10436 347 Example# Calcd. Observed Calcd. M s S %Yield Mass SpecMass Spec Mass Spec

(M+H)

B-0152 F-o 39 383 B-0153 F 96 427 428 B-0154 F- 44 459 460 B-0155 74 479 480 B-0156 F 44 459 460 B-0157 F- 72 415 416 B-0158 FN 96 445 446 0 B-0159 F 97 411 412 B-0160 F 49 417 418 B-0161 F- o I 93 459 460 8UBSlTUTE8HEET(RULE26) WO 98/52940 WO 9852940PCTIUS98/1 Q436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) B-01 62 91 405 406

CN

o B-01 63 -I 94 455 456

H

C11 B-0164 F 84 455 456 B-0165 'F2 41 1 B-0166 IF HN> 72 417 418 B-01 67 1F \7 66 447 448 B-0168 IF-Q- 27 415 416

H

B-01 69 IF-) 91 415 416 B-0170 IF Q 'J'N T 8 351 352 [B-01]71 437 438 Ili-wi EEl 81(RULEs) WO 98/52940 WO 9852940PCT/US98/I 0436 Example# Calcd. Observed %Yied Mss pecMass Spec %Yiel MassSpec (M+H) B-01 72 F I 62 471 472 B-0173 F, 40 455 456 B-07 92 405 406 B-0175 96 387 388 B-0176 NH 25 415 416 B-0177 1 100 397 398 B-01 78 34 429 430 B-01 79 72 429 430 B-01 80 F0 1 0 N91 463 464 B-0181 F100 463 464 P U-I ItSHEUr(RULEM WO 98/52940 PCT/US98/10436 350 Example# Calcd. Observed a c Mass Spec %Yield Mass Spec (M+H) B-0182 F- 50 447 448 _B-01 83 F< c 22 455 456 B-0184 63 465 466 B-01 85 jF-Sj I 65 471 472 B-0186 IF I 42 429 430 B-0187 F 62 481 482 B-0188 F 98 439 440 B-0189 F 21 453 454 B-0190 F 57 417 418 B-0191 F 1 24 477 478 WLflESHEET(RULE2e) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec

(M+H)

IJ~LUTESHEET(ffJLI WO 98/52940 WO 9852940PCTIUS98/1 0436 352 Example# Cac. Observed %Yield Cac. Mass Spec .Mass Spec

(M+H)

B-01 93 42 378 379 0 B0194 65 365 366 B-0195 !F Q~ Lo~ 93 587 588 0 B-0197 F-Q 0100 587 588 B-0198 IF-Q- 86 373 374

N:

B-0199 IF 81 373 374 0 WO 98/52940 PCT/US98/10436 353 Example# SCalcd. Observed %Yield MasSe Mass Spec MMssSpec MassSpec(M+H) B-0200 IF 78 373 374 0 B-0201 IF Q 95 352 353 B-0202 F O 100 416 417 B-0203 F 69 354 355 B-0204 IFo 93 340 341 B-0205 F o 94 354 355 B-0206 IF 79 424 425

L/

8-0207 F-0 1 0 82 326 327 B-0208 F 88 378 379 0 0-20 F83 362 363 0 SUBfl1UTES11EEr(RuLE~) WO 98/52940 PCT/US98/19436 Example# Observed %Yield MasSe Mass Spec Mass Spec (M+H) B-0210 F- CF 100 364 365 B-0211 F NH 60 325 326 B-0212 F 79 339 340 B-23 H71 353 354 B-0214 F N2 77 311 312 B-0215 N 24 353 354 B-0216 ~339 340 B-27381 382 0 0 B-0219 FNH--- 401 402

SUBWUSHEET(RUEW

WO 98/52940 WO 9852940PCTIUS98/1 0436 355 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec

(M+H)

~~5gr1TLrFE6H~Er (RULE 26) WO 98/52940 PCT/US98/1 0436 Example# Observed %Yield MasSe Mass Spec Mass Spec M+H) B-0220 96 486 487 B-0223 F 100 465 466 B-0224 IF-Q %0 486 509a B-0225 F\ 100 442 443

I

B-0226 IF- i 0 11 >!W 88 482 483 0 B-0227 73 482 483 1 0 37 452 ~awgUTEBiEEr

(R$LEI)

WO 98/52940 PCTIUS98/1 0436 Example# Observed %Yield MasSe Mass Spec Mass Spec(M+H)

CI

B-0229 F -D

L

0 \c 100 476 477 0 11 B-0230

F

CI 94 476 477 C1 B-0231 F1 0 100 460 461 B-0232 Fa' S 0 F 90 440 441 C1 B-0233 F C 99 476 477 Br B -0234 F II 100 486 487,489 0 B-0235 !F O -O 0 B 89 486 487,489 B-01236 F--0 0 Q C5 100 476 477 B-0237 I 100 476 477 B-0238 F- 0 92 438- SW1=Sr8HEET WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac. Observed %Yield Mas Spe Mass Spec MassSpec (M+H) B-0239

S

o I 100 442 443

CI

B-0240 F-0 /1 100 442 443

CI

B-0241 1F-(

S~.

0\f~ /ci 100 476 477 B-0242 JF-0

F

100 460 461 B-0243 iF 111 0 87 456 457 B-0244 F \0 100 436 437 B-0245 S 100 422 423 0 0 B-0247 F- S~/F 100 476 477 1 73 1 468 1 SUBS=MWEET(RULE26) WO 98/52940 PCTIUS98/1 0436 359 Example# Observed %Yield MasSe Mass Spec Mass Spec(M+H) \Br B-0249 F I Q 100 516 517,519 0 72 458 B-0251 IF 11 0 100 427 428 I N-0 100 450 451 i sI~ B-0253 F-Q Ss 0 C, 100 472 473 B-0254 'F 100 433 434 I0 84 547 548 0 B-0256 0 100 484 507a B-0257 F- 0I\/ 534 535 1 100 1491 492 SOwMMSH(EE(RAZ) WO 98/52940 PCTIUS98/10Q436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) B-0259 F~ OR 100 554 555 B-0260 F S1 0 S" 91 500 501 B-0261 JF s N 0 100 54 555 0 B-0262 F-i( I 0171 459 460 B-0,263 100 54 413

&WM=&WUTEHERM~EM

WO 98/52940 WO 9852940PCT/US98/1 0436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) 6-0267 100 386 387 0 01 B-0268 IFQ-.-1 9 40 407 0 B-0272 N'57 498 499 B-0273 100 440 441 C1i SLaSmlJFESHEET(RuLEM) WO 98/52940 PCTIUS98/1 0436 362 2 Calcd. Observed Example# R R %Yield MascSpe Mass Spec MassSpec (M+H) SHELT(RAE26) WO 98/52940 WO 9852940PCT/US98/I 0436 Example# Cac. Observed %Yield Cac. Mass Spec Mass Spec

(M+H)

B-0284 CFF 100 458 459 0F B-0285 iF -CF 3 94 458 459 0 CF 31 B-0286 IF 100 458 459 0 B-0287 iFQ. F 96 458 0 CF 3 B-0288 100 458 459 C1 B-0289 96 406 407 B-0290 IF-Q- I 96 386 387

CI

B-0292 IF~94 390 391 B-0293 100 408 409 F E-Co0 S$W8TFESTE(RULEM) WO 98/52940 WO 9852940PCT/US98/1 0436 Example# Calcd. Observed %Yield Mass SpecSe MassSpec (M+H) C1 BN029 100 440 441

C,

B-0295 F 91 408 409 o F B-0296 ~96 426 427

F

B-0297 88 390 391

F

B-0298 IF-Q-- 95 408 409

F

B-0299 IF F~90 408 409 B-0300 FN' 95 406 407 B-0301 F 99 450 451,453 B-0302 T -O CF 3 94 440 441 0 B-0303 S100 378 379 Slit 11TU1E8HEEr(RLA.E2M WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) 8Le81UuE&WE~(RALEAQ) WO 98/52940 WO 9852940PCTIUS98/1 0436 360' Example# Cac. Observed %Yield Mas Spe Mass Spec MassSpec (M+H) B-0305 i 70 326 327 B-0306 -59 340 341 C1 B-0307 59 354 355 B-0308 60 368 369 B-0309 I P30 61 352 C1 B-0311 65 356 357 L -0 "Ju E 2 WO 98/52940 WO 9852940PCTIUS98/1 0436 367 2 Calcd.Observed Exampl# R R%Yield MasSc Mass Spec Examle#R 2 Mss pec(M+H) SBI11UTEBHEUT(RULE26) WO 98/52940 WO 9852940PCT/US98/I 0436 Example# %Yield Calcd.

Mass Spec Observed Mass Spec

(M+H)

&BN1UTEBEUE(RULEs) WO 98/52940 WO 9852940PCT/US98/I 0436 369 Observed Example# R2R%Yield Calcd. Mass Spec Mass Spec

(M+H)

8UBnrrE8EW(RULEN) WO 98/52940 PCTIUS98/10436 370 Example# Cac. Observed %Yield Mascdpe Mass Spec MassSpec (M+H) WO 98/52940 WO 9852940PCT/US98/1 0436 371 2 Calcd.Observed Example# R j%Yield MasscSpe Mass Spec MassSpec

(M+H)

suen~rqsEW(XuLE2-) WO 98/52940 WO 9852940PCTIUS98/1 0436 N -NH

N

R 2 NR CH3 Example# Cld Observed %Yield Cac.Mass Spec Mass Spec

(M+H)

B-0353 71 382 383 B-0354 F~35 512 513 B-0355 IF 37 352 353 B-0356 57 404 405 B-0357 Q- iK88 366 367 B-0358 088 410 411 B-0359

F-

a1 324 324 325 AllW q TW,

EET(RULEE

WO 98/52940 WO 9852940PCT/US98/1 0436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M.H) B-0360 F56 364 365 0 B-0361 \70 350 351 0 B-0362 iBr 100 464 465 0 B-0363 F- 73 512 513 B-0364 88 377 378 B-0365 1F-Q- 70 396 397 B-0366 100 354 355 0' B-0367 F-0 71 416 417 B-0369 FF 40 440 441 0 a~Ms=E(ffjLE2M WO 98/52940 WO 9852940PCT/US98/10436 374 Example# CcdObserved %Yield d' Mass Spec %YedMass Spec

(M+H)

B-0370 F94 364 365 0 B-37 88 460 461 0~~ B-0372 F1 0 6 430 431 B-0373 100 430 431 0- B-0374 F75 400 401 B-0375 F 74 386 387 0

N

B-0377 1~ 71 387 388 0 B-0378 F~ 69 387 388 B-0379 F 66 387 388 am*fWT8Er TRULE2M WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Calcd. Observed %Yied Mss pecMass Spec %Yie~ MassSpec (M+iH) B-038 1 K, 85 416 417 0 B-0381 93Q~-~ 430 431 0 B-0382 IF 84 382 383 B-0383 ILF-0 74 583 584 B-0384 F 63 438 439 W~11 OWE(RULEgM WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) B-0385 IF 83 440 441 B-0386 IF99 422 423 0 B-0387 IF-Q S 47 388 38 0 0 B-0389 IF 71 436 437

F

B-0390 IF-Q F 100 458 459 0 B-0391 IF-scF 45 414 415 SUBSflTESHEEr (RULE26) WO 98/52940 WO 9852940PCT/US98/1 0436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M.H)

F

B-0392 F 100 440 441 1 0 B-0393 F75 388 389 0 B-0394 JF- 87 34 43 0 B-0396 JF-0-s 816 360 361 0 B-0397 T 81 452 453 6-39 FK=~1 ii88 428 429 0 B-0399 FlI /99 436 437 0 5-0400 F 82 482 483 0- B-0401 F0 IK- 94 367 368 q8UBSrm=9ET(RULE%) WO 98/52940 PCT/US98/1 G436 Example# Observed %Yield Calcd Mass Spec Mass Spec (M+H) B-0402 73 325 326 NH- 2 B-0403 F91 415 416 00 B-.04a pu 41 379 380 B-0405 Fyj V-r 88 395 396 I0 F-Q- 100 419 420 L i

IF-

B-0407 IF V 1 N$ 52 353 354 B-0408 Q83 339 340

N

H

B-0409 74 415 416 B-0410 100 419 420

H

B-0411 94 429 430 SuEBIInEsMHEEr (RUE2) WO 98/52940 PCT/US98/10436 379 Example# SObserved %Yield MaS Mass Spec Mass Spec (M+H) B-0412 F- j 7 91 365 366 0

H

B-0413 F s.7 79 367 368 i H"9 429 430 B-0414 F O0. 85 429 430 o0

H

N

B-0415 F- 82 401 402 0 B-0416 IF- 93 429 430 H- 7\ B-0417 IF-Q H IJ 97 429 430 B-0418 F 100 419 420 B-0419 100 431 432 B-0420 F 36 381 382 B-0421 F- 7 N 96 353 354 0 sL~mUrESHEEr (RULE WO 98/52940 WO 9852940PCT[US98/10436 380 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) B-0422 100 461 462 B-0423 IF 1 100 406 407 B-0424 F- ~76 366 367 B-0425 21 368 369 1-0026 I 0 0 5 B-0426 IF-Q 100 379 380

HN

T0.

0 SUB==%EET(RJLE26) WO 98/52940 WO 9852940PCT/US98/1 0436 Example# Calcd. Observed %Yied Mss pecMass Spec %Yiel MassSpec (M+H) B-0430 IF 51 500 501 B-41 F76 479 480 Br B-43 I Q~ S 1I 90 500 501 B-0433 iFQ-: C 96 456 B-0434 0 75 496 497 B-0435 1F Q 52 496 497 0 B-0436 0 7 506 &g~nfuTSHEff(KLE* WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac.Observed %Yield asSpe Mass Spec %Yiel MassSpec (M+H) B-0437 19 466 B-0438 FKj I 100 490 491 0- 67 464 465 B 0 4 3 9_ F S 07 B\0/4\ 96 472 473 B-0441 F- 87 472 473 B-0442 F-72 481 482 B-0443 F~ 66 473 474 B-0444 F- 80 515 516 B-0445 F -Q 94 490 491 a B-0446 F84 464 465 0 aSU=%E(RULE-E6) WO 98/52940 WO 9852940PCTIUS98/1 0436 383 Example# Cac. Observed %Yield asSpe Mass Spec %Yie~ MassSpec (M+H) B-47 89 470 471 0 0 C1 B-0448 F100 490 491 C1 B-0449 l100 474 475 B-0450 IF-L 100 447 448 B-0451 F j j \100 454 455 B-0452 IF Q 95 496 497 Ci B-0453 100 490 491 0 B-0~454 11ii 100 So0 501 Br B-0455 F 2 96 500 501 0 B-0456 F 089 494 495 0 SU9BfUTEGHEEr(RLE2M WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) F0 I 93 482 483 B-0458 IF 100 490 491 B-0459 F 100 490 491 SUBWfTUTE8HE7r(RLEs6) WO 98/52940 WO 9852940PCTIUS98/ 0436 Example# Cac.Observed %Yield asSpe Mass Spec %Yie~ MassSpec

(M+H)

s lTUTEBHE t (BLE WO 98/52940 PCTIUS98/1 0436 386 2 Calcd. Observed Example# R R %Yield MascSpe Mass Spec MassSpec (M+H) VJB9rMAE8HEU(RA.E2M WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# CcdObserved %Yield d" Mass Spec %YedMass Spec

(M+H)

8U8It HEETUE WO 98/52940 WO 9852940PCTIUS98/1 0436 388 2 Calcd. Observed Exampl# R CaYiel Mass Spec Exaple R 2 %Yild Mass Spec (MH) SUBSW TUWsHE7(F0JLE26) WO 98/52940 PCTIUS98/10436 Example# Observed %Yield MasSe Mass Spec Mass Spec(M+H) B-04921F ''89 400 401 0 B-0493 IF 100 420 421 B-0494 F Q--i100 400 401 0 B-0495 I F CF 3 100 454 455 B-0496 IF S 100 442 443 B-0497 j o50 512 513 B-0498 I Z 100 454 455 0C1 &J8s8fUlMUHEERULE1 WO 98/52940 WO 9852940PCTIUS98/1 0436 .390 Example# Cac. Observed %Yield asSpe Mass Spec %Yieci ass pec (M+H)

CN

B-04919 98 411 412 B-0500 F-I--I100 436 437 B-05C0l ~F 100 422 423 B-0502 F- F 100 422 423 IIF

F

B-0503 IF- 92 440 441

F

C,

C

B-0504 F67 454 455 0 B-0505 FQ.- 68 428 429

CF

3 B-0506 F-C 98 472 473 o F

F

B-57 I 82 440 441

CF

3 B-0508 F 99 472 473 0 ag~MiTE8HErt(RA.E2) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac.Observed %Yield asSpe Mass Spec %Yie~ MassSpec (M+H) 0 B-0509 100 472 473 0F B-0510 Nt CF 3 96 472 473 0 B-051F F3C B-51100 472 473 0 B-0512 F~ 100 472 473 B-0513 0 4 L 3 100 472 473 B-54 F- 100 420 421 B- 5 5 F Q 100 400 401 F-51 F 100 454 455

F

B-0517 100 404 405 B-0518 F0 N 99 422 423 yjU=&E&7PAE)M WO 98/52940 WO 9852940PCTIUS98/1 0436 392 Example# Cld Observed %Yield Cac.Mass Spec Mass Spec

(M.H)

C1 B-0519 N/ 100 454 455 0

F

B-0520 IF- 1 98 422 423 0 F

F

B-0522 IF 99 44 441

F

B-0523 IF Q 100 422 423 0 L F B-54IF-KI--- C F 100 422 423 100 420 421 Br B-0526 F- 100 464 465 B-57CF 3 100 454 455 B-0528 S100 392 393 GJ~L1UTE8HEff(RLLE9) WO 98/52940 WO 9852940PCTIUS98/1 0436 393 2 Calcd.Observed Example# R j%Yield masSc Mass Spec MassSpec S W~JTE V (RULE 26) WO 98/52940 WO 9852940PCTIUS98/I Q436 Example# Cac. Observed %Yield Cac. Mass Spec Mass Spec

(M+H)

0 B-0530 0 67 382 383 0 B-0531 IF66 512 513 0 B-0533 IF-Q- 56 404 405 B-0534 100 366 367 B-0535 IF-Q 0 100 410 411 B-0536 F QI 0 325

SUBSMMSHEU(P"N)

WO 98/52940 WO 9852940PCTIUS98/1 0436 ~395 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) B-0537 F100 364 365 0 B-0538 F29 350 351 B-0539 IF 70 464 465 0 B-0541 F- 61 377 53 0 B-0542 FV61 396 397 B-0543 F59 354 355 B-0544 45 416 417 B-0545 F 100 454 455 B-0546 F0 44F 440 441 8"UITUEWT(RULEM) WO 98/52940 WO 9852940PCTJUS98/10Q436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) B-0547 64 364 365 0 B-0548 089 460 461 B-0549 100 430 431 B-0550 jF- 1 100 430 431 0 0-1 B-0551 IF- 81 400 401 B-0552 IFQ-- 38 386 387 B-0553 IF- 31 378 379 B-0554 100 387 388 B-0555 66 387 388 B-0556 IF-0 32 387 388 L I 0 SJ6BnUnE8HEEr(RULE~) WO 98/52940 WO 9852940PCTIUS98/1 0436 397 2 Calcd. Observed Example# R R %Yield MascSpe Mass Spec 8UBJ1E8HE~r wlE WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac. Observed %Yield Mas Spe Mass Spec MassSpec (M+H) B-0562 IF- 88 440 441 0 1-53 i Q 68 422 423 -0 B-0565 IFQ-- -~100 448 449 0 B-0568 I4 -C 3 45 414 415 S -Cl3 0_

OLWOMSHEU(MAEM

W;O 98/52940 PCTIUS98/1 0436 399 Example# Calcd. Observed %Yield Mass Spec Mass Spec(M+H) B-0569 11 88 440 441 I, B-0570 FQ61 388 389 0 B-0571 -1 58 402 403 0 0 i 1II B-0572 75 74 37 73 72 360 361 B-0574 I /97 452 453 lo B-0575 71 428 429 I I 0 B-0577 F 72 482 483 B-0578 89 367 368 L I l H 1 1 1 I 8aqmWffEMiG.E(RLE" WO 98/52940 WO 9852940PCT/US98/1 0436 400 Observed Example# R i%Yield Calcd. Mass Spec SJ9S~hESHEETRUAMA WO 98/52940 PCTIUS98/10 436 Example# Observed %Yield MasSe Mass Spec Mass Spec(M+H) B-0589 F -78 365 366

H

B-0590 F/y 82 367 368 B-0591 IF H 72 429 430

H

B-0592 F0 N 82 401 402 B-0593 F 88 429 430 B-0594 1F 100 429 430 0 B-0595 F ~99 419 420 B-0596 F 93 431 432 B-0597 F\ 7 I 40 381 382 B-0598 F 93 353 354 8snrfE8HMT(RLfEE(J WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Calcd. Observed %Yield Mass SpecSe MassSpec (M+H) B-0599 F*c* 100 461 462 B-0600 98 406 407 Of B-0601 66 366 367 B-0602 F 25 368 369 B-0603 IF- r- 90 354 355 B-0604 F86 379 380 B-0605 Q N87 379 380 B-0606 72 368 369 SUaS~frma88wr(RE26) WO 98/52940 PCT/US98/1 0436 403 Example# Calcd. Observed %Yield Mass Spec Mass Spec

(M+H)

B-0607 IF 34 500 501

H

00 B-0608 IF 100 479 480 B-0609 iF Q 82 500 501 0 B-0610 CiF-)- sC1 100 456 457 0 0 B-0612 IF 69 496 497 SI 0 C1 B-0613 IF61 506 aruBffTswHETr(REm WO 98/52940 WO 9852940PCTIUS98/10436 404 Example# Cac. Observed %/Yield MascSpe Mass Spec MassSpec (M+H) B-0614 18 466 0 B-0615 F-IP- 100 490 491

C,

B-0616 77 464 465 B-0617 F 93 472 473 B-0618 1F 0 84 472 473 B-0619 IF- 1 71 481 482 00 B-0620 IF- SN-- 89 473 474 B-0621 IF-Q 68 515 516 CI C B-0622 II/ 70 490 491 0 0 SaUrflT1MMEr(RLM) WO 98/52940 WO 9852940PCT/US98/1 0436 405 Example# CldObserved %Yield d* Mass Spec %YedMass Spec

(M+H)

-0- B-0624 98 470 471 0 B-0625 IF-I\ 96 490 491 C1 if' FT B-0626 1F 100 474 475 B-67 F 100 447 448 B-0628 IF /64 454 455 0 C1 B-0629 F 100 496 497 B-63 85 490 491 B-0630 3 0 0 B-0631 IF 7 /05 494 &g88f=&TEffET(RULW) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac.Observed %Yield asSpe Mass Spec %Yiel MassSpec

(M+H)

B-0634 IF H 63 482 483

CF~

B-035 95 490 491 B-6 6 I -100 490 491 SU8"TUTE8HEE(RLUW WO 98/52940 PCTIUS98/1 0436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) B-0637 ;F I 91 450 451 0 0 B-0638 I 96 436 437 B-0639 F 100 456 457 B-0640 -o 100 456 457 0 i

C,

I 88' 49-9 B-0641 -0 1 B-62 I l099 490 491 B-\43/ 92 474 475 ow(SaJLm WO 98/52940 WO 9852940PCT/US98/I 0436 408 Example# %Yied Cacd.Observed Mase s Scd Mass Spec MassSpec (M+H) B-0644 I 10 47 7 B-0645 FIP 92 450 451 B-0646 11/ 100 436 437 0 B-067 9 46 46 0

CF

3 i B-0648 IF-S 94 490 491 0 B-0650 F -EUZ5 462 46 0 B-0651 0 100 530 531 B-0652 53 472 0 B-0653 F-Q- j 84 441 442 GUBSfUTE8HET (RULE* WO 98/52940 WO 9852940PCT/US98/I 0436 409 Example# Cac.Observed %Yield asSp. Mass Spec %Yie~ MassSpec (M+H)

N

B-0654 F 4 1 92 464 465 0 B-0655 IF-Q--1 100 486 487 B-0656 98 447 448 0 B-0657 F 11 85 561 562 B-0658 92 498 499 B-0659 F-IP 0% 46 548 549 0 U B-0660 IF I I80 505 506 B-0661 F-0 100 568 569 B-66 FN 98 495 496 0 B-0663 F- 74 426 427 SLBffM%(WPAEM WO 98/52940 WO 9852940PCT/US98/I 0436 410 Example# Cac.Observed %Yield asSpe Mass Spec %Yiel MassSpec (M+H) B-0664 IF S N30 389 390 B-0665 F100 568 569 B-0666 93 500 501 B-0667 F 54 473 474 B-0668 66 514 515 SU6Ml1TEHEET(RUES) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac. Observed %Yield asSpe Mass Spec %Yiel MassSpec (M+H) 6-66 N/ 65 400 401 0 B-0670 IFx 45 420 421 0 B-0671 43 400 401 01 B-0672 i CF 3 45 454 455 B-073~ S41 442 443 B-0674 6-074F---- ~(I16 512 513 0 6-0675 IF- C 39 45 455i I 0: 8tJBTn.)TSHEr(RLE 26) I 1.

WO 98/52940 WO 985294PCTIUS98/ 0436 412 Example# Calcd. MasseSpec %Yield Mass SpecH SUB~nrTE8 IEfr (RULE 26) WO 98/52940 WO 9852940PCT/US98/1 0436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) 0- CF 3 B-0686 F 66 472 473

OF

B-0687 j CF 3 57 472 473 0 B-0688F F3/1 B-6852 472 473 0 B-0689 F- C j 42 1472 473 0 CF 3 B-0690 F 472 473 C1 B-0691 52 420 421 B-0692 F 41 400 401 B-69 FCI 56 454 455

-F

B-0694 38 404 405 B-0695 I 43 422 423 $U88rTIf=E9~Er(RUL20) WO 98/52940 WO 9852940PCT/US98/1 0436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+iH) C1 B-0696 F- CI 57 454 455

F

F

F

B-0698 59 440 441 0 F B-0699 F 46 404 405 B-0700 IFQ 47 422 423 0

F

F1 B-0701 46 422 423 B-0702 IF-N' 43 420 421 B-0703 F- Br 57 464 465 B-0704 F- -F 44 454 0 SuBrrTfaHEWr(RLE 26) WO 98/52940 WO 9852940PCTIUS98/10436 415 Observed Example# R 2 R%Yield Calcd. Mass Spec Mass Spec

(M.H)

N_

I B-0706 IF35 405 406 SUB~UTE SHRET (RUE26) WO 98/52940 WO 9852940PCTIUS98/10f436 416 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+eH) 0- B-0707 F-Q 76 516 517 B-0708 F-0 61 498 499 B-0709 F11--~ 37 464 465 0 B-071 0 F- 76 524 525 0 B-0711 j 0 i 7 512 513 0

F

B-0712 F S- F 91 534 535 0 7 B-0713 F- 42 490 491 $UBBffTUTE$HEM(RLEs WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cae.Observed %Yield asSpe Mass Spec %Yiel MassSpec (M+H) B-0714 F 1 U 87 516 517 0 0 B-0715 IF-Q 65 46 437 0 0- 0 B-0719 F86 504 505 0 B-0720 63 512 513 0 B-0721 F- 68 558 559 0 B-0723 F 68jL4468444

LH

8UBSTffMTSWE-r(RULE26) WO 98/52940 PCTIUS98/10436 418 Example# Observed Calcd.MasSe %Yield Mass SpecMass Spec

(M+H)

B-0724 F 75 401 402 NH 2 B-0725 F>83 491 492 B-0726 Fo 24 455 456 B-0727 F- O 67 471 472 0 B-0728 H F 89 495 496 B-0729 F 38 429 430 0 B-0730 F 76 415 416

H

B-0731 F 60 491 492 B-0732 F 86 495 496 B-0733 F-0 K 81 505 506 0 8BT~UTESHEET(RULE26) WO 98/52940 PCTIUS98/1 Q436 419 Example# Observed Calcd. Mass Spec %Yield Mass Spec (M+H) B-0734 F- 87 441 442

H

6-0735 I 83 443 444 B-0736 F-0 6 H 91 505 506

H

6-0737 F -0 9 477 B-0738 87 505 506 B-0739 N/ 82 505 506 B-0740 F0 85 495 496 6-0741 F-0 68 507 508 B-0742 F-(Q 14 457 B-0743 F NH 77 429 430 SU6S11TUE6~ffEt(RUL&EB) WO 98/52940 PCT/US98/1 0436 420 Example# Observed %Yield C Mass Spec Mass Spec (M+H) B-0744 F-i 86 537 538 B-0745 F- 82 482 483 Of B-0746 IF 74 442 443 B-0747 F- Q 83 444 445 B-0748 IF- 94 430 431

HN

B-0749 iF i. 100 455 456 I ii B-0750 F- N 100 455 456

H

B-0751 F I 48 444 445 01bI ,qjBmSTrCESET (RULEs) WO 98/52940 WO 9852940PCTIUS98/1 0436 421 1 N-NH I

NH--

R2

N

Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) B-0752 \I/F 84 516 517 0 B-0753 I F- 1 67 498 499 0 B-0754 S31 464 465 0 0 B-0755 F 85 524 525 0 1 B-0756 FI 77 512 513 B-0757 F Vsb 7 57 534 535 0 0 suBsnuTEHE~rUL 26) WO 98/52940 WO 9852940PCT/US98/1-0436 422 Example# Calcd. Observed %Yield Mass SpecSe MassSpec (M+H) F -0 B-0759 IF 79 516 517 0 0 B-0760 50 478 479 0 B-0761 IFQO J-s- 6! 0 450 451 0 B-0762 JF-Q9-- 756 436 437 B-0763 F 43 528 529 0 0 B-76 IF B-76 I 75 512 513 0 B-0766 IF 67 558 559 IF/ 0 B-0768 F- 0- 78 443 444 VJWTM&-E1--7(RULE26) WO 98/52940 WO 9852940PCT/US98/1 0436 Example# Cld Observed %Yield *acd Mass Spec Mass Spec

(M+H)

-0 B-0769 76 401 402 NH 2! B-0770 F~j- 57 491 492 B-0771 F /\N14 455 456 B-0772 72 471 472 'KY B-0773 jF -100 495 496 7-00 0 B-0774 IFQ~N 41 429 430

N

B-0775 F 91 415 416

N'

B-0776 F F 64 491 492 I I B-0777 90 495 496

H

N-78 19 505 506 1 0 S1T=JESHET (RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac.Observed %Yield asSpe Mass Spec %Yiel MassSpec (M+H) B-0779 IF-jP 79 441 442 B-0780 F I H40 443 444 B-0781 IF 411" 93 505 506

H

B-0782 477 478 0 B-0783 99J--- 505 506 B-07134 505 506 B-78 92 495 496 B-78 91 507 508 B-0787 ~1 15 457 458 B-0788 IFQ 48 429 430 W=WME7 (RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 425 Example# Ccd Observed %Yield *acd Mass Spec Mass Spec (M+H) B-0789 !F 91 537 538 B-0790 IF-\ 93 482 483 B-0791 1F- 76 442 443 B-0792 FQ 96 444 445 B-0793 IF Q IV f' 54 430 431 B-0794 IF 100 455 456 B-0795 FQ.- N 100 455 456 B-0796 IFQ-- 094 444 445 SUUffSnusHM(RQL~-fi) WO 98/52940 WO 9852940PCTIUS98/1 0436 426 Example# Calcd. Observed %Yield Mass Spec Mass Spec

(M+H)

SMEEr (RULE WO 98/52940 WO 9852940PCT/US98/1 0436 427 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) B-0804 F87 440 441 B-0805 1F100 426 427 B-0806 Br 9 540 541 B-0807 1F 96 588 589 0-

N

B-0808 182 453 454 0 B-0809 IF 92 472 473 0 F-81 98 430 431 B-0811 88 492 49 B-0812 F.4 I 81 530 531 B-081 98P 516 517 L0

F

VuBnwR=%w~r(RULE26) WO 98/52940 WO 9852940PCT/1JS98/1 0436 428 Example# Cac.Observed %Yield asSpe Mass Spec %Yiel MassSpec

(M+H)

B-0815 0 I 100 536 537 0 B-0817 99 506 507 0 B-0818 IF 86 476 477 B-0819 iF 90 462 463 0 B-0820 IF Q -j091 454 455 N D 0 B-0821 IF 7T 9 463 464 0

N

B-0823 I 79 463 464 SU6811UT EE T (RU)LE 2) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# CcdObserved %Yield d. Mass Spec %YedMass Spec

(M+H)

B-0824 F'.82 492 493 B-0825 F 4 100 506 507 B-0826 F 97 458 459 B-0827 F 100 659 660 B-0828 iF~~ 7 514 515 MOM.SHEM(RuL WO 98/52940 WO 9852940PCTIUS98/1 0436 430 Example# Calcd. Observed %Yield Mass SpecSe B- 82 F063 458 459 B- 30 i F Q 070 588 589 100 428 429 B-0832

IF

073 442 443 B-0834 0 0 79 1 486 487 B-0835 iF -03 401 9UBSTIT TESET(RUE2 WO 98/52940 WO 9852940PCT[US98/10436 Example# Ccd ObserVed %Yield 'acd Mass Spec Mass Spec

(M+H)

B-0836F o28 440 441 B-0837 F/ o81 426 427 B-0838 F

BI!

o84 540 541 B-0839 II 1 80 588 589

-N

B-0840 071 453 454 B-0841 V 055 1 472 473 B-0842 430 431 B-0843F\/ 68 492 493 B-0844 F--1 61 530 531 B-0845 F-4Q--f

F

L_ 0 F 1 84 1 516 1 517 su981TUTEHEEr(RULE 26) WO 98/52940 WO 9852940PCT/US9 8/10436 Example# Cac.Observed I/o~el ascSpe Mass Spec %Yie~ MassSpec (M+H) B-0846 IF- 0 87 440 441 B-0847 F 0 536 537 B-0848 I- 079 506 507 B-0849 IF-Q-- 0 81 506 507 B-0850 IF~~-j 1_ 0 69 476 477 o83 462 463 B-052IFQ---~ 077 454 1455

N

B-0853 0 187 463 464 B-085 4 F 0 73 463 464 B-0855 F- 0 92 463 464 SUB=TUTE SHEU(RULE2M WO 98/52940 WO 9852940PCTIUS98/1 0436 433 Example# Cac. Observed %Yield mas Spe Mass Spec MassSpec (M+H) B-0856 FN o75 492 493 B-0857F 86 1 506 507 B 85 458 1459 B-0859F 80 659 660 1 514 515 8U6SlTUT8HET(RULE9M WO 98/52940 WO 9852940PCTIUS98/1 0436 434 R2.

Example#

H

N

0 NHCH 3 i Calcd. Observed %Yield Mass SpecSe MassSpec (M+H) B-86 F84 583 584 B-0860 F1 B-0862 96 475 476 B-0863 'F69 423 424 0 B-0864 tF 86 437 438 B-0865 iF ~6 9 B-0866 TF 81 421 422 B-0867 IF 100 535 536 WSU9SITTEHErUUEM WO 98/52940 WO 9852940PCTIUS98/1 0436 435 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec

(M+H)

VjMn1UESHU(R=LE 26) WO 98/52940 PCTIUS98/1 0436 436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) WO 98/52940 WO 9852940PCTIUS98/I (1436 437 N- N H H

N

2 R R H 0 NHCH 3 2 Calcd. Observed Example# RR %Yield Mass SpecSe MassSpec(M+H) SUB~M1JrSWI-MM(UE 3 WO 98/52940 WO 9852940PCTIUS98/I 0436 438 Cac.Observed Rj *%Yield MasscSpe Mass Spec MassSpec (M+H) Example# ,jEGflTUTEBHEEr(RLEzf) WO 98/52940 WO 9852940PCT/US98/1 0436 439 2 Calcd.Observed Example# R j%Yield MasSc Mass Spec MassSpec(M+H) &wBnT=E9E(RUEM WO 98/52940 PCT/US98/1.0436 440 N-NH H I N R

OCH

3

N

2 Calcd. Observed Example# R j%Yield Mass Spec MssSpe VJB3Tff=WMT(R&E9M WO 98/52940 WO 9852940PCTIUS98/1 0436 441 Examle# 2 j */~ied Cacd.Observed Mas Scd Mass Spec Exam le# %Ye~d ass pec (M+H) 8UBSTMM8EHEMr(RUJLE26) WO 98/52940 WO 9852940PCTIUS98/I 0436 442 2 Calcd.Observed Example# R j%Yield Cac.Mass Spec Mass Spec

(M+H)

SUBSTrITESHEEr(RULEag) WO 98/52940 WO 9852940PCTIUS98/10Q436 443

N-NH

R2/

H'

NN

2 Cacd. assObserved Example# R j%Yield ScdMs Mass Spec Spec (M+H) SUBSfUSHEEU(RLUEM WO 98/52940 WO 9852940PCTIUS98/10~436 Exam ple# %Yed Calcd. Mass %YieldSpec Observed Mass Spec

(M+H)

B-0940 IF36 397 398 B-0D941 41 441 442 B-0942 'F-0 H 27 473 474 B-04 F1 55 493 494 B-0944 IF-{D- 53 173 474 B-94 F 7 H82 429 430 B-0945 0 5 6 ~-00

H

N

B-0946 100 431 432 B-0947 IF 98 473 474 SUBSTUTEHEEr(RULE26) WO 98/52940 WO 9852940PCT/US 98/10436 445 Example# Cald. assObserved %Yield ScdMs Mass Spec Spec (M+H)

F

I

HN-

B-0950 64 419 420 0 B-0951 F-0 -I 100 469 470

FN

H

B-0952 !F HN 61 469 470 B-0953 IF- 67 425 426 B-0954 62 4342 B-0955 F-Q- 0 39 461 462 0 B-0956 1 66 429 430

N

H

8-0957 F -0 93 429 430 B-0958 86 365 366 B-0959 73 451 452 8UB8TfTUTSHMT~(RLUE2 WO 98/52940 WO 9852940PCTIUS98/1 0436 Example#t Cald. assObserved %Yield ScdMs Mass Spec Spec

(M+H)

WsUesTfuTESHEEJ 'wP WO 98/52940 WO 9852940PCTJUS98/1 0436 447 Example# Cald. ass Observed %Yield ScdMs Mass Spec Spec (M+H) /0 B-C0970 IF 38 461 462 /CI1 B-0971 F/ N 95 469 470 B-0972 98 479 480 B-0973 IF 96 485 486 B-0974 F-Q N 74 443 444 B-0975 I F-o 100 495 496 B-97 0 70 453 454 B-0977 iF-o Ci-- 100 467 468 B-0978 F 91 431 432 B-0979 F 54 491 492 6U6B=flUTr(RULE26) WO 98/52940 WO 9852940PCT, US98/1 0436 448 Example# Cald. assObserved %Yield ScdMs Mass Spec Spec

(M+H)

su~~ITEsiEt (RL2) WO 98/52940 WO 9852940PCTIUS98/1 0436 449 Example# Cac. Observed %Yield Mass Spe Mass Spec MassSpec

(M+H)

SUBB~JTEBHEU (VULE96 WO 98/52940 WO 9852940PCTIUS98/1 0436 450 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) 0 B-0988 91 364 365 0 B-0989 88 350 351 0 Br B-0990 68 464 465 0 B-09.91 86 512 513 0 B-0992 F--79 377 378 0 B-0993 81 396 397 B-0994 100 354 355 0 B-0995 75~i~1 416 417.

0 CF 3 B-0996 1 65 45445 GAUBMM1FUE88E(RULE26) WO 98/52940 WO 9852940PCTIUS98/I 0436 451 Cac. Observed Example# %Yield Mass Spec MssSpe 8U98TnUTMSHEUr(R-U20 WO 98/52940 PCT/US98/10436 452 Example# Calcd Observed %Yield Mass Spec Mass Spec MassSpec (M+H) 0 B-1006 80 387 388 B-1007 F-to-- 54 387 388 B-1008 F- 64 416 417 B- 009 F 81 430 431 B-1010 81 382 383 B-l011 F- 66 583 584 B-1012 N 10 69 438 439 SUBSnTUTESHEEr(RULEa) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# %Yed Calcd. Mass %Yield Spec Observed Mass Spec

(M+H)

B-1013 440 441 B-1014 61 422 423 0 0 B-i1016 IF-- 448 449 B-1017 FQ 63 436 437 B-1018 82 458 459 0 6-1019 iF Q- C 41 414 415 I 1UBTTTSHW~(RMN 2) WO 98/52940 WO 9852940PCT/UJS98/1 0436 Example# Cald. assObserved */Yield ScdMs Mass Spec Spec (M+H)

F

B-1 020 I F-Q- 1 100 440 441 0 BA1021 F 100 388 389 0 B-1 022 S 74 402 403 0 B-1023 IFQ-- I 76 374 375 0 0 B-i 024 73 360 361 B-1 025 __~100 452 453 0 B-1026 IF95 428 429 B-i 02 H~ 98 436I43 0 B-1028 /100 482 483 0- 0 B-1 029 'N 98 367 368 su~rrnmst(RULEW) WO 98/52940 PCT/US98/10436 Example# Observed Calcd. Mass O b s e r e d %Yield Spec Mass Spec pec (M+H) 0 B-i 030 F- S^ 88 325 326 ~NH 2 B-1031 F7 97 415 416 0 B-1032 64 379 380 0 B-1033 F-y -N 83 395 396 1 B-1034 F- 67 419 420 0 B-i1035 iF- -I N BA035 N' 73 353 354 0 B-1036 F- 79 339 340 B-1037 F- 78 415 416 B-1038 F 100 419 420 B-1039 F 95 429 430 8UBSTUE 8HEE(RlUE26) WO 98/52940 WO 9852940PCTJUS98/1 0436 456 Cald. assObserved Rj%Yield Scd.Ms Mass Spec Spec (M+H) Example# 8UBSWTUTE ET (RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 457 Example# Cald. assObserved %Yield ScdMs Mass Spec Spec (M+H) B-1 050 F100 461 462 B-1051 IF88 406 407 B-1052 IF82 366 367 B-i1053 F.fI- o21 368 B-1054 98 354 355

HN

B-1 055 IFQ...t~s.LIII 100 379 380 B-1056 N 85 379 380 0 B-1057 o30 368 369

'-L

&ATM7=%iM(WuLE2% WO 98/52940 WO 9852940PCT/UJS98/I 0436 Example# %Yed Calcd. Mass %Yield Spec Observed Mass Spec

(M+H)

B- 08 35 500 501 B-1059 F- 2\KJ 77 479 480 Br B-1 060 IFS37 500 501 0 B-1061 IF-) 0 8 496 497 0 B-1 063 1 59 496 497 0 B-i 064 /5 0 F 5850 SUBSTMSHEET(RULE 26) WO 98/52940 WO 9852940PCTIUS98/1-0436 459 Example# Cald. assObserved %Yield ScdMs Mass Spec Spec (M+H) B-1 065 F-1j-- 24 466-

OH_

B-i1066 IF/N. 100 490 491 B-1 067 IF\ 74 464 465 0 B-1071 NF -7 473 474 0 B-1 074 \6/10 464 465 0 SU96Mt3TSHEr(WUE98) WO 98/52940 WO 9852940PCTIUS98/1 0436 460 Example# Cald. assObserved %Yield ScdMs Mass Spec Spec (M+H) 100 470 471 0 C B-11076 IF /93 490 491 0 B-1077 1F\ 100 474 475 B-1078 F 80 447 448 B-i1079 IF 85 45 455 B-1080 F 1 100 496 497 Ci C1 B-1 082 IF~ -j 100 500 501 Br B-i1083 \93 500 501 B-i1084 FK-- 081 494 495 W~nMSfEET (RULE 26) WO 98/52940 WO 9852940PCTJUS98/1 0436 Example# Cald. assObserved %Yield ScdMs Mass Spec Spec (M+H) B-1 085 F 93 482 483

CF,

B-1086 92 490 491 B-1087 i 100 490 491 SUBSTIUjtESWUE(RULEMB WO 98/52940 WO 9852940PCT/US98/1 0436 462 Example# Cald. assObserved %Yield ScdMs Mass Spec Spec (M+H) B-1088 iF97 450 451 B-i 089 I 100 436 437 B-1090 B-og 100 456 457 II 6 B-1091 \100 456 457

C,

B-i1092 I F- 7 'i 96 490 491 B-1093 C' 100 490 491 C1 C1 0 SUBSTrUrE SHEET (RULE 26) WO 98/52940 WO 9852940PCT/US98/1 0436 463 Example# Cald. assObserved %Yield ScdMs Mass Spec Spec (M+H) B-1 095 F S 1 81 470 471 B-1 096 77 450 451 B- 09 F~ 100 436 437 B-i1098 93 466 467 0 3 B-1 099 F- G- 1. /1110 490 491 0 13-1100 F 47 482-

CI,

B-1 101 64 462 463 0 B-1 102 F- 98 530 531 B-i 103 G 65 472- B-1 104 F0 I 88 441 442 ISUBSTITUTESHEET(RLE2M) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cald. assObserved %Yield ScdMs Mass Spec Spec (M+H) B-1105 i 100 464 465 B-1106 IFI 91 486 487 B-1107 jF /96 447 448 B-11108 'I0 5 561 562 0 B-1110 73 548 549 B-11111~ 94 505 506 B-1112 S100 568 569 B-1113 IF 100 495 496 B-1114 F- 11 1- 73 426 427 II__0 MuWTfruT8-Ur(RULE26) WO 98/52940 WO 9852940PCT/US98/1 0436 465 2 Cacd. assObserved Exapl# RRj%Yield ScdMs Mass Spec Examle# pec (M+H) 8UBBFIUT =HEET (RtAE2B) WO 98/52940 WO 9852940PCTIUS98/1 0436 466 Example# %YedCalcd. Mass %YietdSpec Observed Mass Spec

(M+H)

B-1 120 84 400 401 0 B-1 121 86 420 421I B-1 122 F /-90 400 401 0 B-1 123 F-f-v CF 3 100 454 455 B-1124 91 442 443 B-1125 C 50 512 513 0 B-1126 454 455 01 8u%7ffMJTESE&(RA.E26) WO 98/52940 WO 9852940PCTIUS98/1 0436 467 2 Cacd. assObserved Example# R j%Yield Scd.Ms Mass Spec Spec (M+H) Waff mj=Eff~r(RULEf=26)~ WO 98/52940 PCT/US98/1 0436 468 Cald. assObserved Rj%Yield ScdMs Mass Spec Spec (M+H) Example# VJ=WM&F-F7-(RA.E26) WO 98/52940 WO 9852940PCTIUS98/1 0436 469 Examle# 2 Yiel Cacd. assObserved %Yel ScdMs Mass Spec E x a m p e R 2 S p e c(M H &UBMMMlUTETE~(RULE 26) WO 98/52940 PCTIUS98/1 0436 470 Example# Cald. assObserved %Yield ScdMs Mass Spec Spec (M+H) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac.Observed %Yield asdpe Mass Spec %Yie~ MassSpec

(M+H)

jw11TwTEiMEt(RULE 2) WO 98/52940 WO 9852940PCTIUS98/1 0436 472 2 Calcd.Observed Example# R j%Yield as S Mass Spec Mas Sec

(M+H)

SU6S11TUTEU~E(WUE') WO 98/52940 PCTIUS9811 0436 Exam ple# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) WO 98/52940 WO 9852940PCTIUS98/1 0436 474 Example# R 2 Rj%Yield Calcd. Observed RasSe Mass Spec MassSpec(M+H) BUB&F~UTE8HEEU(RULE~) WO 98/52940 WO 9852940PCT/US98/I 0436 475 Example# Cac. Observed %Yield Cac.Mass Spec Mass Spec

(M+H)

19 /F 444545 B-1 191 F 47 436 437 0 B-1192 FS50 402 403 B-1 193 62 462 463 0 B-1194 49 450 451

F

B-1195 :F 61 472 473 o 0 0 B-1196 52 428 429 SUBMfTUrESHEEr (RUE 2) WO 98/52940 WO 9852940PCT[US98/I 0436 476 Example# Ccd Observed %Yield MasScd Mass Spec MsSpe (M+H) B-1 197 54Q~-- 45 455 0 B-1198 44 402 403 0 B-i1200 IF~ Q 45 388 389 0 B-1201 F 5 91 2 743 0 00 0 B-1206 N 97 381 382 &SUff UTEnS*-E(RuLEM) WO 98/52940 PCT/US98/10436 Example# Observed %Yield Calcd Mass Spec Mass Spec

(M+H)

B-1207 F 100 339 340 B-1208 IF 90 429 430 B-1209 l 69 393 394 B-1210 F- 35 409 410 0 B-1211 F 100 433 434 B-1212 F N 83 367 368 0 B-1213 F 78 353 354 B-1214 F 68 429 430 B-1215 F 65 433 434 B-1216 F 9 1 4 4 3 4 4 4 UBSmTUTESHEET(RULE26) WO 98/52940 PCT/US98/10436 478 Example# Observed %Yield MasdpeMass Spec Mass Spec(M+H) B-1217 F 99 379 380

H

B-1218 F Q92 381 382 0 B-1219 F Q74 443 444

H

N

B-1220 67 415 416 B-1221 F F 14 443 444 B-1222 F 19 443 444 B-1223 F §71 433 434

F

B-1224 1F 100 445 446 B-1225 F 75 395 396 B-1226 F 58 367 368 SWTM EET(FULEsM WO 98/52940 WO 9852940PCTIUS98/1-0436 479 Example# Observed %Yield Calcd. Mass Spec Mass Spec

(M+H)

B-1227F 0o- 98 475 476 B-1228 71 420 421 B-1229 IF 8 380 381 B-1230 IF-Q~~ 10 382 B-1231 66 368 369 B-1232 F100 393 394 Bi23F-0\- ii -r N 96 393 394 B-1234 066 382 383 SUBSTTUTSHEM(RLE 26) WO 98/52940 PCTIUS98/ 0436 Example# Calcd. Observed %Yield Mass Spec Mass Spec(M+H) B-1235 F iI t t 0 50 514 515 0 B-I 236 100 493 494 Br B-1237 S 91 514 515

CI

B-1238 100 470 471 S 0 B-1239 F 71 510 511

V

o B-1240 11 1 1 27 510 511 B-1241 /73 520

C,

suWsTMsiTESHEET(RULE26) PCT/US98/1 0436 WO 98/52940 Observed %Yield Calcd. Mass Spec mass Spec (M+H) Example# wuawnwrEBHEF-(RULE2M) WO 98/52940 WO 9852940PCT/US98/I 0436 482 2Yel Calcd. Observed Example# RRYed M s Sp cMass Spec 8UB~nUTESH~r (R AMY3 WO 98/52940 WO 9852940PCT/US98/1 0436 483 Example# Cac.Observed %Yiel MasSpe Mass Spec: MassSpec (Mi-H) su~nmEBHET uACA PCTIUS98/1 0436 WO 98/52940 484 Calcd. Observed %/Yield Mass SpecSe MassSpec

(M+H)

Example# GLWM8FzUr(RULE=2) WO 98/52940 WO 9852940PCT/US98/1 0436 485 2Calcd. Observed Example# R R %Yield Mass SpecSe MassSpec (M+H) SAM S1RFUE8E(RULEW) WO 98/52940 WO 9852940PCTIUS98/1 0436 486 2Yel Calcd. Observed Examle#R RjYild Mss pecMass Spec Examle# ass pec (M+H)

SUBMIMTTSHEEULE-)

WO 98/52940 WO 9852940PCT/US9 8/10436 487 2Catcd. Observed Example# R R %Yield Mass SpecSe MassSpec (M+H) $UBwffTUT&iMT(RULE28)"; WO 98152940 WO 9852940PCT/US98/10436 488 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) 12762 447 448

H

B-1300 iF- NH 71 444

N

B-1301 rF /65' 0 472 43 0

NH;

B-1302 -375 410 411 B-1303 iF74 424 425 sSTUTEBHEET(RULE3) WO 98/52940 PCT/US98/10436 489 2 JCalcd. Observed Example# R2 Rj %Yield Mass SpecSe MassSpec (M+H) SHEET (RULE 26) WO 98/52940 WO 9852940PCTIUS98/I 0436 490 Example# Calcd. Observed %Yield Mass Spec Mass Spec

(M.H)

B-1314 F- Q H- 69 444 445 B-1315 F (N 57 450 451 B-1316 H75 393 394 B-1317 j 100 461 462

NH

B-1319 ~23 464 465 B-1 320 512 513

H-

8Um8 HEET (RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Calcd. Observed %Yield Mass SpecsSe MassSpec (M+H) B-1 321 i F 63 414 415 0 B -1 3 2 F 4 54 3 4 4 3 B-1 323 F-0 53 414 415 B-1 324

C

3 32 468 469 B-i1325 I456 457 B-1326 IFQ-~~50 526 527 B-i1327 iF-Q-- 55 468 469 6Ue~gff=BSHEr(RWE26) WO 98/52940 WO 9852940PCTIUS98/10436 492 2 Calcd.Observed Example# R j%Yield Mas Spe Mass Spec 8U8~UTESHEE~ (RULE 26) WO 98/52940 PCTIUS98110436 493 Example# Calcd. Observed %Yield Mass Spec Mass Spec(M+H) 0 B-1338 39 486 487 0F OF B-i1339 F CF 3 61 486 487 B-1340 \F3 49 486 487 0 B-i 341 55 486 487

F

B-1342 F 51 486 487 C1 B-1343 72 434 435 B-1344 F 1 52 414 415 o

CI

B-1345 CI 43 468 469 0 40 418 419

F

B-13476 40 418 419 -14 N 67 436 437 -SU8TLOUTESHEERUEM) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Cac. Observed %Yield MascSpe Mass Spec MassSpec (M+H) C1 B-1348 F-0 39 468 469

CI

B-134 68 46 43 F1 F1 B-1350 F- i 73 454 455 0 F:

F

B-135 54 418 419 B-i1351 F7 43-3 B-1353 66Q-~ NI 7 436 437 B-1354 II 58 434 435 B-1355 Br~ 77 478 479 B-i1356 F- 1 50 s 468 469 6-1357 36 406 407 SUBgm1JTESHEE(FUE2 WO 98/52940 WO 9852940PCTIUS98/1 0436 495 Example# Cld Observed %Yield MasSpe Mass Spec MassSpec (Mi-H) bqBSTIT EUE~ (RULEO26 WO 98/52940 WO 9852940PCTIUS98/1 0436 496 Example# Cald. assObserved %Yield ScdMs Mass Spec Spec (M+H) 0 B-1359 jF 552 553 0

F

B-1 361 FQ~-I100 392 393 B-i1362 IF-O -I 85 406 407 0 B-1 364 F -0 990 390 391 0 B-1365 F Q 92 504 505 SflTsHEEFrnuLE2 WO 98/52940PCUS8103 PCTIUS98/10436 497 2 LCalcd. Mass Observed Example# R 2 RL %Yield Spc Mass Spec Spec (M+H) 8UB8flTUTESHEET rULE 26) WO 98152940 PCT/US98/I 0436 Example# Calcd. Mass Observed %Yield Spc Mass Spec Spec (M+H) $uBBTn=&LfLT (RULE 96) WO 98/52940 PCT/US98/10436 49 9 Example# Calcd. Mass %YieldSpec Observed Mass Spec

(M+H)

B-1 383 46 .416 417 o B-1384 IF 56 432 433 0 B-1 385 59 426 427 B-1386 iF-x 50 427 428 6-1387 IF 12 427 428

N

B I B-1388 FI 66 504 505 B-1389 j F Ic 48 460 461 0 JBSUTEBET (RuLAE) WO 98/52940 PCT/US98/10436 500 2 L Clcd.Mass Observed Example# R 2 RL %Yield ScdMs Mass Spec Spec "Mmm MET (MAE Pool) WO 98/52940 WO 9852940PCTJUS98/I Q436 501 2 LCalcd. Mass Observed Example# R 2 RL %Yield Spc Mass Spec Spec (M+H) &US 8H~T(RUL=26) WO 98/52940 PCT/S98/1 0436 502 Example# Calcd. Mass Observed %Yield SMass Spec Spec (MH)

F

B-1410 42 512 513 o CF 3

FF

B-1411 F 1 19 462 463 F F B-1412 IF--o 74 462 463 0

CI

B-i 413 F 75 494 495 L 0

C

F

B-1414 iF I1 68 462 463

IFF

B-1415 F F-0 1 48 462 463 Ir

F

o B-1416 jF-0 t 48 494 495 0 B-i417 F 57 494 495 0 C1 B-1418 I 49 494 495 I 3 494 495 oC S=TfUTESHEEI- (RULE29) WO 98/52940 PCTIUS98/1 0436 503 Example# Observed Calcd. Mass Osre %Yield Sc Mass Spec

(M+H)

B-1420 F 72 378 379 B-1421 F 0. 74 406 407 0 B-1422 F Q 68 394 395

V

B-1423 F 1 57 408 409 B-1424 IF- j- 0a 77 422 423 0 B-1425 26 408 409 B-1426 IF-Q 0 41 406 407 B-1427 0 37 404 405 B-1428 Ff 60 456 457

CF

3 B-1429 F- 2 418 419 SUse==TESHE (RULE 26) WVO 98/52940 PCT/US98/10436 Example# Calcd. Mass Spec Observed Mass Spec

(M+H)

0 B-1430 F- j. 61 442 443 0 0 B-1431 FS 64 428 429 0 B-1432 F 1 71 429 430 I

S-N

0 0 B-1433 1F 74 462 463

N

B-1434 I 88 466 467 B-1435 iF \9 75 481 482 B-1436 71 504 505 0 %TwUTE88E(RuLEM) WO 98/52940 PCT/US98/1 0436 505 Example# Calcd. Mass %YieldSpec Observed Mass Spec

(M+H)

0 B-1437 F 63 468 469 0 B-1438 -F I I 78 502 503 o I a B-43 Fi 70 545 546 13-1440 F 62 535 536

I

B-1441 F82 608 B-44 i 9~ 79 555 556 0 11 0 0 t/ 0 B-i443 FII 28 513 514 0 0 B-1444 F 75 522 523 0 B-1445 74 526 527 B-1446 F a 70 570 571 suWWIuMTESHEM (RLE26) WO 98/52940 WO 9852940PCT/US98/1 0436 506 Cald. assObserved Example# R RL %Yield ac.Ms Mass Spec Spec

(M+H)

WU6SflfEWSH&7r(RUJLE...) WO 98/52940 WO 9852940PCTIUS98/I 0436 Example# Cald. ass Observed %Yield Spcd.Ms Mass Spec Spec

(M+H)

mgumBrTsmEu

(RULEN)

WO 98/52940 PCT/US98/1 0436 Example# Calcd. Mass Spec Observed Mass Spec

(M+H)

B-1467 IFQ 114Jci 79 476 477 0 B-11468 F 79 530 531 B-1469 IF-( 0 75 487 488

CNI

B-14701 112I I 449 9 480 481 -z 8-1470 B-1473 IF-\/-74 496 497 1 0 I B-1 474 Fj%1 L4JJK81 30 53 0 0 B-1 476 I ~~j~75 540 541 0 B-1473 IF-0 77 476 477 B-1474 jF 1181 530 531 cN B-1475 IF 70 487 488 i ~11 I~ 54 540 541 1 iUl1UJEs *Er (RULE26) WO 98/52940 WO 9852940PCTIUS98/I Q436 509 2 L Clcd.Mass Observed Example# RR%Yield ScdMs Mass Spec Spec (M+H) 8UBST=iEE(RLUE 2 WO 98/52940 PCTIUS98/1 0436 Example# R 2

RL

Calcd. Observed %Yield Mass SpecSe MassSpec (M+H) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Calcd. Observed %Yield Mass SpecSe MassSpec

(M+H)

view n=ESHE4r(RLUE WO 98/52940 WO 9852940PCTIUS98/10436 512 2 L Calcd. Observed Example# RLR %Yield Mass SpecSe MassSpec(M+H) %UW11UTEMWEEr (RAE 2) WO 98/52940 WO 9852940PCTIUS9/I 0436 513 Example# Calcd. Observed %Yield Mass SpecSe MassSpec

(M+H)

SUB TITL~ES~'LL~~ WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# Calcd. Observed %Yield Mass SpecsSe MassSpec (M+H) suesrrUnSWEU("--2 WO 98/52940 WO 9852940PCT/US98/1 0436 Example# Calcd. Observed %Yield Mass SpecSe MassSpec (M.H) B-1 525 -y NO 57 419 420 aM6W=SE~(RujL2) WO 98/52940 PCTIUS98/1 0436 516 Example# Cald. ass Observed %Yield ScdMs Mass Spec Spec (M+H) 11JUIESHEIET(RULEM WO 98/52940 WO 9852940PCT/US98/1 0436 517 2 L Clcd.MassObserved Exml# RR%Yield ScdMs Mass Spec Exampe# RLSpec

(M+H)

SUBnTTESE~(ROULE

M)A

WO 98/52940 PCT/US98/1 0436 Example# %Yield Calcd. Mass %Yield Spec Observed Mass Spec

(M+H)

WO 98/52940 WO 9852940PCTIUS98/1 0436 519 Example# RR2L %Yield Calcd. Mass MasseSpec Spec (M+H) B-1 553 '~.N83 55657 B-1554 84 478 479 0

CIF

B-1555 93 512 513 B-1 556 I \N83 496 497 B-1 557 62 430 431 B-1 558 -S 45 416 417 B-1 559 HI748 8 B-1 560 I I16 492 493 0 B-1561 I \84 556 557 B-1562 I74 546 547 gU8BTMWH~r(RuLEs) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# %Yield Calcd. Mass %Yield Spec Observed Mass Spec

(M+H)

8HEEr(RULE2~) WO 98/52940 WO 9852940PCT/US98/1 0436 521 R L Calcd. Mass Osre Example# RR%Yield Spec Mass Spec

(M+H)

VUBZilT EE-r(RULEf26) WO 98/52940 WO 9852940PCT/US98/1Q1436 522 Proton NMR data for selected members from Examples B-0001 through B-1573 are shown in the following table.

WO 98/52940 WO 9852940PCTIUS981-0436 Plate ID 1 H NMR(solvent), d ppm (DMF-d7) d 8.53(bd, J 4.99Hz, 2H), 7.44-7.24(m, 11 4.41 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, 1 7.38-7.34(m, B-0235 2H), 7.21 -7.13(m, 4H), 4.20(br, 2H) (CDCI3/CD300) d 8.38(d, J =5.38 Hz, 1 7.62-7.32(m, 9H), 7.04-6.95(m, B-0244 4H), 6.86-6.80(m, 2H), 4.52(g, J 6.96 Hz, 1 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), 4.1 7(br, 2H), 5.12(br, 1 7.50(m, 6H), B-0426 8.77(m, 2H), 13.54(br, 1H).

(DMSO), 1. 1 4(t, J 6.9 Hz, 3H), 4.54(m, 1 6.99(br, 2H), 7.21 (br, 4H), B-0438 7.45(s, 1 7.61 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, 1 7.25(m, 6H), 7.65(m, 3H), B-0466 8.59(br, 2H), 13.34(brd, J 34.8 Hz, 1 H).

(CD3OD), 1 .53(d, J 7.2 Hz, 3H), 4.59(q, J 7.2 Hz, 1 6.88(d, J 4 Hz, 1 7.09(m, 3H), 7.1 5(dd, J 4.4, 1.6 Hz, 2H), 7.26(m, 2H), 8.46(d, J B-0473 Hz, 2H).

(DMF), 1 .80(br, 3H), 2.35(s, 1 4.98(br, 1 7.38(m. 6H), 7.85(m, 2H), B-0477 8.45(br, 1 8.75(d, J 6.0 Hz, 2H).

(Methanol-d4), 1 .57(d, J =5.6 Hz, 3H), 4.74(br, I1H), 7.23(m, 4H), 7.60(m, 2H), B-0479 7.81 4H), 8.67(br, 2H).

(DMF), 1.78(s, 3H), 2.76(br, 6H), 4.85(br, 1 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, 1 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, 1 7.1 7(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, 1 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, 1 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, 1 7.70(dd, J 9.0, 5.8Hz, 1 H), B-0643 8.43(dd, J 4.8, 3.2_Hz, 2H).

(CD3OD), 1.58(br, 3H), 4.62(q, J 6.6 Hz, 1 6.93(br, 1 7.17(m, B-0650 7.31 (br, 2H), 8.51 (br, 2H).

(CDCI3/CD3OD) d 8.48 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(g, J 7.57Hz, 1 1.43(d, J 7.26Hz, 3H) (CD3OD), 1 .52(d, J 6.8 Hz, 3H), 3.75(s, 3H), 7.21 (in, 2H), 7.42(m, 2H), B-0663 7.57(s, 1 7.76(s, 1 7.98(br, 2H), 8.76(br, 2H).

Hz, 2H), 3.06(m, 1 3.43(q, J 6.1 Hz, 2H), 7.02(m, 2H), 7.14(m, 2H), B-1 165 7.41 2H), 8-59(d, J 5.6 Hz, 2H).

1.6 Hz, 1 7.04(t, J 8.6 Hz, 2H), 7.14(m, 2H), 7.36(m, 2H), 8.39(d, J 1.8 B-1 169 Hz, 1 8.60(m, 2H).

6.83(br, 1 7.02(t, J 8.7 Hz, 2H), 7.15(d, J 5.6 Hz, 2H), 7.40(m, 2H), B-1 171 8.59(d, J 5.0 Hz, 2H).

8tJWrTUTmswfEr(uLm WO 98/52940 WO 9852940PCTIUS98/1 0436 Plate ID 1 H 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-1 179 6.15(br, 1 7.04(m, 3H), 7.22(m, 3H), 7.41 (br, 4H), 8.60(br, 2H).

(CDCI3), 2.O0(br, 2H), 2.85(br, 2H), 3.64(br, 2H), 7.03(br, 3H), 7.17(br, 2H), B-1 183 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, B-1 194 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-i1200 7.36(br, 2H), 8.54(br, 2H).

(DMSO), 1.03(s, 6H), 1.68(br, 2H), 2.63(br, 2H), 3.0Q(br, 2H), 3.65(br, 1 H), 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), 3.10O(br, 2H), 7.04(br, 3H), B-1216 7.18(br, 4H), 7.35(m, 2H), 7.47(br, 1 8.54(d, J 4.8 Hz, 2H).

(DMF), 1 .25(br, 3H), 2.01 (br, 2H), 3.35(br, 4H), 6.20(s, 1 6.30(s, 1 H), B-1226 7.42(br, 4H), 7.65(br, 2H), 8.77(s, 2H).

(DMSO-d6), 1.80(br, 4H), 2.B2(br, 1 2.94(br, 1 3.1QO(br, 1 3.60(br, 1 H), B-1360 4.54(br, 1 7.1 8(mn, 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, 1 4.04(br, 2H), B-1 361 4.44(m, 1 7.1 8(m, 4H), 7.30(m, 2H), 8.57(d, J 4.64 Hz, 2H).

(DMSO-d6), 1.78(br, 4H), 2.01 3H), 2.89(br, 1 3.05(br, 1 3.34(br, 1 H), B-1363 3.85(br, 1 4.48(br, 1 7.12(br, 2H), 7.21 (br, 2H), 7.30(br, 2H), 8.69(br, 2H).

(CDC13), 0.78(dd, J 3.0, 2.9 Hz, 2H), 1 .00(s, 2H), 1 .78(m, 1 1 .86(b, 4H), 2.64(m, 1 2.99(m, 1 3.16(m, 1 4.33(br, 1 4.70(br, 1 6.99(m, 2H), B-1 364 7.14(s, 2H), 7.29(m, 2H), 8.64(s, 2H).

(CDCI3), 1.89(s, 4H), 2.65(m, 1 2.96(m, 1 3.06(m, 1 3.43(s, 3H), 3.93(d, J 13.2 Hz, 1 4.09(d, J 13.5 Hz, 1 4.18(d, J 13.5 Hz, 1 H), B-1 368 4.68(d, J 12.4 Hz, 1 7.60(m, 2H), 7.12(s, 2H), 7.26(m, 2H), 8.63(s, 2H).

8U6STMTEHEEM(RLEs) WO 98/52940 PCT/US98/10436 525 By analogy to the procedure identified above for the preparation of Examples B0001-B0048, the following examples B-1574 through B-2269 are prepared.

su~sTImuns~HEE(r(uEnaw WO 98/52940 WO 9852940PCTIUS98/1 0436 526

N-NH

R

2 N-RLf

N

Examples B-i1574 through B-i1597 are prepared from Scaffold C-27 Example# R 2 SUBfilTUTEE(RLE26) WO 98/52940 WO 9852940PCT/US98/1 0436 527 8UBM1TMJTSHEET(RULE 26) WO 98/52940 WO 9852940PCT/US 98/10436 BS1TUTESHEEr(RLU"S WO 98/52940 WO 9852940PCT/US98/10436 529

N-NH

RN=2

N

Examples B-1 598 through B-i 621 are prepared from Scaffold C-28 Example# R 2

RL

SU6SflUTEHEET(REM WO 98/52940 WO 9852940PCTUS9810436 530 Example# "SSU6UEHuET(KULE) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# &MU WO 98/52940 WO 9852940PCTIUS98/1 0A36

N-NH

R2

N

Examples B-i 622 through B-i 645 are prepared from Scaffold C-38 Example# B-1 622 IF/0 0 B-1623 IF I F B-1624 F0 B-1625 IF-Q-- L B-1626

I

B-1628 F

N

SUBOfTUTESHEEr(RULE26) WO 98/52940 WO 9852940PCTJUS98/1 0436 533 Exam ple# SUGSThUTESET (RLE 28 WO 98/52940 WO 9852940PCT/US98/1 0436 534 Example# SUWMlUMT8EE9ML WO 98/52940 WO 9852940PCTIUS98/1 0436 535

N-NH

N-RLI

Examples B-1 646 through B-i 669 are prepared from Scaffold C-39 R 2

RL

Example# B-1 646 IF-Q-~ B_ 64 IF j~~i 0 6-1647 B-1650 B-1651 IF-Q-I a B-1651 F SUoBrfUTSHEUT(RULE26) WO 98/52940 PCTIUS98/ 0436 Example# R 2 RL B-1653 -1654 F

I

0 0 0 B-1657 IF Q B-1658

F

F

B-1659 IF

O

I :I B-1660 IF JJpJ 0 N-66

F

B-1661 1 0 B-1662

SO

SuqESTREr B(RLEs) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# 8U6WETSHET(RLM26 WO 98/52940 WO 9852940PCTIUS98/1 0436 R2N-NH 7 0

NH

0 Examples 13-1670 through 13-1693 are prepared from Scaffold 0-65 R 2 Example# B-167o0 0 B-1 671F B-1672 0 B-1674 B-1675 F B-1 676 F- qWfjXMEsHEU (RUEs) WO 98/52940 WO 9852940PCT/US98/1 p436 Example# SU6EflTUFSHET (RLUE 26 WO 98/52940 PCTIUS98/1 0436 540 Example# WO 98/52940 PCTIUS98/1 0436 541 N 0

H

Examples B-1 694 through B-1 717 are prepared from Scaffold C-66 Example# 0 B-1694 jF /I B-1695 IF

I

F

0 B-1696

I

I

B-i 698 f-Q.- 0 B-1699

F

B-1700

IF~O

W-8,111fl MET (RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 542 Example# B-1701 B-1702 IF-Q-

LOO

0 i B-1705 F B-170 I-- B-1707 SUS TUTES%-E(RULES) WO 98/52940 WO 9852940PCTIUS98/1 0436 543 Example# R 2 B-1711o 0 0 B-i 713F ry I ~NH 1 4'I B-1714 F-O

N

HN

B-1717 SU9MMTUTEHW~(RULEgm WO 98/52940 WO 9852940PCT/US98/1 0436 Examples B-1 718 through B-1 741 are prepared f rom Scaff old C-69 Example# B-1718 IF B-1719 F B-1720F-'j-

I

B-i17231 01 B__1722 IF- R SuBS11UTSHr (RULE 26) WO 98/52940 PCTIUS98/1 0436 545 Example# R2

RL

0 B-1725 F B-i726 jF- B-1 7279

N;

IF- 0 6-1728 iF B-1729 r B-1730 IF jrJB r B-1731

FS

B-1733 o B-1734S %o

SUTMMH~(JL%

WO 98/52940 WO 9852940PCT/US98/1 0436 546 Example# SUBSmTMSMET(ULEW WO 98/52940 WO 9852940PCTIUS98/10436

N-NH

R 7 0

NH

I0 Examples B-i 742 through B-i 765 are prepared f rom Scaff old Example# B-1 742 0 B-1743

F

B-1744 0 B-i1745

I

B-i 746 IFQ- a 0 B-i1747 F B-1748 i

___BR

SUBMnTMMSHM~(MMNE) WO 98/52940 WO 9852940PCT/US98/I 0436 Example# I 0 B-1 749 N 6-1750 0 1 B-1751 0 B-1752 F0-~ B-1753

F

B-1754 /0

IFF

B-1756 ~I~

N

0 B-17580 VM11-11 SHEU(RLUgm WO 98/52940 WO 9852940PCTJUS98/I 0436 549 Example# R2RL B-1759

S-

B-1760

-F

FF

B 7 6 2 I J -1 Y B-1762 B-1764 -H 0- B-1765

I

SU1 TUEHE/RUE WO 98/52940 WO 9852940PCTIUS98/1 0436 550

N-NH

0 0 CH 3 Examples B-1 766 through B-1 789 are prepared from Scaffold C-71 Example# 8=InMHEUt(KU9M WO 98/52940 WO 9852940PCTIUS98/I 0436 Example# I U-9nIUESHEEM(ULEU) WO 98/52940 WO 9852940PCTIUS98/1 Q436 552 Example# R R B-1783

S-

FF

B-i1784 B-1786 B-1787 B-i1788 H

HN-

WO 98/52940 WO 9852940PCTIUS98/1 0436 553 N-NH

RL

2 N

R

0 0 'CH 3 Examples B-i 790 through B-1 813 are prepared from Scaff old C-72 R 2 RL Example# 0 1790-.- B-i1792 B-i17943 F Q-- B-1795 IF-Q -0 B-1796 FI L _B VSB8111UEU~(RE26) WO 98/52940 PCT/US98/1 0436 Example# B-1797I

F

B-1798 IF B-1799 IF-Q LZ 0 B0 i B-1800 B-1801 F ii B-i 802 F 0 B-1 803 I F B-i 80346

F-

B-1805 1 I 0 B-1806 0 M- I r~ SHEETU(RULE26) WO 98/52940 WO 9852940PCT/US98/1 0436 Example# S9SII M:I ISHEE(RLE) WO 98/52940 WO 9852940PCTIUS98/1 0436 Examples B-i 814 through B-i 837 are prepared from Scaffold C-73 Example# B-1814 F Q -0 0 B-1815 FF B-1816 F~ 0 B-18189 B-1820F-~--0 _0 VjWMSHEET (RLE 2f) WO 98/52940 WO 9852940PCTIUS98/10Q436 557 Example# R 2

RL

0 B-1 821 0 B-1823 B-1 824 -0~ B-1 826 F B-1 8267 F Q rr

FF

B-i1829 ciI B-1830s0 SUBSTMUTSHEEr RULEg28 WO 98/52940 WO 9852940PCT/US98/10Q436 558 Example# 81MEHEET (RULEs6) WO 98/52940 WO 9852940PCTIUS98/1 0436

N-NH

R 2R

N

Examples B-i1838 through B-1861 are prepared from Scaffold C-33 Example# 0 B-1 8398 0 B-1 840 B-1841 B-i1842 IF Q- 0 B-1843F 0 B-1844 F

NQ

WQUT-IEHEET (LE2B) WO 98/52940 PCTIUS98/10436 560 Example#

R

2

RL

0 B-1845

-I

0 B-1846 IF

LO

B-1 848 jF- B-1848 B-1849 B- 850 F B-1851

I

I 0 B-18540 SU6MMStHMETr(RULEW) WO 98/52940 WO 9852940PCT/US98/1 0436 561 Example# R2R B-1 855 B-1 856 IF6 0 NH H N- B___1861 0

F-Q-N

WO 98/52940 WO 9852940PCT/US98/10436

N-NH

R 2

IRR

N

Examples B-i1862 through B-i1885 are prepared from Scaffold R 2

RL

Example# B-1862 F 0 B-i 867 IF-~- 0 B-1 865 I 866_ R SUBBSTffM8HEET (RLE2 WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# VU9BM1TMSHM~(RLUE WO 98/52940 PCTIUS98/10436 564 Example# R2RL B-1879 Sf~J B-i 88 B-1880 F-F6- B- 881 B-1 8843H B-i885 0sunvTEM-ET(RULE6 WO 98/52940 WO 9852940PCT[US98/1 0436 565

N-NH

Examples B-i 886 through B-i 909 prepared from Scaffold C-42 Example# B-1 886 IF-Q- B-1 887 F-0 1 B-1 888 F B-1 889 IF B-1890 F' 0 B-i891 F k 0 B-1892 F R, VUBST=MffSHET(RLE2M WO 98/52940 PCTIUS98/1 0436 Example# 0 B-1 893 N I

VI

B-1894 F B-1895 I 0 B-1897 F 01 B-1897- B-1898 IF

F

B-1909 I N 0 B-i19010

NC

-12 B-1 902 S 6-0 0i SUB 8T-EEU (RE2S) WO 98/52940 WO 9852940PCT/US98/1 0436 567 Example# SUBBMrIUfMTE~(RLUEM WO 98/52940 WO 9852940PCTIUS98/1 0436 Examples B3-i 1910 through B3-i 1933 are prepared f rom Scaffold C-44 Example# 0 B-1 911 F- Q--H 0 B-1 911 F Q-- B-1 914 F 0 B-1913 IF B-1915 B-1916 IF-Q- I 8UBSTM~TSHEEM (RULE2B) WO 98/52940 PCT/US98/1 0436 569 Example# R2

RL

B-1917 B-1918 I 0 F0 B-1919 B-1920 F- 1 B-i 921 F B-1 922 iF H 0 B-1923 F B-1924 I01

F

B-i925 F I u B-1926 s'O 8u6BsfuTE8H(Rr(JEee) WO 98/52940 PCT/US98/10436 Example# SUlsmMMWEU ErRuL--E WO 98/52940 WO 9852940PCTIUS98/10Q436 Examples B-i1934 through B-i1957 are prepared from Scaffold 0-41 Example# 0 B-1 934

F,

B-1935 0 B-1936 IF 0 B-1 938F B-1939 B-1940 F-(j1- q~qM=$HEEr(RULE2) WO 98/52940 WO 9852940PCT/US98/1 0436 Example# aW=MEET (RLE2 WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# -sU8TffTv3T(MufEo) WO 98/52940 PCTIUS98/10436 Examples B-1958 through B-1981 are prepared from Scaffold C-43 Example# 0 B-1958

IF

0

F

B-i 960 B-1961

F

B-1962F B-1963 0 -1964 GUB~flTUTESHE (RLEUsW WO 98/52940 PCT/US98/I 0436 575 Example# R2

RL

oIb B-1966 0 B-1967 IF 0~

I

B-1969

F

LI

B-1970 1F B-1971 B-1972 0

N

B-1 973 s- I S\ 0 B-1974 'S%0 8 UMfTMSHMT~s~Er(RL(ea) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# qXMTMHjEU(RULEW) WO 98/52940 WO 9852940PCT/US98/1 0436 Examples B-1982 through B-2005 are prepared from Scaffold Example# F- 0 B-1 982 S I- 0 B-1 983 s/ 7

-F

B-1984 s 0 B-1 985 ,S: B-1 986 ~Q B-1 987 S/ 0 B-1988 S/ S wjMlTEEV(RULEM2) WO 98/52940 WO 9852940PCT/US98/I 0436 Example# 8UWflTLM8HEEU(RULE~) WO 98/52940 WO 9852940PCT/US98/1 Q436 Example# V8TffWM(ruLEJ% WO 98/52940 WO 9852940PCTIUS98/1 0436 580

H

through B-2029 are prepared from Scat 0 0 110"

F

0 W~EET (ULE 21) WO 98/52940 WO 9852940PCT/US98/1 0436 SjeBMMnTEHW~(RLUE) WO 98/52940 WO 9852940PCTIUS98/I 0436 8S11TUTEHEU(RLE26) WO 98/52940 WO 9852940PCTIUS98/1 0436 583

N-NH

R2'/ \/NH

N

Examples B-2030 through B-2053 are prepared from Scaffold C-36 Example# FeR SuLMMMHM(RuLEU WO 98/52940 PCT/US98/10436 Example# wilot II-IUIESHEEr(RULE26) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# 8BU MSr1JEHW~(RtL2B) WO 98/52940 PCTIUS98/1 0436 586

NH

Examples B-2054 through B-2077 are prepared from Scaffold C-34 Example# R 2Rj GLWM=%EET(MMAaw9I)I WO 98/52940 PCTIUS98/1 0436 587 Example# R2 Rj B-2061 IFQ-i 0 0 B-2062 F 0 1 01 B-2063 0 B-2064 F- 13-2065 IFF 0/ B-2066 B-2067 F0Q-j 01r B-2068 F- N, 0 B-2069 I9

O

B-2070 WS% 0 susrmsHE(Rh0e WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# wwwBim~rEU(RLEM) WO 98/52940 WO 9852940PCTIUS98/1 0436 589 Examples B-2078 through B-2101 are prepared from Scaffold C-57 Example# WO 98/52940 WO 9852940PCTIUS98/1-0436 590 Example#R2 0 B-2085 H 0 B-2086 H 0 B-2087 H0 0 B-2088 H B-2089 H B-2090 H B-2091 H B-2092 HI\ 0 B-2093 Bsz:= B 0\_ MMMMMEt(PULEM) WO 98/52940 WO 9852940PCTIUS98/10Q436 Example# GMB1UTMsEMr(U"Iu) WO 98/52940 WO 9852940PCT/US98/1 0436 R N-NH HN 21-

N

Examples B-2102 through B-2125 are prepared from Scaffold 0-52 Example# SUBSITMBMET

R)L&

WO 98/52940 WO 9852940PCTIUS98/1 0436 593 Example# R2R 0 B-21 09

H~-

B-21 B-21 11 B -2 113H-j B-2114/0 B-2115 B-2116 _II

A__

B-2117 HSO 0 B-2118 Hir-

RLB

WO 98/52940 PCT/US98/I 0436 594 Example# VJBsTffuMsKu(RLu9o WO 98/52940 WO 9852940PCTIUS98/1 0436 Ri N -NH HN2

N

Examples B-2126 through B-2149 are prepared from Scaffold C-56 Example# SUMBIM~EBS*.Er(RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 Example# 8Lj~rff stE=.Ti LE~k WO 98/52940 WO 9852940PCTIUS98/1 0436 597 Example# R2R B-2143 s%: 0

I

0 B-21445 B-2145 Hi6 B-2146 A-VI~ B-2148

H--

0- B-2149

H-

WO 98/52940 WO 9852940PCTIUS98/1 0436 598 N -NH H 2 1 N Rj

R

SN

N

msufusHEMt(MYLEs) WO 98/52940 WO 9852940PCTIUS98/1 0436 599 0 04 0 0 0 0t~rl/ awmucmim WO 98/52940 WO 9852940PCT/US98/1 0436 600 vj~fmmF..-=(MLEw6 WO 98/52940 WO 9852940PCTIUS98/1 0436 N-NH

H

R 2 ZN IRj

NH

0 ammSnTUTESHEMrRUES) WO 98/52940 WO 9852940PCTIUS98/1 0436 UFlUESHW~(RLE WO 98/52940 WO 9852940PCT/US98/11J436 603 0

NH

YN

HN-

0- SUBSWMM1SW-E-r(RULE 28) WO 98/52940 WO 9852940PCTIUS98/1 0436 N -NH

H

N RJ USLTUTMEWMET

(RUEM)

WO 98/52940 PCTIUS98/1 0436 605 WO 98/52940 WO 9852940PCT/US98/I 0436 606 SUBSmSHM(RU..Eff) WO 98/52940 WO 9852940PCT/US98/1 0436 607 N -NH H R2

N-R

N

Examples B-2222 through B-2245 are prepared from Scaffold C-29 Exam ple# R2R SUBTmTEMSHEMr(RULE6) WO 98/52940 WO 9852940PCT[US98/I 0436 Example# 608 0 'i_I 0 0 0 0 00 bA lo aMMUESHMAE0 WO 98/52940 PCT[US98/10436 609 Example# R 2 B-2238 s So 0 B-2240 0 B-2241 s o

NH

B-2242S/I B-2243 Lit B-2244 s/0 0- B-2245 -0 WWM=4EF-(ffUL" WO 98/52940 WO 9852940PCTIUS98/1 0436 su8mmmw(muLE WO 98/52940 WO 9852940PCTIUS98/1 0436 611 SUBSTntn=8HMTr(RULE 26) WO 98/52940 PCTIUS98/10436 612 0 0 HN_ 0. HNg~rTBN~ WO 98/52940 PCT/US98/10436 613 Examples B-2270 through B-2317 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- 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 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 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 USmUHE8HEE(RULEA WO 98/52940 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 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 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 in this manner are listed below.

SUBTMEHEEr (RULEM) WO 98/52940 WO 9852940PCT/US98/1 0436 615 N -R C N 7N 0 iR 2 C H R

B

N-R

0 Calcd. Mass Observed Yield Spec. Mass Spec

M+H

B-2270 NH/ 12 352 353 B-2271 39 432 433 B-2272 FJLNC\/ 26 400- B-2273 F 396 397 B-2274 30 434 435 0 B-2275 43 443H B-2276 I-NH 35 364 365 SU6MflU1SHEUT(RUE26 WO 98/52940 WO 9852940PCTIUS98/1 0436 616)

RB

N-R

0 Catcd. Mass Observed Yield Spec. Mass Spec

M+H

SU3MflTU EEr~(RLUEB) WO 98/52940 WO 9852940PCT/US98/1 0436 617

RB

Observed N-~RC Yed Calcd. Mass Mass Spec >Yed Spec. M+H 6"N N 437 438 0 8 435 436 VJ 4- 450 451 9 456 457 oN. 415 416

H

0- 0 0-NH 381 382

N-

0o 16 410 411 -H 4 483 WO 98/52940 WO 9852940PCT/US98/I 0436 618 RB1

N-RC

Calcd. Mass Observed Yield Spec. Mass Spec

M+H

WO 98/52940 WO 9852940PCTIUS98/1 0436 619

RB

N-fl Cacd. ass Observed N- C Yield sc. Ms Mass Spec 0 NO 5 421 422 s 26 470- 0 -N 0 J" 9 348 L/21 338 339 Jl/ 0 28 398 399

JNH

0

JNH

6 410-

CN

0 363 364 o11 444

H

0 11 418- WO 98/52940 WO 9852940PCT/US98/I 0436 620

RB

N-R Yil Calcd.

ield Spe 0 ~36 42 WO 98/52940 WO 9852940PCT/US98/1 0436 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.

OYU M 11 U IESHEET(ULE6) WO 98/52940 WO 9852940PCTIUS98/1 0436 622

R

N -R R

B

I Observed 2 ~N-R C Calcd. MassMasSe R 2Yield Spec. Ms Se B-2318 T'F 23 426 427 B-2319 F ~NH 23 394- 0 N H B-2321 F ''49 426 427 0 B-2322 iF NH 40 366 367 B-2323 'IF /\'CNH 68 410 411 0 B-2324 ;F 57 456 457 8U8SnME8EEr (RULE26) WO 98/52940 WO 9852940PCT/US98/1 0436 623 IfB11UTSHEM(RULE26) WO 98/52940PCIS/143 PCTIUS98/10436 624

RB

2 N-ci Clcd.MassObserved Yield Scd. M s Mass Spec Spec. M+H 0 7 B-2334 F j41 428 429

NH

B-2335 F H3346 47 B-2339 F /7jj NHN 1 42 518 519 0 B-2338 F 6 4 4 \o B-2339 F 41 58 519 0, B-2340 F 6 4 442 415 0 8UWIWMiEU(RULE26) WO 98/52940 WO 9852940PCTIUS98/1 0436 625

RB

C Observed N- Yield Cc.MasMass Spec Spec. MH

H+

B-2343 'F 29 424 425 0 B-2344 F 1i 33 492 493 B-2345 F NH30 420 421 B-2346 IF N 35 474 475 kNH B-2347 F 34 392 393 0 B-2349 IF 73 517 518 B-2350 IIF I 22 448 449

NH

B-2351 'F 64 486 487 &IJMlEMWr(RULEa2) WO 98/52940 WO 9852940PCT/US98/I 0436 626

RB

I C Calcd. Mass MasseSpec 2R- R- Yield Spec. Spec 0 B-2352 FN 0 41 482 483 0- B-2353 FT CNH6 8 8 B-2354 'F 28 536

N

B-2356 F 29 408 409 0 B-2357 F NH41 43643 B 2358 F H41 451 452 B-2359 jF 57 502 503 B-2360 IFN 46 496 497 0 011 BUBSTE8 EU (R1LE26) WO 98/52940 WO 9852940PCT/US98/1 0436

B

C!Cld.Ms Observed N-R ac.Ms RYield Se. Mass Spec

M+H

B-2361 F 13 476 477 N L B-2362 IFLr 46 493 494 0-

NH

B-2363 FT -o 57 396 397 0 N B-2364 F 0; 61 438 439 N NH B-2365 F ~72 424 425 8Bftl1UTHEEr (RULE 26) WO 98/52940 WO 9852940PCTIUS98/1 0436 628 N -R R

B

N-RC

Calcd. Mass Observed Yield Se. Mass Spec Spec.

M+H

1 B-2366 ,F N34 380 381 0 Cl B-2367 N~52 480 481 0 B-2368 35 407 407 F

I

B-2369 F NC 31 435 436 0 B-2370 N 33 414 415 F I 0 B-2371 F \N 28 366 367 II K B-2372 F \N 37 422 423 aoMMSW.U(RLA-E26) WO 98/52940 PCT/US98/10436

B

R

N-RFl

O

Observed Calcd. Mass Observed Yield cdMass ass Spec Spec. M+H B-2373 Fj 50 432 433

FO

B-2374 F 29 382 383 0 B-2375 F 35 395 396 o i o B-2376 F 36 428 429 -B-2377 F NH 68 438 439 0 B-2378 F /N 55 446 447 0 B-2379 F 3 3 364 365 o B-2380 51 421 422 0 B0 0 B-2381 TFI N 52 429 430 IFII K SUBfSTUTESHEET(RU M) WO 98/52940 WO 9852940PCTIIUS98/10436 630

RB

R-

A>RC

Cald. assObserved Yield Scd. Ms Mass Spec Spec Mi-H B-2382 N 48 407 408

:F

0 B-2384 338 8 B-3438 447 448 o B-2385 F0 N59 498 450 B-2386 'F45 429 430 B-2387 FI 7 B-2388 53 475- B-2389 IFN 33 493 494

N

B-2390 CN 53 487 488 WqMTTSHEUT(RUEM WO 98/52940 WO 9852940PCT/tJS98/10436 631 R

B

N-R Calcd. Mass MasseSpec Yield Spec. M Se B-2391 F No 30 435 436 -Jo 0N 6-23923 !L 57 464 465 B-2393 6F3 5 418 489 B-2394 j'F 59 48843 0 B-2395 L,0 34 594 438

C

B-2397 0 32i 51 N1

'F

B-2:398 81 53 534~'~ t 8 F N 1 qfSBnTTEBHE(RULE 26) WO 98/52940 PCT/US98/10436 632

RB

R

N-RC:

0 Observed Calcd. Mass Osre Yield Sc. Mass Spec Spec. M+H B-2400 F NFI 34 381 382 0 B-2401 K 32 378 379 o N B-2402 71 519 520 0 Ni B-2403 N68 527 528 0 B-2404 \Y N N. 62 447 448 0 B-2405 F 71 536 537 B-2406 47 394 395 B-2406

N

0 B-2407 i 65 508 509

I

B-2408 34 495 496 susrr ESHr(RLE2) WO 98/52940 WO 9852940PCTIUS98/I 0436 633

B

R

Cald. assObserved Yield.S Mass Mass Spec Yield Spec.

M+H

47 448 449 IF S B-2410 B-2411 FI 81 489 490 B-2412 F 'N~i 54 409 410 B-213F \Z-N3~37 493 494 $UB~nmsr$%EU(RuLE2% WO 98/52940 WO 9852940PCT/US98/1 0436 634

N-

N

N

RB

I Observed R~RC Yield al.MssMass Spec Spec. MH B-2414 F 14 473 474 0 B-2415 F 19 421 422 F Q i-jtH B-2417 F\ NH29 414 415 I 0 B-2418 /6 420 421 F 6 0 B-2419 F /NH10 454- IF_ CF 3: B-2420 F NH5 442 443 WSffMTEE(RULEW WO 98/52940 WO 9852940PCT/UJS98/I 0436

RB

N-Rc Cacd. assObserved RzYield Scd.Ms Mass Spec

NH+

0 B-2422 I47 420 421 N H B-2423 F/53 400 401 0 B-2424 F Is"NH1 400 401 B-2425 F 18 522 523 iF 3 C B-2426 F 38 464 465 Br 0 B-2427 F NHcI~ 26 468 469 0 B-2428 F22 432 433 B-2429 F' NI41 404 405 F t WO 98/52940 WO 9852940PCT/US98/1fi436 636

RB

N-CI a.Ms Observed RYield CldMasMass Spec Spec. MH 8-2430 NH 15 476 477

F

NH

B-2431 /-0,1O 6 446 447 0

SNH

B-2432 F ~F 37 404 405

F

B-2433 F/ NH 8 428 429 0 B-2434 F 13 476 477 B-2435 23 442 443

NNH

B-2436 F 5 486 487 0

NH

B-2437 0F/ 4 492 493 0 B-2438 IFNH 58 422 423 F qjffi=&-Er

(RLEW)

WO 98/52940 WO 9852940PCTIUS98/ 1436 637

RB

I C Observed 2N -R Calcd. Mass R Yield Se. Mass Spec

M+H

F I B-F3 F 12__454_455

NNH

B-2440 F ~8 521 522 0 B-2441 F J~6 443 444 B-2442 F37 514 515 B-2443 -15 518- B-2444 IF 11 I 552- B-2445 F 33 517 518 *0 13-2446 F70 500 501 F oc s-K.

o F. B-2447

F

S 489 L I aJ~nurSHEU(MULI) WO 98/52940 WO 9852940PCTIUS98/1 0436

RB

Observed

R

2 N-C Calcd. MassMasSe R- Yield S Mes. Spec B-2448 'F51 522 523 0 B-2449 0 19 512 513 I 0 A 0 B-2450 'F~/Iy 16 538 539 NH 0 B-2451 71 500 512 B-43F e 0 CF 6 B-2452 /713 520 'F1 0 B-2453 NH /6 1 53353 FN 'F3 0 SU8BTff1SM8WME(RUL2) WO 98/52940 WO 9852940PCT/U598/1 0436 639

RB

C Observed 2 ~Yield aldMssMass Spec R N~RC~ Spec. MH _0 '0 B-2457 F H55 540- 0 B-2458 F 22 488 489 B-49F obN 8-45 486 487 B-2460 \AN 13 534 535 B-2461 F H1?13 542-

HN,&

8LJBSTffE~ro (RULE 26) WO 98/52940 PCT/US98/10436 640 Example C-1 4- (4-PYRIDYL) (4-FLUOROPHENYL) PYRAZOLE

N-NH

NH

2

F

N

l-(4-fluorophenyl)-2-(4-pyridyl)-l-ethanone. 4picoline (40 g, 0.43 mol) was added to a LiHMDS solution (0.45 mol, 450 mL of a 1.0 M solution in THF) over minutes at room temperature (a slight exotherm was observed) The resulting solution was stirred for 1 h.

This solution was added to ethyl 4-fluorobenzoate (75.8 g, 0.45 mol, neat) over 1 h. The mixture was stirred overnight (16 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 SUBfm

EHEET(RULES)

WO 98/52940 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%): H NMR (CDC1 3 8 8.58 J 5.7 Hz, 2H), 8.02 (dd, J 8.0, 2H), 7.12-7.21 4H), 4.23 2H) 19F NMR (CDC1 3 6 -104.38 LC/MS, tr 2.14 minutes (5 to acetonitrile/water over 15 minutes at 1 mL/min, at 254 nm at 50 0 C) M+H 216; High Resolution MS Calcd for

C

23

H

20

N

4 0 2 F 216.0825. Found: 216.0830 (A mmu N-benzyloxycarbonyl-5-aminomethyl-4-(4-pyridyl)-3- (4-fluorophenyl) pyrazole. A 3L round bottom flask 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 g, 0.28 mol) was dissolved in 600 mL of THF and added to the stirred mixture at room temperature. A yellow 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 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 the layers were separated. The aqueous layer was extracted with EtOAc (3x300 mL). The organic layer was ut I MES I H EI RMOULE" WO 98/52940 PCT/US98/10436 642 dried (Na 2 S0 4 filtered and evaporated to leave 157 g of a crude reddish oil.

The oil was suspended in CH 2 C12 and filtered to remove any insoluble material (DCU, hydrazone of the monoketone). The solution was split into two portions and each portion was chromatographed (Biotage 75L, 3% EtOH/CH 2 C12 then 6% EtOH/CH 2 C12) The appropriate fractions were concentrated (some contamination from the monoketone and the hydrazone) from each portion to leave 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): IH NMR (DMF-d 7 5 13.36 1H), 8.57 J 5.8 Hz, 2H), 7.16-7.52 11H), 5.11 2H), 4.48 J 5.4 Hz, 2H) "F NMR (DMF-d 7 5 -114.9 -116.8 (split fluorine signal is due to the pyrazole tautomers); LC/MS, tr 3.52 minutes (5 to 95% acetonitrile/water over minutes at 1 mL/min, at 254 nm at 50 0 M+H 403; High Resolution MS Calcd for C 23

H

20

N

4 0 2 F 403.1570.

Found: 403.1581 (A mmu 1.1).

5-aminomethyl-4-(4-pyridyl)-3-(4-fluorophenyl) pyrazole. To a 1L Parr bottle was added 7 g (17.4 mmol) 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 E101) 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 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 suBs1Tff= HEE(RLU26) WO 98/52940 PCT/US98/1Q436 643 the filtrate was concentrated to give 4.5 g of an offwhite solid IH NMR (DMSO-d 6 6 8.52 J 4.63 Hz, 2H), 7.36 (dd, J 5.64, 8.1 Hz, 2H), 7.16-7.30 (m, 4H), 3.79 2H); 19F NMR (DMSO-d 6 6 -114.56 LC/MS, tr 1.21 minutes (5 to 95% acetonitrile/water over minutes at 1 mL/min, at 254 nm at 50 0 M+H 269 m/z; High Resolution MS Calcd for C1 5 Hi 4

N

4 F 269.1202.

Found: 269.1229 (A mmu 2.7).

The following pyridylpyrazoles (C-2 through C-21, Table C-l) were prepared according to the experimental procedure described above for example C-1.

Table C-l.

Exampl Structure MW, M IH NMR (solvent), ppm e No. H Calculat ed Found C-2 N-NH 323.1672 (DMF-d 7 8.77 J F -H 323.1670 4.4 Hz, 2H), 7.60 2H), N 7.44 J 4.4 Hz, 2H), 7.35 2H), 3.22 (bd, 2H), 3.01 (septet, J 5.3 Hz, 1H), 2.74 2H), 1.95 4H) susIMnflJEUSMSEr (LEM WO 98/52940 WO 9852940PCTIUS98/1 0436 644 N-NH 282.127 (DMF-d 7 8.77 (br s, I NH 2 F cH 3 2H), 7.64-7.62 (mn, 2H), ~N282.1245 7.50 (br s, 2H), 7.38-7.34 El) (mn, 2H), 4.40-4.37 (mn, 1H), 1.56 (br s, 3H) N-NH 282.127 (DMF-d 7 8.77 (br s,

NH

2 F -H 3 2H), 7.64-7.62 (mn, 2H), N282.1147 7.50 (br s, 2H), 7.38-7.35 El) (mn, 2H), 4.40-4.37 (in, 1Hi), 1.57 (br s, 3H) N-NH 323.1672 (DMSO-d 6 8.56 (br, 2H),

NH

F -323.1687 7.32 (mn, 2H), 7.18 (mn, N 4H), 2.91 (mn, 2H), 2.71 (mn, 2H) 1. 88 (in, 1H) 1. (mn, 2H), 1.40 (mn, 2H) I-N NH 2 39(DMSO-d 6 8.46 J F -359 4.6 Hz, 2H), 7.32-7.13 (in, 'N 7H), 6.98-6.96 (mn, 4H), 4.06 J =7.0 Hz, 1H), 2.98-2.95 (in, 2H)

NH

2 35 (DMSO-d 6 8.46 (d,J F -359 5.4 Hz, 2H), 7.32-7.28 (mn, N 2H), 7.20-7.12 (in, 6.98-6.96 (in, 4H), 4.06 J 7.0 Hz, 1H), 2.98- 2.94 (in, 2H) N-NH 313.1465 (DMSO-d 6 13.83 (bs,

NH

2 F 31.42 d z

OCH

3 3319 N,86 d z N 2H), 8.33 (bs, 1H), 7.33 (in, 6H), 4.44 (in, 1H), 3.63 (in, 2H), 3.27 3H) =M=EiEU(RJLEW) WO 98/52940 WO 9852940PCTIUS98/1 0436 C-9 I 313.145 313.1457 (DMSO-d 6 8. 55 (dd, J 1.5, 4.4 Hz, 2H), 7.37- 7 .32 (in, 2H) 7.26 (dd, J 1.6, 4.4 Hz, 2H), 7.22- 7. 16 (in, 2H) 4. 06 J 6. 5 Hz, 1H) 3. 49 J 6 .6 Hz, 2H) 3 .20 3H) 1 3541 354 (DMSO-d 6 13 .03 (bs, 1H), 8.50 (dd, J=1.6, 2.7 Hz, 2H), 7.58 (bq, J=4.3 Hz, 1H), 7.3 2H), 7.12-7.21 (mn, 4H), 3.77 J= 6.3 Hz, 1H), 2.45 J=4.5 Hz, 3H), 1.97 J= 7.4 Hz, 2H), 1.85 Cdt, J=7.3, 7.1 Hz, 2H) 1- I .4c-11

N-NH

NH 2 CONHCH

N

354 354 (DMSO-d 6 13 .03 (bs, 1H), 8.50 (dd, J=1.6, 2.7 Hz, 2H), 7.58 (bq, J=4.3 Hz, 1H), 7.3 2H), 7.12-7.21 4H), 3.77 J= 6.3 Hz, 1H), 2.45 J=4.5 Hz, 3H), 1.97 J= 7.4 Hz, 2H), 1.85 (dt, J=7.3, 7.1 Hz, 2H) 59 (DMSO-d 6 8.53 J= 63 5.0 Hz, 2H), 7.37-7.32 m 2H), 7.21-7.17 (mn, 4H), 2.83(d, 1 6.0 Hz, 2H), 2.77 Cd, J =6.0 Hz, 2H) (DMSO-d 6 8.53 J 5.4 Hz, 2H) 7.34 (dd, J= 5.8, 8.2 Hz, 2H), 7.18 SUBSfUTESHET (RJLE26) WO 98/52940 WO 9852940PCTIUS98/1 0436 646 (dd, J 5.8, 9.8 Hz, 4H), 2 .68 J 7. 3 Hz, 2H) 2. 52 (in, 2H) 1. 64 (mn, 2H) C-14 cI N-NH N2284.0829 CD 3 OD): 8.74 (br, 2H), -284.0806 7.77 (br, 2H), 7.45-7.58 I(in, 3H), 7.30-7.40 (in,

N

1H), 4.43 2H) C1 NNH 2 285 (DMvSO-d 6 8.53 (br, 2H), cl 285 7.56 (br, 2H), 7.26 (in, NI 4H) 3.75 (br, 2H)

N

C-16 N-NH 329, 331 (DMSO-d 6 8.53 J I NH 2 Br -329, 331 4.4 Hz, 2H), 7.42 J N7.9 Hz, 2H), 7.34 J

N

Hz, 2H), 7.24 J 4.6 Hz, 2H), 3.76 (bs, 2H) 0-17 CI N-NH 339 (DMSO-d 6 :8.53 J NH 339 4. 3 Hz, 2H), 7.33 (mn, 3H), N7. 19 J =4.6 Hz, 2H),

N

7.14 J =7.3 Hz, 1H), 3.23 (in, 2H), 2.88, (in, 3H), 1.92, (mn, 3H), 1.70 (in, 1H) C-18 N-NH 339 (DMSO-d 6 8.57 J= Ci-NH 339 4. 6 Hz, 2H) 7.41 J 'N 8.3 Hz, 2H), 7.29 J Hz, 2H), 7.20 J 4.8 Hz, 2H), 3.18 (bd, 2H), 2.88 (mn, 1H), 2.76 (in, 2H), 1.82 (br, 4H) C-19 N-NH 383, 385 (DMSO-d 6 8.56 (br, 2H), Br -NH 383, 385 7.52 (br, 2H), 7.14-7.29 N (mn, 4H), 2.99 (br, 2H), SUBSTWJESHME(MUE26) WO 98/52940 WO 9852940PCT/US98/1 0436 2. 71 (br, 1H) 2. 51 (br, 2H), 1.68 (br, 4H) 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 C-1 above.

Table C-2 STffSME(RLE~d WO 98/52940 WO 9852940PCTIUS98/1 0436 VjBMfT=&EBEET(RLEW) WO 98/52940 WO 9852940PCTIUS98/1 0436 VU6STff=ESHET (RULEM2) WO 98/52940 WO 9852940PCTIUS98/1 0436 650 Example C-49 F

CH

N

Step A The pyrazole (2.60 g, 10.3 mmol) from example 4 was suspended in 52 mL of dichioroethane and 52 mL of 2 .5 M SUBST8jEETM(RULEM) 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 temperature for 4 h. The mixture was poured onto 200 mL of CH 2 C12 and 200 mL of H 2 0. The phases were separated and the organic phase was washed with water (1x100 mL) and brine (1x100 mL). The organic layer was dried over Na 2

SO

4 and was filtered. The solvent was removed to leave 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 Step B 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 with propylene oxide (10.3 mmol) and was stirred for Ih 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 Et 2 0 and the title compound Example C-49 was isolated by filtration to afford 3.0 g of an off-white solid Mass spec: M+H cald: 312; found 312. 1H NMR (DMSO-d6): 8.81 J 6.4 Hz, 2H), 7.73 J Mu8sDT=UE8HEET(RULE WO 98/52940 WO 9852940PCTIUS98/1 0436 652 8 Hz, 2H) 7. 40 (in, 2H) 7.23 J 8. 5 Hz, 1H) 5.16 2H), 2.40 3H).

Example N.=N /'--C02H F

H

N.

According to the procedure described above in Example C- 49, Example C-50 was also prepared starting from fluorophenyl) -1H-pyrazole-4-yllpyridine. Mass spec: M+H cald: 298; found 298. 1H NMR (DMSO-d6): 8.75 J 6.4 Hz, 2H) 8.68 1H) 7.78 J =6.6 Hz, 2H), 7.52 (dd, J 4, 8.5 Hz, 2H) 7.31 Ct, 1 8.9 Hz, 2H), 5.16 2H).

Example C-51

Z'-CO

2

H

N-N

F

Boo

NI

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.

8UBMTm=rEEE(RUM2B) WO 98/52940 PCT/US98/10436 653 Example C-52 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 from -78 OC to 50 OC 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 Nhydroxysuccinimide. The reaction is allowed to stir from minutes to 48 hours during which time the temperature may range from -20 OC 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.

Step B: A solution of the pyridyl monoketone in ether, THF, tBuOH, or dioxane is added to a base chosen from but aUBTnmUESHEET(RULM) WO 98/52940 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 solution in THF, ether, or dioxane to the monoketone anion while the temperature is maintained between -50 °C and 50 OC. The resulting mixture is allowed to stir at the specified temperature for a period of time from minutes to several hours. The resulting pyridyl diketone intermediate is utilized without purification in Step C.

0 0

HN

Cbz H

N

Step C: The solution containing the pyridyl diketone 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 HN03. 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 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 chromatography or crystallization.

=8sMueWTUTE8UEETRULEM) WO 98/52940 PCT/US98/10436 Cb< 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

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 SUBtn8tJESKE§r (RLE 26) WO 98/52940 WO 9852940PCT/US98/1 0436 656 C-54 N-NH

H

2 N

'NN,

N

N-NH

H

2 N N NB

N

C-56 H 2 N N-NH

N-

C-57 HN N-NH

~H

N

N

C-59 H 2 N N-NH N-o

N

Exampe C-N HteN N-HAH: 7o rtce yiyprzl stetdwt bezadeyd i mtylnechordeatromtepeatrei 9N SUBBffM$TEHEE(RULE 26) WO 98/52940 PCT/US98/10436 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.

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 under nitrogen at temperatures ranging from -78 to -20 OC.

A base such as LDA, n-BuLi, or LiHMDS is added dropwise to the mixture which is then stirred for an additional minutes to 3 h. Two equivalents of a methyl iodide 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 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 purified 8UBMMTuMtSHMEO(UEM)01 WO 98/52940 WO 9852940PCTIUS98/1 0436 Step B N-NHBoc Ph J/ L'

NH-

2 1) Base 2) Mel 3) Acid, H 2 0 Example C-61

N-NH

Example C-61 is prepared according to the method described in example C-60, substituting 1,4-dibromobutane for methyl iodide.

Example C-62 SULWTff=%EE7(RULE26) WO 98/52940 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.

Example C-63 The synthesis of compound C-63 starts with the 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 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 cleaved with ceric ammonium nitrate (CAN) to give the title compound C-63.

8ussTmUTEsHEE(RULEM) WO 98/52940 WO 9852940PCTIUS98/10436 660 OMe0 0 OMe OMe

H

2 N F4 J Br1 1.0O Bri -6 Pd 2 (dba) 3 Na0Bu-t 0 2. AC 2 0 0 OMe B77 B78 0 0 IK Oe (CH-1),COCH[N(CH 3 2 2 09

N-N-

NH

2

NH

2

CA

F 0/ 0CA N 0 \OMe MeO B81

N-NH

F 0

NH

0 C-63 Example C-64

N-NH

NH

2 7F 0

N,

0

H

Using the method described in Schemes C-6 and C-7, Example 64 is prepared.

8u68TMJTEBHE-(RLEff WO 98/52940 WO 9852940PCTIUS98/I 0436 661 Example Using the method described in Schemes C-6 and C-7, Example 65 is prepared.

Example C-66 Using the method described in Schemes C-6 and C-7, Example C-66 is synthesized, substituting N-2,4dimethoxybenzyl-4-bromopyridone for B78.

8Uun1JrEHET(RuLI@) WO 98/52940 WO 9852940PCTIUS98/10436 662 Example C-67

NH

2 Using the method described in Schemes C-6 and C-7, Example C-67 is synthesized, substituting N-2,4dimethoxybenzyl-4-bromopyridone for B78, and substituting N-Boc-glycyl N-hydroxysuccinimide for B82.

Example C-68

N-NH

.NH

2 Using the method described in Schemes C-6 and C-7, Example C-68 is synthesized, substituting N-2,4dinethoxybenzyl-4-bromopyridone for B78.

S9UBSfTUF8HEE(RLE2M WO 98/52940 WO 9852940PCTIUS98/1 0436 663 Example C-69 Using the method described in Schemes C-6 and C-7, Example 69 is prepared, substituting N-Boc-nipecotyl Nhydroxysuccinimide for B83.

Example N-NH H F 0

H

Using the method described in Schemes C-6 and C-7, Example 70 is prepared, substituting N-Boc-nipecotyl Nhydroxysuccinimide for B83.

Example C-71 WU9OMM1SHEMT (LE 26) 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-3bromomaleimide for B78.

Example C-72 Using the method described in Schemes C-6 and C-7, Example 72 is prepared, substituting N-methyl-3bromomaleimide for B78, and substituting N-Boc-nipecotyl N-hydroxysuccinimide for B83.

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

WM~;Kf =v6HEMT(RLEX22U' WO 98/52940 PCT/US98/10436 665 Biological data from compounds of Examples B-0001 through B-1573 and of Examples B-2270 through B-2462 are shown in the following tables.

In vitro P38-alpha kinase inhibitory data are shown in the column identified as: "P38 alpha kinase IC 5 0 uM or inhib cone. (uM)" 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 identified as: "U937 Cell ICs 0 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 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 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: "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 SBSu TESHEET(RULE26) WO 98/52940 PCT/US98/10436 666 indicates the number of hours before LPS challenge when the compound is administered.

ausn s HEETRUL WO 98/52940 WO 9852940PCTIUS98/1 0436 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model Rat LPS Model 1C50,uM or or TNF inhib @d dose inhib @dlose inhib~conc. (uM) inhib~aconc. (uM) @predlose time @predose time Example# B-0001 53.0%@1 .OuM 40.0% @1 .OuM B-0002 71.0%@1.OuM 28.0%@10.OuM B-0003 70.0%@1.OuMI 76.0% 10.OuM B-0004 80.0%@1.OuM 4.6lu M B-0005 95.0%@1.OuM 2.97uM B-0006 82.0%@1.OuM 80%/@10.OuM B-0007 74.0%@l1.OuM 85.0% @1 0.OuM B-0008 42.0%@ 1 .OuM 1 0.OuM B-0009 0.04 uM B-001 0 0.52 uM B-001 1 0.03 uM B-001 2 30.0%@1.OuM 44.0% @1.OuM B-001 3 70.0%@1.OuIM 84.0%@10.OuM B-001 4 79.0%@1.OuM 80.0%/@10.OuM B-aol 5 82.0%@ 1.OuM 80.0%@ B-001 6 94.0%@1.OuM 3.98uM B-0017 56.0%@l1.OuM 79.O%@ 10.OuM B-001 8 60.0%@ 1.OuM 59.0%@ B-0019 84.0%@ 1.OuM 1 00.0%@ 10.OuM B-0020 73.0%@1.OuM 81.0%@10.OuM B-0021 68.0%@l1.OuM 76.0%@ 10.OuM B-0022 69.0%@1.OuM [email protected] B-0023 90.0%@1 .OuM 77.0%@1O.OuM B-0024 94.0%@1.OuM 52.0%@1.OuM B-0025 89.0%@1 .OuM 79.0%@ 1 .OuM B-0026 96.0%@1.OuM 3.27uM B-0027 94.0%@l1.OuM 1 1 .OuM B-0028 69.O%@1.OuM 45.0%@10.OuM B-0029 91.0%@1.OuM B-0030 92.0%@1 .OuM 75.0%/@1O.OuM B-0031 94.0%@1.OuM 100.0%@10.OuM B-0032 94.0%@1.OuM B-0033 97.0%@l.OuM 10.0uM B-0034 95.0%@1.OuM 10.0uM B-0035 94.0%@1.OuM 1 O.OuM B-0036 92.0%@1.OuM 8.24uM B-0037 91.0%@1.OuM 86.0%0/@10.OuM 5-0038 71.0%@1.OuM 84.0%/@10.OuM B-0039 89.0%@1 .OuM 72.0%@ 10.OuM B-0040 93.0%@1.OuM B-0041 65.0%@1.OuM 66.0%@10.OuM 004 2 194.0%@1 .OuM 2.76uM &SSMrIUTEBWiEJr (RULs) WO 98/52940 WO 9852940PCT/US98/1 0436 P38 alpha kinase U937 Cell 1C50,uM Mouse LPS Model Rat LPS Model or or. TNF inhib Ca dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-0043 0.22 uM O.54uM B-0044 0.14 uM 0.l9uM B-0045 94.0%@1.0uM 1.01UM B-0046 96.0%@1.OuM 54.0%@1.OuM B-0047 94.0%@1.OuM 74.0%@10.OuM B-0048 94.0%@1.OuM 76.0%@10.OuM B-0049 88%@1.OuM 33.0%@1.OuM 8-0050 73%@l.OuM 34.0%@1.OuM B-0051 3.3uM 2.l5uM 47%@lO0mpk@-6h 79%@3mpk@-4h B-0052 92%@1.OuM 15.0%@1.OuM B-0053 95%@l.OuM 34.0%@l.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 B-0065 83%@1.OuM 21.0%@1.OuM B-0066 94%@1.OuM 28.0%@1.OuM B-0067 91%@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 32.0%@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 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 8B-0083 0.22uM 6.5luM 8B-0084 56%@1.OuM I30.0%@1.OuM suSUTMHEU(RUi2) WO 98/52940 WO 9852940PCT/US98/1 0436 P38 alpha kinase U937 Cell 1C50,uM Mouse LIDS Model Rat LIDS Model or or TNF inhib dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-0085 83%@l.OuM 21.0%@1I.OuM B-0086 91%@1.0uM 37.O%@1.OuM B-0087 O.55uM 2.26uM 38% @3Ompk@-6h B-0088 96%@1.OuM 9.0%@1.OuM B-0089 0.O4uM 3.33uM B-0090 98%@1 .OuM 52.0%@1 .OuM B-0091 96%@1.OuM B-0092 97%@1.OuM 34.0%@1.OuM B-0093 3.18 uM 1.25uM 30%@30mpk@-6h B-0094 96%@1.OuM 52.0%@1.OuM B-0095 98%@1I.0uM 38.0%@1 .OuM B-0096 91%@1.OuM 22.0%@1.OuM B-0097 72.0%/@10.OuM 38.0%@1.OuM B -0098 66.0%@1O.0uM 12.0%@1.OuM B-0099 43.0% @1.OuM >1.OuM B-01 00 75.0% @1.0uM 5.OuM B-0101 71.0%/ @1.OuM 2.11luM B-01 02 81.0%@1.OuM 15.0%@1.OuM B-0103 71.0%@1.OuM 6.0%/@1.OuM B-01 04 56.0% @1.OuM 2.78uM B-01 05 78.0%@1.OuM B-0106 62.0%@1 .DuM B-01 07 0.27uM B-01l08 61.0%@1.OuM 4.85uM B-0109 45.0%@1.OuM 19.0%@1.OuM B-01 10 66.0%@1.OuM 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.O%@1.OuM 2.0%@1.OuM B-01 16 73.O%@1.OuM 35.0%@1.OuM B-01 17 0.46 uM 1.78 uM 30%@30mpk@-6h B-01 18 1.18 Um 1.29 uM B-01 19 89.0%@10.OuM B-0120 0.008 uM 0.21 uM 77%@lO0mpk@-6h 70%@a3mpk@-4h B-0121 79.O%@1.OuM 1.22uM B-01 22 79.0%/@10.OuM 2.0%/@1.OuM B-0123 59.0%@1.OuM >1.OuM B-0124 73.0%@.OZM 15.0%@1.OuM [B0125 70.0% 10.OuM 17.0%@ .OuM 8- 0126 66.O%@l1.OLIM 1.57uM

SUBBTTUEBHEEI(RULEB)

WO 98/52940 WO 9852940PCTIUS98/I 0436 670 P38 alpha kinase U937 Cell IC50,uM Mouse LIPS Model Rat LIPS Model or or. TNF inhib dose inhib @dlose inhib~conc. (uM) inhib~conc. (uM) @predlose time @predose time Example# B-01 27 82.0%@1 .OuM B-01 28 78.O%@1.OuM 1.81u B-01 29 51.0%@1.OuM B-01 30 69.0%@1 .0uM 58.0%@1 .OuM B-0131 43.0%@1.OuM 46.0%@1.OuM B-0132 76.0%@1.OuM 8.0%@1.OuM B-0133 51.O%@1.OuM B-01 34 60.0%@1.OuM B-01 35 78.0%@1.OuM B-01 36 77.O%@1.OuM 44.0%@1.OuM B-0137 41.0%@1.OuM 37.0%@1.OuM B-0138 50.0%@1.OuM 32.0%@1.OuM B-0139 54.0%@10.OuM 17.0%@1.OuM B-0140 67%@10.OuM 9.0*%@1.OuM B-0141 78.0%@1.OuM 10.0%@1.OuM B-0142 86.0%@1.OuM -12.0%@1.OuM B-01 43 42.0% @1.OuM 3.63uM B-0144 86.0% @1.OuM 43.0%@1.OuM B-01 45 54.0% @10.0uM 12.0% @1.OuM B-0146 77.0% @1O.OuM 28.0% @1.OuM B-0147 44.0% @1.OuM 22.0% @1.OuM B-0148 51.0% @1.OuM 1.CluM B-0149 1.15 Um 10.0OUm B-01 50 27.0% @10.OuM 35.0% @1.OuM B-0151 43.0% @1.0uM 30.0% @1.OuM B-01 52 51.0% @1.OuM 24.0% B-0153 57.0% @1.OuM 21.0% @1.OuM B-01 54 65.0% @10.OuM 14.0% @1.OuM B-0155 40.0% @10.OuM 26.0% @1.OuM B-01 56 42.0% @10.OuM 13.0% @1.OuM 8-01 57 48.0% @10.OuM @1.OuM B-01 58 58.0% @10.OuM 39.0% @1.OuM B-0159 54.0% @10.OuM 5.0% @1.OuM 8-01 60 59.0% @10.OuM 26.0% @1.OuM B-0161 72.0% @10.OuM 13.0% @1.OuM B-01 62 23%@1.OuM 2.05 uM B-0163 20.0% @10.OuM 10.0% @1.OuM B-0164 37.0% @10.OuM 20.0% @1.OuM B-0165 70.0% @10.OuM 19.0%/ @1.OuM B-0166 45.0% @10.OuM 37.0% @1.OuM B-0167 40.0% @1.OuM 37.0% @1 8-01C68 44%@1.OLIM 2.36 uM siamff maiamwERM WO 98/52940 WO 9852940PCTIUS98/1 0436 P38 alpha kinase U937 Cell IC50,uM Mouse LIPS Model Rat LPS Model or or. TNF inhib Ca dose inhib @adose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time B-01 69 143.0% @1.OuM 21.0% @1.OuM B-0170 43.0% @1.OuM 30.0% B-01 71 61.0% @1O.OuM 21.0% O1.OuM B-01 72 16.0% @1O.OuM 11.0% @1.OuM B-01 73 33.0% @1O.OuM 48.0% @1.OuM 8-01 74 54.0% @1O.OuM 43.0% @1.OuM 8-01 75 41.0% @1O.OuM 31.0% B-01 76 50.0% @1.OuM 30.0% @1.OuM B-01 77 70.0% @1 0.OuM 27.0% @1 .OuM B-01 78 12.0% @10.OuM 35.0% @1.OuM B-01 79 27.0% @10.OuM 37.0% @1.OuM B-01 80 34.0% @10.OuM 23.0% @1.OuM B-01 81 5.0%@l.OuM 2.0% @1.OuM B-0182 39.0% @10.OuM 40.0% B-01 83 12.0% @10.OuM 34.0% @1.OuM 8-0184 66.0% @10.OuM 17.0% @1.OuM B-01 85 65.0% @10.OuM 25.0% @1.OuM B-01 86 40.0% @1.OuM 25.0% @1 .OuM B-01 87 4.0% @10.OuM 14.0% @1.OuM B-01 88 70.0% @10.OuM 35.0% @1.OuM B-01 89 42.0% @10.OuM 9.0% @1.OuM B-01 90 59.0% @10.OuM 31.0% @1.OuM B-0l191 40.0% @1 .OuM 29.0% @1 .OuM B-01 92 12.0% @10.OuM 47.0% @1.OuM B-0193 0.54 uM 6%@1.OuM B01 94 1.31 uMl B-01 95 1.03 uM 55%@1.OuM B-0196 2.24 uM >1.OuM B-01 97 2.0 uM 14%@1.OuM B-01 98 1.2 uM B-01 99 1.34 uMl 3%@1.OuM B-0200 1.31 uM 16%@1.OuM B-0201 0.29 uMl 59%@1.OuM B-0202 0.55 uMI 2.26 uM B-0203 0.16 uMI 65%@1.OuM B-0204 0.21 uM 48%@l.OuM B-0205 0.096 uMl 54%@1.OuM B-0206 5.76 uM 14%@1.OuM B-0207 0.12 uM -52%@1.OuM B-0208 0.067 uMI >1.OuM B-0209 0.29 UM 8%@1.OuM 8- 0210 0.057 uMI 67%@1.OuM1 mlm)TE8HW(RLE2B) WO 98/52940 WO 9852940PCTIUS98/1 0436 672 P38 alpha kinase U937,Cell IC50,uM Mouse LPS Model Rat LPS Model or% or TNF inhib 0 dose inhib @dose inhib~conc. (uM) inhib@conc. (uM) @predose time @predose time B-0211 0.25 tiM 30%@1.OuM B-0212 0.12 tiM -28%@1.OuM B-0213 0.31 ulM 39%@1.OuM B-0214 0.16 uM 50%@1.OuM B-0215 0.11 uM 51%@1.OuM B-0216 0.56 uM >1.OluM B-0217 0.55 tiM >1.OuM B-0218 0.53 uMV 18%@1.OuM B-0219 0.91 tiM 18%@1.OuM B-0220 0.13 uMl 40%@1.OuM B-0221 2.4 uM >1.OuM B-0222 0.4uM 29.0%@1.OuM B-0223 O.2uM 1.O%@1).OuM B-0224 <0.lum B-0225 0.047uM 37.0%@ B-0226 0.074uM 20.0%@l1.OuM B-0227 0.045uM 1.0%@1 B-0228 0.l1iiM B-0229 <0.l Um 61.0%@1.OuM B-0230 0.04luNI 30.0%@1.OuM B-0231 0.055uM 40.0%1 .OuM B-0232 0.048uM B-0233 0.095uM B-0234 0.lluM -68.0%@1.OuM B-0235 1.31luM 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%@l.OuM B-0239 5.73uM 84.0%@1.OuM B-0240 0.2uM 70.0%@1 .OuM B-0241 0.1u 4N -5.0%@1.oum B-0242 <091 um 78.0%@1.OuM B-0243 0.O39iiM 53.0%@1 .OuM B-0244 0.O2uM 57.0%@l1.OuM B-0245 0.l3uM 24.0%@1.OuM B-0246 <0.1 uM >1.OuM B-0247 0.082uM 75.0%@1 .OuM B-0248 <0.l uM 11.0%@ 1.OuM B-0249 <0.l um 75.0%@1.OuM B-0250 0.28tiM 36.0%@1 .OuM IB-0251 O.31uM 1.O%@1.OUM B0252 0.041 UM 54.0%@1 .OuM

SUBSIMUTESHM~(RULEMOV

WO 98/52940 WO 9852940PCTJUS98/10436 673 P38 alpha kinase U937 Cell IC50,uM Mouse LPDS Model Rat LPS Model or or TNF inhib dose inhib @dose inhib~conc. (uM) inhib@conc. (uM) @predose time @predose time B-0253 0.061luMV 74.0%@1.OuM 8-0254 O.l2uM -59.0%@1.OuM B-0255 0.32uM 68.0%@1.OuM B-0256 <0.1 uMI 88.O%@ 1.OuM B-0257 1.71luMV 11.0%@1.OuM B-0258 0.37uM 63.O%@1 .OuM B-0259 O.35uM 58.O%@1 .OuM B-0260 0.56uM 23.0%@1 .OuM B-0261 0.49uM 23.O%@1.OuM B-0262 0.41luMV 89.0%@1.OuM B-0263 0.62uM 64.0%@l1.OuM B-0264 O.l4uM 18.0%@1.OuM B-0265 0.92uM 24.0%@l1.OuM B-0266 O.25uM 24.O%@1 B-0267 O.48uM B-0268 3.39uM B-0269 9.81lUm 19.0%@ B-0270 5.79uM B-0271 7.55uM 12.0%@1 .OuM B-0272 1.8luMI B-0273 5.O3uM 13.0%@1.OuM B-0274 2.68uM 25.O%@1 .OuM B-0275 2.67uM 33.0%@1 .OuM B-0276 1.25uM 26.0%@1 .OuM B-0277 0.68uM 34.O%@1 .OuM B-0278 1.26uM 36.0%@1.OuM B-0279 1.39uM 33.0%@1 .OuM B-0280 0.86uM 1 8.0%@l1.OuM B-0281 7.37uM 24.0%@1 .OuM B-0282 0.75uM 38.0%@1 .OuM B-0283 6.66uM 29.0%@1 .OuM B-0284 0.083uM 65.O%@1 .OuM B-0285 4.57uM 29.0%@1 .OuM B-0286 0.33uM 50.O%@1 .OuM B-0287 4.OuM 22.0%@1 .OuM B-0288 4.46uM 26.O%@1 B-0289 0.l5uM 55.O%@1.OuM B-0290 O.66uM 44.0%@1 .OuM B-0291 1 .33uM 1.OuM B-0292 0.22uM 28.0%@1 .OuM B-0293 0.66uM 53.0%@1 .OuM B-0294 0.68uM 45.0%@l1.OuM SUBSfl1UTE8HEEr(RuLE~) WO 98/52940 PCT/US98/1 0436 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model Rat LIPS Model or or. TNF inhib dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Exam ple# B-0295 0.82uM 45.0%@1 .OuM B-0296 8.03uM 36.0%@1.OuM 6-0297 0.78uM 30.0%@1 .OuM B-0298 0.58uM 48.0%@1.OuM B-0299 0.87uM 54.0%@1.OuM B-0300 0.78uM 32.0%@1 .OuM B-0301 0.l9uM 50.0%@1.OuM B-0302 4.O2uM 24.O%@l.OuM B-0303 O.22uM 1O.0%@1.OuM B-0304 0.56uM 28.O%@1.OuM B-0305 B-0306 B-0307 B-0308 B-0309 B-031 0 B-0311 B-0312 B-031 3 B-0314 B-031 5 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 SUBSTffLITSHME(RULJE3)* WO 98/52940 WO 9852940PCTIUS98/10436 P38 alpha kinase U937 Cell IC50,uM Mouse LPDS Model Rat LPS Model 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-0342 B-0344 B-0345 B-0346 B-0347 B-0348 B-0349 B-0350 B-0351 B-0352 B-0353 1.37uM B-0354 1 .OuM 0.66uM 51% @?30mpk@-6h 54%@ 3mpk@-4h B-0355 0.75uM 40.O%@1 B-0356 O.66uM 24.0%@1 B-0357 1 .46uM B-0358 0.37uM 17.0%@1 .OuM B-0359 0.45uM 47.0%@1.OuM B-0360 1.6iiM -19.0%@1.OuM B-0361 0.33uM 46.0%@l1.OuM B-0362 O.52uM -27.0%@1.OuM B-0363 4.67uM 25.0%@1.OuM B-0364 1 .44uM 27.0%@l1.OuM B-0365 O.96uM 27.0%@1 .OuM B-0366 O.7uM -46.O%@1.OuM B-0367 1 .OuM 23.0%@1 .OuM B-0368 1.Oum O.64uM 37%@3Ompk@-6h B-0369 O.l6uM 57.0%@1.OuM B-0370 O.65uM 28.0%@ 1.OuM B-0371 Oi.49um 28.0%@1.OuM B-0372 0.35uM 29.0%@1.OuM B-0373 0.45uM 18.O%@1.OuM B-0374 1.38uM 12.0%@1.OuM B-0375 1.Oum 19.O%@1.OuM B-0376 2.99uM 12.0%@1 .OuM B-0377 1 .29uM 36.0%@1 .OuM B- 0378 1.luNI 36.0%@1.OuM q8 wM TE8EE(MU2, 0 WO 98/52940 PTU9/03 PCTIUS98/10436 676 P38 alpha kinase U937 Cell IC50,uM Mouse LIPS Model Rat LIDS Model or or TNF inhib @a dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time B-0379 0.53uM 24.0%@1.OuM B-0380 1.41luM 32.0%@1.OuM B-0381 0.22uM 47.0%@1.OuM B-0382 0.4luM 32.0%@1.OuM B-0383 1.43uM 10.0%@1.0uM B-0384 4.O2uM 16.0%@1.OuM B-0385 0.O57uM O.9uM 30%@3Ompk@c-6h 0%@3mpk@-4h B-0386 0.l3uM -54.0%@1.OuM B-0387 0.4lu M 52.0%@1.OuM B-0388 <0.1 uM 36.0%@1 .OuM B-0389 0.01 uM 0.O5uM 62%@3mpk@-4h B-0390 0.089uM 55.O%@1.OuM B-0391 O.86uM 1 1 .OuM B-0392 0.l3uM 57.0%@1.OuM B-0393 0.043uM 66.0%@ 1.OuM B-0394 0.l3uM 45.0%@1.OuM B-0395 0.087uM 48.0%@1.OuM B-0396 0.097uIM 0.44uM 8-0397 0.l7uM 41.0%@1.OuM B-0398 O.054uM 66.0%@1.OuM B-0399 0.l4uM 39.0%@1.OuM B-0400 0.l6ulM 25.0%@1.OuM B-0401 O.46uM 52.0%@1.OuM B-0402 0.14uM 1.5luM B-0403 1 .77uM 2.42uM B-0404 0.31 uM 48.0%@ 1.OuM B-0405 0.79uM 30.0%@1.OuM B-0406 O.54uM 35.0%@l1.OuM B-0407 0.76uM 27.0%@1.OuM B-0408 O.5uM 50.0%@1.OuM B-0409 0.53uM 30.0%@1.OuM B-0410 0.38uM 44.0%@1.OuM B-0411 0.62uM 50.0%@1.OuM B-0412 0.24uM 48.0%@1.OuM B-0413 0.lSUM 55.0%@1.OuM B-0414 2.54uM 25.O%@1.OuM B-0415 0.42uM 43.0%@1.OuM B-0416 0.32uM 34.0%@1.OuM B-0417 0.91lUM 28.0%@1.OuM B-041 8 0.22uM 270%@1.OuM B-0419 0.85UM 41.0%21.OuM B-0420 O.83uM 49.0%@1.OuM WMBTffUM&ESET(RULE= WO 98/52940 WO 9852940PCTIUS98/10436 677 P38 alpha kinase U937 Cell 1C50,uM Mouse LPS Model Rat LPS Model or or TNF inhib Ca dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time B-0421 0.46uM 57.0%@1.OuM B-0422 <0.1 uM 40.0%@l1.OuM B-0423 Ol18uM 33.0%@1.OuM B-0424 O.083uM 32.0%@1 .OuM B-0425 O.26uM 54.0%@1 .OuM B-0426 0.O55uM 0.74uM @3mpk@-4h B-0427 O.63uM 39.O%@1.OuM B-0428 0.99uM 27.0%@l1.OuM B-0429 0.27uM 45.O%@1 .OuM B-0430 O.29uM 75.0%@1.OuM B-0431 0.2luM 64.O%@1.OuM B-0432 <0.l uM 89.O%@1.OuM B-0433 <0.l uM 92.0%@1.OuM B-0434 0.l2uM 65.O%@1.OuM B-0435 O.3uM 61.0%@1.OuM B-0436 1.11u U 71.0%@1.OuM B-0437 0.58uM 59.0%@1 .OuM B-0438 <0.l Um 91.O%@1.OuM B-0439 2.l2uM 65.0%@l.OuM B-0440 0.66uM 63.0%@1 .OuM B-0441 0.8uM 58.0%@1.OuM B-0442 <0.l UM 91.0%@1.OuM B-0443 2.0luM 71.0%@1.OuM B-0444 1.01lUM 51.0%@1.OuM B-0445 <0.1 uM 83.0%@ 1.OuM B-0446 0.78uM 80.0%@1.OuM B-0447 0.l9uM 71.0%@1.OuM B-0448 0.4uM 79.O%@1.OuM B-0449 0.83uM 81.0%@1.OuM B-0450 0.26uM 81 1.OuM B-0451 0.07luMI 83.O%@1.OuM 42%@30mpk@-6h B-0452 0.7uM 75.0%@1 .OuM B-0453 0.47uM -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 1.8luM 67.0%@1.OuM B-0457 0.089UM 81.0%@1.OuM B-0458 0.O33uM 70.O%@1 .OuM B-0459 0.099uM 76.0%@1 .OuM B-0460 0.061LiM 92.0%@1 .OuM B-0461 0.025uM 96.0%@1 .OuM B-0462 <0.1 uM I 97.0%@l1.OuM SUBmnmmSHET(ULaS) WO 98/52940 WO 9852940PCTIUS98/10436 P38 alpha kinase U937 Cell IC50,uM Mouse LIDS Model Rat LIPS Model 1C50,uM or or TNF inhib dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time B-0463 0.052uM 95.0%@ 1.OuM B-0464 <0.l uM 91.0%@1.OuM B-0465 0.084uM 98.0%@1.OuM B-0466 <0.1 uMI 98.0%@ 1.OuM -0%@3mpk@-4h B-0467 <0.l UM 77.0%@1.OuM B-0468 0.031luMV 93.O%@1.OuM B-0469 0.056uM 92.0%@ 1.OuM B-0470 0.063uM -92.O%@1 .OuM B-0471 0.027uM 97.0%@1 .OuM B-0472 0.l9uM 54.0%@1.OuM B-0473 0.OO4uM 95.0%@1.OuM B-0474 0.024uM 86.0%@l1.OuM B-0475 0.2luM 74.0%@1.OuMI B-0476 O.56uM 69.0%@1.OuMI B-0477 1 .48uM 96.O%@l1.OuM B-0478 0.034uM 87.0%@1 .OuM B-0479 0.031 uM 90.O%@ 1.OuM 15%@3mpk@-4h B-0480 0.l2uM 88.0%@1.OuM B-0481 0.01 4uM 95.0%@ 1 OuM 56% @3mpk@-4h B-0482 0.97uM 68.O%@1.OuM B-0483 0.57uM 68.O%@1.OuM B-0484 0.28uM 62.0%@1.OuM B-0485 0.O4uM 95.0%@1.OuMI B-0486 0.24uM 80.0%@&1.OuM B-0487 0.11 uM 89.0%@l1.OuM 54%@3mpk@-4h B-0488 0.62uM 88.0%@1 .OuM B-0489 0.3uM 80.0%@l1.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 OA13uM B-0495 O.l2uM 25O0%@l.OuM B-0496 0.83uM 16.0%@l.OuM B-0497 0.44uM -310%@l.OuM B-0498 0.33uM 11.0%@t~OuM B-0499 0.39uM 37.0%@1.OuM B-0500 0.26uM 41.0%@l.OuM B-0501 0.049uM 52.0%@l.OuM B-0502 0.065uM 48.0%@l.OuM B-0503 0.l6uM 73.0%@1.OuM B-0504 O.4uM 43.0%@1 OuM S~gUBTffE~ =K(RLEqk WO 98/52940 WO 9852940PCT/US98/1 0436 679 P38 alpha kinase U937 Cell IC50,uM Mouse LIPS Model Rat LPS Model or or TNF inhib dose inhib @dose inhlb@conc. (uM) inhib@conc. (uM) @predlose time @predose time Example# B-0505 0.28uM B-0506 0.94uM 43.O%@l1.OuM B-0507 0.l8uM 75.O%@1 .OuM B-0508 2.OuM 48.O%@1 .OuM B-0509 0.lUM 86.0%@1.OuM B-051 0 O.69uM 61.0%@1.OuM B-0511 0.0O7uM B-0512 1.OuM 53.0%@1.OuM B-0513 0.72uM 52.0%@1.OuM B-051 4 0.l4uM 87.0%@1.OuM B-0515 0.42uM B-0516 0.37uM 84.0%@1.OuM B-0517 0.094uM B-0518 0.11lUM 64.O%@1.OuM B-0519 O.043uM B-0520 0.4uM 67.O%@1.OuM B-0521 1.37uM B-0522 0.1l5uM 75.O%@1.OuM B-0523 0.l9uM B-0524 O.4uM B-0525 0.l6uM 76.O%@1.OuM B-0526 0.031luMV 87.O%@1.OuM B-0527 1.O9uM 63.O%@1.OuM B-0528 0.l4uM 70.0%@1.OuM B-0529 0.lluM B-0530 5.53uM B-0531 0.5uM 48.O%@1.OuM B-0532 0.45uM 1.0luMI 41%@3Ompk@-6h B-0533 1 .23uM 47.O%@1 .OuM B-0534 0.4luM 54.0%@1.OuM B-0535 0.44uM 0.87uM B-0536 0.46uM 0.1 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 3.62uIM -54.O%@1 B-0541 3.24uM 28.0%@1 .OuM B-0542 1.5SuM B-0543 1 .56uM 43.0%@1 .OuM B-0544 1.l2uM B-0545 1.O6uM 41.O%@1.OuM B-0546 1.O4uM 18.0%@1.OuM B-0547 1.24uM 21.0%@l.OuM 9B-0548 1 .77uM 28.0%@l1.OuM 91-0549 1 2.22uM I 22.0%@1 .OuM E~Er(RUL~) WO 98/52940PCIS8I03 PCT/US98/10436 680 P38 alpha kinase U93.7 Cell IC50,uM Mouse LIPS Model Rat LPS Model 1C50,uM or or TNF inhib dose inhib @dose Examle#inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time B-0550 1 2.41luM 14.O%@1.OuM B-0551 1.O8uM 56.0%@1.OuM B-0552 0.l3uM 46.0%@1 .OuM B-0553 1 .44uM 47.0%@1 .OuM B-0554 2.58uM 20.0%@1 B-0555 I 1.87uM 34.O%@1.OuM B-0556 0.49uM 39.0%@1.OuM B-0557 1 .37uM 32.O%@1 .OuM B-0558 0.85uM 33.O%@1.OuM B-0559 O.53uM 49.0%@1.OuM B-0560 2.57uM B-0561 2.07uM 40.0%@1.OuM B-0562 0.22uM 0.3uM 5%@3mpk@-4h B-0563 OAlSuM 0.l3uM B-0564 0.82uM 58%@1.OuM B-0565 I 0.23uM O.59uM B-0566 <0OluM 0.l7uM 0%@3mpk@-4h B-0567 0.l4uM 0.28uM B-0568 1.22uM 46.0%@1.OuM B-0569 0.l5uM 0.26uM B-0570 0.27uM 46.0%@1.OuM B-0571 0.3BuM -44.0%@1.OuM B-0572 0.27uM 41.0%@1.OuM B-0573 0.36uM 1 .7uM B-0574 0.l3uM 0.66uM B-0575 0.032uM 0.1 7uM B-0576 0.068uM 0.39uM B-0577 0.091 uM 66.0%@l1.OuM B-0578 1.88uM 47.0%@1.OuM B-0579 0.llum 79.O%@1.OuM B-0580 2.23uM O.B4uM B-0581 0.26uM 2.l7uM B-0582 1.O3uM 37.O%@1.OuM B-0583 3.93uM 26.0%@1.OuM B-0584 0.66uM 54.0%@1 .OuM B-0585 0.83uM 79.0%@l1.OuM 50%@3ompk @-6h B-0586 0.81luM 51.0%@1.OuM B-0587 6.84uM 38%@1.OuM 8-0588 12.8uM 42%@1.OuM B-0589 1.71luM 42%@1.OuM B-0590 1 .57uM 38.OuM B-0591 3.59uM 29.0%@1.OuM B-0592 1 .62uM 45.0%@ 1 .OuM B-0593 1.22uM 36.0%@1.OuM B-0594 -41.0%@1.OuM B-0595 2.42uM 22.0%@1 .OuM B-0596 20.OuM 41 .0%@l1.OuM B-0597 1.68uM 63.O%@1.OuM B-0598 2.l2uM 50.0%@1.OuM SU6~fl1U EE(RULE 28) WO 98/52940 WO 9852940PCTIUS98/1 0436 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model Rat LPS Model or or TNF inhib dose inhib @dose inhib@conc. (uM) inhib(Pconc. (uM) @predose time @predose time Example# B-0599 4.l6uM 21.O%@1.OuM B-0600 0.0O2uM -28.O%@1 .OuM B-0601 0.089uM 1.31luM 43%03mpk%-4h B-0602 0.97uM 61.O%@1.OuM B-0603 O.O9uM B-0604 0.3uM 20.O%@1 OuM B-0605 0.l8uM -47.0%@1.OuM B-0606 Oi17uM 53.O%@1 B-0607 2.79uM 70.O%@1 .OuM B-0608 0.059uM 73.O%@1 .OuM B-0609 <0.l uM 87.O%@1.OuM B-061 0 <0OluM 88.O%@11.OuM B-0611 0.65uM 60.O%@1.OuM B-0612 0.l6uM 60.O%@1.OuM B-0613 0.l7uM 76.O%@l.OuM B-0614 0.76uM 70.O%@l1.OuM %@3mpk@P-4h B-0615 O.08uM 83.0%@1.OuM B-0616 0.38uM 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 88.0%@1.OuM B-0620 1.59uM 58.O%@1.OuM B-0621 0.36uM 68.0%@l.OuM B-0622 0.076uM 78.O%@1l.OuM B-0623 0.12uM 76.0%@1.OuM B-0624 0.085uM 54.O%@1.OuM B-0625 0.023uM -88.0%@&1.OuM B-0626 <0.l uM B-0627 0.25uM B-0628 0.023uM 72.0%@1.OuM B-0629 0.2uM 79.O%@1 OuM B-0630 0.O6uM -77.O%@1.OuM B-0631 0.065uM 81 .OuM B-0632 <0.luM 79.0%@1.OuM B-0633 0.6uM 80.O%@1 OuM B-0634 0.6uM 40.O%@1.OuM B-0635 0.lSuM -55.O%@1.OuM B-0636 <0.Ilium -86.O%@1.OuM B-0637 .lluM 92.O%@1.OuM B-0638 0.25uM 89.O%@1 .OuM B-0639 0.051luM 93.O%@1.OuM B-0640 0.36uM -94.O%@1.OuM B-0641 0.58uM 65.O%@1.OuM B-0642 0.49uM 90.O%@11.OuM B-0643 0.069uM 85.O%@1 OuM B-0644 0.058uM 89.O%@11.OuM B-0645 0.58uM -80.0%@1.OuM B-0646 O.26uM 94.O%[email protected] B-0647 1.6luM 76.O%@1.OuM 8uB=u1UrE8HEL) WO 98/52940 WO 9852940PCT/US98/1 0436 682 P38 alpha kinase U937 Cell IC50,uM Mouse LPDS Model Rat LPS Model or or TNF inhib 0 dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-0648 I <0.l UM 83.O%@1.OuM B-0649 O.83uM 39.O%@ 1.OuM B-0650 0.OO6uM 95.O%@1.Oum 8%@3mpk@-4h B-0651 1.78uM 81.O%@l.OuM B-0652 .9uM 83.O%@1.OuM B-0653 2.OluM 74.O%@1.OuM B-0654 5.97uM 78.O%@1.OuM B-0655 1.25uM 76.O%@1.OuM B-0656 0.OO7uM 95.O%@1 .OuM 28%@3mpk@-4h B-0657 .7uM 83.O%@1.OuM B-0658 1.l4uM 91.O%@1.OuM B-0659 2.64uM 87.O%@1.OuM B-0660 O.OB8uM 92.O%@ 1.OuM B-0661 <0OluM B-0662 <0.l UM 95.O%@l.OuM B-0663 O.88uM 74.O%@1 .OuM B-0664 O.39uM -8O.O%@1 .OuM B-0665 0.47uM 72.O%@l.OuM B-0666 .7uM 73.0%@1.OuM B-0667 0.83uM 75.O%@1.OuM B-0668 0.27uM 78.0%@1 .OuM B-0669 0.89uM 34.O%@1 .OuM B-0670 3.l5uM 32.O%@1.OuM B-0671 6.38uM 36.O%@l1.OuM B-0672 6.59uM 32.O%@1.OuM B-0673 8.54uM B-0674 2.8luM 42.O%@1.OuM B-0675 5.42uM 3.O%@1.OuM B-0676 2.O9uM 22.O%@1 .OuM B-0677 1 .63uM 25.O%@1 .OuM B-0678 O.38uM 52.O%@1 .OuM B-0679 0.O62uM -45.O%@1.OuM B-0680 O.42uM 67.O%@1 .OuM B-0681 1.96uM 17.O%@l.OuM B-0682 0.76uM 39.O%@1 .OuM B-0683 13.OuM 32.O%@l.OuM B-0684 O.54uM -68.O%@1.OuM B-0685 15.4uM -33.0%@1.OuM B-0686 O.42uM 59.O%@1 .OuM B-0687 l0.luM 15.O%@l.OuM B-0688 O.66uM 58.O%@1.OuM B-0689 14.6uM 27.O%@1.OuM B-0690 27.luM 36.O%@1.OuM B-0691 0.l6uM 48.O%@1.OuM B-0692 O.38uM 29.O%@1.OuM B-0693 O.39uM 28.O%@ 1.OuM B-0694 O.62uM 21.0%@1.OuMl B-0695 O.23uM B-0696 O.085uM -35.O%@l.OuM summusmUTBHER) WO 98/52940 PCTIUS98/1 0436 P38 alpha kinase U937 Cell 1C50,uM Mouse LIPS Model Rat LIPS Model or or TNF inhib dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-0697 I 0.45uM 44.0%@1.OuM B-0698 2.33uM 43.0%@l1.OuM B-0699 0.34uM 31 .O%@l1.OuM B-0700 0.24uM 56.0%@1.OuM B-0701 O.39uM 45.0%@ 1.OuM B-0702 0.036uM 39.0%@1.OuM B-0703 0.12uM 39.0%@l.OuM B-0704 2.l9uM 29.0%@1.OuM B-0705 0.44uM 21 .0%@l.OuM B-0706 0.44uM 32.0%@1 .OuM B-0707 B-0708 2.luM___ B-0709 B-071 0 1.99uM B-0711 1.99uM B-0712 B-0713 B-0714 3.7uM B-071 5 3.2uM B-0716 4.6uM B-0717 4.3uM B-0718 1.4uM 6-0719 3.4uM B-0720 1.3uM B-0721 B-0722 0.O7uM >1.OuM B-0723 B-0724 0.O6uM 17.O%@1.OuM B-0725 B-0726 B-0727 0.5l UM B-0728 20.OuM B-0729 0.87uIM B-0730 0.25uM 11.0%@ B-0731 0.87uM >1.OuM B-0732 B-0733 32.OuM B-0734 0.92uM B-0735 1 B-0736 26.OuM B-0737 2.6uM B-0738 2.7uM B-0739 4.luM B-0740 B-0741 26.OuM B-0742 B-0743 1.2uM B-0744 B-0745 6.OUM suesTflUrEBHEE1 (RUILEM2) WO 98/52940 PCTIUS98/1-0436 P38 alpha kinase U93.7 Cell IC50,uM Mouse LIDS Model Rat LPDS Model ICSO,uM or or TNF inhib dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-0746 0.01lUm 22.0%@1.OuM B-0747 1.l1uM B-0748 1.2uM__ B-0749 4.4uM B-0750 0.92uM B-0751 1 .6uM B-0752 0.33uM B-0753 0.37uM B-0754 0.55uM B-0755 2.3uM B-0756 0.94uM B-0757 O.54uM 16.0%@1.OuM B-0758 1 .5uM B-0759 O.3uM B-0760 O.OluM 13.0%@1.OuM B-0761 <OAluM B-0762 0.l3uM 5.0%@1 .OuM B-0763 0.Ol5uM 17.0o%@1.OuM B-0764 0.67uM 26.0%@1.OuM B-0765 O.3uM 29.0%@1.OuM B-0766 O.95uM B-0767 O.O8uM B-0768 1 .4uM B-0769 12.7uM B-0770 2.3uM 5-0771 O.5uM B-0772 O.8uM B-0773 B-0774 1.5uM___ B-0775 0.6uM >1.OuM B-0776 O.9uM >1.OuM B-0777 21.OuM__ B-0778 51.OuM B-0779 B-0780 1.luM B-0781 B-0782 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 0.3uM >1.OLIM B-0792 1.luM B-0793 O.3uM B-0794 2.9uM 2.0%@1.OuM BUBW1TUESEEr(RLU)M WO 98/52940 WO 9852940PCT/US9S 1 0436 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model Rat LPDS Model 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 .O4uM B-0798 1.73uM B-0799 B-0800 1.01lUm >1.OUM B-0801 0.67uM B-0802 >.OuM B-0803 O.O57uM B-0804 0.3uM B-0805 O.7luM >1.OuM B-0806 3.28uM >1.OuM B-0807 10.8uM B-0808 3.O9uM >1.OuM B-0809 1.22uM 7.0%@1.OuM B-081 0 1.11lUM >1.OuM B-0811 2.79uM 2.0%@1.OuM B-0812 2.l2uM >1.OuM B-0813 3.O2uM >1.OuM B-0814 >1.OuM B-0815 2.11luM >1.OuM B-081 6 3.46uM >1.OuM B-0817 3.O7uM 33.0%@1.OuM B-081 8 4.97uM >1.OuM B-0819 1.08uM >1.OuM B-0820 1.64uM 3.0%@1.OuM B-0821 1 .44uM- B-0822 1 .33uM- B-0823 2.39uM >1.OuM B-0824 3.41luM 6-0825- B-0826 1 .74uM- 6-0827 15.6uM B-0828 B-0829 0.61 uM 65.0%@l1.OuM B-0830 O.S4uM 34.0%@ 11.OuM B-0831 O.9um >1.OuM B-0832 1 .49uM- B-0833 0.95uM 23.0%@1 .OuM B-0834 1 B-0835 ft B-0836 1 .24uM- B-0837 1.96uM >1.OuM B-0838 B-0839 4.3uM B-0840 O.63uM 47.0%@l1.OuM B-0841 0.32uM 36.O%@1 .OuM B-0842 0.74uM 63.0%@1 B-0843 O.6luM >1.OuM SUBBTflUFE 8HEE~ (RULE 26) WO 98/52940 PCT/US98/I 0436 686 P38 alpha kinase U937 Cell IC50,uM Mouse LIPS Model Rat LIPS Model or or TNF inhib dose inhib @dlose inhib@conc. (uM) inhib~conc. (uM) @predose time @predose time B-0844 I 0.4uM 25.O%@1 .OuM 8-0845 1 B-0846 B-0847 0.73uM 21 .0%@l1.OuM B-0848 1 B-0849 1 B-0850 1.8luM__ B-0851 0.91lUM 39.0%@1.OuM B-0852 B-0853 -38.0%@.1.OuM B-0854 1.OuM B-0855 -8.0%@11.OuM B-0856 -38.O%@1 .OuM B-0857 6.25uM B-0858 2.luM 48.0%@1.OuM B-0859 39.5uM- B-0860 38.luM- B-0861 1.32uM 12.0%@1.OuM B-0862 2.l5uM 4.0%@1.OuM B-0863 0.81 uMV 25.0%@l1.OuM B-0864 0.39uM 40.%@&1.OuM B-0865 O.66uM -46.0%@1l.0uM B-0866 1.38uM 28.0%@1.OuM B-0867 0.62uM >1.OuM B-0868 3.28uM 8.0%@1 .OuM B-0869 4.19uM B-0870 3.13uM >1.OuM B-0871 1.9uM >1.OuM B-0872 3.l3uM 3.0%@1.OuM B-0873 6.92uM >1.OuM B-0874 1 .92uM >1.OuM B-0875 2.l3uM 8%@1.0uM B-0876 0.89uM >1.OuM B-0877 1.l7uM 13.0%@1D.OuM B-0878 0.65uM 19.0%@11.OuM 8-0879 0.87uM 1.0%/@11.OuM B-0880 0.l6uM 40.0%@1.OuM B-0881 1.36uM >1.OuM B-0882 1.48uM 9%@1.OuM B-0883 1.O6uM >1.OuM B-0884 1.89uM- B-0886 B-0887 B-0888 B-0889 B-0890 B-0891 IB-0892 su&MFLjrESHU(RULE- WO 98/52940 PCTIUS98/1-0436 687 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model Rat LIPS Model or or TNF inhib dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-0894 B-0896 B-0899 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-0923 B-0927 B-0928 B-0929 B-0930 B-0931 B-0932 B-0933 47.O%@l.OuM 37.O%@1.OuM B-0934 67.O%@1.OuM 36.O%@1.OuM B-0935 69.O%@1 OuM 54.O%@1 B-0936 69.O%@l.OuM >1.OUM B-0937 64.O%@1.OuM B-0938 51.O%@1.OuM 29.O%@1.OuM B-0939 78.O%@1.OuM 14.O%@1.OuM B-0940 56.O%@1.OuM 22.O%@1.OuM B-0941 81.O%@1.OuM 25.O%@1.OuM &WesMtrSHEMr(RLUM) WO 98/52940 WO 9852940PCTIUS98/10436 688 P38 alpha kinase U937 Cell lC5O,uM Mouse LPS Model Rat LIPS Model 1C50,uM or or TNF inhib dose inhib @dose inhib~conc. (uM) inhib@conc. (uM) @predose time @predose time B-0942 182.O%@1.OuM 2.O%@1.0uM B-0943 63.0% @10.OuM 24.0%@1 .OuM B-0944 45.0%@1.OuM 27.0%@ 1.OuM B-0945 96.O%@1 .OuM 0.93uM B-0946 76.0%@1.OuM 31.0%@1.OuIM B-0947 69.O%@1.OuM 34.O%@1.OuM B-0948 68.O%@1.OuM 1.81 UM B-0949 90.0%@1.OuM 17.0%@1.OuM B-0950 81.0%@11.OuM O.58uM B-0951 82.0%@l.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 6-0955 49.0%@1.OuM 0.54uM B-0956 56.0%@1.OuM 1.33uM B-0957 79.0%@1.OuM 22.0%@1.OuM B-0958 74.0%@1.OuM 0.38uM B-0959 83.0%@1.OuM 39.0%@1.OuM B-0960 48.0%@1.OuM 4.0%@1.OuM B-0961 79.0%@1.OuM 23.0%@1.OuM B-0962 85.0%@1.OuM 2.71luM___ B-0963 76.0%@1.OuM -39.0%@1.OuM B-0964 94.0%@1.OuM B-0965 74.0%@1.OuM 1.l1uM____ B-0966 50.0%@1.OuM 5.0%@1.OuM B-0967 80.0%@1.OuM 29.0%@1.OuIM B-0968 35.0%@1.OuM 26.0%@1.OuM B-0969 63.0%@1.OuM 35.0%@1.OuM B-0970 76.0%@10.OuM 0.88uM B-0971 61.0%@1.OuM 39.0%@1.OuM B-0972 85.0%@1.OuM 2.0%@1.OuM B-0973 66.O%@10.OuM 48.0%@1.OuM B-0974 57.0%@1.OuM 47.0%@1.OuM B-0975 82.0%@1.OuM 32.0%@1.OuM B-0976 79.0%@1.OuM 36.0%@1.OuM B-0977 60.0%@1.OuM 26.0%@1.OuM B-0978 59.0%@1.OuM 36.0%@1.OuM B-0979 56.0%@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.O%@1.OuM B-0984 60.0%@1.OuM 51.0%@1.OuM B-0985 86.0%/@1.OuM 0.75uM B-0986 70.0%@1.OuM 71.0%@1.OuM B-0987 78.0%@l.OuM 79.0%@1.OuM B-0988 72.0%@1.OuM 65.0%@1.OuM B-0989 85.0%@l.OuM 0.B5uM B-0990 I 26.0%@1 OuM SU2STrrL MSH=EI-r (RUJLE W WO 98/52940 WO 9852940PCT/UJS98/I 0436 689 P38 alpha kinase U937 Cell lC5O,uM Mouse LIDS Model Rat LPS Model or% or TNF inhib @9 dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-0991 I58.0%@i.OuM 33.0%@1 .OuM B-0992 77.0%@1.OuM 45.0%@1 B-0993 57.O%@i.OuM 73.0%@1.OuM B-0994 55.O%@i .OuM 43.0%@1 B-0995 53.0%@1.0uM 14.0%@i.OuM B-0996 54.O%@1 .OuM 27.0%@1 B-0997 69.0%@1.OuM 22.0%@1 B-0998 67.0%@&1.OuM 25.0%@1 B-0999 61.0%@i.OuM 24.0%@1.OuM B-1 000 55.O%@1 .OuM 42.O%@1 B-1001 63.O%@1.OuM 31.0%@1.OuM B-1002 70.0%@1l.OuM 41.0%@1.OuM 5-1 003 74.0%@1.OuM 29.0%@1.OuM B-1 004 79.0%@1.OuM 45.O%@1.OuM B-1 005 58.0%@1 OuM 23.O%@1 .OuM B-i 006 69.O%@1 .OuM 38.0%@1 .OuM B-1 007 52.0%@1.OuM 34.O%@1.OuM B-1 008 54.0%@i.OuM -23.0%@1.OuM B-i 009 80.0%@1.OuM 55.O%@1 .OuM B-1010 75.0%@l.OuM 1.OuM B-l011 72.0%2i.OuM 17.0%@1.OuM B-1012 20.0%@l.OuM B-1 013 85.O%@1.OuM 7.0%@l.OuM B-1014 88.O%@l.OuM 20.O%@1.OuM B-1 015 77.O%@1.OuM 34.0%@1.OuM B-1016 58.O%@1.OuM 10.O%@1.OuM B-1017 96.0%@al.OuM 58.O%@1.OuM B-lol8 88.0%@1.OuM 34.0%@1.OuM B-1019 82.O%@1.OuM 66.0%@1.OuM B-1 020 87.O%@i.OuM 36.0%@1.OuM B-1021 82.O%@1.OuM 35.0%@l.OuM 8-1 022 84.O%@l.OuM 53.0%@1.OuM B-1 023 93.0%@1.OuM 70.O%@1 B-1 024 89.0%@1.OuM 57.0%@1.OuM B-1 025 61.O%@1.OuM 23.0%@1.OuM B-1 026 87.0%@l.OuM 53.0%@l.OuM B-1 027 58.0%@1.OuM 18.O%@1.OuM B-1028 70.O%@1.OuM 17.0%@1.OuM B-1029 69.0%@i.OuM 54.O%@1.OuM 8-1 030 76.0%@1.OuM 60.0%@1.OuM B-1 031 69.0%@i .OuM 42.0%@1 .OuM B-1 032 76.0%@1 .OuM 37.O%@1 .OuM B-1 033 86.0%@1.OuM 34.0%@1.OuM B-1 034 66.0%@1.OuM 39.0%@1.OuM B-1 035 75.0%@ 1 OuM 52.0%@l1.OuM 8-1036 68.0%@1.OuM 68.0%@1.OuM B-1 037 -41.0%@l.OuM B-1038 57.0%/@i.OUM 0.57uM 8-1 039 -1 .33L1M 8ueBnUTEHMTr(RUE2 WO 98/52940 PCTIUS98/1 0436 690 P38 alpha kinase U93.7 Cell ICS0,uM Mouse LIDS Model Rat LPS Model or or TNF inhib dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time 6-1 040 172.0%@1.OuM 0.38uM B-1 041 70.0%@1.0uM 73.0%@1.OuM B-1 042 79.0%@1.OuM 12.0%@1.OuM B-1 043 64.O%@1.0uM 53.0%@1.OuM 6-1 044 94.0%@1.OuM 0.93uM____ 6-1 045 78.0%@1.OuM 25.0%@1.OuM B-1 046 72.0%@1.OuM 66.0%@1.OuM B-1 047 72.0%@1.OuM 58.0%@1.OuM B-1 048 67.0%@1.OuM 19.0%@1.OuM B-1049 67.O%@1.OuM 65.0%@1.OuM B-1 050 B-1 051 68.0%@1.OuM 41%@1.0uM B-1052 69.0%@1.OuM 66%@1.OuM B-i 053 78.0%@1.OuM B-1 054 79.0%@1.OuM 55.0%@1.OuM B-lo055 89.0%@1.OuM 63.0%@1.OuM B-1 056 89.0%@1.OuM 0.76uM___ B-1 057 85.0%@1.OuM 0.72uM____ B-1 058 0.66uM 43.0%@1 .OuM B-1059 0.l8uM 24.0%@l.OuM B-1 060 Oll1uM 32.O%@1.OuM B-1061 0.O3uM 19.0%@1.OuM 6-1 062 <0.1 uMI 26.0%@l1.OuM B-1 063 O.l6uM 44.0%@1.OuM B-1 064 0.39uM 50.0%@1.OuM B-1 065 O.56uM 40.0%@1 .OuM B-1 066 <0.1 uMI 39.0%@l1.OuM B-1 067 1.6uM 32.0%@l.OuM B-1 068 O.48uM 24.0%@1.OuM B-1069 0.22uM 27.0%@1.OuM B-1 070 <0.l Um 44.0%@1.OuM B-1 071 <0.luM 48.0%@1.OuM B-1 072 0.38uM 28.0%@1 .OuM B-1 073 <0.lum 21.0%@1.OuM B-1 074 0.23uM 33.0%@1.OuM B-1 075 0.03uM 29.0%@1.OuM B-1 076 0.O8uM -31.0%@1.OuM B-1 077 <0.l UM 38.O%@1.OuM 6-1078 0.26uM 1.OuM B-1 079 <0.l UM 40.0%@1.OuM B-1080 6.l9um 28.0%@1.OuM B-1 081 <0.1 uM 37.0%@ 1 .OuM B-i 082 <0.1 uM 54.0%@ 1.OuM B-1 083 <0.1 uM 23.0%@1.OuM B-1084 0.43uM 29.0%@1.OuM B-1 085 <O.IuM 29.0%@1.OuM B-1086 <0.1uM 42.0%@1.OuM B-1 087 0.O5uM 32.0%@1 .OuM B-1088 0.73uM 49.0%@1.OuM 8UBS1TUTE8HWE(RULE WO 98/52940 WO 9852940PCTIUS98/1 0436 P38 alpha kinase U937 Cell 1C50,uM Mouse LPS Model Rat LPS Model or or TNF inhib dose inhib @dose inhib~gconc. (uM) inhib~conc. (uM) @predose time @predose time Example# B-1 089 1 <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-1093 O.33uM 36.O%@1.OuM B-1094 0.01l3uM 69.O%@1.OuM B-1095 <0.l Um 70.O%@1.OuM B-1 096 <0.l UM 32.O%@1.OuM B-1097 <0.l uM B-1 098 <0.l UM 82.O%@1.OuM B-1 099 O.26uM 74.O%@1.OuM B-1lO 10O.22uM 56.0%@1.OuM B-1 10 O.O26uM 82.O%@1.OuM B-1 102 O.O35uM 83.O%@l.OuM B-1 103 O.O94uM B-1104 O.l2uM 69.O%@1.OuM B-1 105 <Ol1uM 84.O%@1.OuM B-1 106 <0.l uM 86.O%@1.OuM B-1 107 O.O57uM 84.O%@1.OuM B-1108 O.22uM B1.O%@1.OuM B-1 109 O.O54uM 80.O%@1.OuM B-1110 O.47uM 64.O%@1.OuM B-1111 O.l19uM 64.O%@1.OuM B-1 112 O.58uM 43.O%@1.OuM B-1 113 <0.1 uM 72.O%@1.OuM B-1 114 O.O69uM 51.O%@l.OuM B-1 115 O.O24uM -89.O%@l.Oum B-1 116 O.4luM 81.O%@1.OuM B-1 117 O.l3uM 73.O%@l.OuM B-lil 11O.33uM 91.O%@11.Oum B-1 119 O.35uM 80.O%@1.OuM B-1 120 O.47uM 9.O%@1.OuM B-1121 3.58uM 29.O%@1.OuM B-1 122 1.84uM 32.O%@1.OuM B-1 123 2.93uM 27.O%@1.OuM B-1124 i.49uM 52.O%@1.OuM B-1 125 O.56uM 41.O%@1.OuM B-1126 1.5uM B-1127 0.71luM 7.O%@1.OuM B-1 128 2.55uM 26.O%@l.OuM B-1129 1 .O7uM 46.O%@1 .OuM B-1 130 0.5uM 29.O%@1.OuM B-1 131 O.O76uM B-1132 O.72uM hl.O%@1.OuM B-1 133 O.38uM B-1134 1.7luM 33.O%@l.OuM B-1 135 O.23uM B-1136 1.l7uM 40.O%@1.OuM B-1 137 O.O38uM 35.O%@1.OuM SnmTEHW(RLEgm WO 98/52940 WO 9852940PCTIUS98/1 0436 P38 alpha kinase U937 Cell IC50,uM Mouse LIPS Model Rat LIPS Model or or TINF inhib dose inhib @dose inhib@conc. (uM) inhlb@conc. (uM) @predlose time @predose time Exam ple# B-1 138 1.82uM >1.OuM B-1 139 0.041luM 29.O%@1.OuM B-1 140 1 .6BuM 39.O%@1 .OuM B-1 141 2.47uM 32.O%@1.OuM B-1 142 .llum 37.O%@1.OuM B-1 143 O.l7uM 40.O%@1.OuM B-1 144 O.44uM 72.O%@1.OuM B-1 145 1.O7uM B-1 146 O.47uM 61.0%@1.OuM B-1 147 O.O9SuM 53.0%@1.OuM B-1 148 O.43uM 61.0%@1.OuM B-1 149 1.55uM -48.O%@1.OuM B-1150 O.47uM 75.O%@1.OuM B-1 151 O.32uM 72.O%@1.OuM B-1 152 O.73uM 53.O%@1.OuM B-1 153 2.22uM B-1 154 O.O85uM 46.O%@1 .OuM B-1 155 3.22uM 30.O%@1.OuM B-1 156 O.27uM B-1 157 O.26uM B-i 158 74%@l1.OuM 0.68uM 53%@30mpk@-6h B-i 159 66.O%@l1.OuM 1 .O3uM 60%@30mpk@-6h B-1 160 79.O%@1.OuM O.38uM B-1 161 64.O%21.OuM 0.93uM 40%@3Ompk@-6h 45%@c3mpk@-4h B-1 162 79.O%@1.OuM 0.59uM 40%@30mpk@-6h B-1 163 74.O%@1.OuM O.37uM B-1 164 .35uM B-1 165 66.O%@1.OuM 0.99uM B-1 166 77.O%@1.OuM 0.39uM 50%@3Ompk@-6h 50%@3mpk@-4h B-1 167 70.O%@1.OuM 1.O6uM B-1168 66.O%@1.OuM O.63uM B-1169 80.O%@1.OuM .luM B-1 170 82.O%@1.OuM O.57uM B-i 171 78.O%@1 .OuM O.23uM B-1 172 68.O%@1.OuM 1.95uM B-1 173 65.O%@1.OuM 62%@1.OuM B-1 174 80.O%@l.OuM O.86uM B-1 175 72.O%@1.OuM 1.83uM B-1 176 67.O%@1.OuM 67.O%@1.OuM B-1 177 70.O%@1.OuM 1.16uM B-1 178 92.O%@1.OuM 1.6luM B-1 179 86.O%@1.OuM O.4luM B-1 180 78.O%@1.OuM O.53uM B-1 18 79.O%@1.OuM 66%@1.OuM B-1 182 72.O%@1.OuM 0.65uM B-1 183 77.O%@1.OuM 0.2uM B-1 184 69.O%@1.OuM O.63uM B-1 185 71.O%@1.OuM O.79uM B-1186 183.O%@1.OuM 60%@1.OuM SUBS1Tff=EET(RUE) WO 98/52940 WO 9852940PCTIUS98/1 0436 P38 alpha kinase U937 Cell IC50,uM Mouse LIPS Model Rat LIPS Model or or TINF inhib dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @preclose time Example# B-1 187 76.O%@1.OuM 1.89uM B-1 188 -36.0%@1.OuM B-1 189 68.O%@1.OuM 0.83uM B-1 190 78.0%@1.OuM 62.O%@1.OuM B-1 191 74.O%@1.OuM 57.O%@1.OuM B-1 192 84.O%@1.OuM 0.47uM B-1 193 69.0%@1.OuM -65.0%@1.OuM B-1 194 87.0%@1I.OuMl 0.58uM B-1 195 52.0%@1.OuM 60.O%@1.OuM B-1 196 74.0%@l.OuM 68.0%@1.OuM B-1 197 77.0%@1.OuM 45.0%@1.OuM B-1 198 92.O%@1.OuM B-1 199 87.0%@1.OuM 49.0%@1.OuM B-1 200 95.0%@1.OuM 0.64uM B-1201 84.0%@1.OuM B-1202 71.0%@l.OuM 58.0%@1.OuM B-1203 84.O%@1.OuM 58.O%@1.OuM B-1204 68.0%@1.OuM 59.O%@1.OuM B-1 205 74.O%@1.OuM 46.0%@1 .OuM B-1 206 81.O%@1.OuM 0.34uM B-1 207 90.0%@11.OuMI 58.0%@1 .OuM B-1 208 82.O%@1.OuM 51.0%@1.OuM B-1 209 86.0%@1 .OuM 55.O%@1 .OuM B-1210 82.0%@1.OuM 57.0%@1.OuM B-1211 88&0%@11.OuN 59.0%@1.OuM 8-1212 90.0%@1.OuM 57.O%@1.OuM B-1 213 84.0%@1.OuM 0.62uM B-1214 76.0%@1.OuM 58.0%@1.OuM B-1215 86.0%@1.OuM 0.23uM B-1216 88.0%@1.OuM 0.l8uM B-1217 87.0%@1.OuM 0.46uM 8-1 218 88.O%@1.OuM 76.O%@1.OuM B-1219 85.O%@1.OuM 37.O%@1.OuM B-1 220 81.0%@1.OuM 53.0%@1.OuM B-1221 82.0%@l.OuM 44.0%@1.OuM B-1222 65.0%@1.OuM 9.O@1 .OuM B-1 223 80.0%@11.OuM 61.O%@1.OuM B-1224 82.0%@1.OuM 74.O%@1.OuM B-1225 89.0%@1.OuM 73.O%@l.OuM B-1 226 89.O%@1.OuM 0.l8uM 8-1227 83.0%@l.OuM O.22uM B-1228 90.O%@1.OuM 0.72uM B-1229 87.0%@1.OuM 0.65uM B-1 230 90.0%@L.0uM 0.25uM B-1 231 94.0%@1.OuM O.56uM B-1232 81.O%@1.OuM 54.O%@1.OuM 8-123 8.O .louM 0.36uM B-1 234 89.0%@1.OuM 0.49uM B-i 235 O.O4uM 76.0%@1 .OuM suq&ITffSHWE("UEcD) WO 98/52940 WO 9852940PCT/US98/1 0436 P38 alpha kinase U937 Cell 1C50,uM Mouse LIPS Model Rat LPS Model or or TNF inhib dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time B-1 236 OAlUM 53.0%@l.OuM B-1 237 O.22uM 39.0%@1.OuM B-1 238 O.l4uM 16.O%@1.OuM B-1 239 <0.l uM 3B.O%@1.OuM B-1 240 <0.l UM 59.O%@1.OuM B-1 241 0.O4uM 81.O%@1.OuM B-1 242 O.O8uM 83.O%@1.OuM B-1 243 0.O4uM 47.0%@1.OuM B-1 244 0.26uM 44.0%@1.OuM B-1 245 O.49uM 42.O%@1.OuM B-1 246 0.27uM 40.0%@1.OuM B-1 247 <0.l uM 58.0%@1.OuM B-1 248 <0.l uM 68.0%@1.OuM B-1 249 O.24uM 60.0%@1.OuM B-1 250 0.l4uM 18.0%@1.OuM B-1251 O.41luM B-1 252 0.l7uM 46.0%@1.OuM B-1 253 O.l5uM 57.0%@1.OuM B-1 254 0.l6uM 68.0%@1.OuM B-1 255 12.9uM 75.0%@l.OuM B-1 256 O.l2uM 41.O%@1.OuM B-i 257 1 .48uM 40.0%@l1.OuM B-1 258 0.O7uM 56.O%@1.OuM B-1 259 <O.luM 0.48uM B-1 260 .l1uM 48.0%@1.OuM B-1261 0.74uM 44.0%@l.OuM B-1 262 <0.l UM 63.0%@1.OuM B-1 263 1.O5uM 57.O%@1.OuM B-1 264 O.32uM 47.0%@l1.OuM B-1 265 O.43uM 51.O%@1 .OuM B-1 266 <0.luM 58.0%@ 1.OuM B-1 267 <O.luM 73.0%@1.OuM B-1 268 <0.l uM 79.0%@1.OuM B-1 269 0.46uM 84.O%@1 .OuM B-i 270 O.47uM 83.0%@l1.OuM B-1271 0.l3uM .74.0%@1.OuM B-1 272 0.Ol4uM B-1 273 <13.11UM 36.0%@1.OuM B-1 274 <0.l UM 41.O%@1.OuM 8-1 275 <0.1 UM 50.0%@l1.OuM B-1 276 0.062uM 11.0%@1.OuM B-1 277 <0.l UM 47.0%@1.OuM B-1 278 0.l2uM 85.0%@1.OuM B-1 279 <0.l uM 79.0%@1.OuM B-1 280 0.039uM 83.0%@l1.OuM B-1281 <0.l uM 85.0%@1.OuM B-1282 <0.luM 75.0%@1.OuM B-1 283 <0.1 uM 64.0%@l1.OuM B-1284 <0.luM 75.0%@1.OuM SUBS-nU9SESWXT XRLE W) WO 98/52940 WO 9852940PCTIUS98/1 0436 P38 alpha krnase U937 Cell 1C50,uM Mouse LPS Model Rat LPS Model or or TNF inhib dose inhib @dlose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Example# B-1285 I 0.057uM 80.0%@1.OuM B-1 286 .5uM 78.O%/21.OuM B-1 287 0.25uM 595.O%@1 .OuM B-1 288 .5uM 74.O%@1.OuM B-i 289 O.73uM 35.0%@l1.OuM B-1 290 O.26uM B-1 291 O.O97uM B-1 292 O.OluM B-1 293 O.3luM B-1 294 0.01l3uM B-1 295 0.O79uM 74.0%@ B-1296 0.O38uM B-1 297 0.O2uM >1.OuM B-1298 0.O55uM 20.0%@1.OuM B-1 299 0.091lUM >1.OuM B-1 300 0.071luM 18.0%@1.OuM B-1301 0.l2uM 15.0%@1.OuM B-1302 O.023uM 11.0%@1.OuM B-1303 0.O8uM B-1 304 .ll1uM B-1305 0.64uM 9.0%@11.OuM B-1306 0.11u Um1.OuM B-1307 0.OO9UM 16.0%@l.OuM B-1 308 <0.lu >1I B-1 309 0.045uM B-1310 0.l2uM B-1311 0.05uM B-1312 0.35uM >1.OuM B-1313 0.035uM B-1314 0.O45uM B-1315 O.O55uM 12.0%@1 B-i1316 O.026uM 36.0%@1 B-1317 O.Ol19uM [email protected] B-1318 <0OluM 1.O%@1.OuM B-1319 O.24uM >1.OUM B-i 320* O.O47uM 43.O%@1 .OuM B-1321 O.47uM B-1322 O.l2uM 87.0%@1.OuM B-1 323 0.01 UM B-1 324 O.l6uM 83.0%@1.OuM B-1325 O.27uM 95.0%@1.OuM B-1 326 O.092L1M -84.O%@i.OuM B-1327 .3uM 65.0%@1.OuM B-i1328 O.O32uM 86.O%@1 B-1 329 O.66uM 54.0%@1 B-1330 O.O53uM 85.O%@1.OuM B-i1331 0.OO4UM -85.0%@1 .OuM B-1 332 0.OO7uM -81.0%@1 .OuM B-1333 0.45uM 76.0%@ 1.OuM suwnm8"MTPJMW) WO 98/52940 WO 9852940PCTIUS98/1 0436 P38 alpha kinase U937 Cell 1C50,uM Mouse LIPS Model Rat LIPS Model or or TNF inhib dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time Exam B-1334 I 0.l3uM 73.0%@1.OuM B-1335 0.097uM B-1 336 0.072uM 83.0%@1.OuM B-1 337 0.4UM 90.0%@1.OuM B-1338 0.l8uM 73.0%@1.OuM B-1339 O.l2uM 67.0%@1.OuM B-1340 0.043uM 63.0%@1.OuM B-1341 O.42uM 52.O%@1.OuM B-1 342 0.25uM 59.0%@1.OuM B-1 343 O.O65uM 83.0%@l.OuM B-1344 0.Ol4uM B-1345 0.27uM 73.0%@1.OuM B-1 346 0.043uM 86.0%@1.OuM B-1 347 0.021luM 84.0%@1.OuM B-1 348 0.OO9UM 69.0%@1 OuM B-i1349 O.037uM 86.0%@1 OuM B-1350 0.Ol9uM 78.0%@1.0uM B-i1351 0.O68uM 78.O%@1 .OuM B-1352 0.0l3uM 76.0%@1.OuM B-1 353 0.O62uM 80.0%@1.OuM B-1354 0.Ol3uM 83.O%@1.OuM B-1 355 0.07uM 75.0%@1 .0uM B-1356 0.O59uM 91.0%@1.OuM B-1 357 0.l8uM 84.O%@1.OuM B-1358 0.l6uM 76.O%@1.OuM B-1 359 0.005 84.0%@1 .OuM B-1360 0.11 0.l5uM 54%@3mpkO-4h B-1 361 0.03 0.29uM B-1 362 0.003 0.29uM B-330.009 0.28uM 51.0%@30pmk 53%@3mpk@-4h B_1363 6H -16 0.009 0.27uM 53.0%@30mpk@- 17%@3mpk@-4h B-16 6.OH B-1365 0.17 88.O%@1.OuM B-i 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 0.4luM 48.0%@30mpk B-1373 0.016 0.17uM 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 .04uM B-1 379 <0.1 0.092uM IB-1 380 <0.1 sueanumEET(RLEo WO 98/52940 WO 9852940PCTIUS98/1 0436 697 P38 alpha kinase U937 Cell lC5O,uM Mouse LPS Model Rat LPS Model or or TNF inhib Ca dose inhib @dose inhib@conc. (uM) inhib@conc. (uM) @predose time predose time Example# B-1 381 1 0.055 B-i 382 <0.1 B-1 383 0.0012 B-i 384 0.57 B-1 385 <0.1 B-i 386 <0.1 B-i 387 <0.1 B-1388 0.57 1.38uM B-1 389 0.06 0.57uM B-1 390 <0.1 71.0%@1.OuM B-1 391 0.0l6uM 82.0%@1.OuM B-1392 0.059uM 82.0%@1.OuM B-1393 3.l7uM -80.0%@1.OuM B-i1394 0.32uM 78.0%@1 .OuM B-1 395 1.48 61.0%@1.OuM B-1396 1.55 73.0%@1.OuM B-1 397 0.92 B-1398 0.67 -83.0%@1.OuM 9-1399 0.14 B-i 400 0.024 83.0%@1 B-1401 0.033 75.0%@l.OuM B-1 402 0.12 76.0%@l.OuM B-1 403 4.54 71%@1.OuM B-1404 0.6 -70%@1.OuM B-1405 0.28 70%@1.OuM B-1406 1.39 B-1407 0.4 71.0%@1.OuM B-i1408 0.27 -69.0%@1 .OuM B-i1409 <0.1 72.0%@1 .OuM B-1410 <0.1 69%@1.OuM B-1411 <0.1 81.0%@1.OuM B-i1412 0.097 80.0%@1 .OuM B-1413 0.016 78.0%@1.OuM B-i1414 0.025 83.0%@1 B-1415 1.41 79.0%@1.OuM B-1416 0.14 81.0%@l.OuM B-1417 0.069 69.0%@l.OuM B-1418 1.01 -82.0%@l.OuM B-1419 0.3 84.0%@1.OuM B-1420 <0.1 B-1421 0.014 B-1422 0.58 68.0%@l.OuM B-1423 1.58 84.0%@l.OuM B-i1424 0.86 76.0%@1 .OuM B-1425 0.09 83.0%@l.OuM B-1 426 0.19 80.0%@1.OuM B-1427 <0.1 84.0%@1.OuM B-1428 <0.1 86.0%@1 .OuM B-1429 <0.1 87.0%@l.OuM SUn=VMTESHEWP WO 98/52940 WO 9852940PCTIUS98/1 0436 P38 alpha kinase U937 Cell 1C50,uM Mouse LPS Model Rat LPS Model 1C50,UM or or TNF inhib 0 dose inhib @dcose inhib@conc. (uM) inhib@conc. (uM) @predose time @predose time B-i1430 I 0.75uM 35.0% @P1.OuM B-1 431 0.36uM 58.0% @1.OuM B-1432 Oll1uM 51.0% B-1433 0.26uM 21.0% @1.OuM B-1434 0.l9uM 28.0% @1l.OuM B-1435 1.8uM 45.0% @1.OuM B-1436 1.OuM 20.0% @1.OuM B-1437 0.3uM 23.0% @1.OuM B-1 438 2.01luM 270-0 @1.Ou B-1439 1.7uM 17.0% @1.OuM B-1440 0.87uM 3.0% @1.OuM B-1 441 1.95uMI 66.0% @1.OuM B-1442 1.54uM 18.0% B-1443 0.Ol4uM 83.0% [email protected] B-1 444 0.3uM 24.0% B-1445 0.43uM 27.0% @1.OuM B-1446 0.77uM 36.0% @1 .OuM B-1447 0.5UMI 34.0% @&1.OuM B-1 448 1.43uM 22.0% @1l.OuM B-1449 1.6luM 50.0%@1.OuM B-1450 2.luM 49.0%@1.OuM B-i1451 2.88uM 50% @1 .OuM B-1452 2.4luM 47.0%@ 1.OuM B-1453 2.53uM 49.0% @1 .OuM B-1454 1.6uM 12.0% @1.OuM B-1455 1.2luM 8.0% B-1456 1.29uM >1.OuM B-1457 O.43uM 43.0% B-1458 0.95uM 65.0% @1.OuM B-1459 0.67uM 46.0% B-1460 0.96uM 29.0% @1.OuM B-1461 0.4uM 39.0% @1l.OuM B-1462 0.22uM 50.0% @1.OuM B-1463 2.34uM 26.0% B-1464 1.l8uM 27.0% B-1465 3.23uM 31.0% @1.OuM B-1466 1.69uM >1.OuM B-1467 1.22uM 1.0% @1.OuM B-1468 1.6luM 10.0%/ @1l.OuM B-1469 0.37uM 14.0% @1.OuM B-1470 0.6uM 28.0% @1.OuM B-1471 0.85uM 25.0% @1.OuM B-1472 0.93uM 12.0%@1.OuM B-1473 1.24uM 14.0% @1.OuM B-1474 1.23uM 31.0% @1'b.OuM B-1475 2.luM 24.0% @1.OuM B-1 476 0.047uM 42.0% @1 .OuM B-1477 2.5uM 34.0% @1l.OuM 8UjEBTrfluTEE(KU KOS WO 98/52940 WO 9852940PCT/US98/1 0436 699 P38 alpha kinase U937.Cell IC50,uM Mouse LIPS 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-1 479 SUBSTUESHEEr(RULEau" WO 98/52940 WO 9852940PCT/US98/1-0436 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 @prediose time B-2270 0.72uM 31%@10.OuM B-2271 0.93uM 38%@10.OuM B-2272 0.26uM 53.0%@10.OuM B-2273 1.92uM 39.0%@10.OuM B-2274 0.26uM -59.0%@10.OuM B-2275 2.l6uM B-2276 11.5uM 37.0%@10.OuM B-2277 14.9uIM 44.0%@10.OuM B-2278 0.8uM 51.0%@10.OuM B-2279 0.32uM 36.0%@10.OuM B-2280 O.4uM 57.0%@10.OuM B-2281 0.81lUm 60.0%@1O.OuM B-2282 0.9luMV 41.0%@10.OuM B-2283 0.O4uM 53.0%@10.OuM B-2284 4.6luM 62.0%/@10.OuM B-2285 2.29uM 49.0%@10.OuM B-2286 0.01 7uM 0.78uM 25%@3Ompk@-lh B-2287 2.56uM B-2288 6.5luM 46.O%@10.OuM B-2289 3.OuM 30.0%@10.OuM B-2290 2.37uM 59.0%@10.OuM B-2291 0.Ol9uM 41%@1O.OuM B-2292 8.82uM 57.0%@10.OuM B-2293 2.lluM 56.0%@10.OuM B-2294 1.68uM 50.O%@10.OuM B-2295 1.79uM 56.O%@10.OuM B-2296 17.3uM 63.0%@10.OuM B-2297 3.59uM 57.0%@10.OuM B-2298 0.29uM 4.22uM B-2299 1.97uM 62.0%@10.OuM 6-2300 0.O7uM 43.0%@10.OuM B-2301 0.l8uM 44.0%@1O.OuM B-2302 1.0uM 58.0%@1.OuM B-2303 0.011 uMI 54.0%@ B-2304 1.4lu M 50.0%@10.OuM B-2305 0.54uM .60.0%@10.OuM B-2306 5.88uM 39.0%@1O.OuM B-2307 2.29uM 69.0%0/@10.OuM B-2308 0.66uM 56.0%@10.OuM B-2309 0.29uM 47.0%@10.OuM SUBS11TJTEHEUT(RUE£) WO 98/52940 WO 9852940PCTIUS98/1 0436 P38 alpha kinase U937 Cell 1C50,uM Mouse LIPS Model Rat LPS Model Example* 1C50,uM or or, TNF inhib inhib @dose inhlb@conc. (uM) inhib@conc. (uM) dose @predose time @predose time B-231 0 0.l2uM 1.2uM B-2311 7.l8uM 60%@10.OuM B-2312 2.93uM 43.0%@1O.OuM B-2313 42.3uM B-2314 11I.OuM 66.0%@10.OuM B-2315 0.49uM B-2316 0.46uM B-2317 1.0uM B-2318 73.0%@10.OUM B-2319 75.0%@10.OuM 40.0%@10.OuM B-2320 44.0%@10.OuM 35.O%@10.OuM B-2321 69.O%@10.OuM 27.0%@10.OuM B-2322 76.0%@10.OuM 38.0%@10.OuM B-2323 69.0%@10.OuM 46.0%@1O.OuM B-2324 58.0%@10.OuM 36.0o%@10.OuM B-2325 60.0%@?10.OuM 51.0%@10.OuM B-2326 76.0%/@10.OuM 33.0%@10.OEM B-2327 76.0%@10.OuM 23.0%/[email protected] B-2328 65.0%@ 10.OuM 28.0%@ 1 B-2329 72.0% @1 0.OuM 53.0%@ 10.OuM B-2330 81 10.OuM 37.0% @1 .OuM B-2331 74.0%@10.OuM 44.0%@10.OuM B-2332 70.0%@10.OuM 47.0%/@10.OuM B-2333 58.0%@10.OuM 36.0%@10.OuM B-2334 81.0%@10.OuM 45.0%@10.OuM B-2335 82.0%@10.OuM 50.0%@10.OuM B-2336 48.0% @1 .OuM 35.0%@ 10.OuM B-2337 46.0%@10.OuM 59.0%@1O.OuM B-2338 73.0%@ 10.OuM 50.O%@ 1 .OuM B-2339 84.0%/@10.OuM B-2340 35.0%@10.OuM 12.0%@10.OuM B-2341 75.0%@ 10.OuM 50.0%@ B-2342 83.0%@ 10.OuM B-2343 10.OuM 27.0%@ 1 B-2344 71 10.OuM 50.0%@ B-2345 64.0%@ 10.OuM 38.0%@ 1 .OuM 6-2346 45.0%@10.OuM 48.0%/@10.OuM B-2347 49.0%@ 1 .OuM 50.O%@ 10.OuM B-2348 76.0%@10.OuM 48.0%@10.OuM 6-2349 75.O%/@10.OuM 27.0%@10.OuM Su9UMOMMHET(RUBMI"I) WO 98/52940 WO 9852940PCTIUS98/1-0436 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.O%@10.OuM 1.O%@10.OuM B-2352 37.O%@ 10.OuM 1 1 B-2353 38.O%@1O.OuM 33.0%@1O.OuM B-2354 65.0%@1O.OuM 25.0%@10.OuM B-2355 84.0%@ 10.OuM 50.0%@ 10.OuM B-2356 77.O%@ 10.OuM 10.OuM B-2357 47.O%@10.OuM -41.0%/@1O.OuM B-2358 1 1 .OuM 52.0% @1 0.OuM B-2359 76.0%@Cc10.OuM 35.0%@1O.OuM B-2360 45.0%@10.OuM >10.OuM B-2361 19.O%@10.OuM 46.0%@10.OuM B-2362 60% 100.Ou M 39.0%@10.OuM B-2363 44.0%@10.OuM 1.0%@10.OuM B-2364 47.0%@10.OuM 4.0%/@1O.OuM B-2365 82.0%@10.OuM -43.O%@10.OuM B-2366 70.0%@10.OuM 59.0%@1O.OuM B-2367 46.0%@10.OuM 40.0%@1.OuIM B-2368 65.0%@10.OuM 55.0%@10.OuM B-2369 32.0%/@10.OuM B-2370 73%@100.OuM 20.0%@10.OuM B-2371 54.0%@10.OuM 36.0%@1O.OuM B-2372 55.0%@100.OUM B-2373 50.O%@100.OuM B-2374 35.O%@1O.OuM 20.0%@1O.OuM B-2375 62.0%@100.OuM >10.OuM 6-2376 32.0%@ 1 .OuM 1 B-2377 34.0%@10.OuM 17.0%@10.OuM 6-2378 48.O%@ 1 .OuM 61 1 .OuM B-2379 73.0%@100.OuM -45.0%@1 .OuM B-2380 81%@100.OuM -53.0%@1O.OuM B-2381 68%@100.OuM 2.0%@10.OuM B-2382 51.O%@10.OuM 24.0%/@10.OuM B-2383 63.0%@ 10.OuM 35.0%@ 1 .OuM B-2384 49%@100.OuM 1O.0%@10.OuM 6-2385 79.O%@10.OuM 19.0%@10.OuM B-2386 38.0%@ 1 .OuM 1 6-2387 50.O%@100.OUM >10.OuM 6-2388 42.0% @1 0.OuM 1 O.uM B-2389 39.0%@10.OuM I29.0%@1O.OuM SUBBSTUMEHT(RLE96) WO 98/52940 WO 9852940PCTIUS98/1 0436 P38 alpha kinase U937 Cell 1C50,uM Mouse LIPS Model Rat LPS Model Example# IC50,uM or% or TNF inhib inhib @dose inhib@conc. (uM) inhib@conc. (uM) dose Opredose time @predose time B-2390 34.O%@10.OuM 27.0%@1.0uM B-2391 40.0%@10.OuM 59.O%@10.OuM B-2392 63.0%@10.OuM 46.0%@10.OuM B-2393 43.0%@10.OuM B-2394 37.0%@10.OuM 22.0%@10.OuM B-2395 32.0%@10.OuM 28.0%@10.OuM B-2396 75.0%@10.OuM >10.OuM B-2397 83.0%@10.OuM 22.O%@10.OuM B-2398 55%@ 100.OuM 8-2399 69.0%@10.OuM 18.0%@10.OuM B-2400 60.0% @1 0.0uM 1 B-2401 78.0%@ 10.OuM 1 B-2402 43.0%@ 1 .OuM 52.0% @1 B-2403 72%@100.OuM 52.0%@10.OuM B-2404 58%@100.0uM 52.0%@10.OuM B-2405 47%@100.OuM >10.0uM B-2406 45.0%@10.OuM 24.0%@10.OuM B-2407 47%@ 100.OuM 27.O%@ B-2408 39.0%@10.OuM 10.O%@10.OuM B-2409 78.0%@1O.OUM 26.0%@10.OUM B-2410 33.0%@10.OUM 32.0%@10.OuM B-2411 26%@100.OuM 13.0%@10.OuM B-241 2 40.0% 1 0.Ou M 31 0.OuM B-2413 75.0%@10.OUM 37.0%@10.OuM B-2414 86.0%@ 10.OuM 38.0%@10.OuM B-2415 94.0%@10.OuM 50.0%@10.OuM B-2416 85.0%0/@10.OuM 43.0%@1.OuM B-2417 83.0% @1 0.OuM 1 B-2418 88.0%@10.OuM 34.0%@10.OuM B-241 9 86.0%@ 10.OuM 66.0%@ B-2420 70.0%@10.OuM 34.0%@10.OuM B-2421 89.0%210.OuM 38.O%@10.OuM B-2422 90.0%@ 10.0uM 1 B-2423 85.0%@10.OuM >10.OuM B-2424 86.0%@10.OUM 43.O%@10.OuM B-2425 79.0%@10.OuM 42.O%@10.OuM B-2426 88.0%@10.OuM 53.0%@10.OuM B-2427 87.0%@10.OuM 59.O%@10.OuM 8-2428 82.0%@10.OuM 50.0%@10.OuM 8-2429 92.0%@10.OuM 32.0%@10.OuM SUBB1flUESHEUK(RLE26) WO 98/52940 WO 9852940PCTIUS98/1 0436 P38 alpha kinase U937 Cell IC50,uM Mouse LPS Model Rat LPS Model Example# lC50,uM or or TNF inhib inhib @dose inhib@conc. (uM) inhib@conc. (uM) dose @predose time @predose time B-2430 90.0%@1O.OuM 61.O%@1O.OuM B-2431 85.0%210.OuM 68.O%@1O.OuM B-2432 86.O%/210.OuM 40.O%@1O.OuM B-2433 94.0o%@1O.OuM 84.O%@10.OuM B-2434 92.0%@1O.OuM 63.O%@10.OuM B-2435 84.0%@10.OuM 4.O%@10.OuM B-2436 80.0%@10.OuM 54.O%@10.OuM B-2437 82.0%@110.OuM B-2438 75.0%@10.OuM B-2439 81.0%@10.OuM 44.O%@10.OuM B-2440 77.0%@10.OuM 78.O%@10.OuM B-2441 86.O%@10.OuM 46.O%@1O.OuM B-2442 86.O%@10.OuM >10.OuM B-2443 84.0%@10.OuM 44.O%@1O.OuM B-2444 89.O%@1O.OuM 7.O%@10.OuM B-2445 94.O%@10.OuM 15.O%@10.OuM B-2446 90.O%@10.OuM 28.O%@1O.OuM B-2447 94.0%@10.OuM >10O.OuM B-2448 75.O%@10.OuM 30.O%@1O.OuM B-2449 86.O%@ 10.OuM 42.O%@ 1 B-2450 87.O%@l0.OUM 46.0%@l.OuM B-2451 87.O%@1O.OuM 45.0%@10.OuM B-2452 89.O%@10.OuM B-2453 91.0o%@10.OuM B-2454 88.0%/@10.OuM B-2455 87.0%@1O.OuM B-2456 86.O%@10.OuM 6-2457 90.O%@10.OuM 6-2458 83.O%@10.OuM B-2459 82.O%@10.OuM 81.O%@1O.OuM 6-2460 80.0%@10.OuM 79.0%@10.OuM B-2461 67.0%@ 1 .OuM 59.0%@ 1

SSTEBHEE(MUENOW

704a It is to be understood that a reference herein to a prior art document does not constitute an admission that the document forms part of the common general knowledge in the art in Australia or in any other country.

In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due.to express language or necessary implication, the word "comprising" and grammatical variations thereof are used in the sense of "including", i.e. the features specified may be associated with further features in various embodiments of the invention.

S

Si.o

SO

oo S S 5 o @5 o

Claims (64)

1. A compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein: the compound corresponds in structure to Formula I: R 3 R /i~f5 1 N1 1 N i R as to R 1 R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, aryiheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, 706 alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, and heterocyclylcarbonyloxyalkylene, or R' corresponds in structure to formula (II): R 25 0 -C (CH 2 C-N R2 i is an integer from zero to 9; 0 0 R 25 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, 10 aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; as toR 26and R 27 R 26is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, .00. alkoxycarbonylalkylene, and alkylaminoalkyl, and: o .0 R 27 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, 0000 cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, eoo 20 cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkyiheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, Salkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, 707 arylaminocarbonylalkylee, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisiting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R27 isH28 29 O *R 21is -CHR 2R 2, or 262 R 6 and R 27 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkyiheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or 708 more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy; R 28 is alkoxycarbonyl; R 29 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene, wherein: said aralkyl and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl and nitro; as to R2: *2 R is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, 20 cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl, wherein: the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, Sheterocyclylalkyl, epoxyalkyl, 709 amino(hydroxyalkyl)carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, hydroxyalkylcarbonyl, alkoxycarbonyl, arylsulfonyl, and aralkylsulfonyl, or R 2 corresponds in structure to formula (III): R 30 H I I R 32 C--(CH 2 C N 31 14R33 R3 R 3 4 S m (III), or R 2 is -CR 4 1 R 42 R2 is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl, and cycloalkenyl when R 4 is hydrogen; j is an integer from zero to 8; m is selected from the group consisting of zero and 1; 15 R 30 and R 31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; R 32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R 33 is selected from the group consisting of hydrogen, alkyl, -C(0)R 35 -C(0)OR 35 -S0 2 R, -C NRR 38 and -SO 2 NR 3 9 R 4 0 R 35 R 36 R 37 R 38 R 39 and R 40 are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon, and heterocyclyl; 710 R 34 is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; *41 is aryl; R42 is hydroxy; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, C C and 143 wherein: the pyridinyl, pyrimidinyl, quinolinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, aryihydrazinyl, and _NR 4 4 R 4 1; R 3 is not 2-pyridinyl when R 4 is a phenyl ring !ontaining a 2-hydroxy substituent and when R 1 is hydrogen; *0 @0 0 0* 0 00 0 00 711 R 43 is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; R 44 is selected from the group consisting of alkylcarbonyl and amino; R 45 is selected from the group consisting of alkyl and aralkyl; and R 4 is selected from the group consisting of hydrogen, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein: the alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, 15 heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, 20 alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy.

2. A compound, tautomer, or salt of claim 1, wherein: as to R 1 R 1 is selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower haloalkyl, lower hydroxyalkyl, lower aralkyl, lower alkoxyalkyl, lower mercaptoalkyl, lower alkylthioalkylene, amino, lower alkylamino, lower arylamino, lower alkylaminoalkylene, and lower heterocyclylalkylene, or sR 1 corresponds in structure to formula (II): *0 0 0000 0 *000 00000 *0 00 0 0 000 0 0 712 R 25 0 1 II R 2 6 C--(CH2)i---C--NR H (II); i is selected from the group consisting of zero, 1, and R 25 is selected from the group consisting of hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, lower phenoxyalkylene, lower aminoalkyl, lower alkylaminoalkyl, lower phenoxyaminoalkyl, lower alkylcarbonylalkylene, lower phenoxycarbonylalkylene, 10 and lower heterocyclylcarbonylaminoalkylene; as to R 26 and R 27 R 26 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkylalkylene, lower phenylalkyl, lower 15 alkoxycarbonylalkylene, and lower alkylaminoalkyl, and: R 27 is selected from the group consisting of lower alkyl, lower cycloalkyl, lower alkynyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower phenylalkyl, lower cycloalkylalkylene, lower cycloalkenylalkylene, lower 20 cycloalkylarylene, lower cycloalkylcycloalkyl, lower heterocyclylalkylene, lower alkylphenylene, lower alkylphenylalkyl, lower phenylalkylphenylene, lower alkylheterocyclyl, lower alkylheterocyclylalkylene, lower alkylheterocyclylphenylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl, lower alkoxyheterocyclyl, lower alkoxyalkoxyphenylene, lower phenoxyphenylene, lower phenylalkoxyphenylene, lower alkoxyheterocyclylalkylene, lower phenoxyalkoxyphenylene, lower alkoxycarbonylalkylene, 1 41% a;wer alkoxycarbonylheterocyclyl, lower 713 alkoxycarbonylheterocyclylcarbonylalkylene, lower aminoalkyl, lower alkylaminoalkylene, lower phenylaminocarbonylalkylene, lower alkoxyphenylaminocarbonylalkylene, lower aminocarbonylalkylene, arylaminocarbonylalkylene, lower alkylaminocarbonylalkylene, lower phenylcarbonylalkylene, lower alkoxycarbonylphenylene, lower phenoxycarbonylphenylene, lower alkylphenoxycarbonylphenylene, lower phenylcarbonylphenylene, lower alkylphenylcarbonylphenylene, lower alkoxycarbonylheterocyclylphenylene, lower alkoxycarbonylalkoxylphenylene, lower heterocyclylcarbonylalkylphenylene, lower alkylthioalkylene, cycloalkylthioalkylene, lower alkylthiophenylene, lower 150 phenylalkylthiophenylene, lower heterocyclylthiophenylene, o'15 lower phenylthioalklylphenylene, lower phenylsulfonylaminoalkylene, lower alkylsulfonylphenylene, lower alkylaminosulfonylphenylene, wherein: 0* said lower alkyl, lower cycloalkyl, phenyl, 0.00.0 biphenyl, naphthyl, lower heterocyclyl, lower 20 phenylalkyl, lower heterocyclylalkylene, lower alkylheterocyclylphenylene, lower alkoxyphenylene, lower phenoxyphenylene, lower phenylaminocarbonylalkylene, lower phenoxycarbonylphenylene, lower phenylcarbonylphenylene, lower alkylthiophenylene, lower heterocyclylthiophenylene, lower phenylthioalklylphenylene, and lower alkylsulfonylphenylene are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, lower haloalkyl, lower alkoxy, keto, amino, nitro, and cyano, or R 27 is -CHR 46 R 4 7 1 or 26 2 R and R 27 together with the nitrogen to which they are tached, form a 4-8 membered ring heterocycle, wherein: 714 said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, phenyl, biphenyl, naphthyl, heterocyclyl, heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenoxyalkylene, lower alkoxyphenylene, lower alkylphenoxyalkylene, lower alkylcarbonyl, lower alkoxycarbonyl, lower phenylalkoxycarbonyl, lower alkylamino, and lower alkoxycarbonylamino, wherein: said phenyl, biphenyl, naphthyl, lower heterocyclylalkylene, and lower phenoxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, lower alkyl, and lower alkoxy; 15 R 4 is lower alkoxycarbonyl; R 47 is selected from the group consisting of lower phenylalkyl, lower phenylalkoxyalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower *o \alkoxycarbonylalkylene, lower alkylthioalkylene, and lower 20 phenylalkylthioalkylene, wherein: the phenylalkyl and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl and nitro; as to R2: R 2 is selected from the group consisting of hydrogen, halogen, lower alkyl, phenyl, biphenyl, naphthyl, lower haloalkyl, lower hydroxyalkyl, 5- to 6-membered heterocyclyl, lower alkylheterocyclyl, lower heterocyclylalkyl, lower alkylamino, lower alkynylamino, phenylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkylaminoalkylamino, lower cycloalkyl, lower alkenyl, r 715 lower alkoxycarbonylalkyl, lower cycloalkenyl, lower carboxyalkylamino, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, lower alkoxycarbonylheterocyclylcarbonyl, alkoxycarbonylalkyl, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylsulfonyl, lower heterocyclyloxy, and lower heterocyclylthio, wherein: the phenyl, biphenyl, naphthyl, heterocylyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, keto, lower alkyl, lower alkynyl, phenyl, 5- to

6-membered heterocyclyl, lower phenylalkyl, lower heterocyclylalkyl, lower epoxyalkyl, carboxy, lower alkoxy, lower aryloxy, lower phenylalkoxy, lower haloalkyl, lower alkylamino, lower alkylaminoalkylamino, lower alkynylamino, lower amino(hydroxyalkyl), lower heterocyclylalkylamino, lower alkylcarbonyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower 20 phenylalkylsulfonyl, and phenylsulfonyl, or R is -CR"R or R 2 corresponds in structure to a formula selected from the group consisting of: R 3 0 R 3 1 R32 "R33 (III), 716 R 58 R58R8 R 5 7 IIJ (CH2)k- N 0 (CH 2 )k- (VI) (C2)k- (VIII); (VI I) and j is selected from the group consisting of zero, 1, and 2; m is zero; R 30and R 31 are independently selected from the group 5 consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; R R 32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R 33 is selected from the group consisting of hydrogen, 35_ 5 365 -C)N 37R 38 n alkyl, -C(O)R 3 5 -(O)OR -SO 2 R n -S0 2 NR39R 4 0 as to R 3 R 35 is selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclyl, aralkyl, arylcycloalkyl, cycloalkenylalkylene, heterocyclylalkylene, alkylarylene, alkyiheterocyclyl, arylarylene, arylheterocyclyl, alkoxy, alkenoxy, alkoxyalkylene, alkoxyaralkyl, alkoxyarylene, aryloxyalkylene, aralkoxyalkylene, cycloalkyloxyalkylene, alkoxycarbonyl, heterocyclylcarbonyl, alkylcarbonyloxyalkylene, alkylcarbonyloxyarylene, alkoxycarbonylalkylene, akxroyaryen, aralkoxycarbonylheterocyclyl, 717 alkylcarbonylheterocyclyl, arylcarbonyloxyalkylarylene, and alkylthioalkylene, wherein: said aryl, heterocyclyl, aralkyl, alkylarylene, arylheterocyclyl, alkoxyarylene, aryloxyalkylene, cycloalkoxyalkylene, alkoxycarbonylalkylene, and alkylcarbonylheterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano, or R 35 is CHR 8 R 49 or R 35 is -NRORS 51 R 36 is selected from the group consisting of alkyl, haloalkyl, aryl, heterocyclyl, cycloalkylalkylene, alkylarylene, alkenylarylene, arylarylene, aralkyl, 15 aralkenyl, heterocyclylheterocyclyl, carboxyarylene, alkoxyarylene, alkoxycarbonylarylene, alkylcarbonylaminoarylene, alkylcarbonylaminoheterocyclyl, arylcarbonylaminoalkylheterocyclyl, alkylaminoarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, 20 alkylsulfonylaralkyl, and arylsulfonylheterocyclyl, wherein: o* said aryl, heterocyclyl, cycloalkylalkylene, aralkyl, alkylcarbonylaminoheterocyclyl, and alkylsulfonylarylene groups are optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; R 48 is selected from the group consisting of arylsulfonylamino, and alkylarylsulfonylamino; R 50 is alkyl; R 51 is aryl; as to R 37 and R 38 R 37 is selected from the group consisting of hydrogen ST ,d alkyl, and: 718 R38 is selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, heterocyclyl, aralkyl, alkylarylene, arylcycloalkyl, arylarylene, cycloalkylalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, aralkyiheterocyclyl, alkoxyalkylene, alkoxyarylene, aryloxyarylene, arylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylene, alkoxycarbonylarylene, alkylcarbonylcarbonylalkylene, alkylaminoalkylene, alkylaminoaralkyl, alkylcarbonylaminoalkylene, alkylthioarylene, alkylsulfonylaralkyl, and aminosulfonylaralkyl, wherein: said aryl, heterocyclyl, aralkyl, and heterocyclylalkylene are optionally substituted with one or more radicals independently selected from the group 15 consisting of alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano, or R38 i C52 53 o R 31is -CR"R 3, or R 37 and R 38 together with the nitrogen to which they are attached, form a heterocycle; R 5 2 is alkoxycarbonyl; p53 SR is alkylthioalkylene; as to R 39 and R 40 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: R 4 0 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, koxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, 719 aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonyiheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclyithioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosul fonylarylene, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisiting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or 3928 29 R" is CHR 'R or 39 4 R and R 40 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, 720 heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy; R 28 is alkoxycarbonyl; R 29 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, i alkylheterocyclylalkylene, alkoxycarbonylalkylene, 99 .9 alkylthioalkylene, and aralkylthioalkylene, wherein: said aralkyl and heterocyclyl are optionally 15 substituted with one or more radicals independently selected from the group consisting of alkyl and nitro; R 41 is phenyl; R 4 2 is hydroxy; 00 k is an integer from zero to 3; 0 20 as to R 56 and R 57 R 5 6 is selected from the group consisting of hydrogen and lower alkyl, and R 57 is selected from the group consisting of hydrogen and lower alkyl, or R 56 and R 57 form a lower alkylene bridge; R 58 is selected from the group consisting of hydrogen, alkyl, aralkyl, aryl, heterocyclyl, heterocyclylalkyl, alkoxycarbonyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, -C(O)R 59 -S0 2 R 6 0 and -C(O)NHR61; R 59 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, alkylarylene, aralkyl, alkylheterocyclyl, alkoxy, alkenoxy, aralkoxy, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, wherein: 721 said aryl, heterocyclyl, and aralkyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; and R 60 is selected from the group consisting of alkyl, aryl, heterocyclyl, alkylarylene, alkylheterocyclyl, aralkyl, heterocyclylheterocyclyl, alkoxyarylene, alkylamino, alkylaminoarylene, alkylsulfonylarylene, and arylsulfonylheterocyclyl, wherein: said aryl, heterocyclyl, and aralkyl are optionally substituted with one or more radicals independently **0 selected from the group consisting of alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, 15 nitro, and cyano; R 6 1 is selected from the group consisting of alkyl, aryl, alkylarylene, and alkoxyarylene, wherein: said aryl group is optionally substituted with one or more radicals independently selected from the group 20 consisting of alkyl, halo, hydroxy, haloalkyl, alkoxy, haloalkoxy, keto, amino, nitro, and cyano; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, and r 0 N 0 R 3 wherein: the pyridinyl, pyrimidinyl, quinolinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of lower alkylthio, halo, lower alkyl, lower aralkyl, lower phenylalkenyl, lower phenylheterocyclyl, carboxy, cyano, lower alkoxycarbonyl, aminocarbonyl, lower 722 alkylcarbonylamino, lower haloalkyl, hydroxy, lower alkoxy, amino, lower cycloalkylamino, lower alkylamino, lower alkenylamino, lower alkynylamino, lower aminoalkyl, arylamino, lower aralkylamino, nitro, halosulfonyl, lower alkylcarbonyl, lower alkoxycarbonylamino, lower alkoxyphenylalkylamino, lower alkylaminoalkylamino, lower hydroxyalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower phenylalkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyphenylalkylamino, hydrazinyl, lower alkylhydrazinyl, and -NRR 45 R 43 is selected from the group consisting of hydrogen, lower alkyl, lower aminoalkyl, lower alkoxyalkyl, lower alkenoxyalkyl, and lower aryloxyalkyl; R 44 is selected from the group consisting of lower alkylcarbonyl and amino; R 45 is selected from the group consisting of lower alkyl and lower phenylalkyl; and R is selected from the group consisting of hydrogen, lower cycloalkyl, lower cycloalkenyl, phenyl, biphenyl, '"naphthyl, and 5- to 10- membered heterocyclyl, wherein: the lower cycloalkyl, lower cycloalkenyl, phenyl, o biphenyl, naphthyl, and 5-10 membered heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of lower alkylthio, halo, lower alkyl, lower alkynyl, lower alkoxy, lower aryloxy, lower aralkoxy, lower heterocyclyl, lower haloalkyl, amino, cyano, nitro, lower alkylamino, and hydroxy. 3. A compound, tautomer, or salt of claim 2, wherein: R 1 is selected from the group consisting of hydrogen, zgthyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, -723 fluoromethyl, difluoromethyl, trifluoromethyl, chioromethyl, dichioromethyl, trichioroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichiorofluoromethyl, difluoroethyl, difluoropropyl, dichioroethyl, dichioropropyl, ethenyl, propenyl, ethynyl, propargyl, 1 -propynyl, 2 -propynyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxyrnethyl, amino, methylamino, dimethylamino, phenylamino, iethylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methyithiomethyl; as to R 2 R R 2 is selected from the group consisting of hydrogen, chioro, fluoro, bromo, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, phenyl, biphenyl, fluoromethyl, difluoromethyl, trifluoromethyl, chiorornethyl, dichioromethyl, trichioromethyl, pentafluoroethyl, heptafluoropropyl, difluorochioromethyl, dichiorofluoromethyl, difluoroethyl, difluoropropyl, dichioroethyl, dichioropropyl, hydroxymethyl, hydroxyethyl, pyridinyl, isothiazolyl, isoxazolyl, thienyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, piperidinyl, piperazinyl, morpholinyl, N-methylpiperazinyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-N-propylamino, N,N-dimethylamino, N-methyl-N-phenylamino, N-phenylamino, piperadinylamino, N-benzylamino, N-propargylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 724 cyclohexadienyl, aminomethyl, amiroethyl, aminoethylamino, aminopropylamino, N,N-dimethylaminoethylamino, N,N-dimethylaminopropylamino, morpholinylethylamino, morpholinyipropylamino, carboxymethylamino, methoxyethylamino, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1,1-dimethylethoxycarbonyl, 1,1-dimethylethoxycarbonylaminoethylamino, 1,1-dimethylethoxycarbonylaminopropylamino, piperazinylcarbonyl, and 1,1 -dimethylethoxycarbonylpiperazinylcarbonyl, wherein: the aryl, heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, chloro, bromo, keto, methyl, ethyl, isopropyl, tert-butyl, isobutyl, benzyl, carboxy, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, dimethylamino, methoxycarbonyl, ethoxycarbonyl, and 1,1 -dimethylethylcarbonyl, or 2 -41 42 R is -CRR; 41 R is phenyl; R42 is hydroxy; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, and purinyl, wherein: the pyridinyl, pyrimidinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chioro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichloromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, 725 chiorophenylmethyl, chiorophenylethyl, fluorophenylethenyl, chiorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamiio, diethylamino, 2 -methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl -N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chiorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (l-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methyl-hydrazinyl, and -NR 4 R 45 44 R is selected from the group consisting of methylcarbonyl and amino; *45 R 4 is selected from the group consisting of methyl, ethyl, and phenylmethyl; and R 4 is selected from the group consisting of hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, 726 tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl, wherein: the cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, and hydroxy. 4. A compound, tautomer, or salt of claim 3, wherein: R is selected from the group consisting of hydrogen, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, 15 diethylaminoethyl, and morpholinylethyl; R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, trifluoromethyl, methoxycarbonylethyl, N,N-dimethylamino, N-phenylamino, piperidinyl, piperazinyl, pyridinyl, N-methylpiperazinyl, and piperazinylamino, wherein: the phenyl, piperidinyl, and pyridinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, chloro, bromo, methyl, ethyl, and trifluoromethyl; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, and quinolinyl, wherein: pyridinyl, pyrimidinyl, and quinolinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, 727 methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; R 4 is selected from the group consisting of phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl, wherein: the phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy. R 1 is selected from the group consisting of hydrogen and methyl; R 2 is selected from the group consisting of hydrogen, methyl, and ethyl; R 3 is selected from the group consisting of pyridinyl, S pyrimidinyl, and quinolinyl, wherein: pyridinyl, pyrimidinyl, and quinolinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; R 4 is phenyl optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, -imethylamino, and hydroxy. 728 6. A compound, tautomer, or salt of claim 2, wherein: R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloroethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, ethenyl, propenyl, ethynyl, propargyl, 1-propynyl, 2-propynyl, piperidinyl, piperazinyl, morpholinyl, benzyl, phenylethyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperazinylmethyl, piperidinylmethyl, pyridinylmethyl, thienylmethyl, methoxymethyl, ethoxymethyl, amino, methylamino, 15 dimethylamino, phenylamino, methylaminomethyl, dimethylaminomethyl, methylarninoethyl, dimethylaminoethyl, ethylaminoethyl, diethylaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, hydroxymethyl, hydroxyethyl, mercaptomethyl, and methylthiomethyl; 20 R 2 corresponds in structure to a formula selected from the group consisting of: a a a. S. a S a a aa S. S S 55 a* S S *a* a a 131 R 58 R 57 IC (CH 2 )k- (VI), Ii (VI I) and R 5 8 0 (CH2)k- (VIII); 729 j is selected from the group consisting of zero, 1, and 2; m is zero; R 30 and R 31 are independently selected from the group consisting of hydrogen and lower alkyl; R 32 is selected from the group consisting of hydrogen, lower alkyl, lower phenylalkyl, lower heterocyclylalkyl, lower alkoxyalkylene, aryloxyalkylene, aminoalkyl, lower alkylaminoalkyl, lower phenylaminoalkyl, lower alkylcarbonylalkylene, lower phenylcarbonylalkylene, and lower heterocyclylcarbonylaminoalkylene; R 33 is selected from the group consisting of hydrogen, lower alkyl, -C(O)R 3 5 -C(O)OR 35 -SO 2 R 36 -C(O)NR3R 38 and -SO 2 NR R 40 35 15 as to R 5 R 35 is selected from the group consisting of lower alkyl, lower cycloalkyl, lower haloalkyl, lower alkenyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower phenylalkyl, lower phenylcycloalkyl, lower cycloalkenylalkylene, lower heterocyclylalkylene, lower alkylphenylene, lower alkylheterocyclyl, phenylphenylene, lower phenylheterocyclyl, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower alkoxyphenylalkyl, lower alkoxyphenylene, lower phenoxyalkylene, lower phenylalkoxyalkylene, lower cycloalkyloxyalkylene, lower alkoxycarbonyl, lower heterocyclylcarbonyl, lower alkylcarbonyloxyalkylene, lower alkylcarbonyloxyphenylene, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower phenylalkoxycarbonylheterocyclyl, lower alkylcarbonylheterocyclyl, lower phenylcarbonyloxyalkylphenylene, and lower alkylthioalkylene, wherein: 730 said phenyl, biphenyl, naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylheterocyclyl, lower alkoxyphenylene, lower phenoxyalkylene, lower cycloalkoxyalkylene, lower alkoxycarbonylalkylene, and lower alkylcarbonylheterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano, R 35 is CHR 4 R 49 or R 35 is -NRs 5 R 51 R 48 is selected from the group consisting of phenylsulfonylamino and lower alkylphenylsulfonylamino; R 49 is selected from the group consisting of lower phenylalkyl, amino, lower alkylamino, and lower phenylalkylamino; R 50 is lower alkyl; R 51 is selected from the group consisting of phenyl, biphenyl, and naphthyl; 36 R 36 is selected from the group consisting of lower alkyl, lower haloalkyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower alkylphenylene, lower alkenylphenylene, phenylphenylene, lower phenylalkyl, lower phenylalkenyl, lower heterocyclylheterocyclyl, carboxyphenylene, lower alkoxyphenylene, lower alkoxycarbonylphenylene, lower alkylcarbonylaminophenylene, lower alkylcarbonylaminoheterocyclyl, lower phenylcarbonylaminoalkylheterocyclyl, lower alkylaminophenylene, lower alkylamino, lower alkylaminophenylene, lower alkylsulfonylphenylene, lower alkylsulfonylphenylalkyl, and lower -aphenylsulfonylheterocyclyl, wherein: 731 said phenyl, biphenyl, naphthyl, lower heterocyclyl, lower cycloalkylalkylene, lower phenylalkyl, lower alkylcarbonylaminoheterocyclyl, and lower alkylsulfonylphenylene are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; as to R 37 and R 38 R 37 is selected from the group consisting of hydrogen and lower alkyl, and: R 38 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower phenylalkyl, lower alkylphenylene, lower phenylcycloalkyl, phenylphenylene, lower cycloalkylalkylene, lower heterocyclylalkylene, lower alkylheterocyclylalkylene, lower phenylalkylheterocyclyl, lower alkoxyalkylene, lower alkoxyphenylene, lower phenoxyphenylene, phenylcarbonyl, lower alkoxycarbonyl, lower alkoxycarbonylalkylene, lower alkoxycarbonylphenylene, lower alkylcarbonylcarbonylalkylene, *f* lower alkylaminoalkylene, lower alkylaminophenylalkyl, lower alkylcarbonylaminoalkylene, lower alkylthiophenylene, lower alkylsulfonylphenylalkyl, and lower aminosulfonylphenylalkyl, wherein: said phenyl, biphenyl, naphthyl, lower heterocyclyl, lower phenylalkyl, and lower heterocyclylalkylene are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano, or R 38 is -CR 52 R 53 or 732 37 3 R and R 38 together with the nitrogen to which they are attached, form a 4-to 8- membered ring heterocycle; as to R 39 and R 40 R 39 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkyiheterocyclyl, alkyiheterocyclylalkylene, alkyiheterocyclylarylene, aralkyiheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, 15 aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, 000 aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonyiheterocyclyl, .000 alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, ooe.* alkylaminoalkylene, arylaminocarbonylalkylene, 20 alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, 0 0 aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonyiheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkyiheterocyclylarylene, 733 alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisiting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R 39 is -CHRR 29 or R 39 and R 40 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, 15 heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy; k is an integer from zero to 2; R 56 is selected from the group consisting of hydrogen and lower alkyl; R 57 is selected from the group consisting of hydrogen and lower alkyl; R 58 is selected from the group consisting of hydrogen, lower alkyl, lower phenylalkyl, aryl selected from the group consisting of phenyl, biphenyl and naphthyl, lower heterocyclyl, lower heterocyclylalkyl, lower alkoxycarbonyl, lower alkylsulfonyl, lower phenylalkylsulfonyl, lower enylsulfonyl, -C(O)R 59 -SO 2 R 6 0 and -C(O)NHR 61 734 R 59 is selected from the group consisting of lower alkyl, lower haloalkyl, lower cycloalkyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower alkylphenylene, lower phenylalkyl, lower alkylheterocyclyl, lower alkoxy, lower alkenoxy, lower phenylalkoxy, lower alkoxyalkylene, lower alkoxyphenylene, lower alkoxyphenylalkyl, wherein: said phenyl, biphenyl, naphthyl, lower heterocyclyl, and lower phenylalkyl groups are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, hydroxy, lower haloalkyl, lower ,i alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; R 6 is selected from the group consisting of lower alkyl, phenyl, biphenyl, naphthyl, lower heterocyclyl, lower alkylphenylene, lower alkylheterocyclyl, lower phenylalkyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene, lower alkylamino, lower alkylaminophenylene, lower Salkylsulfonylphenylene, and lower phenylsulfonylheterocyclyl, wherein: 20 said phenyl, biphenyl, naphthyl, lower heterocyclyl, and lower phenylalkyl groups are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; R 61 is selected from the group consisting of lower alkyl, phenyl, biphenyl, naphthyl, lower alkylphenylene, and lower alkoxyphenylene, wherein: said phenyl, biphenyl, and naphthyl are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower s haloalkoxy, keto, amino, nitro, and cyano; 1 735 R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, and purinyl, wherein: the pyridinyl, pyrimidinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, methylsulfinyl, methylsulfonyl, fluoro, chioro, bromo, aminosulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, cyano, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylcarbonylamino, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, dichioromethyl, chloromethyl, hydroxy, fluorophenylmethyl, fluorophenylethyl, chiorophenylmethyl, chlorophenylethyl, fluorophenylethenyl, chlorophenylethenyl, fluorophenylpyrazolyl, chlorophenylpyrazolyl, carboxy, methoxy, ethoxy, propyloxy, n-butoxy, methylamino, ethylamino, dimethylamino, diethylamino, 2-methylbutylamino, propargylamino, aminomethyl, aminoethyl, N-methyl-N-phenylamino, phenylamino, diphenylamino, benzylamino, phenethylamino, cyclopropylamino, nitro, chiorosulfonyl, amino, methylcarbonyl, methoxycarbonylamino, ethoxycarbonylamino, methoxyphenylmethylamino, N, N-dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylethylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, ethylaminocarbonyl, methylcarbonyl, methoxyphenylmethylamino, hydrazinyl, 1-methyl-hydrazinyl, and -NR 44 R 4 5 736 R 44 is selected from the group consisting of methylcarbonyl and amino; R 45 is selected from the group consisting of methyl, ethyl, and phenylmethyl; and R 4 is selected from the group consisting of hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, biphenyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, pyridinyl, thienyl, isothiazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrimidinyl, quinolyl, isoquinolinyl, imidazolyl, benzimidazolyl, furyl, pyrazinyl, dihydropyranyl, dihydropyridinyl, dihydrofuryl, tetrahydropyranyl, tetrahydrofuryl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl, wherein: 15 the cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, methylsulfinyl, S* methylsulfonyl, fluoro, chloro, bromo, methyl, ethyl, isopropyl, tert-butyl, isobutyl, ethynyl, methoxy, I ethoxy, phenoxy, benzyloxy, trifluoromethyl, fluoromethyl, difluoromethyl, amino, cyano, nitro, dimethylamino, and hydroxy

7. A compound, tautomer, or salt of claim 6, wherein: R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethylaminoethyl, and morpholinylethyl; R 2 corresponds in structure to a formula selected from the group consisting of: 737 I j C- (CH2) R (III), R 5 7 R 58 R 58 R 58 (CH2)k-- N O (CH)k (CH 2 )k (VIII); (VII), and j is selected from the group consisting of zero, 1, and S S. S m is zero; 5 R 30 is hydrogen; R 31 is selected from the group consisting of hydrogen and lower alkyl; R 32 is selected from the group consisting of hydrogen and lower alkyl; R 33 is selected from the group consisting of lower alkyl, -C(O)R 35 -C(O)OR 35 -SO 2 R 36 -C(O)NR 37 R 38 and -SO 2 NR39R 40 R 35 is selected from the group consisting of lower alkyl, lower cycloalkyl, phenyl, lower heterocyclyl, lower alkylphenylene, lower alkoxy, lower alkenoxy, lower alkoxyalkylene, lower phenoxyalkylene, and lower phenylalkoxyalkylene, wherein: said phenyl and lower phenoxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, and lower haloalkyl; R 36 is selected from the group consisting of lower 3ST^kyl, phenyl, lower heterocyclyl, lower alkylphenylene, 738 phenylphenylene, lower phenylalkyl, lower alkyiheterocyclyl, lower heterocyclylheterocyclyl, lower alkoxyphenylene, and lower alkylamino, wherein: said phenyl and lower heterocyclyl groups are optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; R 3 7 is hydrogen; R 38 is selected from the group consisting of lower alkyl, phenyl, and lower alkylphenylene; as to R 39 and R 40 R 39 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: R 40 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, yl carbonylarylene, alkylarylcarbonylarylene, 739 alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one 15 or more radicals independently selected from the group consisiting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R 39 is -CHR"R 29 or R 39 and R 40 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy; k is selected from the group consisting of zero and 1; R 56 is hydrogen; 740 R 57 is hydrogen; R 58 is selected from the group consisting of -C(O)R 59 and -SO 2 R 60 R 59 is selected from the group consisting of lower alkyl, lower cycloalkyl, phenyl, lower alkylphenylene, and lower alkoxyalkylene, wherein: said phenyl is optionally substituted with one or more radicals independently selected from the group consisting of lower alkyl, halo, hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, keto, amino, nitro, and cyano; R 60 is lower alkyl; SR 3 is selected from the group consisting of pyridinyl, pyrimidinyl, and quinolinyl, wherein: 15 the pyridinyl, pyrimidinyl, an quinolinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; R 4 is selected from the group consisting of phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl, wherein: the phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy. 741

8. A compound, tautomer, or salt of claim 7, wherein: R 1 is selected from the group consisting of hydrogen and methyl; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, and quinolinyl, wherein: the pyridinyl, pyrimidinyl, and quinolinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, methoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl; R 4 is phenyl optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy. g*

9. A compound, tautomer, or salt of claim 1, wherein R 1 is 20 hydrogen.

10. A compound, tautomer, or salt of claim 2, wherein R 1 is hydrogen.

11. A compound, tautomer, or salt of claim 3, wherein R 1 is hydrogen.

12. A compound, tautomer, or salt of claim 6, wherein R 1 is hydrogen.

13. A compound, tautomer, or salt of claim 3, wherein R 1 is selected from the group consisting of methyl and ethyl. 742

14. A compound, tautomer, or salt of claim 6, wherein R 1 is selected from the group consisting of methyl and ethyl. A compound, tautomer, or salt of claim 2, wherein R 2 is hydrogen.

16. A compound, tautomer, or salt of claim 3, wherein R 2 is hydrogen.

17. A compound, tautomer, or salt of claim optionally substituted phenyl.

18. A compound, tautomer, or salt of claim optionally substituted phenyl.

19. A compound, tautomer, or salt of claim optionally substituted phenyl. 2, wherein R 4 is 3, wherein R 4 is 6, wherein R 4 is A compound, tautomer, or salt of claim 2, wherein R 1 and R 2 are selected independently from hydrogen, methyl, and ethyl.

21. A compound, tautomer, or salt of claim 3, wherein R 1 and R 2 are selected independently from hydrogen, methyl, and ethyl.

22. A compound, tautomer, or salt of claim 2, wherein: R 1 and R 2 are selected independently from hydrogen, methyl, and ethyl; R 4 is optionally substituted phenyl.

23. A compound, tautomer, or salt of claim 3, wherein: 743 R 1 and R 2 are selected independently from hydrogen, methyl, and ethyl; R 4 is optionally substituted phenyl.

24. A compound, tautomer, or salt of claim 1, wherein: the compound corresponds in structure to Formula IX: R2 Z R4 4 N 9. R (IX); Z is selected from the group consisting of and R 1 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, lower alkynyl, lower heterocycyl, lower aralkyl, lower aminoalkyl, and lower alkylaminoalkyl; S: as to R 2 15 R 2 is selected from the group consisting of hydrogen, lower alkyl, phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower 744 heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl, wherein: the phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, and morpholinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl, and lower alkoxycarbonyl, or R 2 is -CR4R 42 R 1 is phenyl; R 42 is hydroxy; R 4 is selected from the group consisting of hydrogen, lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl, 5- to 10- membered heterocyclyl, phenyl, biphenyl, and naphthyl, wherein: the lower cycloalkyl, lower cycloalkenyl, lower cycloalkyldienyl, 5- to 10- membered heterocyclyl, phenyl, biphenyl, and naphthyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, and hydroxy; R 5 is selected from the group consisting of hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower 745 aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyaralkylamino, hydrazinyl, lower alkylhydrazinyl, and -NR 44 R 45 R 44 is selected from the group consisting of lower alkylcarbonyl and amino; and R 45 is selected from the group consisting of lower alkyl and lower phenylalkyl. A compound, tautomer, or salt of claim 24, wherein: R 1 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxyethyl, and propargyl; R2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, *methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, 15 N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, "benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, andl,l-dimethyl-ethylpiperazinylcarbonyl, wherein: the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, and S(1,1l-dimethyl)ethoxycarbonyl; 746 R 4 is selected from the group consisting of cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl, wherein: the cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; R 5 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, .0000 20 (l-ethyl-2-hydroxy) ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylanino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, l-rethylhydrazinyl, and -NR 44 R 45 R 4 4 is selected from the group consisting of methylcarbonyl and amino; and R 45 is selected from the group consisting of methyl and benzyl. 747

26. A compound, tautomer, or salt of claim 24, wherein R 1 is hydrogen.

27. A compound, tautomer, or salt of claim 25, wherein R 1 is hydrogen.

28. A compound, lower alkyl.

29. A compound, lower alkyl. A compound, hydrogen. tautomer, or salt of claim 24, wherein R 1 is tautomer, or salt of claim 25, wherein R 1 is tautomer, or salt of claim 24, wherein R 2 is

31. A compound, hydrogen. tautomer, or salt of claim 25, wherein R 2 is

32. A compound, tautomer, or salt of claim 24, wherein R 1 and R 2 are selected independently from hydrogen, methyl, and ethyl.

33. A compound, tautomer, or salt of claim 25, wherein R 1 and R 2 are selected independently from hydrogen, methyl, and ethyl.

34. A compound, tautomer, or salt of claim 25, wherein Z is 748 A compound, tautomer, or salt of claim 1, wherein: the compound corresponds in structure to Formula X: R z /4 3 5 1N R N 1 1 R 2 R Z is selected from the group consisting of and 5 R 1 is selected from the group consisting of lower alkyl, S: lower hydroxyalkyl, lower alkynyl, lower aminoalkyl, and lower alkylaminoalkyl; as to R 2 R 2 is selected from the group consisting of hydrogen, lower alkyl, phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower .alkylamino, lower alkylaminoalkyl, phenylamino, lower 15 aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl, wherein: the phenyl, biphenyl, and naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, and morpholinyl are optionally substituted with one or more radicals independently selected from the group consisting of 749 halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl, and lower alkoxycarbonyl, or R 2 is -CR4R 42 R 41 is phenyl; R 42 is hydroxy; R 4 is selected from the group consisting of 5- to membered heteroaryl, phenyl, biphenyl, and naphthyl, wherein: the heteroaryl, phenyl, biphenyl, and naphthyl are optionally substituted with one or more radicals sindependently selected from the group consisting of halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower 15 alkylamino, nitro, and hydroxy; R 5 is selected from the group consisting of hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, 20 lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyaralkylamino, hydrazinyl, lower alkylhydrazinyl, and -NR 44 R 45 R 44 is selected from the group consisting of lower alkylcarbonyl and amino; and R 45 is selected from the group consisting of lower alkyl and lower phenylalkyl.

36. A compound, tautomer, or salt of claim 35, wherein: 750 R1 is selected from the group consisting of methyl, ethyl, hydroxyethyl, and propargyl; R 2 is selected from the group consisting of methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, piperadinylamino, dimethylaminoethylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, N-methylpiperazinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, 1-dimethyl) ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, piperazinylcarbonyl, and 1,1-dimethyl-ethylpiperazinylcarbonyl, wherein: the phenyl, piperidinyl, piperazinyl, imidazolyl, 20 morpholinyl, and pyridinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, and (1,1-dimethyl)ethoxycarbonyl; R 4 is selected from the group consisting of phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl, wherein: the phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl are optionally substituted with one or more radicals independently selected from the group 751 consisting of methylthio, fluoro, chioro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; R 5 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, propargylamino, imidazolylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, 15 methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, 1-methyihydrazinyl, and NR 44 45 1 R 44 is selected from the group consisting of methylcarbonyl and amino; and is selected from the group consisting of methyl and benzyl.

37. A compound, tautomer, or salt of claim 35, wherein R' is lower alkyl.

38. A compound, tautomer, or salt of claim 36, wherein R 1 is lower alkyl.

39. A compound, tautomer, or salt of claim 35, wherein R 2 is hydrogen. 752 A compound, tautomer, or salt of claim 36, wherein R 2 is hydrogen.

41. A compound, tautomer, or salt of claim 35, wherein: R 1 is selected from the group consisting of methyl and ethyl, and R 2 is selected from the group consisting of hydrogen, methyl, and ethyl.

42. A compound, tautomer, or salt of claim 36, wherein: R 1 is selected from the group consisting of methyl and ethyl, and R2 is selected from the group consisting of hydrogen, methyl, and ethyl.

43. A compound, tautomer, or salt of claim 35, wherein Z is

44. A compound, tautomer, or salt of claim 1, wherein: the compound corresponds in structure to Formula XI: I 4 /43 R N R (XI); Z is selected from the group consisting of and R 1 is selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl, and lower alkylaminoalkyl; AMSTS as to R 753 R 2 is selected from the group consisting of hydrogen, lower alkyl, phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl, wherein: the phenyl, biphenyl, naphthyl, piperidinyl, %0 15 piperazinyl, imidazolyl, pyridinyl, and morpholinyl are S* optionally substituted with one or more radicals independently selected from the group consisting of halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower 20 heterocyclylalkylamino, lower alkylcarbonyl, and lower alkoxycarbonyl, or t R is -CR R 2 o R 41 is phenyl; R 42 is hydroxy; R 4 is selected from the group consisting of 5- to membered heteroaryl, phenyl, biphenyl, and naphthyl, wherein: the heteroaryl, phenyl, biphenyl, and naphthyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, lower haloalkyl, lower alkylthio, lower alkylamino, nitro, hydroxy; 754 R 5 is selected from the group consisting of hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyaralkylamino, hydrazinyl, lower alkylhydrazinyl, and -NR 44 R 45 iR 44 is selected from the group consisting of lower o alkylcarbonyl and amino; and R 4 is selected from the group consisting of lower alkyl and lower phenylalkyl. A compound, tautomer, or salt of claim 44, wherein: R 1 is selected from the group consisting of methyl, ethyl, hydroxyethyl, and propargyl; R 2 is selected from the group consisting of methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (1,1-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (1,1-dimethyl)ethylcarbonylaminoethylamino, 755 piperazinylcarbonyl, and 1,1-dimethyl-ethylpiperazinylcarbonyl, wherein: the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, chloro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, and (1,1-dimethyl)ethoxycarbonyl; R 4 is selected from the group consisting of phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and go ibenzodioxolyl, wherein: the phenyl, quinolyl, biphenyl, pyridinyl, thienyl, furyl, dihydropyranyl, benzofuryl, dihydrobenzofuryl, and benzodioxolyl are optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; 0 0 R 5 is selected from the group consisting of hydrogen, 0* fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, 756 fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, 1-methylhydrazinyl, and -NR4R 4 R 44 is selected from the group consisting of methylcarbonyl and amino; and R 45 is selected from the group consisting of methyl and benzyl.

46. A compound, tautomer, or salt of claim 44, wherein R 1 is lower alkyl. S* 47. A compound, tautomer, or salt of claim 45, wherein R1 is lower alkyl. hydrogen.

49. A compound, tautomer, or salt of claim 45, wherein R 2 is S. hydrogen.

50. A compound, tautomer, or salt of claim 44, wherein: R 1 is selected from the group consisting of methyl and ethyl, and R 2 is selected from the group consisting of hydrogen, methyl, and ethyl.

51. A compound, tautomer, or salt of claim 45, wherein: R 1 is selected from the group consisting of methyl and ethyl, and R 2 is selected from the group consisting of hydrogen, methyl, and ethyl. 'II 757

52. A compound, tautomer, or salt of claim 44, wherein Z is

53. A compound, tautomer, or salt of claim 1, wherein: the compound corresponds in structure to Formula IX: S S S R' (IX) Z is selected from the group consisting of and R 1 is selected from the group consisting of hydrogen, 10 lower alkyl, lower hydroxyalkyl, lower alkynyl, lower aminoalkyl, and lower alkylaminoalkyl; as to R 2 R 2 is selected from the group consisting of hydrogen, lower alkyl, phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl, lower aralkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lower aminoalkylamino, lower alkynylamino, lower heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl, wherein: 758 the phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, and morpholinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower heterocyclylalkylamino, lower alkylcarbonyl, lower hydroxyalkylcarbonyl, and lower alkoxycarbonyl, or R 2 is -CR 41 R 42 R 41 is phenyl; R 42 is hydroxy; R 4 is phenyl optionally substituted with one or more 4* radicals independently selected from the group consisting of halo, lower alkyl, lower alkoxy, aryloxy, lower aralkoxy, 15 lower haloalkyl, lower alkylthio, lower alkylamino, nitro, and hydroxy; R s is selected from the group consisting of hydrogen, halo, amino, cyano, aminocarbonyl, lower alkyl, lower alkoxy, hydroxy, lower aminoalkyl, lower aralkyl, lower aralkyloxy, 20 lower aralkylamino, lower alkoxycarbonyl, lower alkylamino, lower alkylcarbonyl, lower aralkenyl, lower arylheterocyclyl, carboxy, lower cycloalkylamino, lower alkoxycarbonylamino, lower alkoxyaralkylamino, lower alkylaminoalkylamino, lower heterocyclylamino, lower heterocyclylalkylamino, lower aralkylheterocyclylamino, lower alkylaminocarbonyl, lower alkoxyaralkylamino, hydrazinyl, lower alkylhydrazinyl, and -NR4445 R 44 is selected from the group consisting of lower alkylcarbonyl and amino; and R 45 is selected from the group consisting of lower alkyl and lower phenylalkyl. A compound, tautomer, or salt of claim 53, wherein: 759 R 1 is selected from the group consisting of hydrogen, methyl, ethyl, hydroxyethyl, and propargyl; R 2 is selected from the group consisting of methyl, ethyl, propyl, phenyl, trifluoromethyl, hydroxyethyl, methoxycarbonylethyl, ethoxycarbonylethyl, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-diethylamino, N-propylamino, N-phenylamino, aminomethyl, aminoethyl, aminoethylamino, aminopropylamino, propargylamino, benzylamino, dimethylaminopropylamino, morpholinylpropylamino, morpholinylethylamino, piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyridinyl, carboxymethylamino, methoxyethylamino, (l,l-dimethyl)ethylcarbonyl, (1,1-dimethyl)ethylcarbonylaminopropylamino, (l,l-dimethyl)ethylcarbonylaminoethylamino, ipiperazinylcarbonyl, and 1,1-dimethyl-ethylpiperazinylcarbonyl, wherein: the phenyl, piperidinyl, piperazinyl, imidazolyl, morpholinyl, and pyridinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, chioro, bromo, keto, methyl, ethyl, trifluoromethyl, benzyl, methoxy, methoxycarbonyl, ethoxycarbonyl, and (1,l-dimethyl)ethoxycarbonyl; R 4 is phenyl optionally substituted with one or more radicals independently selected from the group consisting of methylthio, fluoro, chloro, bromo, methyl, ethyl, methoxy, ethoxy, phenoxy, benzyloxy, trifluoromethyl, nitro, dimethylamino, and hydroxy; R 5 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, methyl, fluorophenylethyl, fluorophenylethenyl, fluorophenylpyrazolyl, cyano, methoxycarbonyl, aminocarbonyl, acetyl, hydroxy, carboxy, 760 methoxy, methylamino, dimethylamino, 2-methylbutylamino, ethylamino, dimethylaminoethylamino, hydroxypropylamino, hydroxyethylamino, imidazolylamino, morpholinylethylamino, (l-ethyl-2-hydroxy)ethylamino, piperidinylamino, pyridinylmethylamino, phenylmethylpiperidinylamino, aminomethyl, cyclopropylamino, amino, hydroxy, methylcarbonyl, ethoxycarbonylamino, methoxyphenylmethylamino, phenylmethylamino, fluorophenylmethylamino, fluorophenylethylamino, methylaminocarbonyl, hydrazinyl, 1-methylhydrazinyl, and -NR 44 R 45 R 44 is selected from the group consisting of methylcarbonyl and amino; and SR 45 is selected from the group consisting of methyl and 15 benzyl. A compound, tautomer, or salt of claim 53, wherein R 1 is .selected from the group consisting of hydrogen and lower "alkyl.

56. A compound, tautomer, or salt of claim 54, wherein R 1 is selected from the group consisting of hydrogen and lower alkyl.

57. A compound, tautomer, or salt of claim 53, wherein R 1 is hydrogen.

58. A compound, tautomer, or salt of claim 54, wherein R 1 is hydrogen.

59. A compound, tautomer, or salt of claim 53, wherein R 2 is hydrogen. 761 A compound, tautomer, or salt of claim 54, wherein R 2 is hydrogen.

61. A compound, tautomer, or salt of claim 53, wherein R 4 is phenyl substituted with one or more radicals independently selected from the group consisting of fluoro, chloro, and bromo.

62. A compound, tautomer, or salt of claim 54, wherein R 4 is phenyl substituted with one or more radicals independently selected from the group consisting of fluoro, chloro, and S. bromo.

63. A compound, tautomer, or salt of claim 53, wherein R1 15 and R are selected independently from hydrogen, methyl, and ethyl.

64. A compound, tautomer, or salt of claim 54, wherein R 1 and R are selected independently from hydrogen, methyl, and 20 ethyl.

65. A compound, tautomer, or salt of claim 53, wherein Z is 762

66. A compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein: the compound corresponds in structure to Formula IX: N >4 4 R4 N R 1 (IX); Z is selected from the group consisting of and R 1 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, and lower alkynyl; 10 R 2 is selected from the group consisting of hydrogen and lower alkyl; R 4 is selected from the group consisting of phenyl and benzodioxolyl, wherein: the phenyl is optionally substituted with one or more halo radicals; R 5 is selected from the group consisting of hydrogen, halo, and alkylhydrazinyl.

67. A compound, tautomer, or salt of claim 66, wherein: Z is R 1 is selected from the group consisting of hydrogen, methyl, hydroxyethyl, and propargyl; R 2 is hydrogen; R 4 is selected from the group consisting of phenyl and benzodioxolyl, wherein: 763 the phenyl is optionally substituted with one or more radicals independently selected from the group consisting of chloro, fluoro, and bromo; R 5is selected from the group consisting of hydrogen, fluoro, and 1-methyihydrazinyl.

68. A compound, tautomer, or salt of claim 67, wherein: Z is R 1 is selected from the group consisting of hydrogen and methyl; R2 ishydrogen; R 4is phenyl optionally substituted with one or more radicals independently selected from the group consisting of chloro, fluoro, and bromo; and R 5 is selected from the group consisting of hydrogen and fluoro.

69. A compound, tautomer, or salt of claim 1, wherein the compound. is selected from the group consisting of: 4- (3-f luoro-4-methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine; 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine; 4- [5-methyl-3- (2-methylphenyl) -lH-pyrazol-4-yllpyridine; 4- (4-f luorophenyl) -5-methyl-lH-pyrazol-4-yllpyridine; 4- [5-methyl-3- (4-methyiphenyl) -lH-pyrazol-4-yllpyridine; 4- [5-methyl-3- (methylthio)phenyl] -lH-pyrazol-4- yl] pyridine; 4- (4-chlorohpenyl) -5-methyl-lH-pyrazol-4-yllpyridine; 4- [3-methyl-5- (3-methylphenyl) -lH-pyrazol-4-yllpyridine; 4- (2,5-dimethylphenyl) -3-methyl-lH-pyrazol-4-yllpyridine; 4- [5-(1,3-benzodioxol-5-yl) -3-methyl-lH-pyrazol-4- yl Ipyridine; (4-phenoxyphenyl) -lH-pyrazol-4-yllpyridine;

764- -biphenyl) -4-yl] -3-methyl-lH-pyrazol-4- yl] pyridine; 4- [3-methyl-5- (phenoxyphenyl) -lH-pyrazol-4-yllpyridine; 4- [3-methyl-5- (phenylmethoxy)phenyl] -1H-pyrazol-4- yllpyridine; 4- [3-methyl-5- (phenylmethoxy)phenyll -1H-pyrazol-4- yl] pyridine; 2- [3-methyl-4- (4-pyridinyl) -lH-pyrazol-4-yllphenol; 3- [3-methyl-4- (4-pyridinyl) -lH-pyrazol-4-yllphenol; 1-hydroxy-4- (3-methyl-5-phenyl-1H-pyrazol-4-yllpyridinium; (4-f luorophenyl) N-dimethyl-4- (4-pyridinyl) -1H-pyrazol- 3-amine; (4-i luorophenyl) -N-phenyl-4- (4-pyridinyl) -lH-pyrazol-3- amine; 4- (4-f luorophenyl) -3-phenyl-lH-pyrazol-4- yllpyridine; 4- (3-methyiphenyl) (trifluoromethyl) -1H-pyrazol-4- yllpyridine;4- (4-f luorophenyl)-4- (4-pyridinyl) -1H- pyridine; 4- (5-cyclohexyl) -3-methyl-lH-pyrazol-4-yl)pyridine; 20 4- (3-f luoro-5-methoxyphenyl) -3-rethyl-1H-pyrazol-4- yl] pyridine; 4- (3-methyiphenyl) -3-propyl-lH-pyrazol-4-yllpyridine; 4- [(3-methyl-5-phenyl-lH-pyrazol-4-yl)methyllpyridine; 4- [3,5-bis(3-methylphenyl) -lH-pyrazol-4-yllpyridine; 4- [4-methyl-2- (2-trifluorophenyl) -1H-pyrazol-4-yllpyridine; 4-13- (2-chiorophenyl) -5-methyl-lH-pyrazol-4-yllpyridine; 4- [5-methyl-3- (2,4-dimethyiphenyl) -lH-pyrazol-4-yllpyridine; 4-15- (4-chiorophenyl) 3-dimethyl-1H-pyrazol-4-yl] pyridine; 4- (3-f luoro-2-methylphenyl) -5-methyl-1H-pyrazol-4- yllpyridine; 4- (3,5-dimethyiphenyl) -5-methyl-1H-pyrazol-4-yl]pyridine; 4- 5-dimethoxyphenyl) -5-methyl-lH-pyrazol-4-yllpyridine; 4- [5-methyl-3- (3-nitrophenyl) -1H-pyrazol-4-yllpyridine;

765- N,N-dimethyl-4- [5-methyl-4- (4-pyridinyl) -1H-pyrazol-3 yl] benzenamine; 4- (2,3-dihydrobenzofuran-5-yl) -5-methyl-lH-pyrazol-4- ylIpyridine; 4- (4-bromophenyl) -5-methyl-lH-pyrazol-4-yllpyridine; 4- (2-f luorophenyl) -5-methyl-1H-pyrazol-4-yl]pyridine; 4- (3-f luorophenyl) -5-methyl-lH-pyrazol-4-yllpyridine; 4- [3-methyl-5- (trifluoromethyl)phenyl] -1H-pyrazol-4 yl] pyridine; 4- (3-ethyl-4-phenyl-1H-pyrazol-4-yl)pyridine; 4- (3-methoxyphenyl) -3-methyl-1H-pyrazol-4-yl~pyridine; 4- [3-ethyl-5- (3-methyiphenyl) -lH-pyrazol-4-yllpyridine; 4- (3,4-difluorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine; 4- (3-ethoxyphenyl) -3-methyl-1H-pyrazol-4-yllpyridine; 4- [3-methyl-5- (trifluoromethyl)phenyl] -1H-pyrazol-4- yl] pyridine; 4- [3-rethyl-5- (3-thienyl) -lH-pyrazol-4-yllpyridine; 4- (2,4-dichiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine; 4- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yl] pyridine; 4-15- (3-chloro-4-methoxyphenyl) -3-methyl-1H-pyrazol-4- yl] pyridine; ethyl 3- (4-chiorophenyl) (4-pyridinyl) propanoate; 4- (4-f luorophenyl) -l-methyl-pyrazol-4-yllpyridine; 5- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyrimidin-2- amine; [3-methyl-5- (3-methyiphenyl) -1H-pyrazol-4-yl] pyrimidin-2- amine; [3-methyl-5- (2-methyiphenyl) -1H-pyrazol-4-yl] pyrirnidin-2- amine; (4-chiorophenyl) -3-methyl-1H-pyrazol-4-yl] pyrimidin-2- amine; -766 (4-f luorophenyl) -3-methyl-1H-pyrazol-4-yl]pyrimidin-2- amine; (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yllpyrimidin-2- amine; 5- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2- amine; 4-Es- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2- amine; 4- (3-methyiphenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2- amine; 4- (2-methyiphenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2- amine; 4- (4-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2- :o amine; S .0 15 4- (4-f luorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2- amine; 4- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-ylllpyridin-2- amine; (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yl] -2- 0020 methoxypyridine; [3-methyl-5- (3-methyiphenyl) -1H-pyrazol-4- yl] pyridine; (4-methoxyphenyl) -3-methyl-1H-pyrazol-4- yl] pyridine; 4- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yl] -2- methoxypyridine; 2-methoxy-4- [3-methyl-5- (3-methyiphenyl) -1H-pyrazol-4- yl] pyridine; 2-methoxy-4- [3-methyl-5- (2-methyiphenyl) -1H-pyrazol-4- yllpyridine; 4- S- (4-chiorophenyl) -3-methyl-1H-pyrazol-4-ylI -2- methoxypyridine; 767 4- (4-fluorophenyl) -3--methyl-lH--pyrazol-4-ylI -2- methoxypyridine; 2-methoxy-4- [3-methyl-5- (4-methyiphenyl) -lH-pyrazol-4- yl] pyridine; 5- (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2-ol; 4- (3-chiorophenyl) -3-methyl-lH-pyrazol-4-yllpyridin-2-ol; 4- (3-methyiphenyl) -3-methyl-lH-pyrazol-4-yl]pyridin-2-ol; 4- (2-methylpheiyl) -3-methyl-lH-pyrazol-4-yllpyridin-2-ol; 4- (4-chiorophenyl) -3-methyl-lH-pyrazol-4-yllpyridin-2-ol; 4- (4-f luorophenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2-ol; 4- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yllpyridin-2-ol; (3-chiorophenyl) -3-methyl-lH-pyrazol-4-ylllpyridine-2- methanamine; (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine-2- methananine; (3-methyiphenyl) -3-methyl-1H-pyrazol-4-yllpyridine-2- methananine; 4- (2-methyiphenyl) -3-methyl-lH-pyrazol-4-yllpyridine-2- methanamine; 4- (4-chiorophenyl) -3-methyl-lH-pyrazol-4-yllpyridine-2- methanamine; 4- (4-f luorophenyl) -3-methyl-lH-pyrazol-4-yllpyridine-2- methanamine; 4- (4-methoxyphenyl) -3-methyl-1H-pyrazol-4-yllpyridine-2- methanamine; (3-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine-2- carboxamide; 4- (3-chiorophenyl) -3-methyl-lH-pyrazol-4-yllpyridine-2- carboxamide; 4- (3-methyiphenyl) -3-methyl-1H-pyrazol-4-yllpyridine-2- carboxamide; 4- (2-methyiphenyl) -3-methyl-1H-pyrazol-4-yllpyridine-2- carboxamide;

768- 4- (4-chiorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine-2- carboxamide; 4- (4-f luorophenyl) -3-methyl-1H-pyrazol-4-yllpyridine-2- carboxamide; 4- (4-methoxyphenyl) -3-methyl-lH-pyrazol-4-yllpyridine-2- carboxamide; 4- (3-f luoro-4-methoxyphenyl) -3-methyl-1H-pyrazol-4- yl] pyridine; 4- (4-f luoro-3-methoxyphenyl) -3-methyl-lH-pyrazol-4- yllpyridine; 4- (4-chloro-3-methoxyphenyl) -3-methyl-1H-pyrazol-4- yl] pyridine; 4- (2,3-dihydrobenzofuran-6-yl) -3-methyl-1H-pyrazol-4- yl] pyridine; 4- (benzofuran-6-yl) -3-methyl-lH-pyrazol-4-yllpyridine;, 4- (3-f luoro-5-methoxyphenyl) -3-methyl-lH-pyrazol-4- yl] pyridine; 4- (3-chloro-5-methoxyphenyl) -3-methyl-1H-pyrazol-4- yl] pyridine; 4- (1-cyclohexyen-1-yl) -3-methyl-lH-pyrazol-4-yllpyridine; 4- (1,3-cyclohexadien-1-yl) -3-methyl-lH-pyrazol-4- yl Ipyridine; 4- (5,6-dihydro-2H-pyran-4-yl) -3-methyl-lH-pyrazol-4- yl] pyridine; 4- (5-cyclohexyl-3-methyl-1H-pyrazol-4-yl)pyridine; 4- (4-methoxy-3-methylphenyl) -3-methyl-1H-pyrazol-4- yl] pyridine; 4- (3-methoxy-4-methylphenyl) -3-methyl-1H-pyrazol-4- yll pyridine; 4- (3-methoxy-5-methylphenyl) -3-methyl-1H-pyrazol-4- yl] pyridine; 4- (3-furyl) -3-methyl-lH-pyrazol-4-yllpyridine; 2-methyl-4- (3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridine;

769- 2-methoxy-4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine; methyl 4- (3-methyl-5-phenyl-1H-pyrazol-4-yl)pyri-dine-2- carboxyl ate; 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl) pyridine-2-carboxamide; 1- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridin-2- 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-lH-pyrazol-4-yl)pyridine; methyl 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine-3- carboxylate; 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyridine-3-carboxamide; 1- (3-methyl-5-phenyl-1H-pyrazol-4-yl)pyridin-3- yllethanone; 3-bromo-4- (3-methyl-5-phenyl-lH-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-lH-pyrazol-4-yl)pyrimidine; 4- (3-methyl-5-phenyl-lH-pyrazol-4-yl)pyrimidine; 2-ehx--3-ehl5peyll *ao--y~yiiie 2-meh--(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyrimidaine; 4,-diel4(3-methyl-5-phenyl-lH-pyrazol-4-yl)pyrimidin- 2-amine; 4- (5,6-dihydro-2H-pyran-4-yl) 3-methyl-5-phenyl-4- (3-thienyl) -1H-pyrazole; 4- (3-furyl) 3-methyl-5-phenyl-4- (2-thienyl) -1H-pyrazole; 4- (2-furyl) 4- (3-isothiazolyl) -3-methyl-5-phenyl-1H-pyrazole 4- (3-isoxazolyl) -3-methyl-5-phenyl-1H-pyrazole; 4- (5-isothiazolyl) -3-methyl-5-phenyl-1H-pyrazole; -770 3-methyl-5-phenyl-4- (5-thiazolyl) -1H-pyrazole; 3-methyl-4- (5-oxazolyl) -5-phenyl-1H-pyrazole; 4- (4-f luorophenyl) -1H-pyrazol-4-yllpyridine; 2-methyl-4- (3-methyiphenyl) -lH-pyrazol-4-yllpyridine; 4- (1-methyl-3-phenyl-lH-pyrazol-4-yl)pyridine; 4- (3-phenyl-lH-pyrazol-4-yl)pyridine; 2-methyl-4- (3-phenyl-lH-pyrazol-4-yl)pyridine; 4- (3-chiorophenyl) -1-methyl-pyrazol-4-yllpyridine; 4- (4-chiorophenyl) -1-methyl-pyrazol-4-yllpyridine; 4- (3-chiorophenyl) -1H-pyrazol-4-yllpyridine; 4- (4-chiorophenyl) -lH-pyrazol-4-yl] pyridine; 4- (3-chiorophenyl) -lH-pyrazol-4-ylI -2-rnethylpyridine; 4- (3-f luorophenyl) -1-methyl-lH-pyrazol-4-yllpyridine; 4- (3-fluorophenyl) -lH-pyrazol-4-yllpyridine; 4- (3-chiorophenyl) -1-methyl-pyrazol-4-yl] -2- methylpyridine; (4-chiorophenyl) -N-phenyl-4- (4-pyridinyl) -1H-pyrazol-3- amine; (4-chiorophenyl) -N-methyl-4- (4-pyridinyl) -1H-pyrazol-3- amine; (4-chiorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -lH-pyrazol-3- amine dihydrate; (3-f luorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -lH-pyrazol-3- amine; N,N-dimethyl-5- (3-methyiphenyl) (4-pyridinyl) -1H-pyrazol-3- amine; (3-methyiphenyl) (4-pyridinyl) -1H-pyrazol-3- amine; (3-methyiphenyl) (4-pyridinyl) -lH-pyrazol-3- amine; (3-methyiphenyl) (4-pyridinyl) -lH-pyrazol-3- Samine; 771 (4-chiorophenyl) N,N-diethyl-4- (4-pyridinyl) -1H-pyrazol-3- amine; 4- (4-chiorophenyl) (4-pyridinyl) -lH-pyrazol-3- yl] morpholime; 5- (4-chiorophenyl) -N-propyl-4- (4-pyridinyl) -1H-pyrazol-3- amine; (4-chiorophenyl) (phenylmethyl) (4-pyridinyl) -11-- pyrazol-3-amine hydrate (4-chiorophenyl) (2-methoxyethyl) (4-pyridinyl) -iN- pyrazol-3-amine monohydrate; 1,1-dimethylethyl-4- (4-chiorophenyl) (4-pyridinyl) -iN- pyrazol-3-yll-1-piperazinecarboxylate; 1-[5-(4-chlorophenyl)-4-(4-pyridinyi)-1H-pyrazol-3- ylI piperazine trihydrochioride; 15 1-[5-(4-chiorophenyl)-4-(4-pyridinyi)-1H-pyrazol-3-yl]-4- methylpiperazine; 1,1-dimethylethyl 4- (4-f luorophenyl) (4-pyridinyl) -1H- pyrazol-3-yi] -1-piperazinecarboxylate; 1- (4-f luorophenyl) (4-pyridinyl) -1H-pyrazol-3- yl] piperazine trihydrochioride; 1- (4-chiorophenyl) (4-pyridinyl) -iH-pyrazoi-3- yl] piperazine; N- (4-chiorophenyl) (phenyimethyl)amino] -4-pyridinyl] 1H-pyrazol-3-yi] 3-propanediamine, trihydrochioride; 1- (4-chiorophenyl) (4-pyridinyl) -iH-pyrazol-3-yiI -4- (phenylmethyl) piperazine; 4- (4-f luorophenyl) (1-piperazinyl) -1H-pyrazol-4- yi] pyrimidine, dihydrochioride; 1,1-dimethylethyl (4-chiorophenyl) (4-pyridinyl) -1H- pyrazoi-3-yi] amino] propyl] carbamate; N- [4-chiorophenyl) (4-pyridinyl) -iH-pyrazoi-3-yl] -1,3- propanediamine, trihydrochloride monohydrate;

772- 1,1-dimethylethyl (4-chiorophenyl) (4-pyridinyl) -1H- pyrazol-3-yl] amino] ethyl] carbamate; 1,1-dimethylethyl 4- [5-(4-chiorophenyl) -1-(2-hydroxyethyl) -4- (4-pyridinyl) -lH-pyrazol-3-yl] -1-piperazinecarboxylate; 1,1-ditnethylethyl 4- (4-fluorophenyl) (4-pyrimidinyl) -lH- pyrazol-3-yl] -1-piperazinecarboxylate; 1,1-dimethylethyl (4-chiorophenyl) (2-fluoro-4- pyridinyl) -lH-pyrazol-3-yl] amino] propyl] carbamate; (4-chiorophenyl) (4-pyridinyl) -lH-pyrazol-3-yl] -4- ethylpiperazine; N- (4-chiorophenyl) (4-pyridinyl) -lH-pyrazol-3-yl] -1,2- Voe** ethanediamine; 4- (2,6-difluorophenyl) -5-methyl-1H-pyrazol-4-yl]pyridine; 4- (3-ethyiphenyl) -5-methyl-lH-pyrazol-4-yllpyridine; S. 15 4- (3-chiorophenyl) -5-ethyl-lH-pyrazol-4-yllpyridine; 4- [3-ethyl-5- (3-ethyiphenyl) -lH-pyrazol-4-yllpyridine; 4- (4-chiorophenyl) (1-methylethyl) -lH-pyrazol-4- S. S.:yl] pyridine; 4- [3-cyclopropyl-5- (4-f luorophenyl) -lH-pyrazol-4-yllpyridine; 4- (4-f luorophenyl) (trifluoromethyl) -1H-pyrazol-4- yl] pyridine; 4- (cyclopropyl-3- (fluorophenyl) -1-methyl-1H-pyrazol-4- yl] pyridine; 5-cyclopropyl-3- (4-f luorophenyl) (4-pyridinyl) -lH-pyrazole- 1-ethanol; 3- (4-f luorophenyl) (2-methoxy-4-pyridinyl) (4-pyridinyl) lH-pyrazole- 1-ethanol; 4- (4-fluorophenyl) -1-(2-hydroxyethyl) (4-pyridinyl) -lH- -2 (lH) -pyridinone; 1-acetyl-4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4- pyridinyl) -lH-pyrazol-5-yl] -2 (lH) -pyridinone; Ethyl 2-[3-(4-fluorophenyl)-l-(2-hydroxyethyl)-4-(4- TR-A pyridinyl) -lH-pyrazol-5-yl] cyclopropanecarboxylate; 773 2- (4-f luorophenyl) -1-(2-hydroxyethyl) (4-pyridinyl) -1H- cyclopropanecarboxylic acid; 3- (4-fluorophenyl) (4-imidazolyl) (4-pyridinyl) -1H- pyrazole-l- ethanol; 4- (4-chloro-3-methylphenyl) -lH-pyrazol-4-yllpyridine (4-f luorophenyl) (4-pyridinyl) -1H-pyrazole-3-carboxylic acid; (4-f luorophenyl) (4-pyridinyl) -1H-pyrazole-3-methanol; 1- (4-f luorophenyl) (4-pyridinyl) -1H-pyrazol-3- yl] carbonyilpiperazine; 1,1-dimethylethyl 4- (4-f luorophenyl) (4-pyridinyl) -1H- pyrazol-3-yl] carbonyl] -1-piperazinecarboxylate; 4- (1,5-dimethyl-3-phenyl-lH-pyrazol-4-yl)pyridine; 4- (1,3-dimethyl-5-phenyl-lH-pyrazol-4-yllpyridine; 4- (4-chiorophenyl) -1,5-dimethyl-1H-pyrazol-4-yllpyridine; 4- (4-chiorophenyl) -1,3-dimethyl-lH-pyrazol-4-yllpyridine; 4- [5-ethyl-l-methyl-3- (3-methyiphenyl) -lH-pyrazol-4- yl] pyridine; 4- [3-ethyl-l-methyl-5- (3-methyiphenyl) -lH-pyrazol-4- yllpyridine; 4- (4-chiorophenyl) -1-ethyl-5-methyl-1H-pyrazol-4- yl Ipyridine; 4- (4-chiorophenyl) -2-ethyl-5-methyl-1H-pyrazol-4- yll pyridine; 4- (4-f luorophenyl) -1H-pyrazol-4-yl]pyridine; 4- (2-chiorophenyl) -lH-pyrazol-4-yllpyridine; 3- (4-f luorophenyl) (4-pyridinyl) -1H-pyrazole-1-ethanol; 3- (4-f luorophenyl) (4-pyrimidinyl) -1H-pyrazole-1-ethanol; 4- (4-f luorophenyl) -l-rethyl-lH-pyrazol-4-yllpyridine; 2-[[4-[3-(4-fluorophenyl)-1H-pyrazol-4-ylI-2- pyridinyl] amino] -1-butanol; 4- [5-bromo-3- (4-f luorophenyl) -l-methyl-1H-pyrazol-4- -774 4- (4-f luorophenyl) -lH-pyrazol-4-yl]l-2- pyridinecarbonit rile; 4- (4-f luorophenyl) (4-pyridinyl) -lH-pyrazol-l- yl] ethyl] morpholine; 3- (4-f luorophenyl) -l-methyl-a-phenyl-4- (4-pyridiiyl) -lH- -methanol; N- (4-f luorophenyl) (4-pyridinyl) -1H-pyrazol-3-yl] -4- morpholineethanamine; 4- (3-chiorophenyl) -lH-pyrazol-4-yl] -2(11) -pyridinone hydrazone; 4- (3-chiorophenyl) -lH-pyrazol-4-yl] (phenylmethyl) -2- pyridinamine; 4[3- (3-chlorophenyl) -lH-pyrazol-4-yl] (phenylethyl) -2- pyridinamine; 4- (3-chlorophenyl)-lH-pyrazol-4-yl] -N-ethyl-2- pyridinamine; 4- (4-f luorophenyl) -1H-pyrazol-4-yl] -2-pyridinecarboxamide; *.Methyl 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2-- pyridinecarboxylate; 20 4- (4-f luorophenyl) -lH-pyrazol-4-yl] -N-methyl-2- pyridinecarboxamide; 4- (4-f luorophenyl) -1H-pyrazol-4-ylI -2-pyridinecarboxylic acid; 4- (3-f luorophenyl) -1H-pyrazol-4-yllpyridine; 4- (1,3-benzodioxol-5-yl) -lH-pyrazol-4-yllpyridine; 4- (3-f luorophenyl) -1-methyl-1H-pyrazol-4-yllpyridine; 4- (4-chiorophenyl) -lH-pyrazol-4-yllpyridine; 4- 3-benzodioxol-5-y) -l-methyl-lH-pyrazol-4-yl] pyridine; 4- (4-chlorophenyl) -1-methyl-lH-pyrazol-4-yllpyridine; 4- (3-chlorophenyl) -l-methyl-lH-pyrazol-4-yl] -2- methylpyridine; 4- (3-chiorophenyl) -l-methyl-1H- pyrazol-4 -yl] -2-methylpyridine; 4- (3-chlorophenyl) -1-methyl-lH-pyrazol-4-yl] pyridine; 775 4- [5-(3-chiorophenyl) -1-methyl-1H-pyrazol-4-yllpyridine; 2-methyl-4- [l-methyl-3- (3-methyiphenyl) -1H-pyrazol-4 yl] pyridine; 2-methyl-4- [l-methyl-5- (3-methyiphenyl) -1H-pyrazol-4 yllpyridine; 4- (3-phenyl-1H-pyrazol-4-yl)pyridine; 4- (trifluoromethyl)phenyl] -lH-pyrazol-4-yllpyridine; 4- [1-methyl-3- (trifluoromethyl)phenyl] -1H-pyrazol-4- yl]I pyridine; 4- (3,4-difluorophenyl) -1H-pyrazol-4-ylilpyridine; 4- (4-chiorophenyl) -1H-pyrazol-4-ylI -2-f luoropyridine; 4- (4-bromophenyl) -1H-pyrazol-4y1]pyridine; 4- (3,4-difluorophenyl) -1-methyl-1H-pyrazol-4-yllpyridine; 4- (4-bromophenyl) -1-methyl-1H-pyrazol-4-yllpyridine; (4-fluorophenyl) -1H-pyrazol-4-yl] (2- phenylethenyl) pyridine; (4-chiorophenyl) -1H-pyrazol-4-yl] (2-methylbutyl) 2 -pyridinamine; 4- (4-chiorophenyl) -1H-pyrazol-4-yl] [(4-methoxy- 20 phenyl)methyl]- 2-pyridinamine; N- (4-chiorophenyl) -lH-pyrazol-4-yl] -2-pyridinyl] 2- pyridinemethanamine; N- (4-f luorophenyl) -1H-pyrazol-4-yl] -2-pyridinyl] 2- pyridintemethanamine; 2-f luoro-4- (4-f luorophenyl) -1H-pyrazol-4-yllpyridine; 4- (4-iodophenyl) -lH-pyrazol-4-yllpyridine; 4- (4-iodophenyl) -1-methyl-1H-pyrazol-4-yllpyridine; 4- [1-methyl-3- (trifluoromethyl)phenyl] -1H-pyrazol-4- yl] pyridine; N- luorophenyl)ethyl] (4-f luorophenyl) -1H-pyrazol- 4-yl] -2-pyridinamine; N- luorophenyl)methyl] (4-f luorophenyl) -iw-pyrazol- 4-yl] -2-pyridinamine;

776- 4- (4-fluorophenyl) -l-methyl-lH-pyrazol-4-yl] (1- methyihydrazino) pyridine; 2-f luoro-4-[13- (4-f luorophenyl) -l-methyl-lH-pyrazol-4- yl] pyridine; 4- (3,4-difluorophenyl) -lH-pyrazol-4-yl] -2-f luoro-pyridine; 4- (4-f luorophenyl) -lH-pyrazol-4-ylI -3-methylpyridine; 4- (4-f luorophenyl) -l-methyl-lH-pyrazol-4-yl] -3-methyl- pyridiie; 4- (3,4-difluorophenyl) -l-methyl-lH-pyrazol-4-yl] -2- fluoropyridine; 3- (4-f luorophenyl) -N,N-dimethyl-4- (4-pyridinyl) -1H-pyrazole- 2- 1- ethanamine; 2[2- (4-f luorophenyl)ethyl] (4-fluorophenyl) -1-methyl- lH-pyrazol-4-yl] pyridine; 15 4- (4-fluorophenyl) -1H-pyrazol-4-yl] [1-(phenylmethyl) -4- piperidinyl] -2-pyridinamine; N (4-f luorophenyl) -1H-pyrazol-4-ylI -2-pyridinyl] -N,N- dimethyl ethanediamine; 2,4-bis (4-f luorophenyl) -1H-pyrazol-4-yllpyridine; 20 N- (4-fluorophenyl) -lH-pyrazol-4-ylI -2-pyridinyl] -4- morphol ineethanamine; 3- (4-f luorophenyl) (2-f luoro-4-pyridinyl) -lH-pyrazole-1- ethanol; 4- (4-f luorophenyl) -lH-pyrazol-4-yl] (1H-imidazol-l- yl)ethyl] -2-pyridinamine; 4- (4-f luorophenyl) (2-fluoro-4-pyridinyl) -1H-pyrazol- l-yl] ethyl] morpholine; (4-fluorophenyl) (4-fluorophenyl)ethenyl] -4- pyridinyl] -lH-pyrazole-l-ethanol; 3- (4-f luorophenyl) (2-f luoro-4-pyridinyl) -N,N-dimethyl-lH- pyrazole-1-ethanamine; 3- (4-f luorophenyl) (4-f luorophenyl)ethyl] -4- pyridinyl] -lH-pyrazole-l -ethanol; 777 4- (dimethylamino) ethyl] (4-f luorophenyl) -lH-pyrazol- 4-yl] -N,N-dimethyl-2-pyridinamine; (dimethylamino) ethyl] (4-f luorophenyl) -lH-pyrazol- 4-yl] luorophenyl)methyl] -2-pyridinamine; 3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl)ethyl]-4- pyridinyl] -N,N-dimethyl-lH-pyrazole-l-ethanamine; N-[(4-fluorophenyl)methyl] [3(or 5)-(4-fluorophenyl)-l-[[2- (4-morpholinyl) ethyl] -lH-pyrazol-4-yl] -2-pyridinamine; 4- (4-f luorophenyl) -lH-pyrazol-4-yl] -N-4-piperadinyl-2- pyridinamine; N,N-diethyl-3- (4-f luorophenyl) (2-f luoro-4-pyridinyl) -lH- pyrazole-l1-ethanamiie; (diethylamino) ethyl] -3-(4-fluorophenyl) -1H-pyrazol-4- yl] luorophenyl)methyl] -2-pyridinamine; :9 15 2-[[4-[3-(4-(fluorophenyl)-lH-pyrazol-4-yl]-2- pyridinyl] amino] ethanol; 2- (4-fluorophenyl) -l-methyl-lH-pyrazol-4-yl] -2- *.:pyridinyl] amino] ethanol;. 3-[[4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]-2- 9 20 pyridinyl] amino] -1-propanol; 3- (4-f luorophenyl) [[(4-fluorophenyl)methyl] amino] -4- pyridinyl] -lH-pyrazole-l-ethanol; N,N-diethyl-3- (4-f luorophenyl) (4-pyridinyl) -lH-pyrazole-l- ethanamine; N- [(4-fluorophenyl)methyl] (4-fluorophenyl) (4- morpholinyl) ethyl] -lH-pyrazol-4-yl] -2-pyridinamine; N- (4-f luorophenyl) (4-pyridinyl) -lH-pyrazol-3-yl] -4- morphol inepropanamine; (4-f luorophenyl) (4-pyridinyl) -lH-pyrazol-3-yl] -N,N- dimethyl -1,3 -propanediamine; 778 (4-f luorophenyl) -N-2-propynyl-4- (4-pyridinyl) -1H--pyrazol-3- amine; 3- (4-fluorophenyl) -4-112- luorophenyl)methyl] amino] -4- pyridinyl] -lH-pyrazole-l-ethanol; 5- (4-fluorophenyl) luorophenyl)methyl] amino] -4- pyridinyl] -1H-pyrazole-l-ethanol; 4- luorophenyl) -lH-pyrazol-4-yllquinoline; N- (4-f luorophenyl) (4-pyridinyl) -1H-pyrazol-3-yllglycine methyl ester; N- (4-f luorophenyl) (4-pyridinyl) -lH-pyrazol-3- yl] glycine; (4-f luorophenyl) -1-(2-propynyl) -1H-pyrazol-4- yl] pyridine; 4-[5-(4-fluorophenyl)-l-(2-propynyl)-lH-pyrazol-4- 15 yllpyridine; (lH-pyrazole-3,4-diyl)bis[pyridinel 4-13- (3,4-dichiorophenyl) -1H-pyrazol-4-yllpyridine; (4-chiorophenyl) (4-pyridinyl) -lH-pyrazol-3-yl] -4- piperidinamine; 20 2-Chloro-4- (4-f luorophenyl) -lH-pyrazol-4-yllpyrimidine; 4-13- (4-f luorophenyl) -lH-pyrazol-4-yl] -2 (lH)-pyrimidinone hydrazone; 4-13- (4-f luorophenyl) -1H-pyrazol-4-yl] -N,N-dimethyl-2- pyrimidinamine; 4-113- (4-f luorophenyl) -lH-pyrazol-4-yl] -N-methyl-2- pyrimidinamine; 4- (4-f luorophenyl) -1H-pyrazol-4-yl] (phenylmethyl) -2- pyrimidinamine; N-cyclopropyl-4- (4-f luorophenyl) -1H-pyrazol-4-yl] -2- pyrimidinamine; 4- (4-f luorophenyl) -lH-pyrazol-4-yl] methoxyphenyl) methyl] -2 -pyrimidinamine; 4[3- (4-f luorophenyl) -1H-pyrazol-4-yl] -2-pyrimidinamine; 779 N- (4-f luorophenyl) -lH-pyrazol-4-yl] -2-pyrimidinyl] -N- (phenylmethyl) acetamide; Ethyl (4-f luorophenyl) -lH-pyrazol-4-yl] -2- pyrimidinyl] carbamate; 4- (3-methyiphenyl) -lH-pyrazol-4-ylllpyrimidine; 4- (4-chiorophenyl) -1H-pyrazol-4-yllpyrimidine; 4- (3-f luorophenyl) -1H-pyrazol-4-yllpyrimidine; and 4- (4-f luorophenyl) -lH-pyrazol-4-yllpyrimidine. 70. A compound, tautomer, or salt of claim 1, wherein the compound is selected from the group consisting of: N N 0 F N* N -NH 0 780 :0,0.0 N-NH 781 0 Br o S-N- 11 H 0 HN-N N-NH 0 H Br 782 0000 OVOO: 0.000 0 0 0* 0* 0 0 0 to0 00 0 0 too 0 to0o 0 00 6 0 Ul ;zz 00 0 0C0 785 71. A compound, tautomer, or salt of claim 1, wherein the compound is 4-[5-(4-fluorophenyl)-l-(2-propynyl)-lH-pyrazol-4-yllpyridine. 72. A compound, tautomer, or salt of claim 1, wherein the compound is 4- (4-f luorophenyl) (2-propynyl) -lI-pyrazol-4-yl pyridine. 73. A compound, tautomer, or salt of claim 1, wherein the compound is 3-(4-fluorophenyl)-4-(4-pyridinyl)-lH-pyrazole-l-ethanol. 74. A compound, tautomer, or salt of claim 1, wherein the compound is 4- (4-f luorophenyl) -l-methyl-lH-pyrazol-4-yl] (1-methylhy drazino)pyridine. A compound, tautomer, or salt of claim 1, wherein the compound is 0000 20 1-[5-(4-chiorophenyl)-4-(4-pyridinyl) -lH-pyrazol-3-yl]piperaz ine. 76. A compound, tautomer, or salt of claim 1, wherein the compound is 4-[3-cyclopropyl-5- (4-fluorophenyl) -1H-pyrazol-4-yl] pyridine. 77. A compound, tautomer, or salt of claim 1, wherein the compound is 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yllpyridine. 78. A compound, tautomer, or salt of claim 1, wherein the compound is 1-[5-(4-chiorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4-meth SOiperazi ne. 786 79. A compound, tautomer, or salt of claim 1, wherein the compound is 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyrimidine. 80. A compound, tautomer, or salt of claim 1, wherein the compound is 2-fluoro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine. 81. A compound, tautomer, or salt of claim 1, wherein the compound is 4-[3-(3,4-diflurophenyl)-1-methyl-1H-pyrazol-4 -yl]pyridine. 82. A compound, tautomer, or salt of claim 1, wherein the compound is 4-[3-(4-bromophenyl)-1H-pyrazol-4yl]pyridine. 83. A compound, tautomer, or salt of claim 1, wherein the compound is 4-[3-(4-chlorophenyl) H-pyrazol-4-yl]-2-fluoropyridine. -20 84. A compound, tautomer, or salt of claim 1, wherein the Scompound is 4-[3-(1,3-benzodioxol 5-y)-l-methyl-1H-pyrazol-4-yl]pyridine. A compound, tautomer, or salt of claim 1, wherein the compound is 4-[3-(3-fluorophenyl)l-methyl-lH-pyrazol-4-yl]pyridine. 86. A compound, tautomer, or salt of claim 1, wherein the compound is 4-[3-(3-fluorophenyl)-l-methyl-pyrazol-4-yl]pyridine. 87. A compound, tautomer, or salt of claim 1, wherein the compound is 787 5-(4-fluorophenyl)-N-2-propynyl-4-pyridinyl)-1H-pyrazol-3 -amine. 88. A substituted pyrazole, wherein: the substituted pyrazole is a compound, a tautomer of the compound, or a pharmaceutically-acceptable salt of the compound or tautomer, wherein the compound corresponds in structure to formula (XII): R 3 R2 /4 R4 N N R (XII); 10 R 1 is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl have a molecular weight of less than about 360 atomic mass units; R 2 is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl bind with p38 kinase at an ATP binding site of p38 kinase; R 3 is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl have a hydrogen bond acceptor functionality; R 4 is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: 788 the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl have a molecular weight of less than about 360 atomic mass units; R 3 is not 2-pyridinyl when R 4 is 2-hydroxyphenyl and when R 1 is hydrogen; R 2 is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl, and cycloalkenyl when R 4 is hydrogen; R 4 is not methylsulfonylphenyl; and the substituted pyrazole specifically binds to an ATP binding site of p38 kinase. 89. A substituted pyrazole of claim 88, wherein R 2 is selected from the group consisting of a hydrocarbyl, 0 .0 heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl radical binds with Lyss 2 Glu 69 Leu 73 Ile 82 Leu 84 Leu 101 and Thro 03 sidechains at said ATP binding site of p38 kinase, said radical being 20 substantially disposed within a hydrophobic cavity formed during said binding by p38 kinase at the ATP binding site. A substituted pyrazole of claim 88, wherein R 3 is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl have a hydrogen bond acceptor functionality that hydrogen bonds with the N-H backbone of Met 1 os of p 38 kinase. 789 91. A substituted pyrazole of claim 88, wherein R 1 is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl have a molecular weight of less than about 250 atomic mass units. 92. A substituted pyrazole of claim 88, wherein R 4 is selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl have a molecular weight of less than about 250 atomic mass units. 93. A substituted pyrazole of claim 88, wherein R 1 is selected from the group consisting of a hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and 20 heterocyclyl have a molecular weight of less than about 360 atomic mass units; R is selected from the group consisting of a hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl radical, wherein: said hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl radical binds with Lyss 2 Glu 69 Leu 73 Ile 2 Leu 84 Leuo 01 and Thr 103 sidechains at sadid 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; 790 R 3 is selected from the group consisting of a hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl have a hydrogen bond acceptor functionality that hydrogen bonds with the N-H backbone of Meto 10 of p38 kinase; and R 4 is selected from the group consisting of a hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl, wherein: the hydrocarbyl, heterosubstituted hydrocarbyl, and *360 atomic mass units. 15 94. A substituted pyrazole of claim 93, wherein: 000 R 1 and R 4 are independently selected from the group consisting of hydrocarbyl, heterosubstituted hydrocarbyl, and heterocyclyl; and R 1 and R 4 have a combined molecular weight of less than 20 about 360 atomic mass units. S 95. A pharmaceutical composition, wherein the composistion comprises a therapeutically-effective amount of a compound, salt, or tautomer recited in claim 1. 96. A pharmaceutical composition of claim 95, wherein the composition comprises a therapeutically-effective amount of a compound, salt, or tautomer recited in claim 3. 97. A pharmaceutical composition of claim 95, wherein the composition comprises a therapeutically-effective amount of a compound, salt, or tautomer recited in claim 4. 791 98. A pharmaceutical composition of claim 95, wherein the composition comprises a therapeutically-effective amount of a compound, salt, or tautomer recited in claim 99. A pharmaceutical composition of claim 95, wherein the composition comprises a therapeutically-effective amount of a compound, salt, or tautomer recited in claim 6. 100. A pharmaceutical composition, wherein the composistion comprises a therapeutically-effective amount of a compound, salt, or tautomer recited in claim 24. ~101. A pharmaceutical composition of claim 100, wherein the composition comprises a therapeutically-effective amount of a compound, salt, or tautomer recited in claim 102. A pharmaceutical composition, wherein the composistion comprises a therapeutically-effective amount of a compound, *oo* salt, or tautomer recited in claim 103. A pharmaceutical composition of claim 102, wherein the composition comprises a therapeutically-effective amount of a compound, salt, or tautomer recited in claim 36. 104. A pharmaceutical composition, wherein the composistion comprises a therapeutically-effective amount of a compound, salt, or tautomer recited in claim 44. 105. A pharmaceutical composition of claim 104, wherein the composition comprises a therapeutically-effective amount of a compound, salt, or tautomer recited in claim 792 106. A pharmaceutical composition, wherein the composistion comprises a therapeutically-effective amount of a compound salt, or tautomer recited in claim 53. 107. A pharmaceutical composition of claim 106, wherein the composition comprises a therapeutically-effective amount of a compound, salt, or tautomer recited in claim 54. 108. A pharmaceutical composition, wherein the composistion comprises a therapeutically-effective amount of a compound, salt, or tautomer recited in claim 66. 109. A pharmaceutical composition, wherein the composistion comprises a therapeutically-effective amount of a compound, 15 salt, or tautomer recited in claim 69. 110. A pharmaceutical composition of claim 109, wherein said compound is 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine. 20 111. A use of a therapuetically effective amount of a compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer to prepare a pharmaceutical composition for treating a TNF mediated disorder in a subject having or susceptible to such disorder, wherein: the compound corresponds in structure to Formula I: R R2 51 N N SR1 Pit is to R 1

793- R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloal kenyl, alkynyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, aryiheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, and heterocyclylcarbonyloxyalkylene, or R 1 corresponds in structure to formula (II): C (CH 2 I2 i is an integer from zero to 9; R 25 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and ,yclylcarbonylaminoalkylene; 794 as o R26 and R 27 R 26 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: R 27 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkyiheterocyclyl, alkylheterocyclylalkylene, lyhtrcllale, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonyiheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, 99laboyakyee **oyabnyayee *arylocarbonylaylene, alkyloxycarbonylarylene, arylocarbonylarylene, alkylarylxcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, /~~24a1koxyarylene, aryloxyarylene, 795 arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisiting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R 27 is -CHR28R 29 or R 2 and R 2 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or 20 more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy; R 28 is alkoxycarbonyl; R 29 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene wherein: said aralkyl and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl and nitro, or as to R2: R 2 is selected from the group consisting of hydrogen, XORMo ogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, 796 haloalkyl, hydroxyalkyl, aralkyl, alkyiheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkyithia, arylthio, heterocyclyithic, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl, *wherein: the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl are optionally substituted :with one or more radicals independently selected from group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, 20 heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl, 2 corresponds in structure to formula (III): R 30 H R31R II),or *2 is-R41 R42 797 R 2 is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl, and cycloalkenyl when R 4 is hydrogen; j is an integer from zero to 8; m is selected from the group consisting of zero and 1; R 30 and R 31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; R 32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R 33 is selected from the group consisting of hydrogen, alkyl, -C(O)R 35 -C(O)OR 35 -SOR 3 6 -C(O)NR 3 R 3 8 and S -S0 2 NR 3 9 R 4 0 R 3 s, R 36 R 37 R 38 R 3 9 and R 40 are independently selected from the group consisting of hydrocarbon, heterosubstituted 20 hydrocarbon, and heterocyclyl; R 34 is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; R 4 1 is aryl; R 42 is hydroxy; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, 798 and k3 wherein: the pyridinyl, pyrimidinyl, quinolinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, 10 hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, 0 alkoxyaralkylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, and -NR 44 R 45 R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R 1 is hydrogen; R 43 is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; R 44 is selected from the group consisting of alkylcarbonyl and amino; R 45 is selected from the group consisting of alkyl and ~~~lkyl; and 799 R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxyl. 112. A use of a therapuetically effective amount of a compound, a tautomer of the compound, or a pharmaceutically 20 acceptable salt of the compound or tautomer to prepare a pharmaceutical composition for treating a p38 kinase mediated disorder in a subject having or susceptible to such disorder, wherein: the compound corresponds in structure to Formula I: R3 R 2 R4 43 N N R as to R 1 R 1 is selected from the group consisting of hydrogen, SaR,11, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, 800 cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, aryiheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amn, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, 0 0 0 alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, and heterocyclylcarbonyloxyalkylene, or Ri corresponds in structure to formula (II): 250 (CH2)- R 27 i is an integer from zero to 9; R 25is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; as toR 26and R 27

801- R 26is selected -from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: R 27 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkyiheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkyiheterocyclyl, alkoxyalkylene, alkoxyarylene, V alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonyiheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, S. arylaminocarbonylalkylene, alkylaminocarbonylalkylene, 55555*arylcarbonylalkylene, alkoxycarbonylarylene, ayoyar...yenaklryoyabnyayee 20 arylocarbonylarylene, alkylarylxcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkyiheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, I RA4 rycarbonyarylene, alkylthioarylene, 802 heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisiting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R 2 7 is -CHRR 2 9 or R 26 and R 7 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, 9 heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently S. selected from the group consisting of halogen, 20 alkyl, and alkoxy; R 28 is alkoxycarbonyl; R 2 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene, wherein: said aralkyl and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl and nitro, or as to R2: R 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, ky kyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, 803 heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylarninoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkyithia, aryithia, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl, wherein: *0 the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hy droxyalkyl)carboxy, alkoxy, aryloxy, aralkoxy, 99 9 haloalkyl, alkylamino, alkynylamino, .999 alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl, R 2 corresponds in structure to formula (III): R 30 H C (O H 2 1 C- N R 3 1 1 34Jm"R3 R 31 R (I),or R 2 is -CR 41 R 42 804 R 2 is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl, and cycloalkenyl when R 4 is hydrogen; j is an integer from zero to 8; m is selected from the group conssiting of zero and 1; R 30 and R 31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; R 32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, @0 0 alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; 15 R 33 is selected from the group consisting of hydrogen, alkyl, -C(O)R 35 -C(O)OR 35 -SO 2 R 36 -C(O)NR 3 7 R 3 8 and -SO 2 NR 3 R 4 0 R 35 R 3 R 37 R 38 R 39 and R 40 are independently selected from the group consisting of hydrocarbon, heterosubstituted 20 hydrocarbon, and heterocyclyl; R 34 is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; R 41 is aryl; R 42 is hydroxy; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, 805 and wherein: the pyridinyl, pyrimidinyl, quinolinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, aryiheterocyclyl, 5 carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl., aralkoxy, *heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, 9 heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, 0 S006 15 alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkyihydrazinyl, aryihydrazinyl, and -NR 44 R 4 R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R' is hydrogen; R 43 is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; R 4 4 is selected from the group consisting of ,alkylcarbonyl and amino; 3 R 45 is selected from-the group consisting of alkyl and j and 806 R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, ,*haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxyl. 113. A use of a therapuetically effective amount of a compound, a tautomer of the compound, or a pharmaceutically -20 acceptable salt of the compound or tautomer to prepare a pharmaceutical composition for treating inflammation in a subject having or susceptible to inflammation, wherein: the compound corresponds in structure to Formula I: R 3 R 2 4/k 1N N R as to R 1 R 1 is selected from the group consisting of hydrogen, il, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, ;yc lkylalkylene, cycloalkenylalkylene, 807 heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, aryiheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, antinoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, 15 heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, and heterocyclylcarbonyloxyalkylene, or R 1 corresponds in structure to formula (II): I C 2) 27 20 H i is an integer from zero to 9; R 25 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; as toR 26and R 27 808 R 26is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: R 27 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkyiheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkyiheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, **lmncronllyee *lyaioabnllyee arylamcarbonylalkylene, alk y ancarbonyla lkylene, arylocarbonylaylene, alkyloxycarbonylarylene, 20 arylocarbonylarylene, alkylarylxcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosul fonylarylene, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkyiheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, Zarylcarbonylarylene, alkylthioarylene, 809 heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisiting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R 27 is -CHRR29 or R 2 and R 27 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy; 20 R 28 is alkoxycarbonyl; R 29 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene, wherein: said aralkyl and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl and nitro, or as to R2: R 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, nerocyclylalkyl, alkylamino, alkenylamino, alkynylamino, -810 arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkyithia, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl, wherein: the aryl, heterocyclyl, heterocyclylalkyl, 15cycloalkyl, and cycloalkenyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl, R 2 corresponds in structure to formula (II): R 30 H -C (CH 2 )j :lm R 3 3 R3 (III) or R 2is -CR 41R4 2 R 2is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl, and cycloalkenyl when AIV- s hydrogen; 811 j is an integer from zero to 8; m is selected from the group consisting of zero and 1; R 30 and R 31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; R 32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R 33 is selected from the group consisting of hydrogen, alkyl, -C(O)R 3 5 -C(O)OR 35 -SO 2 R 36 -C(O)NRR 3 8 and -SO2NR 3 9 R 40 15 R 3 5 R 36 R 3 7 R 3 8 R 3 9 and R 4 0 are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon, and heterocyclyl; R 34 is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and 20 arylaminocarbonyl; R 41 is aryl; R 4 2 is hydroxy; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, R3 and N R wherein: the pyridinyl, pyrimidinyl, quinolinyl, and purinyl gT re optionally substituted with one or more radicals 812 independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkyiheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, and -NR 44 R 4 R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R 1 is hydrogen; R 43 is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and 20 aryloxyalkyl; 44 R is selected from the group consisting of alkylcarbonyl and amino; R is selected from the group consisting of alkyl and aralkyl; and R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, At~R A arylthio, alkylthioalkylene, arylthioalkylene, 813 alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxyl. 114. A use of a therapuetically effective amount of a compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer to prepare a pharmaceutical composition for treating arthritis in a subject having or susceptible to arthritis, wherein: the compound corresponds in structure to Formula I: RR R4 14/ RN 1N R as to R': R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, aryiheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, -814 arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, and heterocyclylcarbonyloxyalkylene, or R' corresponds in structure to formula (II): R 2 5 0F 2 R27 *i is an integer from zero to 9; R 25 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, s* alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; as to R 26and R 27 R 26 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: R 27 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkyiheterocyclyl, alkylheterocyclylalkylene, alkyiheterocyclylarylene, aralkyiheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyheterocyclyl, alkoxyalkoxyarylene, 815 aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: *said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisiting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R 2 is -CHR'R 21, or 26 2 R and R 27 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group 4 SSR4sisting of alkyl, aryl, heterocyclyl, 816 heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy; R28 is alkoxycarbonyl; R 2 9 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, *0 0 alkylthioalkylene, and aralkylthioalkylene, wherein: said aralkyl and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl and nitro, or as to R2: R 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, 00 .0 heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, oxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, -o ~tZ-' 817 alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl, wherein: the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl)carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl, 2 R 2 corresponds in structure to formula (III):: R 30 H I I I I R 32 -C-(CH 2 C -N S* m R33 R31 R 3 4 15 L J m (III), or R 2 is -CR R42; R 2 is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl, and cycloalkenyl when R 4 is hydrogen; j is an integer from zero to 8; m is selected from the group consisting of zero and 1; R 30 and R 31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; R 32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, 818 alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R 33 is selected from the group consisting of hydrogen, alkyl, -C(O)R 35 -C(O)OR 35 -S 2 R 36 -C NR 3 R 38 and -S0 2 NR 39 R 40 R 35 R 36 R 37 R 38 R 39 and R 40 are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon, and heterocyclyl; R 34 is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and S, arylaminocarbonyl; o R 4 1 is aryl; t :0 R 42 is hydroxy; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, o \14 3 o and R wherein: the pyridinyl, pyrimidinyl, quinolinyl, and purinyl goo* are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, JC alkoxyaralkylamino, alkylaminoalkylamino, 819 hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, and -NR 4 R 4 R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R 1 is hydrogen; R 43 is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; R 44 is selected from the group consisting of S. alkylcarbonyl and amino; 45 is selected from the group consisting of alkyl and R 4 5 is selected from the group consisting of alkyl and aralkyl; R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally 20 substituted with one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamin'o, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxyl. A use of a therapuetically effective amount of a r comgiiund, a tautomer of the compound, or a pharmaceutically 820 acceptable salt of the compound or tautomer to prepare a pharmaceutical composition for treating a p38 kinase mediated disorder in a subject having or susceptible to such disorder, wherein: the compound corresponds in structure to Formula IX: SR4 5 1 N N 1 R (IX); is selected from the group consisting of and R 1 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, and lower alkynyl; SR 2 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, and lower alkynyl; R 4 is selected from the group consisting of phenyl and benzodioxolyl, wherein 15 the phenyl is optionally substituted with one or more halo radicals; and R 5 is selected from the group consisting of hydrogen, halo, and alkylhydrazinyl. 116. The use of Claim 111, wherein the TNF mediated disorder is selected from the group consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory iPase, cardiac reperfusion injury, renal reperfusion 821 injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and cachexia. 117. The use of Claim 111, wherein the TNF mediated disorder is inflammation. 118. The use of Claim 111, wherein the TNF mediated disease is arthritis. 119. The use of Claim 111, wherein the TNF mediated disorder is asthma. j 120. The use of claim 111, wherein the compound is 4-[3-(4-fluorophenyl)-lH-pyrazol-4-yl]pyridine. 121. The use of claim 111, wherein the compound is 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-lH-pyrazol-3-yl]-4-meth ylpiperazine. 20 122. The use of claim 112, wherein the disorder is a p38a kinase mediated disorder. 123. The use of claim 112, wherein the p38 kinase mediated disorder is selected from the group consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and cachexia. 822 124. The use of claim 112, wherein the p38 kinase mediated disorder is inflammation. 125. The use of claim 112, wherein the p38 kinase mediated disorder is arthritis. 126. The use of claim 112, wherein the p38 kinase mediated disorder is asthma. 127. The use of claim 115, wherein the disorder is a p38a kinase mediated disorder. 128. The use of claim 115, wherein the p38 kinase mediated disorder is selected from the group consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal 20 reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and cachexia. 129. The use of claim 115, wherein the p38 kinase mediated disorder is inflammation. 130. The use of claim 115, wherein the p38 kinase mediated disorder is arthritis. 131. The use of claim 115, wherein the p38 kinase mediated disorder is asthma. 823 132. A method of preparing a substituted pyrazole compound, a tautomer of the substituted pyrazole compound, or a pharmaceutically-acceptable salt of the substituted pyrazole compound or tautomer, wherein: the method comprises forming an acyl hydrazone and condensing to form the substituted pyrazole compound; the substituted pyrazole compound corresponds in structure to Formula I: R 3 N 1 R as to R': R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, /Opcyclyloxycaroylalkylene, alkoxycarbonylarylene, 824 aryloxycarbonylarylene, heterocyclyloxycarbonylarylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene, or R 1 corresponds in structure to formula (II): R250 ~R27 (II) i is an integer from zero to 9; R 25 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; as toR 26and R 27 R 26is slcefrmthe group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: R 27is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkyiheterocyclyl, alkylheterocyclylalkylene, alkyiheterocyclylarylene, aralkyiheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, 3 0 ,Arylene, aralkoxyarylene, alkoxyheterocyclylalkylene, 825 aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylamnocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbornylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, 15 arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosul fonylarylene, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or *R 2 1 is -CHR 2 'R 2 or 2 and R 27 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, 826 aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy; R 28 is alkoxycarbonyl; R 2 9 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene, wherein: said aralkyl and heterocylcyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl and nitro; 999 as to R 2 R 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl, wherein: 827 the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, hydroxyalkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl, or *2 S. R corresponds in structure to formula III: R30 H 32 -N o m (III), or R 2 is C R R 42 15 j is an integer from zero to 8; m is selected from the group consisting of zero and 1; R30 and R 31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; R 32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R 33 is selected from the group consisting of hydrogen, alkyl, -C(O)R 35 -C(O)OR 35 -SO 2 R 36 -C(O)NR 37 R 38 and -S0 2 NR 39 R 40 828 R 35 R 36 R 37 R 38 R 39 and R 40 are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon, and heterocyclyl; R 34 is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; R41 is aryl; R 42 is hydroxy; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, 0 0 0000 IR3 and N -U 3 wherein: the pyridinyl, pyrimidinyl, quinolinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, and -NR 44 9. *9 9 9* 9 9 *9 9 *9 829 R 43 is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; R 44 is selected from the group consisting of alkylcarbonyl and amino; R 45 is selected from the group consisting of alkyl and aralkyl; and R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, 20 aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy. 133. The method of claim 132, wherein the acyl hydrazone is formed by reaction of a ketone with an acyl hydrazide. 134. The method of claim 132, wherein the condensation is performed at a temperature from about 25 0 C to about 200 0 C. 135. A method of preparing a substituted pyrazole compound, a ~uRigtomer of the substituted pyrazole compound, or a 99* o 9* oooo 9 9 oooo o o 830 pharmaceutically-acceptable salt of the substituted pyrazole compound or tautomer, wherein: the method comprises treating a substituted ketone with an acyl hydrazide to produce the substituted pyrazole compound; the substituted pyrazole compound corresponds in structure to Formula I: R4 1 N- N as to RR R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkoxycarbonylarylene, ASF2",loxycarbonylarylene, heterocyclyloxycarbonylarylene, 831 alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonylarylene, arylcarbonylarylene, heterocyclylcarbonylarylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, heterocyclylcarbonyloxyalkylene, alkylcarbonyloxyarylene, arylcarbonyloxyarylene, and heterocyclylcarbonyloxyarylene, or R 1 corresponds in structure to formula (II): R 25 0 C (CH2)- V* R 2 0 i is an integer from zero to 9; S25 R~ is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and 15 heterocyclylcarbonylaminoalkylene; as toR 26and R 27 s* 26 R 2 is selected from the group consisting of hydrogen, :6,0*0 alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, 060000 alkoxycarbonylalkylene, and alkylaminoalkyl, and: R 27is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkyiheterocyclyl, alkylheterocyclylalkylene, alkyiheterocyclylarylene, aralkyiheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, "oxycarbonyleterocyc lyl, 832 alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarboiylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, alkylaminosulfonylarylene, wherein: **15 said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkyithioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R 21is -CHR"R 21wherein R 28is alkoxycarbonyl, and R 29is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene, wherein: said aralkyl and heterocylcyl are optionally substituted with one or more radicals independently 'T selected from the group consisting of alkyl and nitro, 833 R 26 and R 27 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy; I as to R 2 R 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, 20 aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl, wherein: the aryl, heterocyclyl, heterocyclylalkyl, F(RA4 cycloalkyl, and cycloalkenyl are optionally substituted .r ith one or more radicals independently selected from 834 the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, hydroxyalkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl, or R 2 corresponds in structure to formula (III):: R 30 H I-I"R 32 C- (CH2) C- N 33 31 R J m (III), or 2 is CR41R42 R is -CR R 42 j is an integer from zero to 8; m is selected from the group consisting of zero and 1; R* R 30 and R 31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, o* aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; R 32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R 33 is selected from the group consisting of hydrogen, alkyl, -C(0)R 3 5 -C(0)OR 3 5 -S0 2 R 36 -C NRR 3 8 and -S0 2 NR 39 R 4 0 R 3 5 R 36 R 3 7 R 3 8 R 3 9 and R 40 are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon, and heterocyclyl; 835 R 34 is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; R41 is aryl; R 42 is hydroxy; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, R43 and N 3 wherein: the pyridinyl, pyrimidinyl, quinolinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, aminosulfinyl, aminosulfonyl, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkyiheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, and -NR 4 "R 4 5 R 4 3 is selected from the group consisting of hydrogen, .lkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and .Uloxyalkyl; 836 R 44 is selected from the group consisting of alkylcarbonyl and amino; R 45 is selected from the group consisting of alkyl and aralkyl; and R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinyl, alkylsulfinylalkylene, S 15 arylsulfinylalkylene, alkylsulfonyl, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, 20 alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxy. 136. The method of claim 135, wherein the treatment of the substituted ketone with the acyl hydrazide is carried out in an acidic solvent. 137. The method of claim 136, wherein the acidic solvent comprises acetic acid. 138. The method of claim 136, wherein the acidic solvent comprises an organic solvent comprising an acid. 837 139. A compound, tautomer, or salt of claim 1, wherein the compound corresponds in structure to the following formula: 140. A compound, tautomer, or salt of claim 1, wherein the compound corresponds in structure to the following formula: 141. A compound, tautomer, or salt of claim 1, wherein the compound corresponds in structure to the following formula: 142. A compound, tautomer, or salt of claim 1, wherein the compound corresponds in structure to the following formula: 838 143. A compound, tautomer, or salt of claim 1, wherein the compound corresponds in structure to the following formula: 144. A compound, tautomer, or salt of claim 1, wherein the compound corresponds in structure to the following formula: 145. A compound, tautomer, or salt of claim 1, wherein the compound corresponds in structure to the following formula: 839 146. A compound, tautomer, or salt of claim 1, wherein the compound corresponds in structure to the following formula: 147. A compound, tautomer, or salt of claim 1, wherein the compound corresponds in structure to the following formula: N-NH Br 148. A compound, tautomer, or salt of claim 1, wherein the .0 compound corresponds in structure to the following formula: 149. A compound, tautomer, or salt of claim 1, wherein the compound corresponds in structure to the following formula: 840 150. A compound, tautomer, or .salt of claim 9, wherein R 4 is optionally substituted phenyl. 151. A compound, tautomer, or salt of claim 150, wherein R 4 is phenyl substituted with one or more radicals independently selected from the group consisting of fluoro, chloro, and bromo. 152. A compound, tautomer, or salt of claim 151, wherein R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, and quinolinyl, wherein: the pyridinyl, pyrimidinyl, and quinolinyl are optionally substituted with one or more radicals independently selected from the group consisting of fluoro, bromo, methyl, cyano, methoxycarbonyl, aminocarbonyl, benzyl, phenethyl, acetyl, hydroxyl, Smethoxy, dimethylamino, benzylamino, phenethylamino, aminomethyl, amino, hydroxy, and methylcarbonyl. 153. A compound, tautomer, or salt of claim 152, wherein R 3 is selected from the group consisting of unsubstituted pyridinyl, unsubstituted pyrimidinyl, and unsubstituted quinolinyl. 154. A compound, tautomer, or salt of claim 153, wherein R 2 is selected from the group consisting of hydrogen, lower alkyl, phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, morpholinyl, lower haloalkyl, lower hydroxyalkyl, lower alkoxycarbonyl, lower alkylamino, lower alkylaminoalkyl, phenylamino, lower aralkyl,'lower R lkylamino, lower alkylaminoalkylamino, lower aminoalkyl, lowe aminoalkylamino, lower alkynylamino, lower 841 heterocyclylamino, lower heterocyclylalkyl, lower heterocyclylalkylamino, lower alkylheterocyclyl, lower carboxycycloalkyl, lower carboxyalkylamino, lower alkoxyalkylamino, lower alkoxycarbonylaminoalkylamino, lower heterocyclylcarbonyl, lower alkoxycarbonylheterocyclyl, and lower alkoxycarbonylheterocyclylcarbonyl, wherein: the phenyl, biphenyl, naphthyl, piperidinyl, piperazinyl, imidazolyl, pyridinyl, and morpholinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, lower alkyl, keto, aralkyl, carboxy, lower alkylaminoalkylamino, lower alkynylamino, lower So heterocyclylalkylamino, lower alkylcarbonyl, lower 15 hydroxyalkylcarbonyl, and lower alkoxycarbonyl. S 155. A compound, tautomer, or salt of claim 154, wherein R 2 is substituted piperidinyl. 156. A compound, tautomer, or salt of claim 155, wherein the 20 hydroxyalkylcarbonyl of R 2 is selected from the group consisting of hydroxymethylcarbonyl and hydroxyethylcarbonyl. 157. A compound, tautomer, or salt of claim 57, wherein R 4 is optionally substituted phenyl. 158. A compound, tautomer, or salt of claim 157, wherein R 4 is phenyl substituted with one or more radicals independently selected from the group consisting of fluoro, chloro, and bromo. 159. A compound, tautomer, or salt of claim 158, wherein Z is 842 160. A compound, tautomer, or salt of claim 159, wherein R is hydrogen. 161. A compound, tautomer, or salt of claim 160, wherein R 2 is substituted piperidinyl. 162. A compound, tautomer, or salt of claim 161, wherein the hydroxyalkylcarbonyl of R 2 is selected from the group consisting of hydroxymethylcarbonyl and hydroxyethylcarbonyl. 163. A method of treating a TNF mediated disorder in a subject, the method comprising treating a subject having or C susceptible to such disorder with a therapeutically effective 0 amount of a compound, a tautomer of the compound, or a 15 pharmaceutically acceptable salt of the compound or tautomer, wherein: the compound corresponds in structure to Formula I: R 2 R 4 /43 RR 1 N N iR1 as to R 1 R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, 1 iAf baptoalkyl, alkylthioalkylene, alkenylthioalkylene, oooo 843 alkylthioalkenylene, a io aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, and heterocyclylcarbonyloxyalkylene, or R corresponds in structure to formula (II): R 25 0 R I26 C (CH 2 C--N *R J 2 7 i is an integer from zero to 9; 25 R is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; as toR 26and R2 R 26 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: R 27is seetdfrom the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, ~cycloalkylakylene, cycloalkenylalkylene, cycloalkylarylene, ~~~coalklcyloalylheterocyclylalkylene, alkylarylene,

844- alkylaralkyl, aralkylarylene, alkylheterocyclyl, alkylheterocyclylalkylene, alkyiheterocyclylarylene, aralkyiheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arlabnllyee 9 .ycronlryee arylocarbonylaylene, alkyloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, 15 alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, 20 arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: said alkyl, cylakl arl neterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisiting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R 27is-CHR8R 2, or 845 R 2 and R 27 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or :more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy; 2 R 28 is alkoxycarbonyl; R 9 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene wherein: **said aralkyl and heterocyclyl are optionally 20 substituted with one or more radicals independently *i selected from the group consisting of alkyl and nitro, S* or as to R 2 R 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, c cloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, e pcyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, 846 carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyiheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl, wherein: the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, 15 alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl, R 2 corresponds in structure to formula (III):: H R 32 R31 134 (III), or R2 is -CR41 42 R 2 is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl, and cycloalkenyl when R 4 is hydrogen; j is an integer from zero to 8; m is selected from the group consisting of zero and 1; and R31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, /2,ai -gC ,(iminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; S 847 R 3 2 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R 33 is selected from the group consisting of hydrogen, alkyl, -C(O)R 3 5 -C(O)OR 35 -SO 2 R 3 6 C NR37 3 8 and -S0 2 NR 3 9 R 40 R 35, R 36, R 37, R 39, and R 40 are independently. selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon, and heterocyclyl; R 34 is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; R 41 is aryl; R 42 is hydroxy; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, 0 N O \R43 N and R43 wherein: the pyridinyl, pyrimidinyl, quinolinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy,.amino, alkylamino, alkenylamino, 74'" alkynylamino, cycloalkylamino, cycloalkenylamino, I 6 848 arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkyiheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkyihydrazinyl, aryihydrazinyl, and -NR 44 R 4 R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R 1 is hydrogen; R 43 is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; R44 is selected from the group consisting of .9. alkylcarbonyl and amino; R 4 5 is selected from the group consisting of alkyl and aralkyl; and R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, rylaminoalkylene, aminoalkylamino, and hydroxyl. 849 164. A method of treating a p38 kinase mediated disorder in a subject, the method comprising treating a subject having or susceptible to such disorder with a therapeutically effective amount of a compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein: the compound corresponds in structure to Formula I: R4 14 3 RR N as to R': R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkyrylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, ASOM carbonylalkylene, heterocyclylcarbonylalkylene, 850 alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, and heterocyclylcarbonyloxyalkylene, or R 1 corresponds in structure to formula (II): -C-(CH 2 -C N RN 2 is an integer from zero to 9; R 25 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; 26 2 as toR and R 2 R 26is seetdfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, 15 alkoxycarbonylalkylene, and alkylaminoalkyl, and: R 27 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene,.cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkyiheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, ~~yarylaminocarbonylalkylene, aminocarbonylalkylene, 3fary inocarbonylalylene, alkylaminocarbonylalkylene, 851 arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: 0* said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisiting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R 27 is -CHR 2 8 R 2 9 or R26 and R 27 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently 852 selected from the group consisting of halogen, alkyl, and alkoxy; R 2 8 is alkoxycarbonyl; R29 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene, wherein: said aralkyl and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl and nitro, or 2 as to R 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, see* arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, 00900020 alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl, wherein: the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more radicals independently selected from 8' oup consisting of halo, keto, amino, alkyl, ralkygl, alkynyl, aryl, heterocyclyl, aralkyl, 853 heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl)carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl, R 2 corresponds in structure to formula (III): R 30 H I I R 32 c N S1 33 R31 R j M m (III), or 10 R 2 is -CR R 4 2 *2 R 2 is selected from the group consisting of aryl, S*heterocyclyl, unsubstituted cycloalkyl, and cycloalkenyl when R 4 is hydrogen; j is an integer from zero to 8; 15 m is selected from the group conssiting of zero and 1; R 30 and R 31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, S• aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; R 32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R 33 is selected from the group consisting of hydrogen, alkyl, -C(0)R 35 -C(0)OR 3 5 -S0 2 R 36 -C NR 3 7 R 38 and -SO 2 NR 39 R 4 R 35 R 36 R 37 R, R 39 and R 40 are independently selected mthe group consisting of hydrocarbon, heterosubstituted hy carbon, and heterocyclyl; N PC 854 R 34 is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; R 4 1 is aryl; R 4 2 is hydroxy; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, 0 15 0 0.02 and wherein: the pyridinyl, pyrimidinyl, quinolinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, and -NR 44 R 4 5 R is not 2-pyridinyl when R 4 is a phenyl ring ining a 2-hydroxy substituent and when R 1 is hydrogen; 855 R 43 is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; R 44 is selected from the group consisting of alkylcarbonyl and amino; R 45 is selected from the group consisting of alkyl and aralkyl; and R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, cycloalkyl, i cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, S* arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, ***alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, *and hydroxyl. 165. A method of treating inflammation in a subject, the method comprising treating a subject having or susceptible to inflammation with a therapeutically effective amount of a compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein: the compound corresponds in structure to Formula I: 856 RI) as to R': R' is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, aryiheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, 15 arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylaminoalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, and heterocyclylcarbonyloxyalkylene, or R' corresponds in structure to formula (II): 857 1 11 R 26 i is an integer from zero to 9; R 25 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; Sasto R 2 6 and R 27 R 26 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: 27 R is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl, aralkylarylene, alkyiheterocyclyl, alkylheterocyclylalkylene, alkyiheterocyclylarylene, aralkylheterocyclyl, alkoxyalkylene, alkoxyarylene, *20 alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylaminocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, 3 0,41,arbonylarylene, alkylarylcarbonylarylene, 858 alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, alkylheterocyclylarylene, alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, *arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one 15 or more radicals independently selected from the group consisiting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R" is -CHR 8R" or R 26 and R 2 7 together with the nitrogen to which they are attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, heterocyclylalkylene, alkyiheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy; R28 is alkoxycarbonyl; 859 R 29 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene, wherein: said aralkyl and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl and nitro, or 2 as to R R 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, 00, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, 15 aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, 00. cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyiheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl, wherein: the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino(hydroxyalkyl)carboxy, alkoxy, aryloxy, aralkoxy, r5>ha loalkyl, alkylamino, alkynylamino, 860 alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl, R 2 corresponds in structure to formula (II): H I I 32 -C-(CH2)j- C -N R31 R 3 4 (III), or R 2 is -CR41R 42 R 2 is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl, and cycloalkenyl when 10 R 4 is hydrogen; j is an integer from zero to 8; m is selected from the group consisting of zero and 1; R 30 and R 31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; R 32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R 33 is selected from the group consisting of hydrogen, alkyl, -C(O)R 3 5 -C(O)OR 35 -SO 2 R -C (O)NRR 3 and -SO 2 NR 3 R 40 R 35 R 3 6 R 37 R 3 8 R 39 and R 4 0 are independently selected from the group consisting of hydrocarbon, heterosubstituted hydrocarbon, and heterocyclyl; R 34 is selected from the group consisting of hydrogen, iTi 1, aminocarbonyl, alkylaminocarbonyl, and arvf minocarbonyl; 861 R 4 1 is aryl; R42 is hydroxy; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, 0/ N 0O R43 and &4 R wherein: 0* the pyridinyl, pyrimidinyl, quinolinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, arylthio, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, alkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, 15 heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, and -NR 44 R 4 R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R 1 is hydrogen; R 4 3 is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; 862 R 44 is selected from the group consisting of alkylcarbonyl and amino; R 45 is selected from the group consisting of alkyl and aralkyl; and R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinylalkylene, arylsulfinylalkylene, 15 alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, 20 and hydroxyl. 166. A method of treating arthritis in a subject, the method comprising treating a subject having or susceptible to arthritis with a therapeutically effective amount of a compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein: the compound corresponds in structure to Formula I: R 3 R 4 R

863- as to R': R1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkylalkylene, cycloalkenylalkylene, heterocyclylalkylene, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, aralkyl, aralkenyl, aralkynyl, aryiheterocyclyl, carboxy, carboxyalkyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkoxy, mercaptoalkyl, alkylthioalkylene, alkenylthioalkylene, alkylthioalkenylene, amino, aminoalkyl, alkylamino, alkenylamino, aknlmoarylamino, ieterocyclylamino, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heterocyclylsulfonyl, alkylamirioalkylene, alkylsulfonylalkylene, acyl, acyloxycarbonyl, alkoxycarbonylalkylene, aryloxycarbonylalkylene, heterocyclyloxycarbonylalkylene, alkylcarbonylalkylene, :20 arylcarbonylalkylene, heterocyclylcarbonylalkylene, alkylcarbonyloxyalkylene, arylcarbonyloxyalkylene, and heterocyclylcarbonyloxyalkylene, or R 1 corresponds in structure to formula (II): 0 (11); i is an integer from zero to 9; R 25is selected from tegroup consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, 864 alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; as toR 26and R 27 R 26is seetdfrom the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkylene, aralkyl, alkoxycarbonylalkylene, and alkylaminoalkyl, and: R 27 is selected from the group consisting of alkyl, cycloalkyl, alkynyl, aryl, heterocyclyl, aralkyl, cycloalkylalkylene, cycloalkenylalkylene, cycloalkylarylene, cycloalkylcycloalkyl, heterocyclylalkylene, alkylarylene, alkylaralkyl,'aralkylarylene, alkyiheterocyclyl, alkylheterocyclylalkylene, alkylheterocyclylarylene, aralkyiheterocyclyl, alkoxyalkylene, alkoxyarylene, alkoxyaralkyl, alkoxyheterocyclyl, alkoxyalkoxyarylene, aryloxyarylene, aralkoxyarylene, alkoxyheterocyclylalkylene, aryloxyalkoxyarylene, alkoxycarbonylalkylene, alkoxycarbonyiheterocyclyl, alkoxycarbonylheterocyclylcarbonylalkylene, aminoalkyl, alkylaminoalkylene, arylarninocarbonylalkylene, alkoxyarylaminocarbonylalkylene, aminocarbonylalkylene, arylaminocarbonylalkylene, alkylaminocarbonylalkylene, arylcarbonylalkylene, alkoxycarbonylarylene, aryloxycarbonylarylene, alkylaryloxycarbonylarylene, arylcarbonylarylene, alkylarylcarbonylarylene, alkoxycarbonylheterocyclylarylene, alkoxycarbonylalkoxylarylene, heterocyclylcarbonylalkylarylene, alkylthioalkylene, cycloalkylthioalkylene, alkylthioarylene, aralkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, arylsulfonylaminoalkylene, alkylsulfonylarylene, and alkylaminosulfonylarylene, wherein: said alkyl, cycloalkyl, aryl, heterocyclyl, -ralkyl, heterocyclylalkylene, alkylheterocyclylarylene, 865 alkoxyarylene, aryloxyarylene, arylaminocarbonylalkylene, aryloxycarbonylarylene, arylcarbonylarylene, alkylthioarylene, heterocyclylthioarylene, arylthioalklylarylene, and alkylsulfonylarylene are optionally substituted with one or more radicals independently selected from the group consisiting of alkyl, halo, haloalkyl, alkoxy, keto, amino, nitro, and cyano, or R 2 is -CHRR 29 or R 26 and R 27 together with the nitrogen to which they are .attached, form a heterocycle, wherein: said heterocycle is optionally substituted with one or more radicals independently selected from the group consisting of alkyl, aryl, heterocyclyl, S 15 heterocyclylalkylene, alkylheterocyclylalkylene, aryloxyalkylene, alkoxyarylene, alkylaryloxyalkylene, .alkylcarbonyl, alkoxycarbonyl, aralkoxycarbonyl, alkylamino, and alkoxycarbonylamino, wherein: said aryl, heterocyclylalkylene, and 20 aryloxyalkylene are optionally substituted with one or more radicals independently selected from the group consisting of halogen, alkyl, and alkoxy; R 28 is alkoxycarbonyl; R 29 is selected from the group consisting of aralkyl, aralkoxyalkylene, heterocyclylalkylene, alkylheterocyclylalkylene, alkoxycarbonylalkylene, alkylthioalkylene, and aralkylthioalkylene, wherein: said aralkyl and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of alkyl and nitro, or AVTos to R2: 866 R 2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, haloalkyl, hydroxyalkyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, alkylamino, alkenylamino, alkynylamino, arylamino, heterocyclylamino, heterocyclylalkylamino, aralkylamino, aminoalkyl, aminoaryl, aminoalkylamino, arylaminoalkylene, alkylaminoalkylene, arylaminoarylene, alkylaminoarylene, alkylaminoalkylamino, cycloalkyl, cycloalkenyl, alkoxy, heterocyclyloxy, alkylthio, arylthio, heterocyclylthio, carboxy, carboxyalkyl, carboxycycloalkyl, carboxycycloalkenyl, carboxyalkylamino, alkoxycarbonyl, heterocyclylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonylheterocyclyl, alkoxycarbonylheterocyclylcarbonyl, alkoxyalkylamino, alkoxycarbonylaminoalkylamino, and heterocyclylsulfonyl, wherein: :the aryl, heterocyclyl, heterocyclylalkyl, cycloalkyl, and cycloalkenyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, keto, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, aralkyl, heterocyclylalkyl, epoxyalkyl, amino (hydroxyalkyl) carboxy, alkoxy, aryloxy, aralkoxy, haloalkyl, alkylamino, alkynylamino, alkylaminoalkylamino, heterocyclylalkylamino, alkylcarbonyl, alkoxycarbonyl, hydroxyalkylcarbonyl, alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl, R 2corresponds instructure toformula (III): R 30 H 1 H)i C R 3 j~ 1 1 34]Rm3 (III) or 867 R 2 is -CR41R42; R 2 is selected from the group consisting of aryl, heterocyclyl, unsubstituted cycloalkyl, and cycloalkenyl when R 4 is hydrogen; j is an integer from zero to 8; m is selected from the group consisting of zero and 1; R 30 and R 31 are independently selected from the group consisting of hydrogen, alkyl, aryl, heterocyclyl, aralkyl, heterocyclylalkylene, aminoalkyl, alkylaminoalkyl, aminocarbonylalkyl, alkoxyalkyl, and alkylcarbonyloxyalkyl; 32 R32 is selected from the group consisting of hydrogen, alkyl, aralkyl, heterocyclylalkyl, alkoxyalkylene, aryloxyalkylene, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkylcarbonylalkylene, arylcarbonylalkylene, and heterocyclylcarbonylaminoalkylene; R 33 is selected from the group consisting of hydrogen, alkyl, -C(O)R 3 5 -C(O)OR 3 5 -S0 2 R 3 6 -C (O)NRR 3 8 and -S0 2 NR 3 R 40 R 35 R 36 R 37 R 38 R 39 and R 40 are independently selected 20 from the group consisting of hydrocarbon, heterosubstituted hydrocarbon, and heterocyclyl; R' 34 is selected from the group consisting of hydrogen, alkyl, aminocarbonyl, alkylaminocarbonyl, and arylaminocarbonyl; R 41 is aryl; R 42 is hydroxy; R 3 is selected from the group consisting of pyridinyl, pyrimidinyl, quinolinyl, purinyl, 868 N 0 R N 0 and e wherein: the pyridinyl, pyrimidinyl, quinolinyl, and purinyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, aralkyl, aralkenyl, arylheterocyclyl, 5 carboxy, carboxyalkyl, alkoxy, aryloxy, alkylthio, S: arylthio, arylsulfinyl, arylsulfonyl, aralkoxy, heterocyclylalkoxy, amino, alkylamino, alkenylamino, Salkynylamino, cycloalkylamino, cycloalkenylamino, arylamino, heterocyclylamino, aminocarbonyl, cyano, hydroxy, hydroxyalkyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclyloxycarbonyl, alkoxycarbonylamino, alkoxyaralkylamino, alkylaminoalkylamino, hydroxyalkylamino, aralkylamino, heterocyclylalkylamino, aralkylheterocyclylamino, nitro, alkylaminocarbonyl, 15 alkylcarbonylamino, halosulfonyl, aminoalkyl, haloalkyl, alkylcarbonyl, hydrazinyl, alkylhydrazinyl, arylhydrazinyl, and -NR 44 R 45 R 3 is not 2-pyridinyl when R 4 is a phenyl ring containing a 2-hydroxy substituent and when R 1 is hydrogen; R 43 is selected from the group consisting of hydrogen, alkyl, aminoalkyl, alkoxyalkyl, alkenoxyalkyl, and aryloxyalkyl; R 44 is selected from the group consisting of alkylcarbonyl and amino; R 45 is selected from the group consisting of alkyl and aralkyl; 869 R 4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl, wherein: the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, and heterocyclyl are optionally substituted with one or more radicals independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylthio, arylthio, alkylthioalkylene, arylthioalkylene, alkylsulfinylalkylene, arylsulfinylalkylene, alkylsulfonylalkylene, arylsulfonylalkylene, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, cyano, nitro, alkylamino, arylamino, 15 alkylaminoalkylene, arylaminoalkylene, aminoalkylamino, and hydroxyl. 167. A method of treating a p38 kinase mediated disorder in a subject, the method comprising treating a subject having or 20 susceptible to such disorder with a therapeutically effective amount of a compound, a tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein: the compound corresponds in structure to Formula IX: (IX); 870 Z is selected from the group consisting of and R 1 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, and lower alkynyl; R 2 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, and lower alkynyl; R 4 is selected from the group consisting of phenyl and benzodioxolyl, wherein the phenyl is optionally substituted with one or more halo radicals; and I Rs is selected from the group consisting of hydrogen, halo, and alkylhydrazinyl. 168. The method of claim 163, wherein the TNF mediated disorder is selected from the group consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease state, adult respiratory distress syndrome, asthma, chronic pulmonary 20 inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and cachexia. 169. The method of claim 163, wherein the TNF mediated disorder is inflammation. 170. The method of claim 163, wherein the TNF mediated disease is arthritis. 171. The method of claim 163, wherein the TNF mediated -isorder is asthma. 871 172. The method of claim 163, wherein the compound is 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyridine. 173. The method of claim 163, wherein the compound is 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl]-4- methylpiperazine. 174. The method of claim 164, wherein the disorder is a p38a kinase mediated disorder. 175. The method of claim 164, wherein the p38 kinase mediated disorder is selected from the group consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and 20 cachexia. 176. The method of claim 164, wherein the p38 kinase mediated disorder is inflammation. 177. The method of claim 164, wherein the p38 kinase mediated disorder is arthritis. 178. The method of claim 164, wherein the p38 kinase mediated disorder is asthma. 179. The method of claim 167, wherein the disorder is a p38a jkase mediated disorder. 872 180. The method of claim 167, wherein the p38 kinase mediated disorder is selected from the group consisting of bone resorption, graft vs. host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis, topical inflammatory disease state, adult respiratory distress syndrome, asthma, chronic pulmonary inflammatory disease, cardiac reperfusion injury, renal reperfusion injury, thrombus, glomerulonephritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, and cachexia. 181. The method of claim 167, wherein the p38 kinase mediated disorder is inflammation. 182. The method of claim 167, wherein the p38 kinase mediated disorder is arthritis. 183. The method of claim 167, wherein the p38 kinase mediated disorder is asthma. 184. A compound, tautomer or salt of claim 1, substantially as herein described with reference to any one of the Examples. 185. A substituted pyrazole of claim 88, substantially as herein described with reference to any one of the Examples. 186. A pharmaceutical composition of claim 95, substantially as herein described with reference to any one of the Examples. 873 187. The method of any of claims 163 to 167 substantially as herein described with reference to any one of the Examples. Dated this 3rd day of October 2002 G D SEARLE CO By their Patent Attorneys GRIFFITH HACK 00 0 0. S 0 s