Background of the Invention Two classes of effector molecules which are critical for the progression of rheumatoid arthritis are pro-inflammatory cytokines and tissue degrading proteases. Recently, a family of kinases was described which is instrumental in controlling the transcription and translation of the structural genes coding for these effector molecules.

The mitogen-activated protein (MAP) kinase family is made up of a series of structurally related proline-directed serine/threonine kinases which are activated either by growth factors (such as EGF) and phorbol esters (ERK), or by IL-1, TNFa or stress (p38, JNK). The MAP kinases are responsible for the activation of a wide variety of transcription factors and proteins involved in transcriptional control of cytokine production. A pair of novel protein kinases involved in the regulation of cytokine synthesis was recently described by a group from SmithKline Beecham (Lee et al. Nature 1994,372,739). These enzymes were isolated based on their affinity to bond to a class of compounds, named CSAIDSs (cytokine suppressive anti- inflammatory drugs) by SKB. The CSAIDs, bicyclic pyridinyl imidazoles, have been shown to have cytokine inhibitory activity both in vitro and in vivo. The isolated enzymes, CSBP-1 and-2 (CSAID binding protein 1 and 2) have been cloned and expressed. A murine homologue for CSBP-2, p38, has also been reported (Han et al.

Science 1994,265,808).

Early studies suggested that CSAIDs function by interfering with m-RNA translational events during cytokine biosynthesis. Inhibition of p38 has been shown to inhibit both cytokine production (eg., TNFa, IL-1, IL-6, IL-8) and proteolytic enzyme production (eg., MMP-1, MMP-3) in vitro and/or in vivo.

Clinical studies have linked TNFa production and/or signaling to a number of diseases including rheumatoid arthritis (Maini. J. Royal Coll. Physicians London 1996,30,344). In addition, excessive levels of TNFa have been implicated in a wide variety of inflammatory and/or immunomodulatory diseases, including acute rheumatic fever (Yegin et al. Lancet bone resorption (Pacifici et al.

J. Clin. Endocrinol. Metabol. postmenopausal osteoperosis (Pacifici et al. J. Bone Mineral Res. 1996, ll, 1043), sepsis (Blackwell et al. Br. J. Anaesth.

1996,77,110), gram negative sepsis (Debets et al. Prog. Clin. Biol. Res. 1989,308, 463), septic shock (Tracey et al. Nature 1987,330,662; Girardin et al. New England J. Med. endotoxic shock (Beutler et al. Science 1985,229,869; Ashkenasi et al. Proc. Net'1. Acad. Sci. USA toxic shock syndrome, (Saha et al. J. Immunol. Lina et al. FEMS Immunol. Med. Microbiol. systemic inflammatory response syndrome (Anon. Crit. Care Med.

1992,20,864), inflammatory bowel diseases (Stokkers et al. J. Inflamm. 1995-6,47, 97) including Crohn's disease (van Deventer et al. Aliment. Pharmacol. Therapeu.

1996,10 (Suppl. 2), 107; van Dullemen et al. Gastroenterology and ulcerative colitis (Masuda et al. J. Clin. Lab. Immunol. Jarisch- Herxheimer reactions (Fekade et al. New England J. Med. asthma (Amrani et al. Rev. Malad. Respir. adult respiratory distress syndrome (Roten et al. Am. Rev. Respir. Dis. Suter et al. Am. Rev. Respir. Dis. acute pulmonary fibrotic diseases (Pan et al. Pathol. Int. 1996,46, 91), pulmonary sarcoidosis (Ishioka et al. Sarcoidosis Vasculitis Diffuse Lung Dis. allergic respiratory diseases (Casale et al. Am. J. Respir. Cell Mol.

Biol. silicosis (Gossart et al. J. Immunol. Vanhee et al. Eur. Respir. J. coal worker's pneumoconiosis (Borm et al. Am. Rev.

Respir. Dis. alveolar injury (Horinouchi et al. Am. J. Respir. Cell Mol. Biol. hepatic failure (Gantner et al. J. Pharmacol. Exp. Therap.

liver disease during acute inflammation (Kim et al. J. Biol. Chem.

1997,272,1402), severe alcoholic hepatitis (Bird et al. Ann. Intern. Med. 1990,112, 917), malaria (Grau et al. Immunol. Rev. Taverne et al. Parasitol.

Today including Plasmodium falciparum malaria (Perlmann et al.

Infect. Immunit. and cerebral malaria (Rudin et al. Am. J. Pathol. non-insulin-dependent diabetes mellitus (NIDDM; Stephens et al. J.

Biol. Chem. 1997,272,971; Ofei et al. Diabetes congestive heart failure (Doyama et al. Int. J. Cardiol. McMurray et al. Br. Heart J.

1991,66,356), damage following heart disease (Malkiel et al. Mol. Med. Today 1996, 2,336), atherosclerosis (Parums et al. J. Pathol. 1996,179, A46), Alzheimer's disease (Fagarasan et al. Brain Res. 1996,723,231; Aisen et al. Gerontology 1997, 43,143), acute encephalitis (Ichiyama et al. J. NeuroL brain injury (Cannon et al. Crit. Care Med. 1992,20,1414; Hansbrough et al. Surg. Clin. N. Am.

1987,67,69; Marano et al. Surg. Gynecol. Obstetr. multiple sclerosis (M. S.; Coyle. Adv. Neuroimmunol. 1996,6,143; Matusevicius et al. J.

Neuroimmunol. 1996,66,115) including demyelation and oligiodendrocyte loss in multiple sclerosis (Brosnan et al. Brain Pathol. 1996,6,243), advanced cancer (MucWierzgon et al. J. Biol. Regulators Homeostatic Agents 1996, 10,25), lymphoid malignancies (Levy et al. Crit. Rev. Immunol. pancreatitis (Exley et al.

Gut 1992,33,1126) including systemic complications in acute pancreatitis (McKay et al. Br. J. Surg. impaired wound healing in infection inflammation and cancer (Buck et al. Am. J. Pathol. myelodysplastic syndromes (Raza et al. Int. J. Hematol. 1996,63,265), systemic lupus erythematosus (Maury et al. Arthritis Rheum. 1989,32,146), biliary cirrhosis (Miller et al. Am. J.

Gasteroenterolog. bowel necrosis (Sun et al. J. Clin. Invest. 1988,81, 1328), psoriasis (Christophers. Austr. J. Dermatol. 1996,37, S4), radiation injury (Redlich et al. J. Immunol. and toxicity following administration of monoclonal antibodies such as OKT3 (Brod et al. Neurology TNFa levels have also been related to host-versus-graft reactions (Piguet et al. Immunol.

Ser. including ischemia reperfusion injury (Colletti et al. J. Clin.

Invest. and allograft rejections including those of the kidney (Maury et al. J. Exp. Med. liver (Imagawa et al. Transplantation 1990,50, 219), heart (Bolling et al. Transplantation and skin (Stevens et al.

Transplant. Proc. 1990,22,1924), lung allograft rejection (Grossman et al. Immunol. Allergy Clin. N. Am. 1989,9,153) including chronic lung allograft rejection (obliterative bronchitis; LoCicero et al. J. Thorac. Cardiovasc. Surg 1990,99,1059), as well as complications due to total hip replacement (Cirino et al. Life Sci. 1996, 59, 86). TNFa has also been linked to infectious diseases (review: Beutler et al. Crit.

Care Med. Degre. Biotherapy including tuberculosis (Rook et al. Med. Malad. Infect. 1996,26,904), Helicobacter pylori infection during peptic ulcer disease (Beales et al. Gastroenterology Chaga's disease resulting from Trypanosoma cruzi infection (Chandrasekar et al. Biochem. Biophys.

Res. Commun. 1996,223,365), effects of Shiga-like toxin resulting from E. coli infection (Harel et al. J. Clin. Invest. the effects of enterotoxin A resulting from Staphylococcus infection (Fischer et al. J. Immunol. 1990,144,4663), meningococcal infection (Waage et al. Lancet 1987,355; Ossege et al. J. Neurolog.

Sci. and infections from Borrelia burgdorferi (Brandt et al. Infect.

Immunol. Treponema pallidum (Chamberlin et al. Infect. Immunol. cytomegalovirus (CMV; Geist et al. Am. J. Respir. Cell Mol. Biol. influenza virus (Beutler et al. Clin. Res. Sendai virus (Goldfield et al. Proc. Nat'l. Acad. Sci. USA Theiler's encephalomyelitis virus (Sierra et al. Immunology and the human immunodeficiency virus (HIV; Poli. Proc. Nat'l. Acad. Sci. USA ; Vyakaram et al. AIDS Badley et al. J. Exp. Med. 1997,185,55).

Because inhibition of p38 leads to inhibition of TNFa production, p38 inhibitors will be useful in treatment of the above listed diseases.

A number of diseases are thought to be mediated by excess or undesired matrix- destroying metalloprotease (MMP) activity or by an imbalance in the ratio of the MMPs to the tissue inhibitors of metalloproteinases (TIMPs). These include osteoarthritis (Woessner et al. J. Biol. Chem. rheumatoid arthritis (Mullins et al. Biochim. Biophys. Acta Woolley et al. Arthritis Rheum. 1977,20,1231; Gravallese et al. Arthritis Rheum. 1991,34,1076), septic arthritis (Williams et al. Arthritis Rheum. 1990,33,533), tumor metastasis (Reich et al. Cancer Res. 1988, 48,3307; Matrisian et al. Proc. Nat7. Acad Sci., USA 1986,83,

9413), periodontal diseases (Overall et al. J. Periodontal Res. 1987, 22,81), corneal ulceration (Burns et al. Invest. Opthalmol. Vis. Sci. 1989,30,1569), proteinuria (Baricos et al. Biochem. J. coronary thrombosis from atherosclerotic plaque rupture (Henney et al. Proc. Nat'l. Acad. Sci., USA 1991,88,8154), aneurysmal aortic disease (Vine et al. Clin. Sci. birth control (Woessner et al. Steroids dystrophobic epidermolysis bullosa (Kronberger et al. J. Invest. Dermatol. 1982,79,208), degenerative cartilage loss following traumatic joint injury, osteopenias mediated by MMP activity, tempero mandibular joint disease, and demyelating diseases of the nervous system (Chantry et al. J. Neurochem. 1988,50,688).

Because inhibition of p38 leads to inhibition of MMP production, p38 inhibitors will be useful in treatment of the above listed diseases.

Inhibitors of p38 are active in animal models of TNFa production, including a muirne lipopolysaccharide (LPS) model of TNFa production. Inhibitors of p38 are active in a number of standard animal models of inflammatory diseases, including carrageenan- induced edema in the rat paw, arachadonic acid-induced edema in the rat paw, arachadonic acid-induced peritonitis in the mouse, fetal rat long bone resorption, murine type II collagen-induced arthritis, and Fruend's adjuvant-induced arthritis in the rat. Thus, inhibitors of p38 will be useful in treating diseases mediated by one or more of the above-mentioned cytokines and/or proteolytic enzymes.

The need for new therapies is especially important in the case of arthritic diseases.

The primary disabling effect of osteoarthritis, rheumatoid arthritis and septic arthritis is the progressive loss of articular cartilage and thereby normal joint function. No marketed pharmaceutical agent is able to prevent or slow this cartilage loss, although nonsteroidal antiinflammatory drugs (NSAIDs) have been given to control pain and swelling. The end result of these diseases is total loss of joint function which is only treatable by joint replacement surgery. P38 inhibitors will halt or reverse the progression of cartilage loss and obviate or delay surgical intervention.

Several patents have appeared claiming polyarylimidazoles and/or compounds containing polyarylimidazoles as inhibitors of p38 (for example, Lee et al. WO 95/07922; Adams et al. WO 95/02591; Adams et al. WO 95/13067; Adams et al. WO 95/31451). It has been reported that arylimidazoles complex to the ferric form of cytochrome P450cam (Harris et al. Mol. Eng. and references therein), causing concern that these compounds may display structure-related toxicity (Howard-Martin et al. Toxicol. Pathol. Therefore, there remains a need for improved p38 inhibitors.

Summarv of the Invention This invention provides compounds, generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit p38 mediated events and thus inhibit the production of cytokines (such as TNFa, IL-1 and IL-8) and proteolytic enzymes (such as MMP-1 and MMP-3). The invention also provides a method of treating a cytokine mediated disease state in humans or mammals, wherein the cytokine is one whose production is affected by p38. Examples of such cytokines include, but are not limited to TNFa, IL-1 and IL-8. The invention also provides a method of treating a protease mediated disease state in humans or mammals, wherein the protease is one whose production is affected by p38. Examples of such proteases include, but are not limited to collagenase (MMP-1) and stromelysin (MMP-3).

Accordingly, these compounds are useful therapeutic agents for such acute and chronic inflammatory and/or immunomodulatory diseases as rheumatoid arthritis, osteoarthritis, septic arthritis, rheumatic fever, bone resorption, postmenopausal osteoperosis, sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory response syndrome, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, Jarisch-Herxheimer reactions, asthma, adult respiratory distress syndrome, acute pulmonary fibrotic diseases, pulmonary sarcoidosis, allergic respiratory diseases, silicosis, coal worker's pneumoconiosis, alveolar injury, hepatic failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria including Plasmodium falciparum malaria and cerebral malaria, non-insulin-dependent diabetes mellitus (NIDDM), congestive heart failure, damage following heart disease, atherosclerosis, Alzheimer's

disease, acute encephalitis, brain injury, multiple sclerosis including demyelation and oligiodendrocyte loss in multiple sclerosis, advanced cancer, lymphoid malignancies, tumor metastasis, pancreatitis, including systemic complications in acute pancreatitis, impaire wound healing in infection, inflammation and cancer, periodontal diseases, corneal ulceration, proteinuria, myelodysplastic syndromes, systemic lupus erythematosus, biliary cirrhosis, bowel necrosis, psoriasis, radiation injury, toxicity following administration of monoclonal antibodies such as OKT3, host-versus-graft reactions including ischemia reperfusion injury and allograft rejections including kidney, liver, heart, and skin allograft rejections, lung allograft rejection including chronic lung allograft rejection (obliterative bronchitis) as well as complications due to total hip replacement, and infectious diseases including tuberculosis, Helicobacter pylori infection during peptic ulcer disease, Chaga's disease resulting from Trypanosoma cruzi infection, effects of Shiga-like toxin resulting from E. coli infection, effects of enterotoxin A resulting from Staphylococcus infection, meningococcal infection, and infections from Borrelia burgdorferi, Treponema pallidum, cytomegalovirus, influenza virus, Theiler's encephalomyelitis virus, and the human immunodeficiency virus (HIV).

Accordingly, the present invention is directed to a method for the treatment of diseases mediated by one or more cytokine or proteolytic enzyme produced and/or activated by a p38 mediated process, comprising administering a compound of formula I wherein B is generally an unsubstituted or substituted, up to tricyclic, aryl or heteroaryl moiety with up to 30 carbon atoms with at least one 5 or 6 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur. A is a heteroaryl moiety discussed in more detail below.

The aryl and heteroaryl moiety of B may contain separate cyclic structures and can include a combination of aryl, heteroaryl and cycloalkyl structures. The substituents for these aryl and heteroaryl moieties can vary widely and include halogen, hydrogen, hydrosulfide, cyano, nitro, amines and various carbon-based moieties, including those

which contain one or more of sulfur, nitrogen, oxygen and/or halogen and are discussed more particularly below.

Suitable aryl and heteroaryl moieties for B of formula I include, but are not limited to aromatic ring structures containing 4-30 carbon atoms and 1-3 rings, at least one of which is a 5-6 member aromatic ring. One or more of these rings may have 1-4 carbon atoms replaced by oxygen, nitrogen and/or sulfur atoms.

Examples of suitable aromatic ring structures include phenyl, pyridinyl, naphthyl, pyrimidinyl, benzothiazolyl, quinoline, isoquinoline, phthalimidinyl and combinations thereof, such as diphenyl ether (phenyloxyphenyl), diphenyl thioether (phenylthiophenyl), diphenyl amine (phenylaminophenyl), phenylpyridinyl ether (pyridinyloxyphenyl), pyridinylmethylphenyl, phenylpyridinyl thioether (pyridinylthiophenyl), phenylbenzothiazolyl ether (benzothiazolyloxyphenyl), phenylbenzothiazolyl thioether (benzothiazolylthiophenyl), phenylpyrimidinyl ether, phenylquinoline thioether, phenylnaphthyl ether, pyridinylnapthyl ether, pyridinylnaphthyl thioether, and phenylphthalimidylmethyl.

Examples of suitable heteroaryl groups include, but are not limited to, 5-12 carbon- atom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, e. g., 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms. Each ring typically has 3-7 atoms.

For example, B can be 2-or 3-furyl, 2-or 3-thienyl, 2-or 4-triazinyl, 1-, 2-or 3- pyrrolyl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, 1,2,3-triazol-l-,-4-or-5-yl, 1,2,4-triazol-1-,-3-or-5-yl, 1-or 5- tetrazolyl, 1,2,3-oxadiazol-4- or-5-yl, 1,2,4-oxadiazol-3- or-5-yl, 1,3,4-thiadiazol-2- or-5-yl, 1,2,4-oxadiazol-3- or-5-yl, 1,3,4-thiadiazol-2- or-5-yl, 1,3,4-thiadiazol-3- or-5-yl, 1,2,3-thiadiazol-4- or-5-yl, 2-, 3-, 4-, 5-or 6-2H-thiopyranyl, 2-, 3-or 4- 4H-thiopyranyl, 3-or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6-or 7-benzofuryl, 2-, 3-, 4-, 5-, 6-or 7.-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 1-, 2-, 4-or 5- benzimidazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-6-or 7-benzisoxazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 2-, 4-, 5-, 6-or 7-ben-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-

quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-isoquinolinyl, 1-, 2-, 3-, 4-or 9-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridinyl, or 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, or additionally optionally substituted phenyl, 2-or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or 5-thiazolyl, etc. For example, B can be 4-methyl-phenyl, 5-methyl-2- thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyrryl, 1-methyl-3-pyrazolyl, 5-methyl-2- thiazolyl or 5-methyl-1,2,4-thiadiazol-2-yl.

Suitable alkyl groups and alkyl portions of groups, e. g., alkoxy, etc. throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.

Suitable aryl groups include, for example, phenyl and 1-and 2-naphthyl.

Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclohexyl, etc. The term "cycloalkyl", as used herein, refers to cyclic structures with or without alkyl substituents such that, for example,"C4 cycloalkyl"includes methyl substituted cyclopropyl groups as well as cyclobutyl groups. The term"cycloalkyl"also includes saturated heterocyclic groups.

Suitable halogens include F, Cl, Br, and/or I, from one to persubstitution (i. e., all H atoms on the group are replaced by halogen atom), being possible, mixed substitution of halogen atom types also being possible on a given moiety.

As indicated above, these ring systems can be unsubstituted or substituted by substituents such as halogen up to per-halosubstitution. Other suitable substituents for the moieties of B include alkyl, alkoxy, carboxy, cycloalkyl, aryl, heteroaryl, cyano, hydroxy and amine. These other substituents, generally referred to as X and X' herein, include-CN,-C02R5,-C (O) NR5R5,-C (O) R5, -NO2, -OR5, -SR5, -NR5R5', -NR5C (O) oR5,-NR5C (O) R5, C1-Cio alkyl, C2-Clo alkenyl, C1-C10 alkoxy, C3-Cso cycloalkyl, C6-Ci4 aryl, C7-C24 alkaryl, C3-CI3 heteroaryl, C4-C23 alkheteroaryl, substituted Cl-Clo alkyl, substituted C2-Cio alkenyl, substituted Cl-Clo alkoxy, substituted C3-Cio cycloalkyl, substituted C4-C23 alkheteroaryl and-Y-Ar.

Where a substituent, X or X', is a substituted group, it is preferably substituted by one or more substituents independently selected from the group consisting of-CN, -C02R5,-C (O) R5,-C (O) NR5R5', -OR5, -SR5, -NR5R5', -NO2, -NR5C (O) R5,

-NR5C(O)OR5' and halogen up to per-halo substitution.

The moieties Rs and R5' are preferably independently selected from H, Cl-Clo alkyl, C3-C10cycloalkyl,C6-C14aryl,C3-C13heteroaryl,C7-C24alkaryl,C 4-C2-C10alkenyl, C23 alkheteroaryl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C- __ alkenyl; up to per-halosubstituted C3-Clo cycloalkyl, up to per-halosubstituted C6- C14 aryl and up to per-halosubstituted C3-Cl3 heteroaryl.

The bridging group Y is preferably-O-,-S-,-N (R5)-, -(CH2)-m, -C(O)-, -C(O)NR5,-CH(OH)-,-(CH2)mO-,-(CH2)mS-,-NR5C(O)NR5R5',-NR5C(O )-, -(CH2)mN(R5)-, -O (CH2) m,-CHXa,-CXa2-,-S- (CH2) m- and-N (R5) (CH2) m-, where m = 1-3, and Xa is halogen.

The moiety Ar is preferably a 5-10 member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur which is unsubstituted or substituted by halogen up to per-halosubstitution and optionally substituted by Znt, wherein nl is 0 to 3.

Each Z substituent is preferably independently selected from the group consisting of =O,-C(O)NR5R5',-C(O)-NR5,-NO2,-OR5,-SR5,-NR5R5',-CN,-CO2R5, -NR5C(O)R5',-SO2R5,-SO2NR5R5',C1-C10,alkyl,C1-C10-NR5C(O)OR5 ',-C(O)R5, alkoxy, C3-C10 cycloalkyl, C6-Cl4 aryl, C3-C13 heteroaryl, C7-C24 alkaryl, C4-C23 alkheteroaryl, substituted Cl-Cl0 alkyl, substituted C3-C10 cycloalkyl, substituted C7- C24 alkaryl and substituted C4-C23 alkheteroaryl. If Z is a substituted group, it is substituted by the one or more substituents independently selected from the group consisting of-CN,-C02R5,-C (O) NR5R5', =O, -OR5, -SR5, -NO2, -NR5R5', -NR5C(O)R5', -NR5C(O)OR5', C1-C10 alkyl, C1-C10 alkoxy, C3-Clo cycloalkyl, C-CIo heteroaryl, C6-CI4 aryl, C4-C24 alkheteroaryl and C7-C24 alkaryl. The aryl and heteroaryl moieties of B of Formula I are preferably selected from the group consisting of

which are unsubstituted or substituted by halogen, up to per-halosubstitution. X is as defined above and n = 0-3.

The aryl and heteroaryl moieties of B are more preferably of the formula II: wherein Y is selected from the group consisting of-0-,-S-,-CH2-,-SCH2-,-CH2S-, -CH (OH)-,-C (O)-,-CXa2,-CXaH-,-CH20-and-OCH2-and Xa is halogen.

Q is a six member aromatic structure containing 0-2 nitrogen, substituted or unsubstituted by halogen, up to per-halosubstitution and Ql is a mono-or bicyclic aromatic structure of 3 to 10 carbon atoms and 0-4 members of the group consisting of N, O and S, unsubstituted or unsubstituted by halogen up to per-halosubstitution.

X, Z, n and nl are as defined above and s = 0 or 1.

In preferred embodiments, Q is phenyl or pyridinyl, substituted or unsubstituted by halogen, up to per-halosubstitution and Ql is selected from the group consisting of

phenyl, pyridinyl, naphthyl, pyrimidinyl, quinoline, isoquinoline, imidazole and benzothiazolyl, substituted or unsubstituted by halogen, up to per-halo substitution, or -Y-Ql is phthalimidinyl substituted or unsubstituted by halogen up to per-halo substitution. Z and X are preferably independently selected from the group consisting of -R6, -OR6 and -NHR7, wherein R6 is hydrogen, Cl-Clo-alkyl or C3-Clo-cycloalkyl and R7 is preferably selected from the group consisting of hydrogen, C3-Clo-alkyl, C3- C6-cycloalkyl and C6-Clo-aryl, wherein R6 and R7 can be substituted by halogen or up to per-halosubstitution.

The heteroaryl moiety A of formula I is preferably selected from the group consisting of : The substituent R'preferably is selected from the group consisting of halogen, C3-Cio alkyl, Cl-C13 heteroaryl, C6-Cl4 aryl, C7-C24 alkylaryl, C3-C10 cycloalkyl, up to per- halosubstituted Cl-Clo alkyl and up to per-halosubstituted C3-Clo cycloalkyl, up to per-halosubstituted Cl-C13 hetero, up to per-halosubstituted C6-Cl3 aryl and up to per- halosubstituted C7-C24 alkaryl.

The substituent R2 is preferably selected from the group consisting of H,-C (O) R4, C1-C10alkyl,C3-C10cycloalkyl,C7-C24alkaryl,C4-C23-CO2R4,-C(O )NR3R3', alkheteroaryl, substituted Cl-calo alkyl, substituted C3-Clo cycloalkyl, substituted C7- C24 alkaryl and substituted C4-C23 alkheteroaryl. Where R2 is a substituted group, it is preferably substituted by one or more substituents independently selected from the group consisting of-CN,-C02R4,-C (O)-NR3R3,-N02,-OR4,-SR4, and halogen up to per-halosubstitution.

R3 and R3 are preferably independently selected from the group consisting of H, -NR4R4',-C(O)R4,-CO2R4,-C(O)NR4R4',C1-C10alkyl,C3-C10cycloal kyl,-OR4,-SR4, C6-Ci4 4 aryl, C3-C13 heteroaryl, C7-C24 alkaryl, C4-C23 alkheteroaryl, up to per- halosubstituted Cl-Clo alkyl, up to per-halosubstituted C3-CIo cycloalkyl, up to per- halosubstituted C6-Cl4 aryl and up to per-halosubstituted C3-Cl3 heteroaryl.

R4 and R4 are preferably independently selected from the group consisting of H, C,- C10 alkyl, C3-C10 cycloalkyl, C6-C14 aryl, C3-C13 heteroaryl; C7-C24 alkaryl, C4-C23 alkheteroaryl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C3-Cio cycloalkyl, up to per-halosubstituted C6-C14 aryl and up to per-halosubstituted C3-C13 heteroaryl.

Ra is preferably Cl-calo alkyl, C3-Clo cycloalkyl, up to per-halosubstituted C1-C10 alkyl and up to per-halosubstituted C3-CIO cycloalkyl.

Rb is preferably hydrogen or halogen.

Rc is hydrogen, halogen, C-Clo alkyl, up to per-halosubstituted Cl-Cl0 alkyl or combines with R1 and the ring carbon atoms to which R'and R'are bound to form a 5-or 6-membered cycloalkyl, aryl or heteroaryl ring with 0-2 members selected from andS.O,N Preferred pyrazolyl ureas include those wherein B is 2,3-dichlorophenyl or of the formula II above, wherein Q is phenyl, Q'is phenyl or pyridinyl, Y ix-0-,-S-,-CH2 or-SCH2, X is CF3, Z is OH, Cl or-NHC (O)-CpH2p+l, wherein p = 2-4, s = 0 or 1, n = 0 or 1 and nl = 0 or 1. Particular preferred pyrazolyl ureas include: N (3-tert-Butyl-5-pyrazolyl)-N'- (4- (2,3-dichlorophenyl) urea; N-(3-tert-Butyl-5-pyrazolyl)-N'-(3-(4-pyridinyl) thiophenyl) urea; N-(3-tert-Butyl-5-pyrazolyl)-N'-(4-(4-pyridinyl) methylphenyl) urea; N-(3-tert-Butyl-5-pyrazolyl)-N'- (4- (4-pyridinyl)(3-tert-Butyl-5-pyrazolyl)-N'- (4- (4-pyridinyl) oxyphenyl) urea; N-(3-tert-Butyl-5-pyrazolyl)-N'-(4-(4-pyridinyl) thiophenyl) urea; N-(3-tert-Butyl-5-pyrazolyl)-N'-(4-(4-pyridinyl) methylphenyl) urea; N (1-Methyl-3-tert-butyl-5-pyrazolyl)-N'- (2,3-dichlorophenyl) urea;

N (1-Methyl-3-tert-butyl-5-pyrazolyl)-N'- (4- (4-hydroxyphenyl)- thiophenyl) urea; N (1-Methyl-3-tert-butyl-5-pyrazolyl)-N'- (4- (4-ethylaminocarbonylphenyl)- oxyphenyl) urea; N (1-Methyl-3-tert-butyl-5-pyrazolyl)-N'- (4- (4-isobutylaminocarbonyl- phenyl)-thiophenyl) urea; N (1-Methyl-3-tert-butyl-5-pyrazolyl)-N'- (4- (4-pyridinyl) thiophenyl) urea; N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N'- (3- (4-pyridinyl)(1-Methyl-3-tert-butyl-5-pyrazolyl)-N'- (3- (4-pyridinyl) thiophenyl) urea; N (1-Methyl-3-tert-butyl-5-pyrazolyl)-N'- (4- (4-pyridinyl) thio-3- (trifluoromethyl)-phenyl) urea; N (1-Methyl-3-tert-butyl-5-pyrazolyl)-N'- (4- (4-pyridinyl) oxyphenyl) urea; N-(1-Methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-((4-pyndinyl)(1- Methyl-3-tert-butyl-5-pyrazolyl)-N'-(4-((4-pyndinyl) methylthio)- phenyl) urea; N-(1-(2,2,2-Trifluoroethyl)-3-tert-butyl-5-pyrazolyl)-N'-(2, 3-dichloro- phenyl) urea; N-(1-(2-Hydroxyethyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,(1-(2- Hydroxyethyl)-3-tert-butyl-5-pyrazolyl)-N'-(2, 3-dichlorophenyl) urea; N-(1-Ethoxycarbonylmethyl-3-tert-butyl-5-pyrazolyl)-N'-(2,(1 -Ethoxycarbonylmethyl-3-tert-butyl-5-pyrazolyl)-N'-(2, 3-dichloro- phenyl) urea; N-(1-(2-Cyanoethyl)-3-tert-butyl-5-pyrazolyl)-N'-(2,(1-(2-Cy anoethyl)-3-tert-butyl-5-pyrazolyl)-N'-(2, 3-dichlorophenyl) urea; N (1- (3-Hydroxyphenyl) methyl-3-tert-butyl-5-pyrazolyl)-N'- (2,3- dichlorophenyl)-urea; N- (l-Cyclohexyl-3-tert-butyl-5-pyrazolyl)-n'- (4- (4-pyridinyl) methyl- phenyl) urea; N (1-methyl3-phenyl-5-pyrazolyl)-N'- (3- (4- (2-methylcarbamoyl) pyridyl)- thiophenyl) urea; N (l-methyl-3-tert-butyl-5-pyrazolyl)-N'- (4- (4-pyridyl) thiophenyl) urea; N (l-methyl-3-tert-butyl-5-pyrazolyl)-N'- (3- (4-pyridyl) thiophenyl) urea; N (1-methyl-3-tert-butyl-5-pyrazolyl)-N'- (3-trifluoromethyl-4- (4- pyridylthio) phenyl) urea; N-(3-tert-butyl-5-pyrazolyl)-N'- (3- (4-pyridyl)(3-tert-butyl-5-pyrazolyl)-N'- (3- (4-pyridyl) oxyphenyl) urea; and N-(3-tert-butyl-5-pyrazolyl)-N'- (4- (4-pyridyl)(3-tert-butyl-5-pyrazolyl)-N'- (4- (4-pyridyl) oxyphenyl) urea.

Preferred 5,3-isoxazolyl ureas wherein B is of the formula II above, wherein Q is phenyl, Ql is phenyl or pyridinyl, Y is-0-,-S-,-CH2, X is CF3, Z is OH, CF3 or

-OCpH2p+1, wherein p = 2-6, or-C (O)-NH-CH3, s = 1, n = 0 or 1, and n is 0 or 1.

Particular preferred 5,3-isoxazolyl ureas include: N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-hydroxyphenyl) oxyphenyl) urea; N-(S-tert-Butyl-3-isoxazolyl)-N'- (4- (4-isopropoxyphenyl)(S-tert-Butyl-3-isoxazolyl)-N'- (4- (4-isopropoxyphenyl) oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-isobutoxyphenyl)(5-te rt-Butyl-3-isoxazolyl)-N'-(4-(4-isobutoxyphenyl) oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-pentyloxyphenyl)(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-pentyloxyphenyl) oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(4-methylaminocarbonylph enyl)- oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'- (3- (4-pyridinyl)(5-tert-Butyl-3-isoxazolyl)-N'- (3- (4-pyridinyl) thiophenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'- (3- (4-pyridinyl)(5-tert-Butyl-3-isoxazolyl)-N'- (3- (4-pyridinyl) oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-pyridinyl)(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-pyridinyl) oxyphenyl) urea; N- (5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-pyridinyl) thiophenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-pyridinyl)(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-pyridinyl) methylphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-pyridinyl) thio-3- (trifluoromethyl)- phenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'- (3- (3-methyl-4-pyridinyl)(5-tert-Butyl-3-isoxazolyl)-N'- (3- (3-methyl-4-pyridinyl) thiophenyl) urea; N-(S-tert-Butyl-3-isoxazolyl)-N'- (3- (3-methyl-4-pyridinyl)(S-tert-Butyl-3-isoxazolyl)-N'- (3- (3-methyl-4-pyridinyl) oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'- (4- (3-methyl-4-pyridinyl)(5-tert-Butyl-3-isoxazolyl)-N'- (4- (3-methyl-4-pyridinyl) oxyphenyl) urea; N-(5-tert-Butyl-3-isoxazolyl)-N'-(4-(3-methyl-4-pyridinyl) thiophenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'- (4- (4- (2-methylcarbamoyl)(5-tert-butyl-3-isoxazolyl)-N'- (4- (4- (2-methylcarbamoyl) pyridyl)- oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-(3-(4-(2-methylcarbamoyl)py ridyl)- oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'- (4- (4- (2-carbamoyl) pyridyl)(5-tert-butyl-3-isoxazolyl)-N'- (4- (4- (2-carbamoyl) pyridyl) oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'- (3- (4- (2-carbamoyl)(5-tert-butyl-3-isoxazolyl)-N'- (3- (4- (2-carbamoyl) pyridyl) oxyphenyl) urea; N-(5-tert-butyl-3-isoxazolyl)-N'-(3-((4-pyridyl)(5-tert-buty l-3-isoxazolyl)-N'-(3-((4-pyridyl) fluoromethyl) phenyl) urea; and N-(5-tert-butyl-3-isoxazolyl)-N'-(3-((4-pyridyl)oxomethyl)ph enyl)urea.

Preferred 3,5-isoxazolyl ureas include those wherein B is 2,3-dichlorophenyl or of the formula 11 above, wherein Q is phenyl, Ql is phenyl, pyridinyl or benzothiazolyl,

Y is-0-,-S-,-NH-or CH2, Z is Cl,-CH3-or-OCH3, s = 0 or 1, n = 0 and nl is 0 or 1. Particular preferred 3,5-isoxazolyl ureas include: N-(3-Isopropyl-5-isoxazolyl)-N'- (3- (4-pyridinyl)(3-Isopropyl-5-isoxazolyl)-N'- (3- (4-pyridinyl) thiophenyl) urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(2,(3-tert-Butyl-5-isoxazol yl)-N'-(2, 3-dichlorophenyl) urea; N-(3-tert-Butyl-5-isoxazolyl)-N'- (4- (4-methoxyphenyl)(3-tert-Butyl-5-isoxazolyl)-N'- (4- (4-methoxyphenyl) aminophenyl) urea; N-(3-tert-Butyl-5-isoxazolyl)-N'- (4- (4-methoxyphenyl)(3-tert-Butyl-5-isoxazolyl)-N'- (4- (4-methoxyphenyl) oxyphenyl) urea; N-(3-tert-Butyl-5-isoxazolyl)-N'-(4-(4-pyridinyl) oxyphenyl) urea; N-(3-tert-Butyl-5-isoxazolyl)-N'- (4- (4-pyridinyl)(3-tert-Butyl-5-isoxazolyl)-N'- (4- (4-pyridinyl) thiophenyl) urea; N-(3-tert-Butyl-5-isoxazolyl)-N'- (4- (4-pyridinyl)(3-tert-Butyl-5-isoxazolyl)-N'- (4- (4-pyridinyl) methylphenyl) urea; N- (3- (1, 1-Dimethylpropyl)-5-isoxazolyl)-N'- (4- (4-pyridinyl) methyl- phenyl) urea; N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N'-(3-(4-pyridinyl) thiophenyl) urea; N-(3-(1,1-Dimethylpropyl)-5-isoxazolyl)-N'-(4-(2-benzothiazo lyl)oxy- phenyl) urea; N-(3- (1-Methyl-1-ethylpropyl)-5-isoxazolyl)-N'- (4- (4-pyridinyl)- oxyphenyl) urea; N-(3- (l-Methyl-1-ethylpropyl)-5-isoxazolyl)-N'- (4- (4- pyridinyl) methyl-phenyl) urea; N-(3-cyclobutylyl-5-isoxazolyl)-N'- (4- (4-pyridyl)(3-cyclobutylyl-5-isoxazolyl)-N'- (4- (4-pyridyl) oxyphenyl) urea; N-(3-tert-butyl-5-isoxazolyl)-N'- (4- (4-pyridyl)(3-tert-butyl-5-isoxazolyl)-N'- (4- (4-pyridyl) thiophenyl) urea; N-(3- (1-methyl-1-ethylprop-1-yl)-5-isoxazolyl)-N'- (4- (4-pyridyl) oxyphenyl) urea; N-(3-tert-butyl-5-isoxazolyl)-N'- (4- (4-pyridyl)(3-tert-butyl-5-isoxazolyl)-N'- (4- (4-pyridyl) methylphenyl) urea; and N-(3-tert-butyl-5-isoxazolyl)-N'- (4- (4-methoxyphenyl) aminophenyl)(3-tert-butyl-5-isoxazolyl)-N'- (4- (4-methoxyphenyl) aminophenyl) urea.

Preferred thienyl ureas, furyl ureas and thiadiazolyl ureas include those wherein B is 2,3-dichlorophenyl of the formula II above, wherein Q is phenyl, Ql is phenyl or pyridinyl, Y is-0-,-S-or-CH2-, Z = CH3, OH, Cl,-O-C2H4 or-0-C3H7, s = 0 or 1, n = 0 and nl = 0 or 1. Preferred thienyl ureas include: N (2-Bromo-5-tert-butyl-3-thienyl)-N'- (4-methylphenyl)urea; N-(5-tert-Butyl-3-thienyl)-N'- (2,(5-tert-Butyl-3-thienyl)-N'- (2, 3-dichlorophenyl) urea; N-(5-tert-Butyl-3-thienyl)-N'- (4- (4-hydroxyphenyl)(5-tert-Butyl-3-thienyl)-N'- (4- (4-hydroxyphenyl) oxyphenyl) urea; N-(5-tert-Butyl-3-thienyl)-N'- (4- (4-ethoxyphenyl)(5-tert-Butyl-3-thienyl)-N'- (4- (4-ethoxyphenyl) oxyphenyl) urea; N-(5-tert-Butyl-3-thienyl)-N'- (4- (4-isopropoxyphenyl)(5-tert-Butyl-3-thienyl)-N'- (4- (4-isopropoxyphenyl) oxyphenyl) urea;

N-(5-tert-Butyl-3-thienyl)-N'-(4-(3-pyridinyl) oxyphenyl) urea; N-(5-tert-Butyl-3-thienyl)-N'- (4- (4-pyridinyl)(5-tert-Butyl-3-thienyl)-N'- (4- (4-pyridinyl) oxyphenyl) urea; N- (5-tert-Butyl-3-thienyl)-N'- (4- (4-pyridinyl) thiophenyl) urea; and N-(5-tert-Butyl-3-thienyl)-N'-(4-(4-pyridinyl)methylphenyl)u rea.

The invention also relates to which are within the scope of general formula I described above and more specifically include compounds of the formulae: wherein R6 is-O-CH2-phenyl,-NH-C (O)-O-t-butyl,-O-n-pentyl,-O-n-butyl,-C (O)- N (CH3) 2,-0-CH2CH (CH3) 2 or-O-n-propyl;

wherein is-CH2-t-butyl; wherein R2 -C2H4-OH,-CH2-(3-HOC6H4),-CH2C(O)NH3,-CH2-CF3, -CH2C (O) OC2H5, -C2H4CN, or

Preferred compounds also include the following thiadiazoles and thiophenes: N-(5-tert-butyl-2- (l-thia-3, 4-diazolyl))-N'- (4- (4-pyridyl)(5-tert-butyl-2- (l-thia-3, 4-diazolyl))-N'- (4- (4-pyridyl) oxyphenyl) urea; N-(5-tert-butyl-2-(1-thia-3,4-diazolyl))-N'-(3-(4-pyridyl) thiophenyl) urea;

N-(5-tert-butyl-2-(1-thia-3, 4-diazolyl))-N'-(3-(4-methoxyphenyl)(5-tert-butyl-2-(1-thia- 3, 4-diazolyl))-N'-(3-(4-methoxyphenyl) oxyphenyl) urea; N-(5-tert-butyl-2- (l-thia-3, 4-diazolyl))-N'- (3- (4-methylphenyl) oxyphenyl) urea; N-(5-tert-butyl-3-thienyl)-N'- (4- (4-pyridyl)(5-tert-butyl-3-thienyl)-N'- (4- (4-pyridyl) oxyphenyl) urea; N-((5-tert-butyl-3-thienyl)-N'- (4- (4-pyridyl)((5-tert-butyl-3-thienyl)-N'- (4- (4-pyridyl) thiophenyl) urea; N-(5-tert-butyl-3-thienyl)-N'- (4- (4-pyridyl) methylphenyl)(5-tert-butyl-3-thienyl)-N'- (4- (4-pyridyl) methylphenyl) urea; N-(5-tert-butyl-3-thienyl)-N'-(2,(5-tert-butyl-3-thienyl)-N' -(2, 3-dichlorophenyl) urea; N-(5-tert-butyl-3-thienyl)-N'- (4- (4-hydroxyphenyl)(5-tert-butyl-3-thienyl)-N'- (4- (4-hydroxyphenyl) oxyphenyl) urea; N-(5-tert-butyl-3-thienyl)-N'-(4-(4-methoxyphenyl)(5-tert-bu tyl-3-thienyl)-N'-(4-(4-methoxyphenyl) oxyphenyl) urea; N-(5-tert-butyl-3-thienyl)-N'- (4- (4-ethoxyphenyl)(5-tert-butyl-3-thienyl)-N'- (4- (4-ethoxyphenyl) oxyphenyl) urea; and N-(5-tert-butyl-3-thienyl)-N'- (4- (4-isopropoxyphenyl)(5-tert-butyl-3-thienyl)-N'- (4- (4-isopropoxyphenyl) oxyphenyl) urea.

The present invention is also directed to pharmaceutically acceptable salts of formula I. Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, sulphonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e. g., Li+ Na+ or K+), alkaline earth cations (e. g., Mg+2, Ca+2 or Ba+2), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, N, N-diethylamine, N, N-dicyclohexylamine, pyridine, N, N-dimethylaminopyridine (DMAP), 1,4-diazabiclo [2.2.2] octane (DABCO), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,8- diazabicyclo [5.4.0] undec-7-ene (DBU).

A number of the compounds of Formula I possess asymmetric carbons and can therefore exist in racemic and optically active forms. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art.

The present invention encompasses any isolated racemic or optically active form of compounds described in Formula I which possess p38 kinase inhibitory activity.

General Preparative Methods The compounds of Formula I may be prepared by use of known chemical reactions and procedures, some from starting materials which are commercially available.

Nevertheless, the following general preparative methods are presented to aid one of skill in the art in synthesizing the inhibitors, with more detailed particular examples being presented in the experimental section describing the working examples.

Heterocyclic amines may be synthesized utilizing known methodology (Katritzky, et al. Comprehensive Heterocyclic Chemistry; Permagon Press: Oxford, UK (1984).

March. Advanced Organic Chemistry, 3d Ed.; John Wiley: New York (1985)). For example, 3-substituted-5-aminoisoxazoles (3) are available by the reaction of hydroxylamine with an a-cyanoketone (2), as shown in Scheme I. Cyanoketone 2, in turn, is available from the reaction of acetamidate ion with an appropriate acyl derivative, such as an ester, an acid halide, or an acid anhydride. Reaction of an- cyanoketone with hydrazine (R2=H) or a monosubstituted hydrazine affords the 3- substituted-or 1,3-disubstituted-5-aminopyrazole (5). Pyrazoles unsubstituted at N-1 (R=H) may be acylated at N-1, for example using di-tert-butyl dicarbonate, to give pyrazole 7. Similarly, reaction of nitrile 8 with a-thioacetate ester gives the 5- substituted-3-amino-2-thiophenecarboxylate (9, Ishizaki et al. JP 6025221).

Decarboxylation of ester 9 may be achieved by protection of the amine, for example as the tert-butoxy (BOC) carbamate (10), followed by saponification and treatment with acid. When BOC protection is used, decarboxylation may be accompanied by deprotection giving the substituted 3-thiopheneammonium salt 11. Alternatively, ammonium salt 11 may be directly generated through saponification of ester 9 followed by treatment with acid. CH3CN R' 1) base O nez HZNOHHCI NH2 cul ase base 0 RNHNH ? 4 CON R NNHz 0 2 Rz II 0-X ru x RUZ Ruz 2 6 Ri pi NH2 R'HSI---IC02R 0 R S CN f NH2 7 802R 9 1) Oh- 2) H+ II O OO' in 1) OH- + S i NH3 2) H+ f NHBOC CO2R 11 10

Scheme I. Selected General Methods for Heterocyclic Amine Synthesis Substituted anilines may be generated using standard methods (March. Advanced Organic Chemistry, 3rd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme II, aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH4 (Seyden-Penne. Reductions by the Alumino-and Borohydrides in Organic Synthesis ; VCH Publishers: New York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist

for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3rd Ed.; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989)). H2/catalyst / (eg. Ni, Pd, Pt) \ ArNO2 [H] > ArNH2 \ M (O)/ (eg. Fe, Sn, Ca) Scheme II Reduction of Nitroaryls to Aryl Amines Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO3, or an alternative NO2+ source. Nitroaryls may be further elaborated prior to reduction.

Thus, nitroaryls substituted with potential leaving groups (eg. F, Cl, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme III) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme III). ON ars Base 12-\ S-Ar R gr-Ar 13 RjSH /9 13CuO/base 14 Scheme III Selected Nucleophilic Aromatic Substitution using Nitroaryls As shown in Scheme IV, urea formation may involve reaction of a heteroaryl isocyanate (17) with an aryl amine (16). The heteroaryl isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis (trichloromethyl)

carbonate (triphosgene), or N, N'-carbonyldiimidazole (CDI). The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement. Thus, reaction of acid derivative 21 with an azide source, followed by rearrangement affords the isocyanate.

The corresponding carboxylic acid (22) may also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent. A urea may also be generated from the reaction of an aryl isocyanate (20) with a heterocyclic amine. Het-NH2 16 H2N-Ar 19 2 Yv H2N-ArII Het-NH2 Het-NCO HetNN. Ar OCN-Ar N N 17 H H 20 18 N3 DPPA N3 DPPA 0000 O O O O HetX Het"OHX Ar HO Ar 21 22 23 24 Scheme IV Selected Methods of Urea Formation (Het = heterocycle) 1-Amino-2-heterocyclic carboxylic esters (exemplified with thiophene 9, Scheme V) may be converted into an isatoic-like anhydride (25) through saponification, followed by treatment with phosgene or a phosgene equivalent. Reaction of anhydride 25 with an aryl amine can generate acid 26 which may spontaneously decarboxylate, or may be isolated. If isolated, decarboxylation of acid 26 may be induced upon heating. Ri Ri 1) OH- VNH2 2) COC12 t\NH 25 R02C 0 9 ouzo ' R''R II O NIN. Ar S\NN, Ar H H H02C H H 27 ""HCC H H 27 26

Scheme V Urea Formation via Isatoic-like Anhydrides Finally, ureas may be further manipulated using methods familiar to those skilled in the art.

The invention also includes pharmaceutical compositions including a compound of this invention as described above, or a pharmaceutically acceptable salt thereof, and a physiologically acceptable carrier.

The compounds may be administered orally, topically, parenterally, by inhalation or spray, sublingually, or rectally or vaginally in dosage unit formulations. The term 'administration by injection'includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques. Dermal administration may include topical application or transdermal administration. One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.

Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in

order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The compounds may also be in the form of non-aqueous liquid formulations, e. g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.

The compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but

liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.

Compounds of the invention may also be administrated transdermally using methods known to those skilled in the art (see, for example: Chien;"Transdermal Controlled Systemic Medications" ; Marcel Dekker, Inc.; 1987. Lipp et al. W094/04157 3Mar94). For example, a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.

Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane. Suitable solvents may also include mixtures of one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.

Suitable penetration enhancing materials for transdermal delivery system are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated Cg-Cis fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C8-C, 8 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tertbutyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional

penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration enhancing formulations may also include mixtures of one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated Cg-Cis fatty alcohols, saturated or unsaturated C8-C18 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated discarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.

Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrenebutadiene coploymers, and natural and synthetic rubbers. Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components.

Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.

For all regimens of use disclosed herein for compounds of Formula I, the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg. The daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of total body weight.

It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics.

It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.

It will be further appreciated by one skilled in the art that the optimal course of treatment, ie, the mode of treatment and the daily number of doses of a compound of Formulae I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatmment tests.

The entire disclosure of all applications, patents and publications cited above and below are hereby incorporated by reference, including provisional application Attorney Docket No. Bayer 11 VI, filed December 22,1997, as SN 08/995,750, and was converted on December 22,1998.

The following examples are for illustrative purposes only and are not intended, nor should they be construed to limit the invention in any way.

EXAMPLES All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term'concentration under reduced pressure'refers to use of a Buchi rotary evaporator at approximately 15 mmHg.

All temperatures are reported uncorrected in degrees Celsius (°C). Unless otherwise indicated, all parts and percentages are by weight.

Commercial grade reagents and solvents were used without further purification.

Thin-layer chromatography (TLC) was performed on Whatmane pre-coated glass- backed silica gel 60A F-254 250 um plates. Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating. Column chromatography (flash chromatography) was performed using 230-400 mesh EM Science silica gel.

Melting points (mp) were determined using a Thomas-Hoover melting point apparatus or a Mettler FP66 automated melting point apparatus and are uncorrected. Fourier transform intrared spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton (IH) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me4Si (8 0.00) or residual protonated solvent (CHC13 8 7.26; MeOH 8 3.30; DMSO 8 2.49) as standard. Carbon (13C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC13 8 77.0; MeOD-d3; 8 49.0; DMSO-d6 8 39.5) as standard. Low resolution mass spectra (MS) and high resolution mass spectra (HRMS) were either obtained as electron impact (EI) mass spectra or as fast atom bombardment (FAB) mass spectra. Electron impact mass spectra (EI-MS) were obtained with a Hewlett Packard 5989A mass

spectrometer equipped with a Vacumetrics Desorption Chemical Ionization Probe for sample introduction. The ion source was maintained at 250 °C. Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 uA.

Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version of fast atom bombardment were obtained using a Kratos Concept 1-H spectrometer.

Chemical ionization mass spectra (CI-MS) were obtained using a Hewlett Packard MS-Engine (5989A) with methane as the reagent gas (lx10 4 torr to 2.5xl04 torr).

The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared (-1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120-800 amu using a variable ion time according to the number of ions in the source. Gas chromatography -ion selective mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV).

Elemental analyses were conducted by Robertson Microlit Labs, Madison NJ. All ureas displayed NMR spectra, LRMS and either elemental analysis or HRMS consistant with assigned structures.

List of Abbreviations and Acronyms: AcOH acetic acid anh anhydrous BOC tert-butoxycarbonyl conc concentrated dec decomposition DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidinone DMF N, N-dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide

EtOAc ethyl acetate EtOH ethanol (100%) Et2O diethyl ether Et3N triethylamine m-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling range 30-60 °C) THF tetrahydrofuran TFA trifluoroacetic acid Tf trifluoromethanesulfonyl A. General Methods for Synthesis of Hetrocyclic Amines A2. General Synthesis of 5-Amino-3-alkylisoxazoles Step A slurry of sodium hydride (60% in mineral oil; 10.3 g, 258 mmol) in benzene (52 mL) was warmed to 80 °C for 15 min., then a solution of acetonitrile (13.5 mL, 258 mmol) in benzene (52 mL) was added dropwise via addition funnel followed by a solution of ethyl isobutyrate (15 g, 129 mmol) in benzene (52 mL). The reaction mixture was heated overnight, then cooled with an ice water bath and quenched by addition of 2-propanol (50 mL) followed by water (50 mL) via addition funnel. The organic layer was separated and set aside. EtOAc (100 mL) was added to the aqueous layer and the resulting mixture was acidified to approximately pH 1 (conc. HC1) with stirring. The resulting aqueous layer was extracted with EtOAc (2 x 100 mL). The organic layers were combined with the original organic layer, dried (MgS04), and concentrated in vacuo to give the a- cyanoketone as a yellow oil which was used in the next step without further purification.

Step Hydroxylamine hydrochloride (10.3 g, 148 mmol) was slowly added to an ice cold solution of NaOH (25.9 g, 645 mmol) in water (73 mL) and the resulting solution was poured into a solution of crude 3-oxo-4- methylpentanenitrile while stirring. The resulting yellow solution was heated at 50 °C for 2.5 hours to produce a less dense yellow oil. The warm reaction mixture was immediately extracted with CHC13 (3 x 100 mL) without cooling. The combined organic layers were dried (MgS04), and concentrated in vacuo. The resulting oily yellow solid was filtered through a pad of silica (10% acetone/90% CH2C12) to afford the desired isoxazole as a yellow solid (11.3 g, 70%): mp 63-65 °C; TLC Rf (5% acetone/95% CH2Cl2) 0. 19 ; IH-NMR (DMSO-d6) d 1.12 (d, J=7.0 Hz, 6H), 2.72 (sept, J=7.0 Hz, 1H), 4.80 (s, 2H), 6.44 (s, 1H); FAB-MS m/z (rel abundance) 127 ( (M+H) +; 67%).

A3. General Method for the Preparation of 5-Amino-l-alkyl-3-alkylpyrazoles 5-Amino-3-tert-butyl-1-(2-cyanoethyl) pyrazole (2-cyanoethyl) pyrazole A solution of 4,4-dimethyl-3- oxopentanenitrile (5.6 g, 44.3 mmol) and 2-cyanoethyl hydrazine (4.61 g, 48.9 mmol) in EtOH (100 mL) was heated at the reflux temperature overnight after which TLC analysis showed incomplete reaction. The mixture was concentrated under reduced pressure and the residue was filtered through a pad of silica (gradient from 40% EtOAc/60% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated (Et2O/hexane) to afford the desired product (2.5 g, 30%): TLC (30% EtOAc/70% hexane) Rf0.31;'H-NMR (DMSO-d6) 8 1.13 (s, 9H), 2.82 (t, J=6.9 Hz, 2H), 4.04 (t, J=6.9 Hz, 2H), 5.12 (br s, 2H), 5.13 (s, 1H).

A 4. Synthesis of 3-Amino-5-alkylthiophenes- A4a. Synthesis of 3-Amino-5-alkylthiophenes by Thermal Decarboxylation of Thiophenecarboxylic Acids

Step 1.7-tert-Butyl-2H-thieno [3,2-d] oxazine-2,4 (1H)-dione: A mixture of methyl 3-amino-5-tert-butylthiophenecarboxylate (7. 5 g, 35.2 mmol) and KOH (5.92 g) in MeOH (24 mL) and water (24 mL) was stirred at 90 °C for 6 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (600 mL). Phosgene (20% in toluene, 70 mL) was added dropwise over a 2 h period. The resulting mixture was stirred at room temperature overnight and the resulting precipitate was triturated (acetone) to afford the desired anhydride (5.78 g, 73%): lH- NMR (CDC13) 8 1.38 (s, 9H), 2.48 (s, 1H), 6.75 (s, 1H); FAB-MS m/z (rel abundance) 226 ((M+H) +, 100%).

Step 2. N-(5-tert-Butyl-2-carboxy-3-thienyl)-N'- (4- (4-pyridinylmethyl) phenyl)- urea: A solution of 7-tert-butyl-2H-thieno [3,2-d] oxazine-2,4 (1H)-dione (0.176 g, 0.78 mmol) and 4- (4-pyridinylmethyl) aniline (0.144 g, 0.78 mmol) in THF (5 mL) was heated at the reflux temp. for 25 h. After cooling to room temp., the resulting solid was triturated with Et20 to afford the desired urea (0.25 g, 78%): mp 187-189 °C; TLC (50% EtOAc/50% pet. ether) Rf 0.04;'H-NMR (DMSO-d6) 8 1.34 (s, 9H), 3.90 (s, 2H), 7.15 (d, J=7Hz, 2H), 7.20 (d, J=3 Hz, 2H), 7.40 (d, J=7 Hz, 2H), 7.80 (s 1H), 8.45 (d, J=3 Hz, 2H) 9.55 (s, 1H), 9.85 (s, 1H), 12.50 (br s, 1H); FAB-MS m/z (rel abundance) 410 ((M+H) +; 20%).

Step 3. N- (5-tert-Butyl-3-thienyl)-N'- (4- (4-pyridinylmethyl) phenyl) urea: A vial containing N-(5-tert-butyl-2-carboxy-3-thienyl)-N'- (4- (4-pyridinylmethyl) phenyl)- urea (0.068 g, 0.15 mmol) was heated to 199 °C in an oil bath. After gas evolution ceased, the material was cooled and purified by preparative HPLC (C-18 column; gradient from 20% CH3CN/79.9% H2O/0.1% TFA to 99.9% H20/0.1% TFA) to give the desired product (0.024 g, 43%): TLC (50% EtOAc/50% pet. ether) Rf 0.18;'H- NMR (DMSO-d6) 8 1.33 (s, 9H), 4.12 (s, 2H), 6.77 (s, 1H), 6.95 (s, 1H), 7.17 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 2H), 7.69 (d, J=7 Hz, 1H), 8.58 (s, 1H), 8.68 (d, J=7 Hz, 2H), 8.75 (s, 1H); EI-MS m/z 365 (M+) A4b. Synthesis 3-Amino-5-alkylthiophenes from 3-Amino-5-alkyl-2-thiophene- carboxylate esters 5-tert-Butyl-3-thiopheneammonium Chloride: To a solution of methyl 3-amino-5- tert-butyl-2-thiophene-carboxylate (5.07 g, 23.8 mmol, 1.0 equiv) in EtOH (150 mL) was added NaOH (2.0 g, 50 mmol, 2.1 equiv). The resulting solution was heated at the reflux temp. for 2.25 h. A conc. HC1 solution (approximately 10 mL) was added dropwise with stirring and the evolution of gas was observed. Stirring was continued for 1 h, then the solution was concentrated under reduced pressure. The white residue was suspended in EtOAc (150 mL) and a saturated NaHC03 solution (150 mL) was added to dissolve. The organic layer was washed with water (150 mL) and a saturated NaCI solution (150 mL), dried (Na2S04), and concentrated under reduced pressure to give the desired ammonium salt as a yellow oil (3.69 g, 100%). This material was used directly in urea formation without further purification.

Synthesis 3-Amino-5-alkylthiophenes from N-BOC 3-Amino-5-alkyl-2- thiophenecarboxylate esters Step 1. Methyl 3-(tert-Butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxy - late: To a solution of methyl 3-amino-5-tert-butyl-2-thiophenecarboxylate (150 g, 0.70 mol) in pyridine (2.8 L) at 5 °C was added di-tert-butyl dicarbonate (171.08 g, 0.78 mol, 1.1 equiv) and NN-dimethylaminopyridine (86 g, 0.70 mol, 1.00 equiv) and the resulting mixture was stirred at room temp for 7 d. The resulting dark solution was concentrated under reduced pressure (approximately 0.4 mmHg) at approximately 20 °C. The resulting red solids were dissolved in CH2C12 (3 L) and sequentially washed with a 1 M H3PO4 solution (2 x 750 mL), a saturated NaHC03 solution (800 mL) and a saturated NaCI solution (2 x 800 mL), dried (Na2S04) and concentrated under reduced pressure. The resulting orange solids were dissolved in abs. EtOH (2 L) by warming to 49 °C, then treated with water (500 mL) to afford the desired product as an off-white solid (163 g, 74%):'H-NMR (CDC13) 8 1.38 (s, 9H), 1.51 (s, 9H), 3.84 (s, 3H), 7.68 (s, 1H), 9.35 (br s, 1H); FAB-MS m/z (rel abundance) 314 ((M+H) +, 45%).

Step 2.3- (tert-Butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxyli c Acid: To a solution of methyl 3- (tert-butoxycarbonylamino)-5-tert-butyl-2- thiophenecarboxylate (90.0 g, 0.287 mol) in THF (630 mL) and MeOH (630 mL) was added a solution of NaOH (42.5 g, 1.06 mL) in water (630 mL). The resulting mixture was heated at 60 °C for 2 h, concentrated to approximately 700 mL under reduced pressure, and cooled to 0 °C. The pH was adjusted to approximately 7 with a 1.0 N HC1 solution (approximately 1 L) while maintaining the internal temperature at

approximately 0 °C. The resulting mixture was treated with EtOAc (4 L). The pH was adjusted to approximately 2 with a 1.0 N HC1 solution (500 mL). The organic phase was washed with a saturated NaCl solution (4 x 1.5 L), dried (Na2S04), and concentrated to approximately 200 mL under reduced pressure. The residue was treated with hexane (1 L) to form a light pink (41.6 g). Resubmission of the mother liquor to the concentration-precipitation protocol afforded additional product (38.4 g, 93% total yield):'H-NMR (CDC13) 8 1.94 (s, 9H), 1.54 (s, 9H), 7.73 (s, 1H), 9.19 (br s, 1H); FAB-MS m/z (rel abundance) 300 ((M+H) +, 50%).

Step 3. 5-tert-Butyl-3-thiopheneammonium Chloride: A solution of 3-(tert- butoxycarbonylamino)-5-tert-butyl-2-thiophenecarboxylic acid (3.0 g, 0.010 mol) in dioxane (20 mL) was treated with an HC1 solution (4.0 M in dioxane, 12.5 mL, 0.050 mol, 5.0 equiv), and the resulting mixture was heated at 80 °C for 2 h. The resulting cloudy solution was allowed to cool to room temp forming some precipitate. The slurry was diluted with EtOAc (50 mL) and cooled to-20 °C. The resulting solids were collected and dried overnight under reduced pressure to give the desired salt as an off-white solid (1. 72 g, 90%):'H-NMR (DMSO-d6) 8 1.31 (s, 9H), 6.84 (d, J=1.48 Hz, 1H), 7.31 (d, J=1.47 Hz, 1H), 10.27 (br s, 3H).

A5. General Method for the Synthesis of BOC-Protected Pyrazoles 5-Amino-3-tert-butyl-Nl-(tert-butoxyearbonyl) pyrazole (tert-butoxyearbonyl) pyrazole To a solution of 5-amino- 3-tert-butylpyrazole (3.93 g, 28.2 mmol) in CH2C12 (140 mL) was added di-tert-butyl dicarbonate (6.22 g, 28.5 mmol) in one portion. The resulting solution was stirred at room temp. for 13 h, then diluted with EtOAc (500 mL). The organic layer was

washed with water (2 x 300 mL), dried (MgS04) and concentrated under reduced pressure. The solid residue was triturated (100 mL hexane) to give the desired carbamate (6.26 g, 92%): mp 63-64 °C; TLC Rf (5% acetone/95% CH2C12);'H-NMR (DMSO-d6) 8 1.15 (s, 9H), 1.54 (s, 9H), 5.22 (s, 1H), 6.11 (s, 2H); FAB-MS m/z ( (M+H).

A6. General Method for the Synthesis of 2-Aminothiadiazoles 2-Amino-5-(1-(1-ethyl) propyl) thiadiazine (1-(1-ethyl) propyl) thiadiazine To concentrated sulfuric acid (9.1 mL) was slowly added 2-ethylbutyric acid (10.0 g, 86 mmol, 1.2 equiv). To this mixture was slowly added thiosemicarbazide (6.56 g, 72 mmol, 1 equiv). The reaction mixture was heated at 85 °C for 7 h, then cooled to room temperature, and treated with a concentrated NH4OHsolution until basic. The resulting solids were filtered to afford 2-amino-5- (l- (l-ethyl) propyl) thiadiazine product was isolated via vacuum filtration as a beige solid (6.3 g, 51%): mp 155-158 °C; TLC (5% MeOH/95% CHC13) Rf 0.14;'H-NMR (DMSO-d6) 8 0.80 (t, J=7.35 Hz, 6H), 1.42-1.60 (m, 2H), 1.59-1.71 (m, 2H), 2.65-2.74 (m, 1H), 7.00 (br s, 2H); HPLC ES-MS mlz 172 ( (M+H) +).

A7. GeneralMethod for the Synthesis of 2-Aminooxadiazoles Step 1. Isobutyric Hydrazide: A solution of methyl isobutyrate (10.0 g) and hydrazine (2.76 g) in MeOH (500 mL) was heated at the reflux temperature over night then stirred at 60 °C for 2 weeks. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to afford isobutyric hydrazide as a yellow oil (1.0 g, 10%), which was used inb the next step withour further purification.

Step 2.2-Amino-5-isopropyl oxadiazole: To a mixture of isobutyric hydrazide (0.093 g), KHC03 (0.102 g), and water (1 mL) in dioxane (1 mL) at room temperature was added cyanogen bromide (0.10 g). The resulting mixture was heated at the refulx temperature for 5 h, and stirred at room temperature for 2 d, then treated with CH2C12 (5 mL). The organic layer was washed with water (2 x 10 mL), dried (MgS04) and concentrated under reduced pressure to afford 2-amino-5-isopropyl oxadiazole as a white solid: HPLC ES-MS m/z 128 ((M+H) +).

A8. General Method for the Synthesis of 2-Aminooxazoles Step A neat sample of l-bromo-3,3- dimethyl-2-butanone (33.3 g) at 0 °C was treated with a 1N NaOH solution, then was stirred for 1 h. The resulting mixture was extracted with EtOAc (5 x 100 mL). The combined organics were dried (Na2S04) and concentrated under reduced pressure to give 3,3-dimethyl-1-hydroxy-2-butanone (19 g, 100%), which was used inb the next step withour further purification.

Step To a solution of 3,3-dimethyl-1- hydroxy-2-butanone (4.0 g) and cyanimide (50% w/w, 2.86 g) in THF (10 mL) was added a 1N NaOAc solution (8 mL), followed by tetra-n-butylammonium hydroxide (0.4 M, 3.6 mL), then a 1N NaOH solution (1.45 mL). The resulting mixtuire was stirred at room temperature for 2 d. The resulting organic layer was separated, washed with water (3 x 25 mL), and the aqueous layer was extraced with Et20 (3 x 25 mL). The combined organic layers were treated with a 1N NaOH solution tuntil basic, then extracted with CH2C12 (3 x 25 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford 2-Amino-4- isopropyl-1,3-oxazole (1.94 g, 41%): HPLC ES-MS m/z 141 ((M+H) +).

A9. Method for the Synthesis of Substituted-5-aminotetrazoles

: To a solution of 5-aminotetrazole (5 g), NaOH (2.04 g) and water (25 mL) in EtOH (115 mL) at the reflux temperature was added 2-bromopropane (5.9g). The resulting mixture was heated at the reflux temperature for 6 d, then cooled to room temperature, and concentrated under reduced pressure. The resulting aqueous mixture was washed with CH2C12 (3 x 25 mL), then concentrated under reduced pressure with the aid of a lyophlizer to afford a mixture of 1-and 2-isopropyl-5-aminotetrazole (50%), which was used without further purification: HPLC ES-MS m/z 128 ((M+H) +).

B. General Methods for Synthesis of Substituted Anilines Bl. General Method for Substituted Aniline Formation via Hydrogenation of a Nitroarene 4- (4-Pyridinylmethyl) aniline: To a solution of 4- (4-nitrobenzyl) pyridine (7. 0 g, 32.68 mmol) in EtOH (200 mL) was added 10% Pd/C (0.7 g) and the resulting slurry was shaken under a H2 atmosphere (50 psi) using a Parr shaker. After 1 h, TLC and 1H-NMR of an aliquot indicated complete reaction. The mixture was filtered through a short pad of Celite#. The filtrate was concentrated in vacuo to afford a white solid (5.4 g, 90%):'H-NMR (DMSO-d6) 8 3.74 (s, 2H), 4.91 (br s, 2H), 6.48 (d, J=8.46 Hz, 2H), 6.86 (d, J=8.09 Hz, 2H), 7.16 (d, J=5.88 Hz, 2H), 8.40 (d, J=5.88 Hz, 2H); EI- MS m/z 184 (M+). This material was used in urea formation reactions without further purification. B2. General Method for Substituted Aniline Formation via Dissolving Metal Reduction of a Nitroarene

4- (2-Pyridinylthio) aniline: To a solution of 4-(2-pyridinylthio)-1-nitrobenzene (Menai ST 3355A; 0.220 g, 0.95 mmol) and H20 (0.5 mL) in AcOH (5 mL) was added iron powder (0. 317 g, 5.68 mmol) and the resulting slurry stirred for 16 h at room temp. The reaction mixture was diluted with EtOAc (75 mL) and H20 (50 mL), basified to pH 10 by adding solid K2CO3 in portions (Caution: foaming). The organic layer was washed with a saturated NaCI solution, dried (MgS04), concentrated in vacuo. The residual solid was purified by MPLC (30% EtOAc/70% hexane) to give the desired product as a thick oil (0.135 g, 70%): TLC (30% EtOAc/70% hexanes) Rf 0.20.

B3a. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step 1.1-Methoxy4- (4-nitrophenoxy) benzene: To a suspension of NaH (95%, 1.50 g, 59 mmol) in DMF (100 mL) at room temp. was added dropwise a solution of 4-methoxyphenol (7.39 g, 59 mmol) in DMF (50 mL). The reaction was stirred 1 h, then a solution of 1-fluoro-4-nitrobenzene (7.0 g, 49 mmol) in DMF (50 mL) was added dropwise to form a dark green solution. The reaction was heated at 95 °C overnight, then cooled to room temp., quenched with H20, and concentrated in vacuo.

The residue was partitioned between EtOAc (200 mL) and H20 (200 mL). The organic layer was sequentially washed with H20 (2 x 200 mL), a saturated NaHC03 solution (200 mL), and a saturated NaCI solution (200 mL), dried (Na2S04), and concentrated in vacuo. The residue was triturated (Et20/hexane) to afford 1- methoxy-4- (4-nitrophenoxy) benzene (12.2 g, 100%): lH-NMR (CDC13) 6 3.83 (s, 3H), 6.93-7.04 (m, 6H), 8.18 (d, J=9.2 Hz, 2H); EI-MS m/z 245 (M+).

Step To a solution of 1-methoxy-4- (4- nitrophenoxy) benzene (12.0 g, 49 mmol) in EtOAc (250 mL) was added 5% Pt/C (1.5 g) and the resulting slurry was shaken under a H2 atmosphere (50 psi) for 18 h.

The reaction mixture was filtered through a pad of Celiez with the aid of EtOAc and concentrated in vacuo to give an oil which slowly solidified (10.6 g, 100%):'H-NMR (CDC13) 8 3.54 (br s, 2H), 3.78 (s, 3H), 6.65 (d, J=8.8 Hz, 2H), 6.79-6.92 (m, 6H); EI- MS m/z 215 (M+).

B3b. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step 1.3- (Trifluoromethyl)-4- (4-pyridinylthio) nitrobenzene: A solution of 4- mercaptopyridine (2.8 g, 24 mmoles), 2-fluoro-5-nitrobenzotrifluoride (5 g, 23.5 mmoles), and potassium carbonate (6.1 g, 44.3 mmoles) in anhydrous DMF (80 mL) was stirred at room temperature and under argon overnight. TLC showed complete reaction. The mixture was diluted with Et20 (100 mL) and water (100 mL) and the aqueous layer was back-extracted with Et2O (2 x 100 mL). The organic layers were washed with a saturated NaCI solution (100 mL), dried (MgS04), and concentrated under reduced pressure. The solid residue was triturated with Et20 to afford the desired product as a tan solid (3.8 g, 54%): TLC (30% EtOAc/70% hexane) Rf 0.06; 'H-NMR (DMSO-d6) 8 7.33 (dd, J=1.2,4.2 Hz, 2H), 7.78 (d, J=8.7 Hz, 1H), 8.46 (dd, J=2.4,8.7Hz, 1H), 8.54-8.56 (m, 3H).

Step A slurry of 3- trifluoromethyl-4- (4-pyridinylthio) nitrobenzene (3.8 g, 12.7 mmol), iron powder (4.0 g, 71.6 mmol), acetic acid (100 mL), and water (1 mL) were stirred at room temp. for

4 h. The mixture was diluted with Et2O (100 mL) and water (100 mL). The aqueous phase was adjusted to pH 4 with a 4 N NaOH solution. The combined organic layers were washed with a saturated NaCI solution (100 mL), dried (MgS04), and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50% hexane to 60% EtOAc/40% hexane) to afford the desired product (3.3 g): TLC (50% EtOAc/50% hexane) Rf 0.10;'H-NMR (DMSO- d6) 8 6.21 (s, 2H), 6.84-6.87 (m, 3H), 7.10 (d, J=2.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 8.29 (d, J=6.3 Hz, 2H).

B3c. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step A solution of 2-mercapto-4- phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with 1-fluoro-4- nitrobenzene (2.3 mL, 21.7 mmoles) followed by K2C03 (3.18 g, 23 mmol), and the mixture was heated at approximately 65 °C overnight. The reaction mixture was then diluted with EtOAc (100 mL), sequentially washed with water (100 mL) and a saturated NaCI solution (100 mL), dried (MgS04) and concentrated under reduced pressure. The solid residue was triturated with a Et2O/hexane solution to afford the desired product (6.1 g): TLC (25% EtOAc/75% hexane) Rf 0.49;'H-NMR (CDC13) 8 7.35-7.47 (m, 3H), 7.58-7.63 (m, 3H), 7.90 (d, J=6.9 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H).

Step 4- (2- (4-Phenyl) thiazolyl) thio-l-nitro- benzene was reduced in a manner analagous to that used in the preparation of 3- (trifluoromethyl)-4- (4-pyridinylthio) aniline: TLC (25% EtOAc/75% hexane) Rf 0.18; 'H-NMR (CDC13) 8 3.89 (br s, 2H), 6.72-6.77 (m, 2H), 7.26-7.53 (m, 6H), 7.85-7.89 (m, 2H). B3d. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step 1.4- (6-Methyl-3-pyridinyloxy)-1-nitrobenzene : To a solution of 5-hydroxy- 2-methylpyridine (5.0 g, 45.8 mmol) and 1-fluoro-4-nitrobenzene (6.5 g, 45.8 mmol) in anh DMF (50 mL) was added K2CO3 (13.0 g, 91.6 mmol) in one portion. The mixture was heated at the reflux temp. with stirring for 18 h and then allowed to cool to room temp. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na2S04), and concentrated in vacuo to afford the desired product (8.7 g, 83%). The this material was carried to the next step without further purification.

Step 2.4- (6-Methyl-3-pyridinyloxy) aniline: A solution of 4- (6-methyl-3- pyridinyloxy)-l-nitrobenzene (4.0 g, 17.3 mmol) in EtOAc (150 mL) was added to 10% Pd/C (0.500 g, 0.47 mmol) and the resulting mixture was placed under a H2 atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celte and concentrated in vacuo to afford the desired product as a tan solid (3.2 g, 92%): EI-MS mlz 200 (M+).

B3e. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step To a solution of 3,4- dimethoxyphenol (1.0 g, 6.4 mmol) and 1-fluoro-4-nitrobenzene (700 RL, 6.4 mmol) in anh DMF (20 mL) was added K2CO3 (1.8 g, 12.9 mmol) in one portion. The mixture was heated at the reflux temp with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were sequentially washed with water (3 x 50 mL) and a saturated NaCI solution (2 x 50 mL), dried (Na2SO4), and concentrated in vacuo to afford the desired product (0.8 g, 54%). The crude product was carried to the next step without further purification.

Step aniline: A solution of 4-(3, 4Sdimethoxy- phenoxy)-l-nitrobenzene (0.8 g, 3.2 mmol) in EtOAc (50 mL) was added to 10% Pd/C (0.100 g) and the resulting mixture was placed under a H2 atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celite and concentrated in vacuo to afford the desired product as a white solid (0.6 g, 75%): EI-MS m/z 245 (M).

B3f. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step To a solution of 3-hydroxypyridine (2.8 g, 29.0 mmol), 1-bromo-3-nitrobenzene (5.9 g, 29.0 mmol) and copper (I) bromide (5.0 g, 34.8 mmol) in anh DMF (50 mL) was added K2CO3 (8.0 g, 58.1 mmol) in one portion. The resulting mixture was heated at the reflux temp. with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na2S04), and concentrated in vacuo. The resulting oil was purified by flash chromatography (30% EtOAc/70% hexane) to afford the desired product (2.0 g, 32 %). This material was used in the next step without further purification. Step A solution of 3-(3-pyridinyloxy)-1- nitrobenzene (2.0 g, 9.2 mmol) in EtOAc (100 mL) was added to 10% Pd/C (0.200 g) and the resulting mixture was placed under a H2 atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of

Celiez and concentrated in vacuo to afford the desired product as a red oil (1.6 g, 94%): EI-MS m/z 186 (M+).

B3g. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step To a solution of 3-hydroxy- 5-methylpyridine (5.0 g, 45.8 mmol), 1-bromo-3-nitrobenzene (12.0 g, 59.6 mmol) and copper (I) iodide (10.0 g, 73.3 mmol) in anh DMF (50 mL) was added K2C03 (13.0 g, 91.6 mmol) in one portion. The mixture was heated at the reflux temp. with stirring for 18 h and then allowed to cool to room temp. The mixture was then poured into water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organics were sequentially washed with water (3 x 100 mL) and a saturated NaCl solution (2 x 100 mL), dried (Na2S04), and concentrated in vacuo. The resulting oil was purified by flash chromatography (30% EtOAc/70% hexane) to afford the desired product (1.2 g, 13%).

Step 2.3- (5-Methyl-3-pyridinyloxy)-1-nitrobenzene : A solution of 3- (5-methyl-3- pyridinyloxy)-l-nitrobenzene (1.2 g, 5.2 mmol) in EtOAc (50 mL) was added to 10% Pd/C (0.100 g) and the resulting mixture was placed under a H2 atmosphere (balloon) and was allowed to stir for 18 h at room temp. The mixture was then filtered through a pad of Celitee and concentrated in vacuo to afford the desired product as a red oil (0.9 g, 86%): CI-MS m/z 201 ((M+H) +).

B3h. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step To a solution of 2-chloro-5- nitropyridine (6.34 g, 40 mmol) in DMF (200 mL) were added of 4-methylphenol (5.4

g, 50 mmol, 1.25 equiv) and K2CO3 (8.28 g, 60 mmol, 1.5 equiv). The mixture was stirred overnight at room temp. The resulting mixture was treated with water (600 mL) to generate a precipitate. This mixture was stirred for 1 h, and the solids were separated and sequentially washed with a 1 N NaOH solution (25 mL), water (25 mL) and pet ether (25 mL) to give the desired product (7.05 g, 76%): mp 80-82 °C; TLC (30% EtOAc/70% pet ether) Rf 0.79;'H-NMR (DMSO-d6) 8 2.31 (s, 3H), 7.08 (d, J=8.46 Hz, 2H), 7.19 (d, J=9.20 Hz, 1H), 7.24 (d, J=8.09 Hz, 2H), 8.58 (dd, J=2.94, 8.82 Hz, 1H), 8.99 (d, J=2.95 Hz, 1H); FAB-MS mlz (rel abundance) 231 ((M+H) +), 100%).

Step 2.5-Amino-2- (4-methylphenoxy) pyridine Dihydrochloride: A solution 5- nitro-2- (4-methylphenoxy) pyridine (6.94 g, 30 mmol, 1 eq) and EtOH (10 mL) in EtOAc (190 mL) was purged with argon then treated with 10% Pd/C (0.60 g). The reaction mixture was then placed under a H2 atmosphere and was vigorously stirred for 2.5 h. The reaction mixture was filtered through a pad of Celte@. A solution of HC1 in Et20 was added to the filtrate was added dropwise. The resulting precipitate was separated and washed with EtOAc to give the desired product (7.56 g, 92%): mp 208-210 °C (dec); TLC (50% EtOAc/50% pet ether) Rf 0.42;'H-NMR (DMSO-d6) 8 2.25 (s, 3H), 6.98 (d, J=8.45 Hz, 2H), 7.04 (d, J=8.82 Hz, 1H), 7.19 (d, J=8.09 Hz, 2H), 8.46 (dd, J=2.57,8.46 Hz, 1H), 8.63 (d, J=2.57 Hz, 1H); EI-MS mlz (rel abundance) (M+, 100%).

B3i. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction Step To a solution of 4-nitrothiophenol (80% pure; 1.2 g, 6.1 mmol), 3-bromothiophene (1.0 g, 6.1 mmol) and copper (II) oxide (0.5 g, 3.7 mmol) in anhydrous DMF (20 mL) was added KOH (0.3 g, 6.1

mmol), and the resulting mixture was heated at 130 °C with stirring for 42 h and then allowed to cool to room temp. The reaction mixture was then poured into a mixture of ice and a 6N HC1 solution (200 mL) and the resulting aqueous mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were sequentially washed with a 1M NaOH solution (2 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (MgS04), and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; gradient from 10% EtOAc/90% hexane to 5% EtOAc/95% hexane) to afford of the desired product (0.5 g, 34%). GC-MS m/z 237 (M).

Step 4- (3-Thienylthio)-l-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B 1.

B3j. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction 4- (5-Pyrimininyloxy) aniline : 4-Aminophenol (1.0 g, 9.2 mmol) was dissolved in DMF (20 mL) then 5-bromopyrimidine (1.46 g, 9.2 mmol) and K2C03 (1. 9 g, 13.7 mmol) were added. The mixture was heated to 100 °C for 18 h and at 130 °C for 48 h at which GC-MS analysis indicated some remaining starting material. The reaction mixture was cooled to room temp. and diluted with water (50 mL). The resulting solution was extracted with EtOAc (100 mL). The organic layer was washed with a saturated NaCI solution (2 x 50 mL), dried (MgS04), and concentrated in vacuo. The residular solids were purified by MPLC (50% EtOAc/50% hexanes) to give the desired amine (0.650 g, 38%).

B3k. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction

Step A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.76g, 69.6 mmol) in MeOH (60 mL) was heated at 70 °C in a sealed reaction vessel for 42 h, then allowed to cool to room temp. The reaction mixture was treated with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (Na2S04) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95% yield): TLC (10% EtOAc/90% hexane)Rf 0.57.

Step To a stirred solution of 5-bromo-2- methoxypyridine (8.9 g, 47.9 mmol) in THF (175 mL) at-78 °C was added an n- butyllithium solution (2.5 M in hexane; 28.7 mL, 71.8 mmol) dropwise and the resulting mixture was allowed to stir at-78 °C for 45 min. Trimethyl borate (7.06 mL, 62.2 mmol) was added via syringe and the resulting mixture was stirred for an additional 2 h. The bright orange reaction mixture was warmed to 0 °C and was treated with a mixture of a 3 N NaOH solution (25 mL, 71.77 mmol) and a hydrogen peroxide solution (30%; approx. 50 mL). The resulting yellow and slightly turbid reaction mixture was warmed to room temp. for 30 min and then heated to the reflux temp. for 1 h. The reaction mixture was then allowed to cool to room temp. The aqueous layer was neutralized with a IN HC1 solution then extracted with Et20 (2 x 100 mL). The combined organic layers were dried (Na2S04) and concentrated under reduced pressure to give a viscous yellow oil (3.5g, 60%).

Step 3. 4- (5- (2-Methoxy) pyridyl) oxy-l-nitrobenzene: To a stirred slurry of NaH (97%, 1.0 g, 42 mmol) in anh DMF (100 mL) was added a solution of 5-hydroxy-2- methoxypyridine (3.5g, 28 mmol) in DMF (100 mL). The resulting mixture was allowed to stir at room temp. for 1 h, 4-fluoronitrobenzene (3 mL, 28 mmol) was added via syringe. The reaction mnixture was heated to 95 °C overnight, then treated with water (25 mL) and extracted with EtOAc (2 x 75 mL). The organic layer was dried (MgS04) and concentrated under reduced pressure. The residual brown oil was crystalized EtOAc/hexane) to afford yellow crystals (5.23 g, 75%).

Step 4- (5- (2-Methoxy) pyridyl) oxy-l- nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2.

B4a. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine 3- (4-Pyridinylthio) aniline: To a solution of 3-aminothiophenol (3.8 mL, 34 mmoles) in anh DMF (90mL) was added 4-chloropyridine hydrochloride (5.4 g, 35.6 mmoles) followed by K2C03 (16.7 g, 121 mmoles). The reaction mixture was stirred at room temp. for 1.5 h, then diluted with EtOAc (100 mL) and water (lOOmL). The aqueous layer was back-extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCI solution (100 mL), dried (MgS04), and concentrated under reduced pressure. The residue was filtered through a pad of silica (gradient from 50% EtOAc/50% hexane to 70% EtOAc/30% hexane) and the resulting material was triturated with a Et2O/hexane solution to afford the desired product (4.6 g, 66%): TLC (100 % ethyl acetate) Rf 0.29;'H-NMR (DMSO-d6) 8 5.41 (s, 2H), 6.64-6.74 (m, 3H), 7.01 (d, J=4.8,2H), 7.14 (t, J=7.8 Hz, 1H), 8.32 (d, J=4.8, 2H).

B4b. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine 25 4- (2-Methyl-4-pyridinyloxy) aniline: To a solution of 4-aminophenol (3.6 g, 32.8 mmol) and 4-chloropicoline (5.0 g, 39.3 mmol) in anh DMPU (50 mL) was added potassium tert-butoxide (7.4 g, 65.6 mmol) in one portion. The reaction mixture was heated at 100 °C with stirring for 18 h, then was allowed to cool to room temp. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (3 x 150

mL). The combined extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na2S04), and concentrated in vacuo.

The resulting oil was purified by flash chromatography (50 % EtOAc/50% hexane) to afford the desired product as a yellow oil (0.7 g, 9%): CI-MS m/z 201 ( (M+H).

B4c. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine Step 1. Methyl (4-nitrophenyl)-4-pyridylamine: To a suspension of N-methyl-4- nitroaniline (2.0 g, 13.2 mmol) and K2C03 (7.2 g, 52.2 mmol) in DMPU (30mL) was added 4-chloropyridine hydrochloride (2.36 g, 15.77 mmol). The reaction mixture was heated at 90 °C for 20 h, then cooled to room temperature. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with water (100 mL), dried (Na2S04) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, gradient from 80% EtOAc/20% hexanes to 100% EtOAc) to afford methyl (4- nitrophenyl)-4-pyridylamine (0.42 g) Step 2. Methyl (4-aminophenyl)-4-pyridylamine: Methyl (4-nitrophenyl)-4- pyridylamine was reduced in a manner analogous to that described in Method B 1.

B5. General Method of Substituted Aniline Synthesis via Phenol Alkylation Followed by Reduction of a Nitroarene Stepl. 4-(4-Butoxyphenyl) thio-l-nitrobenzene (4-Butoxyphenyl) thio-l-nitrobenzene To a solution of 4- (4-nitrophenyl- thio) phenol (1.50 g, 6.07 mmol) in anh DMF (75 ml) at 0 °C was added NaH (60% in mineral oil, 0.267 g, 6.67 mmol). The brown suspension was stirred at 0 °C until gas

evolution stopped (15 min), then a solution of iodobutane (1.12 g,. 690 ml, 6.07 mmol) in anh DMF (20 mL) was added dropwise over 15 min at 0 °C. The reaction was stirred at room temp. for 18 h at which time TLC indicated the presence of unreacted phenol, and additional iodobutane (56 mg, 0.035 mL, 0.303 mmol, 0.05 equiv) and-NaH (13 mg, 0.334 mmol) were added. The reaction was stirred an additional 6 h room temp., then was quenched by the addition of water (400 mL).

The resulting mixture was extracted with Et20 (2 x 500 mL). The combibed organics were washed with water (2 x 400 mL), dried (MgS04), and concentrated under reduced pressure to give a clear yellow oil, which was purified by silica gel chromatography (gradient from 20% EtOAc/80% hexane to 50% EtOAc/50% hexane) to give the product as a yellow solid (1.24 g, 67%): TLC (20% EtOAc/80% hexane) Rf 0.75;'H-NMR (DMSO-d6) 8 0.92 (t, J= 7. 5 Hz, 3H), 1.42 (app hex, J=7.5 Hz, 2H), 1.70 (m, 2H), 4.01 (t, J= 6.6 Hz, 2H), 7.08 (d, J=8.7 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 7.51 (d, J= 8.7 Hz, 2H), 8.09 (d, J= 9 Hz, 2H).

Step 4- (4-Butoxyphenyl) thio-l-nitrobenzene was reduced to the aniline in a manner analagous to that used in the preparation of 3- (trifluoromethyl)-4- (4-pyridinylthio) aniline (Method B3b, Step 2): TLC (33% EtOAc/77% hexane) Ru 0.38.

B6. General Method for Synthesis of Substituted Anilines by the Acylation of Diaminoarenes 4- (4-tert-Butoxycarbamoylbenzyl) aniline: To a solution of 4,4'-methylenedianiline (3. 00 g, 15.1 mmol) in anh THF (50 mL) at room temp was added a solution of di- tert-butyl dicarbonate (3.30 g, 15.1 mmol) in anh THF (10 mL). The reaction mixture was heated at the reflux temp. for 3 h, at which time TLC indicated the presence of unreacted methylenedianiline. Additional di-tert-butyl dicarbonate (0.664 g, 3.03 mmol, 0.02 equiv) was added and the reaction stirred at the reflux temp. for 16 h. The resulting mixture was diluted with Et20 (200 mL), sequentially washed with a

saturated NaHC03 solution (100 ml), water (100 mL) and a saturated NaCl solution (50 mL), dried (MgS04), and concentrated under reduced pressure. The resulting white solid was purified by silica gel chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane) to afford the desired product as a white solid (2.09 g, 46%): TLC (50% EtOAc/50% hexane) Rf 0.45;'H-NMR (DMSO-d6) 8 1.43 (s, 9H), 3.63 (s, 2H), 4.85 (br s, 2H), 6.44 (d, J=8.4 Hz, 2H), 6.80 (d, J=8. 1 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 9.18 (br s, 1H); FAB-MS m/z 298 (M+).

B7. General Method for the Synthesis of Aryl Amines via Electrophilic Nitration Followed by Reduction

Step A solution of 3-benzylpyridine (4.0 g, 23.6 mmol) and 70% nitric acid (30 mL) was heated overnight at 50 °C. The resulting mixture was allowed to cool to room temp. then poured into ice water (350 mL). The aqueous mixture then made basic with a IN NaOH solution, then extracted with Et20 (4 x 100 mL). The combined extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na2S04), and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; 50 % EtOAc/50% hexane) then recrystallization (EtOAc/hexane) to afford the desired product (1.0 g, 22%): GC- MS m/z 214 (M+).

Step 3- (4-Nitrobenzyl) pyridine was reduced to the aniline in a manner analogous to that described in Method B 1. B8. General Method for Synthesis of Aryl Amines via Substitution with Nitrobenzyl Halides Followed by Reduction

Step 1.4- (1-Imidazolylmethyl)-l-nitrobenzene : To a solution of imidazole (0.5 g, 7.3 mmol) and 4-nitrobenzyl bromide (1.6 g, 7.3 mmol) in anh acetonitrile (30 mL) was added K2CO3 (1.0 g, 7.3 mmol). The resulting mixture was stirred at rooom temp. for 18 h and then poured into water (200 mL) and the resulting aqueous solution wasextracted with EtOAc (3 x 50 mL). The combined organic layers were sequentially washed with water (3 x 50 mL) and a saturated NaCI solution (2 x 50 mL), dried (MgS04), and concentrated in vacuo. The residual oil was purified by MPLC (silica gel; 25% EtOAc/75% hexane) to afford the desired product (1.0 g, 91%): EI-MS m/z 203 (M) Step 4-(1-Imidazolylmethyl)-l-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B2.

B9. Formation of Substituted Hydroxymethylanilines by Oxidation of Nitrobenzyl Compounds Followed by Reduction

Step 1.4- (1-Hydroxy-1-(4-pyridyl) methyl-1-nitrobenzene : To a stirred solution of 3- (4-nitrobenzyl) pyridine (6.0 g, 28 mmol) in CH2C12 (90 mL) was added m-CPBA (5.80 g, 33.6 mmol) at 10 °C, and the mixture was stirred at room temp. overnight.

The reaction mixture was successively washed with a 10% NaHS03 solution (50 mL), a saturated K2CO3 solution (50 mL) and a saturated NaCl solution (50 mL), dried (MgS04) and concentrated under reduced pressure. The resulting yellow solid (2.68 g) was dissolved in anh acetic anhydride (30 mL) and heated at the reflux temperature overnight. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (25 mL) and treated with a 20% aqueous NH3 solution (30 mL).

The mixture was stirred at room temp. for 1 h, then was concentrated under reduced pressure. The residue was poured into a mixture of water (50 mL) and CH2C12 (50 mL). The organic layer was dried (MgS04), concentrated under reduced pressure, and purified by column chromatography (80% EtOAc/20% hexane) to afford the desired product as a white solid. (0.53 g, 8%): mp 110-118 °C; TLC (80% EtOAc/20% hexane) Rf0.12; FAB-MS m/z 367 ((M+H) +, 100%).

Step 4- (l-Hydroxy-l- (4-pyridyl)- methyl-1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2.

B10. Formation of 2- (N-methylcarbamoyl) pyridines via the Menisci reaction Step 1.2- (N-methylcarbamoyl)-4-chloropyridine. (Caution: this is a highly hazardous, potentially explosive reaction.) To a solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) under argon at ambient temp was added conc.

H2SO4 (3.55 mL) (exotherm). To this was added H202 (17 mL, 30% wt in H20) followed by FeS047H20 (0.55 g) to produce an exotherm. The reaction was stirred in the dark at ambient temp for lh then was heated slowly over 4 h at 45 °C. When bubbling subsided, the reaction was heated at 60 °C for 16 h. The opaque brown solution was diluted with H20 (700 mL) fol. lowed by a 10% NaOH solution (250 mL). The aqueous mixture was extracted with EtOAc (3 x 500 mL) and the organic layers were washed separately with a saturated NaCl solution (3 x 150 mIL. The combined organics were dried (MgS04) and filtered through a pad of silica gel eluting with EtOAc. The solvent was removed in vacuo and the brown residue was purified by silica gel chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0 °C over 72 h to give 2- (N-methylcarbamoyl)-4-chloropyridine in yield (0. 61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50; MS;'H NMR (CDC13): d 8.44 (d, 1 H, J = 5.1 Hz, CHN), 8.21 (s, 1H, CHCCO), 7.96 (b s, 1H, NH), 7.43 (dd, 1H, J = 2.4,5.4 Hz, C1CHCN), 3.04 (d, 3H, J = 5.1 Hz, methyl); CI-MS m/z 171 ( (M+H) +).

Bll. Generalmethod for the Synthesis of ea-Sulfonylphenyl Anilines

Step To a solution of 4- (4- methylthiophenoxy)-l-ntirobenzene (2 g, 7.66 mmol) in CH2C12 (75 mL) at 0 °C was slowly added mCPBA (57-86%, 4 g), and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was treated with a 1 N NaOH solution (25 mL). The organic layer was sequentially washed with a 1N NaOH solution (25 mL), water (25 mL) and a saturated NaCl solution (25 mL), dried (MgS04), and concentrated under reduced pressure to give 4- (4-methylsulfonylphenoxy)-1- nitrobenzene as a solid (2.1 g).

Step 4- (4-Methylsulfonylphenoxy)-l- nitrobenzene was reduced to the aniline in a manner anaologous to that described in Method B3d, step 2.

B12. General Method for Synthesis of-Alkoxy-o)-carboxyphenyl Anilines Step To a solution of- (3-carboxy-4-hydroxyphenoxy)-l-nitrobenzene (prepared in a manner analogous to that described in Method B3a, step 1,12 mmol) in acetone (50 mL) was added K2C03 (5 g) and dimethyl sulfate (3.5 mL). The resulting mixture was heated aaaaaat the reflux tempoerature overnight, then cooled to room temperature-and filtered through a pad of Celte@. The resulting solution was concentrrated under reduced pressure, absorbed onto silica gel, and purified by column chromatography (50% EtOAc/50% hexane) to give 4- (3-methoxycarbonyl-4-methoxyphenoxy)-l- nitrobenzene as a yellow powder (3 g): mp 115 118 °C.

Step A mixture of 4- (3- methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene (1.2 g), KOH (0.33 g), and water (5 mL) in MeOH (45 mL) was stirred at room temperature overnight and then heated at the reflux temperature for 4 h. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was made acidic with a 1N HC1 solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgS04) and concentrated under reduced pressure to give 4- (3-carboxy-4- methoxyphenoxy)-l-nitrobenzene (1.04 g).

C. General Methods of Urea Formation Cla. Reaction of a Heterocyclic Amine with an Isocyanate N-(5-tert-Butyl-3-thienyl)-N'- (4-phenoxyphenyl)(5-tert-Butyl-3-thienyl)-N'- (4-phenoxyphenyl) urea: To a solution of 5-tert- butyl-3-thiophene-ammonium chloride (prepared as described in Method A4b; 7.28 g, 46.9 mmol, 1.0 equiv) in anh DMF (80 mL) was added 4-phenoxyphenyl isocyanate (8.92 g, 42.21 mmol, 0.9 equiv) in one portion. The resulting solution was stirred at 50-60 °C overnight, then diluted with EtOAc (300 mL). The resulting solution was sequentially washed with H20 (200 mL), a 1 N HC1 solution (50 mL) and a saturated NaCl solution (50 mL), dried (Na2S04), and concentrated under reduced pressure.

The resulting off-white solid was recrystallized (EtOAc/hexane) to give a white solid (13.7 g, 88%), which was contaminated with approximately 5% of bis (4- phenoxyphenyl) urea. A portion of this material (4.67 g) was purified by flash chromatography (9% EtOAc/27% CH2Cl2/64% cyclohexane) to afforded the desired product as a white solid (3.17 g).

Clb. Reaction of a Heterocyclic Amine with an Isocyanate

N-(3-tert-Butyl-5-isoxazolyl)-N'- (4-phenoxyphenyl)(3-tert-Butyl-5-isoxazolyl)-N'- (4-phenoxyphenyl) urea: To a solution of 5- amino-3-tert-butylisoxazole (8.93 g, 63.7 mmol, 1 eq.) in CH2C12 (60 mL) was added 4-phenyloxyphenyl isocyanate (15.47 g, 73.3 mmol, 1.15 eq.) dropwise. The mixture was heated at the reflux temp. for 2 days, eventually adding additional CH2Cl2 (80 mL). The resulting mixture was poured into water (500 mL) and extracted with Et20 (3 x 200 mL). The organic layer was dried (MgSO4) then concentrated under reduced pressure. The residue was recrystallized (EtOAc) to give the desired product (15.7 g, 70%): mp 182-184 °C; TLC (5% acetone/95% acetone) RfO. 27;'H-NMR (DMSO-d6) 8 1.23 (s, 9H), 6.02 (s, 1H), 6.97 (dd, J=0.2,8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 7.08 (t, J=7.4 Hz, 1H), 7.34 (m, 2H), 7.45 (dd, J=2.2,6.6 Hz, 2H), 8.80 (s, 1H), 10.04 (s, 1H); FAB-MS m/z (rel abundance) 352 ((M+H)+, 70%).

Clc. Reaction of a Heterocyclic Amine with an Isocyanate N (3-tert-Butyl-5-pyrazolyl)-N'- (4- (4-methylphenyl) oxyphenyl) urea: A solution of 5-amino-3-tert-butylpyrazole (0.139 g, 1.0 mmol, 1.0 equiv) and 4- (4- methylphenoxy) phenyl isocyanate (0.225 g, 1.0 mmol 1.0 equiv) in toluene (10 mL) was heated at the reflux temp. overnight. The resulting mixture was cooled to room temp and quenched with MeOH (a few mL). After stirring for 30 min, the mixture was concentrated under reduced pressure. The residue was purified by prep. HPLC (silica, 50% EtOAc/50% hexane) to give the desired product (0.121 g, 33%): mp 204 °C; TLC (5% acetone/95% CH2C12) Rf 0.92;'H-NMR (DMSO-d6) 8 1.22 (s, 9H), 2.24 (s, 3H), 5.92 (s, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H), 8.85 (s, 1H), 9.20 (br s, 1H), 11.94 (br s, 1H); EI-MS m/z 364 (MF).

Cld. Reaction of a Heterocyclic Amine with an Isocyanate

N-(5-tert-Butyl-3-thienyl)-N'- (2, 3-dichlorophenyl)(5-tert-Butyl-3-thienyl)-N'- (2, 3-dichlorophenyl) urea: Pyridine (0.163 mL, 2.02 mmol) was added to a slurry of 5-tert-butylthiopheneammonium chloride (Method A4c; 0. 30 g, 1.56 mmol) and 2,3-dichlorophenyl isocyanate (0.32 mL ; 2.02 mmol) in CH2C12 (10 mL) to clarify the mixture and the resulting solution was stirred at room temp. overnight. The reaction mixture was then concentrated under reduced pressure and the residue was separated between EtOAc (15 mL) and water (15 mL). The organic layer was sequentially washed with a saturated NaHC03 solution (15 mL), a 1N HCl solution (15 mL) and a saturated NaCI solution (15 mL), dried (Na2S04), and concentrated under reduced pressure. A portion of the residue was by preparative HPLC (C-18 column; 60% acetonitrile/40% water/0.05% TFA) to give the desired urea (0.180 g, 34%): mp 169-170 °C; TLC (20% EtOAc/80% hexane) Rf 0.57; lH- NMR (DMSO-d6) 8 1.31 (s, 9H), 6.79 (s, 1H), 7.03 (s, 1H), 7.24-7.33 (m, 2H), 8.16 (dd, J=1.84,7.72 Hz, 1H), 8.35 (s, 1H), 9.60 (s, 1H); 13C-NMR (DMSO-d6) 8 31.9 (3C), 151.7,155.2; FAB-MS m/z (rel abundance) 343 ((M+H) +, 83%), 345 ( (M+H+2) +, 56%), 347 ((M+H+4) +, 12%).

Cle. Reaction of a Heterocyclic Amine with an Isocyanate N-(3-tert-Butyl-5-pyrazolyl)-N'- (3, 4-dichlorophenyl)(3-tert-Butyl-5-pyrazolyl)-N'- (3, 4-dichlorophenyl) urea: A solution of 5-amino- 3-tert-butyl-Nl-(tert-butoxycarbonyl)(tert-butoxycarbonyl) pyrazole (Method A5; 0.150 g, 0.63 mmol) and

3,4-dichlorophenyl isocyanate (0. 118 g, 0.63 mmol) were in toluene (3.1 mL) was stirred at 55 °C for 2 d. The toluene was removed in vacuo and the solid was redissolved in a mixture of CH2C12 (3 mL) and TFA (1.5 mL). After 30 min, the solvent was removed in vacuo and the residue was taken up in EtOAc (10 mL). The resulting mixture was sequentially washed with a saturated NaHC03 solution (10 mL) and a NaCI solution (5 mL), dried (Na2$04), and concentrated in vacuo. The residue was purified by flash chromatography (gradient from 40% EtOAc/60% hexane to 55% EtOAc/ 5% hexane) to give the desired product (0.102 g, 48%): mp 182-184 °C; TLC (40% EtOAc/60% hexane) Rf 0.05, FAB-MS m/z 327 ((M+H) +).

C2a. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate, then Reaction with Substituted Aniline

Step 1.3-tert-Butyl-5-isoxazolyl Isocyanate: To a solution of phosgene (20% in toluene, 1.13 mL, 2.18 mmol) in CHZCl2 (20 mL) at 0 °C was added anh. pyridine (0.176 mL, 2.18 mmol), followed by 5-amino-3-tert-butylisoxazole (0.305 g, 2.18 mmol). The resulting solution was allowed to warm to room temp. over 1 h, and then was concentrated under reduced pressure. The solid residue dried in vacuo for 0.5 h.

Step 2. N- (3-tert-Butyl-5-isoxazolyl)-N'- (4- (4-pyridinylthio) phenyl) urea: The crude 3-tert-butyl-5-isoxazolyl isocyanate was suspended in anh toluene (10 mL) and 4- (4-pyridinylthio) aniline (0.200 g, 0.989 mmol) was rapidly added. The suspension was stirred at 80 °C for 2 h then cooled to room temp. and diluted with an EtOAc/CH2Cl2 solution (4: 1,125 mL). The organic layer was washed with water (100 mL) and a saturated NaCI solution (50 mL), dried (MgS04), and concentrated under reduced pressure. The resulting yellow oil was purified by column chromatography (silica gel, gradient from 2% MeOH/98% CH2C12 to 4% MeOH/6% CH2C12) to afford a foam, which was triturated (Et20/hexane) in combination with sonication to give the product as a white powder (0.18 g, 49%): TLC (5% MeOH/95% CH2CI2) Rf0.21;'H-NMR (DMSO-d6) 8 1.23 (s, 9H), 6.06 (s, 1H), 6.95 (d, J=5 Hz, 2H), 7.51 (d, J=8 Hz, 2H), 7.62 (d, J=8 Hz, 2H), 8.32 (d, J=5 Hz, 2H), 9.13 (s, 1H), 10.19 (s, 1H); FAB-MS m/z 369 ((M+H) +).

C2b. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline

Step 1.5-tert-Butyl-3-isoxazolyl Isocyanate: To a solution of phosgene (148 mL, 1.93 M in toluene, 285 mmol) in anhydrous CHxClx (1 L) was added 3-amino-5-tert- butylisoxazole (10.0 g, 71 mmol) followed by pyridine (46 mL, 569 mmol). The mixture was allowed to warm to room temp and stirred overnight (ca. 16 h), then mixture was concentrated in vacuo. The residue was dissolved in anh. THF (350 mL) and stirred for 10 min. The orange precipitate (pyridinium hydrochloride) was removed and the isocyanate-containing filtrate (approximately 0.2 M in THF) was used as a stock solution: GC-MS (aliquot obtained prior to concentration) m/z 166 (M+).

Step 2. N- (5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-pyridinylthio) phenyl) urea: To a solution of 5-tert-butyl-3-isoxazolyl isocyanate (247 mL, 0.2 M in THF, 49.4 mmol) was added 4- (4-pyridinylthio) aniline (5 g, 24.72 mmol), followed by THF (50 mL) then pyridine (4.0 mL, 49 mmol) to neutralize any residual acid. The mixture was stirred overnight (ca. 18 h) at room temp. Then diluted with EtOAc (300 mL). The organic layer was washed successively with a saturated NaCl solution (100 mL), a saturated NaHC03 solution (100 mL), and a saturated NaCI solution (100 mL), dried (MgS04), and concentrated in vacuo. The resulting material was purified by MPLC (2 x 300 g silica gel, 30 % EtOAc/70% hexane) to afford the desired product as a white solid (8.24 g, 90 %): mp 178-179 °C ; lH-NMR (DMSO-d6) 6 1.28 (s, 9H), 6.51

(s, 1H), 6.96 (d, J=6.25 Hz, 2H), 7.52 (d, J=8.82 Hz, 2H), 7.62 (d, J=8.83 Hz, 2H), 8.33 (d, J=6.25 Hz, 2H), 9.10 (s, 1H), 9.61 (s, 1H); EI-MS m/z 368 (M+).

C2c. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followedby Reaction with Substituted Aniline N (3-tert-Butyl-5-pyrazolyl)-N'- (4- (4-pyridinyloxy) phenyl) urea: To a solution of phosgene (1.9M in toluene, 6.8 mL) in anhydrous CH2Cl2 (13 mL) at 0 °C was slowly added pyridine (0.105 mL) was added slowly over a 5 min, then 4- (4- pyridinyloxy) aniline (0.250 g, 1.3 mmol) was added in one aliquot causing a transient yellow color to appear. The solution was stirred at 0 °C for 1 h, then was allowed to warm to room temp. over 1 h. The resulting solution was concentrated in vacuo then the white solid was suspended in toluene (7 mL). To this slurry, 5-amino-3-tert- butyl-N'-(tert-butoxycarbonyl) pyrazole(tert-butoxycarbonyl) pyrazole (0.160 g, 0.67 mmol) was added in one aliquot and the reaction mixture was heated at 70 °C for 12 h forming a white precipitate. The solids were dissolved in a IN HC1 solution and allowed to stir at room temp. for 1 h to form a new precipitate. The white solid was washed (50% Et20/50% pet. ether) to afford the desired urea (0.139 g, 59%): mp >228 °C dec; TLC (10% MeOH/ 90% CHCl3) Rf 0. 239; lH-NMR (DMSO-d6) 6 1.24 (s, 9H), 5.97 (s, 1H), 6.88 (d, J=6.25 Hz, 2H), 7.10 (d, J=8. 82 Hz, 2H), 7.53 (d, J=9. 2 Hz, 2H), 8.43 (d, J=6.25 Hz, 2H), 8.92 (br s, 1H), 9.25 (br s, 1H), 12.00 (br s, 1H); EI-MS m/z rel abundance 351 (M+, 24%). C3a. Reaction of a Heterocyclic Amine with N, N'-Carbonyldiimidazole Followed by Reaction with a Substituted Aniline

N (3-tert-Butyl-1-methyl-5-pyrazolyl)-N'- (4- (4-pyridinyloxy) phenyl) urea: To a solution of 5-amino-3-tert-butyl-1-methylpyrazole (189 g, 1.24 mol) in anh. CH2C12 (2.3 L) was added N, N'-carbonyldiimidazole (214 g, 1.32 mol) in one portion. The mixture was allowed to stir at ambient temperature for 5 h before adding 4- (4- pyridinyloxy) aniline. The reaction mixture was heated to 36 °C for 16 h. The resulting mixture was cooled to room temp, diluted with EtOAc (2 L) and washed with H20 (8 L) and a saturated NaCl solution (4 L). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by crystallization (44.4% EtOAc/44.4% Et20/11.2% hexane, 2.5 L) to afford the desired urea as a white solid (230 g, 51%): mp 149-152 °C ; IH-NMR (DMSO-dó) 6 1.18 (s, 9H), 3.57 (s, 3H), 6.02 (s, 1H), 6.85 (d, J=6.0 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H), 7.52 (d, J=9.0 Hz, 2H), 8.40 (d, J=6.0 Hz, 2H), 8.46 (s, 1H), 8.97 (s, 1H); FAB-LSIMS m/z 366 ((M+H).

C3b. Reaction of a Heterocyclic Amine with N, N'-Carbonyldiimidazole Followed by Reaction with a Substituted Aniline N-(3-tert-Butyl-5-pyrazolyl)-N'- (3- (4-pyridinylthio)(3-tert-Butyl-5-pyrazolyl)-N'- (3- (4-pyridinylthio) phenyl) urea: To a solution of 5-amino-3-tert-butyl-N-(tert-butoxycarbonyl)(tert-butoxycarb onyl) pyrazole (0.282 g, 1.18 mmol) in CH2C12 (1.2 mL) was added N, N'-carbonyldiimidazole (0.200 g, 1.24 mmol) and the mixture was allowed to stir at room temp. for 1 day. 3- (4-Pyridinylthio) aniline (0.239 g, 1.18 mmol) was added to the reaction solution in one aliquot and the resulting mixture was allowed to stir at room temp. for 1 day. Then resulting solution was treated with a 10% citric acid solution (2 mL) and was allowed to stir for 4 h. The organic layer was extracted with EtOAc (3 x 15 mL), dried (MgS04), and

concentrated in vacuo. The residue was diluted with CH2C12 (5 mL) and trifluoroacetic acid (2 mL) and the resulting solution was allowed to stir for 4 h. The trifluoroacetic reaction mixture was made basic with a saturated NaHC03 solution, then extracted with CH2C12 (3 x 15 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (5% MeOH/95% CH2C12). The resulting brown solid was triturated with sonication (50% Et20/50% pet. ether) to give the desired urea (0.122 g, 28%): mp >224 °C dec; TLC (5% MeOH/95% CHC13) Rf 0.067; IH-NMR (DMSO-d6) 6 1.23 (s, 9H), 5.98 (s, 1H), 7.04 (dm, J=13.24 Hz, 2H), 7.15-7.19 (m, 1H), 7.40-7.47 (m, 2H), 7.80-7.82 (m, 1H), 8.36 (dm, J=15.44 Hz, 2H), 8.96 (br s, 1H), 9.32 (br s, 1H), 11.97 (br s, 1H); FAB-MS m/z (rel abundance) 368 (M, 100%).

C4a. Reaction of Substituted Aniline with N, N'-Carbonyldiimidazole Followed by Reaction with a Heterocyclic Amine N (3-tert-Butyl-l-methyl-5-pyrazolyl)-N'- (4- (4-pyridinylmethyl) phenyl) urea: To a solution of4- (4-pyridinylmethyl) aniline (0.200 g, 1.08 mmol) in CH2CI2 (10 mL) was added N, N'-carbonyldiimidazole (0.200 g, 1.23 mmol). The resulting mixture was stirred at room tempe for 1 h after which TLC analysis indicated no starting aniline. The reaction mixture was then treated with 5-amino-3-tert-butyl-1- methylpyrazole (0.165 g, 1.08 mmol) and stirred at 40-45 °C overnight. The reaction mixture was cooled to room temp and purified by column chromatography (gradient from 20% acetone/80% CH2C12 to 60% acetone/40% CH2Cl2) and the resulting solids were crystallized (Et20) to afford the desired urea (0.227 g, 58%): TLC (4% MeOH/96% CH2C12) Rf 0.15;'H-NMR (DMSO-d6) 8 1.19 (s, 9H), 3.57 (s, 3H), 3.89 (s, 2H), 6.02 (s, 1H), 7.14 (d, J=8. 4 Hz, 2H), 7.21 (d, J=6 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 8.45-8.42 (m, 3H), 8.81 (s, 1H); FAB-MS m/z 364 (M+H) +). C4b. Reaction of Substituted Aniline with NsN'-Carbonyldiimidazole Followed by Reaction with a Heterocyclic Amine

N-(3-tert-Butyl-5-pyrazolyl)-N'- (3- (2-benzothiazolyloxy) phenyl)(3-tert-Butyl-5-pyrazolyl)-N'- (3- (2-benzothiazolyloxy) phenyl) urea: A solution of 3- (2-benzothiazolyloxy) aniline (0.24 g, 1.0 mmol, 1.0 equiv) and N. N'- carbonyldiimidazole (0.162 g, 1.0 mmol, 1.0 equiv) in toluene (10 mL) was stirred at room temp for 1 h. 5-Amino-3-tert-butylpyrazole (0.139 g, 1.0 mmol) was added and the resulting mixture was heated at the reflux temp. overnight. The resulting mixture was poured into water and extracted with CH2C12 (3 x 50 mL). The combined organic layers were concentrated under reduced pressure and dissolved in a minimal amount of CH2C12. Petroleum ether was added and resulting white precipitate was resubmitted to the crystallization protocol to afford the desired product (0.015 g, 4%): mp 110-111 °C; TLC (5% acetone/95% CH2Ck) Rf 0.05;'H-NMR (DMSO-d6) 8 1.24 (s, 9H), 5.97 (s, 1H), 7.00-7.04 (m, 1H), 7.21-7.44 (m, 4H), 7.68 (d, J=5.5 Hz, 1H), 7.92 (d, J=7.7 Hz, 1H), 7.70 (s, 1H), 8.95 (s, 1H), 9.34 (br s, 1H), 11.98 (br s, 1H); EI-MS m/z 408 (M+).

C4c. Reaction of a Heterocyclic Amine with Phosgene to Form an Isocyanate Followed by Reaction with Substituted Aniline N (5-tert-Butyl-3-thienyl)-N'- (4- (4-pyridinyloxy) phenyl) urea: To an ice cold solution phosgene (1.93M in toluene; 0.92 mL, 1.77 mmol) in CH2C12 (5 mL) was added a solution of 4- (4-pyridinyloxy) aniline (0. 30 g, 1.61 mmol) and pyridine (0.255 g, 3.22 mmol) in CH2C12 (5 mL). The resulting mixture was allowed to warm to room temp. and was stirred for 1 h, then was concentrated under reduced pressure. The residue was dissolved in CH2C12 (5 mL), then treated with 5-tert-

butylthiopheneammonium chloride (Method A4c; 0.206 g, 1.07 mmol), followed by pyridine (0.5 mL). The resulting mixture was stirred at room temp for 1 h, then treated with 2- (dimethylamino) ethylamine (1 mL), followed by stirring at room temp an additional 30 min. The reaction mixture was then diluted with EtOAc (50 mL), sequentially washed with a saturated NaHC03 solution (50 mL) and a saturated NaCl solution (50 mL), dried (Na2S04), and concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 30% EtOAc/70% hexane to 100% EtOAc) to give the desired product (0.38 g, 97%): TLC (50% EtOAc/50% hexane) Rf 0.13;'H-NMR (CDC13) 8 1.26 (s, 9H), 6.65 (d, J=1.48 Hz, 1H), 6.76 (dd, J=1.47,4.24 Hz, 2H), 6.86 (d, J=1.47 Hz, 1H), 6.91 (d, J=8.82 Hz, 2H), 7.31 (d, J=8.83 Hz, 2H), 8.39 (br s, 2H), 8.41 (d, J=1.47 Hz, 2H); 13C-NMR (CDC13) 8 32.1 (3C), 34.4,106.2,112.0 (2C), 116.6,121.3 (2C), 121.5 (2C), 134.9, 136.1,149.0,151.0 (2C), 154.0,156.9,165.2; FAB-MS m/z (rel abundance) 368 ((M+H)+,100%).

C5. General Method for the Reaction of a Substituted Aniline with Triphosgene Followed by Reaction with a Second Substituted Amine N-(3-tert-Butyl-4-methyl-5-isoxazolyl)-N'- (2-fluorenyl)(3-tert-Butyl-4-methyl-5-isoxazolyl)-N'- (2-fluorenyl) urea: To a solution of triphosgene (55 mg, 0.185 mmol, 0.37eq) in 1,2-dichloroethane (l. OmL) was added a solution of 5-amino-4-methyl-3-tert-butylisoxazole (77.1 mg, 0.50 mmol, 1.0 eq) and diisopropylethylamine (0.104 mL, 0.60 mmol, 1.2 eq) in 1,2-dichloroethane (1.0 mL).

The reaction mixture was stirred at 70 °C for 2 h, cooled to room temp., and treated with a solution of 2-aminofluorene (30.6 mg, 0.50 mmol, 1.0 eq) and diisopropylethylamine (0.087 mL, 1.0 eq) in 1,2-dichloroethane (1.0 mL). The reaction mixture was stirred at 40 °C for 3 h and then at RT for 17 h to produce a precipitate. The solids were washed with Et20 and hexanes to give the desired urea as a beige solid (25 mg, 14%): mp 179-181 °C ; IH-NMR (DMSO-d6) 6 1.28 (s, 9H), 2.47 (s, 3H), 3.86 (s, 2H), 7.22 (t, J=7.3 Hz, 1H), 7.34 (m, 2H), 7.51 (d, J=7.3 Hz, 1H), 7.76 (m, 3H), 8.89 (s, 1H), 9.03 (s, 1H); HPLC ES-MS m/z 362 ( (M+H). C6. General Method for Urea Formation by Curtius Rearrangement and Carbamate Trapping Step 1.5-Methyl-2- (azidocarbonyl) thiophene: To a solution of 5-Methyl-2- thiophenecarboxylic acid (1.06 g, 7.5 mmol) and Et3N (1.25 mL, 9.0 mmol) in acetone (50 mL) at-10 °C was slowly added ethyl chloroformate (1.07 mL, 11.2 mmol) to keep the internal temperature below 5 °C. A solution of sodium azide (0.83 g, 12.7 mmol) in water (6 mL) was added and the reaction mixture was stirred for 2 h at 0 °C. The resulting mixture was diluted with CH2C12 (10 mL) and washed with a saturated NaCI solution (10 mL). The aqueous layer was back-extracted with CH2C12 (10 mL), and the combined organic layers were dried (MgS04) and concentrated in vacuo. The residue was purified by column chromatography (10% EtOAc/90% hexanes) to give the azidoester (0.94 g, 75%). Azidoester (100 mg, 0.6 mmol) in anhydrous toluene (10 mL) was heated to reflux for 1 h then cooled to rt. This solution was used as a stock solution for subsequent reactions.

Step 2.5-Methyl-2-thiophene Isocyanate: 5-Methyl-2- (azidocarbonyl) thiophene (0.100 g, 0.598 mmol) in anh toluene (10 mL) was heated at the reflux temp. for 1 h then cooled to room temp. This solution was used as a stock solution for subsequent reactions.

Step 3. N- (5-tert-Butyl-3-isoxazolyl)-N'- (5-methyl-2-thienyl) urea: To a solution of 5-methyl-2-thiophene isocyanate (0.598 mmol) in toluene (10 mL) at room temp. was added 3-amino-5-tert-butylisoxazole (0.092 g, 0.658 mmol) and the resulting mixture was stirred overnight. The reaction mixture was diluted with EtOAc (50 mL) and sequentially washed with a 1 N HC1 solution (2 x 25 mL) and a saturated NaCI solution (25 mL), dried (MgS04), and concentrated under reduced pressure. The

residue was purified by MPLC (20% EtOAc/80% hexane) to give the desired urea (0.156 g, 93%): mp 200-201 °C; TLC (20% EtOAc/80% hexane) Rf 0.20; EI-MS m/z 368 (M+).

C7. General Methods for Urea Formation by Curtius Rearrangement and Isocyanate Trapping

Step POC13 (67.2 mL, 0.72 mol) was added to cooled (0 °C) DMF (60.6 mL, 0.78 mol) at rate to keep the internal temperature below 20 °C. The viscous slurry was heated until solids melted (approximately 40 °C), then pinacolone (37.5 mL, 0.30 mol) was added in one portion. The reaction mixture was then to 55 °C for 2h and to 75 °C for an additional 2 h. The resulting mixture was allowed to cool to room temp., then was treated with THF (200 mL) and water (200 mL), stirred vigorously for 3 h, and extracted with EtOAc (500 mL). The organic layer was washed with a saturated NaCI solution (200 mL), dried (Na2S04) and concentrated under reduced pressure. The residue was filtered through a pad of silica (CH2C12) to give the desired aldehyde as an orange oil (15.5 g, 35%): TLC (5% EtOAc/95% hexane) Rf 0.54;'H NMR (CDC13) d 1.26 (s, 9H), 6.15 (d, J=7.0 Hz, 1H), 10.05 (d, J=6.6 Hz, 1H).

Step 2. Methyl 5-tert-butyl-2-thiophenecarboxylate: To a solution of 3-chloro- 4,4-dimethylpent-2-enal (1.93 g, 13.2 mmol) in anh. DMF (60 mL) was added a solution of Na2S (1.23 g, 15.8 mmol) in water (10 mL). The resulting mixture was stirred at room temp. for 15 min to generate a white precipitate, then the slurry was treated with methyl bromoacetate (2.42 g, 15.8 mmol) to slowly dissolve the solids.

The reaction mixture was stirred at room temp. for 1.5 h, then treated with a 1 N HC1 solution (200 mL) and stirred for 1 h. The resulting solution was extracted with EtOAc (300 mL). The organic phase was sequentially washed with a 1 N HC1 solution (200 mL), water (2 x 200 mL) and a saturated NaCI solution (200 mL), dried

(Na2SO4) and concentrated under reduced pressure. The residue was purified using column chromatography (5% EtOAc/95% hexane) to afford the desired product (0.95 g, 36%): TLC (20% EtOAc/80% hexane) Rf 0.79;'H NMR (CDC13) 8 1.39 (s, 9H), 3.85 (s, 3H), 6.84 (d, J=3.7 Hz, 1H), 7.62 (d, J=4.1 Hz, 1H); GC-MS m/z (rel abundance) 198 (M+, 25%).

Step 3.5-tert-Butyl-2-thiophenecarboxylic acid: Methyl 5-tert-butyl-2- thiophenecarboxylate (0.10 g, 0.51 mmol) was added to a KOH solution (0.33 M in 90% MeOH/10% water, 2.4 mL, 0.80 mmol) and the resulting mixture was heated at the reflux temperature for 3 h. EtOAc (5 mL) was added to the reaction mixture, then the pH was adjusted to approximately 3 using a 1 N HCI solution. The resulting organic phase was washed with water (5 mL), dried (Na2S04), and concentrated under reduced pressure (0.4 mmHg) to give the desired carboxylic acid as a yellow solid (0.067 g, 73%): TLC (20% EtOAc/79.5% hexane/0.5% AcOH) Rf 0.29;H NMR (CDC13) 8 1.41 (s, 9H), 6.89 (d, J=3.7 Hz, 1H), 7.73 (d, J=3.7 Hz, 1H), 12.30 (br s, 1H); 13C NMR (CDC13) 8 32.1 (3C), 35.2,122.9,129.2,135.1,167.5,168.2.

Step 4. N (5-tert-Butyl-2-thienyl)-N'- (2, 3-dichlorophenyl) urea: A mixture of 5- tert-butyl-2-thiophenecarboxylic acid (0.066 g, 0.036 mmol), DPPA (0.109 g, 0.39 mmol) and Et3N (0.040 g, 0.39 mmol) in toluene (4 mL) was heated to 80 °C for 2 h, 2,3-dichloroaniline (0.116 g, 0.72 mmol) was added, and the reaction mixture was heated to 80°C for an additional 2 h. The resulting mixture was allowed to cool to room temp. and treated with EtOAc (50 mL). The organic layer was washed with a 1 N HC1 solution (3 x 50 mL), a saturated NaHC03 solution (50 mL), and a saturated NaCI solution (50 mL), dried (Na2S04), and concentrated under reduced pressure.

The residue was purified by column chromatography (5% EtOAc/95% hexane) to afford the desired urea as a purple solid (0.030 g, 24%): TLC (10% EtOAc/90% hexane) Rf 0.28; 1H NMR (CDC13) 8 1.34 (s, 9H), 6.59 (br s, 2H), 7.10-7.13 (m, 2H),

7.66 (br s, 1H), 8.13 (dd, J=2.9,7.8 Hz, 1H); 13C NMR (CDC13) 8 32.2 (3C), 34.6, 15,119.2,121.5,124.4,127.6,132.6,135.2,136.6,153.4; HPLC ES-MS m/z (rel abundance) 343 ((M+H) +, 100%), 345 ((M+H+2) +, 67%), 347 ((M+H+4) +, 14%).

C8. Combinatorial Method for the Synthesis of Diphenyl Ureas Using Triphosgene One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a triphosgene solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.).

The vial was capped and heat at 80 °C for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.

D. Misc. Methods of Urea Synthesis D1. Electrophylic Halogenation N (2-Bromo-5-tert-butyl-3-thienyl)-N'- (4-methylphenyl) urea: To a slurry of N- (5- tert-butyl-3-thienyl)-N'- (4-methylphenyl) urea (0.50 g, 1.7 mmol) in CHC13 (20 mL) at room temp was slowly added a solution of Br2 (0. 09 mL, 1.7 mmol) in CHC13 (10 mL) via addition funnel causing the reaction mixture to become homogeneous.

Stirring was continued 20 min after which TLC analysis indicated complete reaction.

The reaction was concentrated under reduced pressure, and the residue triturated (2 x Et20/hexane) to give the brominated product as a tan powder (0.43 g, 76%): mp 161- 163 °C; TLC (20% EtOAc/80% hexane) Rf 0.71;'H NMR (DMSO-d6) 8 1.29 (s, 9H), 2.22 (s, 3H), 7.07 (d, J=8.46 Hz, 2H), 7.31 (d, J=8.46 Hz, 2H), 7.38 (s, 1H), 8.19

(s, 1H), 9.02 (s, 1H); 13C NMR (DMSO-d6) 8 20.3,31.6 (3C), 34.7,89.6,117.5,118.1 (2C), 129.2 (2C), 130.8,136.0,136.9,151.8,155.2; FAB-MS m/z (rel abundance) 367 ((M+H) +, 98%), 369 (M+2+H) +, 100%).

D2. Synthesis of o-Alkoxy Ureas

Step 1. N (5-tert-Butyl-3-thienyl)-N'- (4- (4-hydroxyphenyl) oxyphenyl) urea: A solution of N- (5-tert-butyl-3-thienyl)-N'-(4-(4-methoxyphenyl) oxyphenyl) urea (1.2 g, 3 mmol) in CH2C12 (50 mL) was cooled to-78 °C and treated with BBr3 (1.0 M in CH2C12,4.5 mL, 4.5 mmol, 1.5 equiv) dropwise via syringe. The resulting bright yellow mixture was warmed slowly to room temp and stirred overnight. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL), then washed with a saturated NaHC03 solution (50 mL) and a saturated NaCI solution (50 mL), dried (Na2S04), and concentrated under reduced pressure. The residue was purified via flash chromatography (gradient from 10% EtOAc/90% hexane to 25% EtOAc/75% hexane) to give the desired phenol as a tan foam (1.1 g, 92%): TLC (20% EtOAc/80% hexane) Rf 0.23;'H NMR (DMSO-d6) 8 1.30 (s, 9H), 6.72-6.84 (m, 7H), 6.97 (d, J=1.47 Hz, 1H), 7.37 (dm, J=9.19 Hz, 2H), 8.49 (s, 1H), 8.69 (s, 1H), 9.25 (s, 1H); FAB-MS m/z (rel abundance) 383 ((M+H) +, 33%).

Step 2. N (5-tert-Butyl-3-thienyl)-N'- (4- (4-ethoxyphenyl) oxyphenyl) urea: To a mixture of N- (5-tert-butyl-3-thienyl)-N- (4- (4-hydroxyphenyl) oxyphenyl) urea (0.20 g, 0.5 mmol) and CS2CO3 (0.18 g, 0.55 mmol, 1.1 equiv) in reagent grade acetone (10 mL) was added ethyl iodide (0.08 mL, 1.0 mmol, 2 equiv) via syringe, and the resulting slurry was heated at the reflux temp. for 17 h. The reaction was cooled, filtered, and the solids were washed with EtOAc. The combined organics were concentrated under reduced pressure, and the residue was purified via preparative

HPLC (60% CH3CN/40% H20/0.05% TFA) to give the desired urea as a colorless powder (0.16 g, 73%): mp 155-156 °C; TLC (20% EtOAC/80% hexane) Rf 0. 40;'H- NMR (DMSO-d6) 5 1.30 (s, 9H), 1.30 (t, J=6.99 Hz, 3H), 3.97 (q, J=6.99 Hz, 2H), 6.80 (d, J=1.47 Hz, 1H), 6.86 (dm, J=8.82 Hz, 2H), 6.90 (s, 4H), 6.98 (d, J=1. 47,1H), 7.40 (dm, J=8. 83 Hz, 2H), 8.54 (s, 1H), 8.73 (s, 1H); 13C-NMR (DMSO-d6) 8 14.7, 32.0 (3C), 33.9,63.3,102.5,115.5 (2C), 116.3,118.4 (2C), 119.7 (2C), 119.8 (2C), 135.0,136.3,150.4,152.1,152.4,154.4,154.7; FAB-MS m/z (rel abundance) 411 ((M+H) +, 15%).

D3. Synthesis of eo-Carbamoyl Ureas N (3-tert-Butyl-l-methyl-5-pyrazolyl)-N- (4- (4- acetaminophenyl) methylphenyl) urea: To a solution of N-(3-tert-butyl-1-methyl-5- pyrazolyl)-N'- (4- (4-aminophenyl) methylphenyl) urea (0.300 g, 0.795 mmol) in CH2C12 (15 mL) at 0 °C was added acetyl chloride (0.057 mL, 0.795 mmol), followed by anhydrous Et3N (0.111 mL, 0.795 mmol). The solution was allowed to warm to room temp over 4 h, then was diluted with EtOAc (200 mL). The organic layer was sequentially washed with a 1M HC1 solution (125 mL) then water (100 mL), dried (MgS04), and concentrated under reduced pressure. The resulting residue was purified by filtration through a pad of silica (EtOAc) to give the desired product as a white solid (0.160 g, 48%): TLC (EtOAc) Rf 0.33; 1H-NMR (DMSO-d6) 8 1.17 (s, 9H), 1.98 (s, 3H), 3.55 (s, 3H), 3.78 (s, 2H), 6.00 (s, 1H), 7.07 (d, J=8. 5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 7.44 (d, J=8. 5 Hz, 2H), 8.38 (s, 1H), 8.75 (s, 1H), 9.82 (s, 1H); FAB-MS m/z 420 ( +).

General Method for the Conversion of Ester-Containing Ureas into Alcohol- Containing Ureas N-(NI- (2-Hydroxyethyl)-3-tert-butyl-5-pyrazolyl)-N'- (2, 3-dichlorophenyl)(NI- (2-Hydroxyethyl)-3-tert-butyl-5-pyrazolyl)-N'- (2, 3-dichlorophenyl) urea: A solution of N (NI- (2- (2,3-dichlorophenylamino) carbonyloxyethyl)-3-tert-butyl-5- pyrazolyl)-N'- (2,3-dichlorophenyl) urea (prepared as described in Method A3; 0.4 g, 0.72 mmoles) and NaOH (0.8 mL, 5N in water, 4.0 mmoles) in EtOH (7 mL) was heated at65 °C for 3 h at which time TLC indicated complete reaction. The reaction mixture was diluted with EtOAc (25 mL) and acidified with a 2N HC1 solution (3 mL). The resulting organic phase was washed with a saturated NaCI solution (25 mL), dried (MgS04) and concentrated under reduced pressure. The residue was crystallized (Et20) to afford the desired product as a white solid (0.17 g, 64 %): TLC (60% EtOAc/40% hexane) Rf 0.16;'H-NMR (DMSO-db) 8 1.23 (s, 9H), 3.70 (t, J=5.7 Hz, 2H), 4.10 (t, J=5.7 Hz, 2H), 6.23 (s, 1H), 7.29-7.32 (m, 2H), 8.06-8.09 (m, 1H), 9.00 (br s, 1H), 9.70 (br s, 1H); FAB-MS m/z (rel abundance) 371 ((M+H)+, 100%).

D5a. General Method for the Conversion of Ester-Containing Ureas into Amide-Containing Ureas Step 1. N-(NI- (Carboxymethyl)-3-tert-butyl-5-pyrazolyl)-N'- (2,3- dichlorophenyl) urea: A solution of N-(NI- (ethoxycarbonylmethyl)-3-tert-butyl-5- pyrazolyl)-N'- (2,3-dichlorophenyl) urea (prepared as described in Method A3,0.46 g, 1.11 mmoles) and NaOH (1.2 mL, 5N in water, 6.0 mmoles) in EtOH (7 mL) was stirred at room temp. for 2 h at which time TLC indicated complete reaction. The reaction mixture was diluted with EtOAc (25 mL) and acidified with a 2N HC1

solution (4 mL). The resulting organic phase was washed with a saturated NaCl solution (25 mL), dried (MgS04) and concentrated under reduced pressure. The residue was crystallized (Et2O/hexane) to afford the desired product as a white solid (0.38 g, 89%): TLC (10% MeOH/90% CH2C12) Rf 0.04;'H-NMR (DMSO-d6) 8 1.21 (s, 9H), 4.81 (s, 2H), 6.19 (s, 1H), 7.28-7.35 (m, 2H), 8.09-8.12 (m, 1H), 8.76 (br s, 1H), 9.52 (br s, 1H); FAB-MS m/z (rel abundance) 385 ((M+H)+, 100%).

Step 2. N-(NI- ( (Methylcarbamoyl) methyl)-3-tert-butyl-5-pyrazolyl)-N'- (2,3- dichlorophenyl) urea: A solution of N-(NI- (carboxymethyl)-3-tert-butyl-5- pyrazolyl)-N'- (2,3-dichlorophenyl) urea (100 mg, 0.26 mmole) and N, N'- carbonyldiimidazole (45 mg, 0.28 mmole) in CH2Cl2 (10 mL) was stirred at room temp. 4 h at which time TLC indicated formation of the corresponding anhydride (TLC (50% acetone/50% CH2Ck) Rf 0.81). Dry methylamine hydrochloride (28 mg, 0.41 mmole) was then added followed by of diisopropylethylamine (0.07 mL, 0.40 mmole). The reaction mixture was stirred at room temp. overnight, then diluted with CH2C12, washed with water (30 mL), a saturated NaCl solution (30 mL), dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 10% acetone/90% CH2C12 to 40% acetone/60% CH2Ck) and the residue was crystallized (Et20/hexane) to afford the desired product (47 mg, 46%): TLC (60% acetone/40% CH2C12) Rf 0.59;'H-NMR (DMSO-d6) 8 1.20 (s, 9H), 2.63 (d, J=4.5 Hz, 3H), 4.59 (s, 2H), 6.15 (s, 1H), 7.28- 7.34 (m, 2H), 8.02-8.12 (m, 2H), 8.79 (br s, 1H), 9.20 (br s, 1H); FAB-MS m/z (rel abundance) 398 ( (M+H) +, 30%). D5b. General Method for the Conversion of Ester-Containing Ureas into Amide-Containing Ureas

Step 1. N- (5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-carboxyphenyl) oxyphenyl) urea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-ethoxyoxycarbonylphen yl)- oxyphenyl) urea (0.524 g, 1.24 mmol) in a mixture of EtOH (4 mL) and THF (4 mL) was added a 1M NaOH solution (2 mL) and the resulting solution was allowed to stir overnight at room temp. The resulting mixture was diluted with water (20 mL) and treated with a 3M HCl solution (20 mL) to form a white precipitate. The solids were washed with water (50 mL) and hexane (50 mL), and then dried (approximately 0.4 mmHg) to afford the desired product (0.368 g, 75 %). This material was carried to the next step without further purification.

Step 2. N-(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4- (N-methylcarbamoyl)- phenyl) oxyphenyl) urea: A solution of N-(5-tert-butyl-3-isoxæolyl)-N'-(4-(4- carboxyphenyl) oxyphenyl) urea (0.100 g, 0.25 mmol), methylamine (2.0 M in THF; 0.140 mL, 0.278 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (76 mg, 0.39 mmol), and N-methylmorpholine (0.030 mL, 0.27 mmol) in a mixture of THF (3 mL) and DMF (3mL) was allowed to stir overnight at room temp. then was poured into a 1M citric acid solution (20 mL) and extracted with EtOAc (3 x 15 mL). The combined extracts were sequentially washed with water (3 x 10 mL) and a saturated NaCI solution (2 x 10 mL), dried (Na2S04), filtered, and concentrated in vacuo. The resulting crude oil was purified by flash chromatography (60 % EtOAc/40% hexane) to afford the desired product as a white solid (42 mg, 40%): EI-MS m/z 409 ((M+H) +). D6. General Method for the Conversion of-Amine-Containing Ureas into Amide-Containing Ureas

N-(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-aminophenyl) oxyphenyl)(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-aminophenyl) oxyphenyl) urea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N'- (4- (4-tert-butoxycarbonylaminophenyl) oxy- phenyl)-urea (prepared in a manner analogous to Methods B6 then C2b; 0.050 g, 0.11 mmol) in anh 1,4-dioxane (3 mL) was added a conc HC1 solution (1 mL) in one portion and the mixture was allowed to stir overnight at room temp. The mixture was then poured into water (10 mL) and EtOAc (10 mL) and made basic using a 1M NaOH solution (5 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na2S04), and concentrated in vacuo to afford the desired product as a white solid (26 mg, 66%). EI-MS m/z 367 ((M+ H) +).

D7. General Method for the Oxidation of Pyridine-Containing Ureas N-(5-tert-Butyl-3-isoxazolyl)-N'- (4- (N-oxo-4-pyridinyl) methylphenyl)(5-tert-Butyl-3-isoxazolyl)-N'- (4- (N-oxo-4-pyridinyl) methylphenyl) urea: To a solution of N- (S-tert-butyl-3-isoxazolyl)-N'- (4- (4-pyridinyl) methylphenyl) urea (0.100 g, 0.29 mmol) in CHC13 (10 mL) was added m-CPBA (70% pure, 0.155 g, 0.63 mmol) and the resulting solution was stirred at room temp for 16 h. The reaction mixture was then treated with a saturated K2CO3 solution (10 mL). After 5 min, the solution was diluted with CHC13 (50 mL). The organic layer was washed successively with a saturated aqueous NaHS03 solution (25 mL), a saturated NaHC03 solution (25 mL) and a saturated NaCI solution (25 mL), dried (MgS04), and concentrated in vacuo. The residual solid was purified by MPLC (15% MeOH/85% EtOAc) to give the N-oxide (0.082 g, 79%).

D8. General Method for the Acylation of a Hydroxy-Containing Urea

N-(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-acetoxyphenyloxy) phenyl)(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4-acetoxyphenyloxy) phenyl) urea: To a solution of N- (5-tert-butyl-3-isoxazolyl)-N- (4- (4-hydroxyphenyloxy) phenyl) urea (0.100 g, 0.272 mmol), NN-dimethylaminopyridine (0.003 g, 0.027 mmol) and Et3N (0.075 mL, 0.544 mmol) in anh THF (5 mL) was added acetic anhydride (0.028 mL, 0.299 mmol), and the resulting mixture was stirred at room temp. for 5 h. The resulting mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL). The resulting solution was sequentially washed with a 5% citric acid solution (10 mL), a saturated NaHC03 solution (10 mL) and a saturated NaCI solution (10 mL), dried (Na2S04), and concentrated under reduced pressure to give an oil which slowly solidified to a glass (0.104 g, 93%) on standing under reduced pressure (approximately 0.4 mmHg): TLC (40% EtOAc/60% hexane) Rf 0.55; FAB-MS m/z 410 ((M+H) +).

D9. Synthesis of o)-Alkoxypyridines Step 1. N : (5-tert-Butyl-3-isoxazolyl)-N'- (4- (2 (1H)-pyridinon-5-yl) oxyphenyl)- urea: A solution of N-(5-tert-butyl-3-isoxazolyl)-N'- (4- (5- (2-methoxy) pyridyl)- oxyaniline (prepared in a manner analogous to that described in Methods B3k and C3b; 1.2 g, 3.14 mmol) and trimethylsilyl iodide (0.89 mL, 6.28 mmol) in CH2C12 (30 mL) was allowed to stir overnight at room temp., then was to 40 °C for 2 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by column chromatography (gradient from 80% EtOAc/20% hexans to 15% MeOH/85% EtOAc) to give the desired product (0.87 g, 75%): mp 175-180 °C; TLC (80% EtOAc/20% hexane) Rf 0.05; FAB-MS m/z 369 ((M+H) +, 100%).

Step 2. A (5-tert-Butyl-3-isoxazolyl)-N'- (4- (5- (2-Ethoxy) pyridyl) oxyphenyl) urea: A slurry of N- (5-tert-butyl-3-isoxazolyl)-N- (4- (2 (lH)-pyridinon-5-yl) oxyphenyl) urea (0.1 g, 0.27 mmol) and Ag2C03 (0.05 g, 0.18 mmol) in benzene (3 mL) was stirred at room temp. for 10 min. Iodoethane (0.023 mL, 0.285 mmol) was added and the resulting mixture was heated at the reflux temp. in dark overnight. The reaction mixture was allowed to cool to room temp., and was filtered through a plug of Celites then concentrated under reduced pressure. The residue was purified by column chromatography (gradient from 25% EtOAc/75% hexane to 40% EtOAc/60% hexane) to afford the desired product (0.041 g, 38%): mp 146 °C; TLC (40% EtOAc/60% hexane) RfO. 49; FAB-MS m/z 397 ((M+H) +, 100%).

D10. Reduction of an Aldehyde-or Ketone-Containing Urea to a Hydroxide- Containing Urea N-(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4- (l-hydroxyethyl) phenyl) oxyphenyl)(5-tert-Butyl-3-isoxazolyl)-N'- (4- (4- (l-hydroxyethyl) phenyl) oxyphenyl) urea: To a solution of N-(5-tert-butyl-3-isoxazolyl)-N'-(4-(4-(1- acetylphenyl) oxyphenyl) urea (prepared in a manner analogous to that described in Methods B1 and C2b; 0.060 g, 0.15 mmol) in MeOH (10 mL) was added NaBH4 (0.008 g, 0.21 mmol) in one portion. The mixture was allowed to stir for 2 h at room temp., then was concentrated in vacuo. Water (20 mL) and a 3M HC1 solution (2 mL) were added and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (3 x 10 mL) and a saturated NaCI solution (2 x 10 mL), dried (MgS04), and concentrated in vacuo. The resulting white solid was purified by trituration (Et20/hexane) to afford the desired product (0.021 g, 32 %): mp 80-85 °C ;'H NMR (DMSO-d6) 8 1.26 (s, 9H), 2.50 (s, 3H), 4.67 (m, 1H), 5.10 (br s, 1H), 6.45 (s, 1H), 6.90 (m, 4H), 7.29 (d, J=9.0 Hz, 2H), 7.42 (d, J=9.0 Hz, 2H), 8.76 (s, 1H), 9.44 (s, 1H); HPLC ES-MS m/z 396 ( (M+H) +). Dll. Synthesis of Nitrogen-Substituted Ureas by Curtius Rearrangement of Carboxy-Substituted Ureas

N-(5-tert-Butyl-3-isoxazolyl)-N'- (4- (3- (benzyloxycarbonylamino) phenyl)- oxyphenyl) urea: To a solution of the N-(5-tert-butyl-3-isoxazolyl)-N'- (4- (3- carboxyphenyl) oxyphenyl) urea (prepared in a manner analogous to that described in Methods B3a, Step 2 and C2b; 1.0 g, 2.5 mmol) in anh toluene (20 mL) was added Et3N (0.395 mL, 2.8 mmol) and DPPA (0.610 mL, 2.8 mmol). The mixture was heated at 80 °C with stirring for 1.5 h then allowed to cool to room temp. Benzyl alcohol (0.370 mL, 3.5 mmol) was added and the mixture was heated at 80 °C with stirring for 3 h then allowed to cool to room temp. The resulting mixture was poured into a 10% HC1 solution (50 mL) and teh resulting solution extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (3 x 50 mL) and a saturated NaCI (2 x 50 mL), dried (Na2S04), and concentrated in vacuo. The crude oil was purified by column chromatography (30% EtOAc/70% hexane) to afford the desired product as a white solid (0.7 g, 60 %): mp 73-75 °C ;'H NMR (DMSO-d6) 8 1.26 (s, 9H), 5.10 (s, 2H), 6.46 (s, 1H), 6.55 (d, J=7.0 Hz, 1H), 6.94 (d, J=7.0 Hz, 2H), 7.70 (m, 7H), 8.78 (s, 1H), 9.46 (s, 1H), 9.81 (s, 1H); HPLC ES-MS m/z 501 ((M+H) +).

The following compounds have been synthesized according to the General Methods listed above: Table 1.5-Substituted-3-isoxazolyl Ureas mp TLC Solvent Mass Synth. Ex. Rl R2 (°C) Rf System Spec. Source Method 1 t-Bu 169-0.45 25% 357 FAB Clb 172 EtOAc/ (M+H) + 75% hexane 2 t-Bu Me Me 0.63 5% 288 FAB C2a MeOH/ (M+H) + 95% CH2C12 3 t-Bu OBu-n 169-424 FAB C2b, D2 171 M+H + 4 t-Bu 0. 19 50% 423 FAB C2b, D3 \=/"'0 EtOAc/ (M+H) + Et 50% hexane 5 t-Bu 202-0.15 60% 409 FAB C2b, D3 p 206 EtOAc/ (M+H) + Me 40% hexane 6 t-Bu NH 214-0.75 60% 463 FAB C2b, D3 p 217 EtOAc/ (M+H) + F3C 40% hexane 7 t-Bu t3O4OBn l57 0.42 40% 458 FAB B3a, EtOAc (M+H) + C2b 60% hexane 8 t-Bu 148-352 FAB Clc 149 (M+H) + 9 t-Bu Cl Cl 0.12 20% 329 HPLC/Clc EtOAc/ (M+H) + ES-MS 80% hexane 10 t-Bu Cl 176-0.50 30% 400 (M+) HPLC/C2b EtOAc/ES-MS O \/Me 70% hexane 11 t-Bu 156-0. 50 30% 366 HPLC/C2b 157 EtOAc (M+H) + ES-MS 70% hexane 12 t-Bu fi5 H2/= l90-0. l5 30% 350 (M+) EI C2b C-N 191 EtOAc/ 70% hexane 13 t-Bu 175-0.25 30% 409 HPLC/B3a 177 EtOAc/ (M+H) + ES-MS Step 1, 0 70% B3b S hexane Step 2, C2b 14 t-Bu _ 0. 35 30% 402 HPLC/B3b, EtOAc/ (M+H) + ES-MS C2b /\ 70% hexane 15 t-Bu 0. 1 10% 350 HPLC/C2b MeOH/ (M+H) + ES-MS 0 90% CH2C12 16 t-Bu 2 240-0.2 15% 352 (M+) EI C2b 243 MeOH/ 85% EtOAc 17 t-Bu 0. 15 30% 367 (M+) EI B3a, O OH EtOAc/C2b, D2 70% Step 1 hexane 18 t-Bu </=\ 178-368 (M+ | EI B4a, vS_N 179 C2b 19 t-Bu H2 N 164-0.25 30% 351 FAB Bl, C2b 165 EtOAc/ (M+H) + 70% hexane 20 t-Bu H2 N 170-0.15 30% 351 FAB B7, B1, e Cç 172 EtOAc/ (M+H) + C2b 70% hexane 21 t-Bu HO 0.3 25% 368 FAB C2b EtOAc/ (M+H) + /\ O \/75% hexane 22 t-Bu H2 188-367 FAB D7 eC<NO 191 (M+H) + 23 t-Bu Me 0. 8 25% 366 FAB B3a, EtOAc/ EtOAc/ (M+H) + C2b /\ O \/75% hexane 24 t-Bu/\ p OMe 155-0.55 30% 382 FAB B3a, 156 EtOAc/ (M+H) + C2b 70% hexane 25 t-Bu/\ pOpm"n 145-0.6 25% 438 FAB B3a, 1 148 EtOAc/ (M+H) + C2b, D2 75% hexane 26 t-Bu 137-0. 62 25% 410 FAB B3a, 26 t-Bu/\ p ppr-n 141 EtOAc/ (M+H) + C2b, D2 75% hexane 27 t-Bu 164-0.6 25% 410 FAB B3a, 166 EtOAc/ (M+H) + C2b, D2 75% hexane 28 t-Bu 69-0.6 25% 424 FAB B3a, 71 EtOAc/ (M+H) + C2b, D2 - ? 5% hexane 29 t-Bu OH 78-0.15 25% 368 FAB C2b _ao_o 80 EtOAc/ (M+H) + \/75% hexane 30 t-Bu 235 0.35 25% 402 FAB B3b, EtOAc/ (M+H) + C2b 0/75% hexane 31 t-Bu S 201-0.35 25% 418 FAB B3b, 202 EtOAc/ (M+H) + C2b 75% hexane 32 t-Bu 158-0.25 30% 369 FAB B4a, 159 EtOAc/ (M+H) + C2b S-\CN 70% hexane 33 t-Bu CFg 180-0.15 30% 437 FAB B3b, son EtOAc/ (M+H) + C2b --S--N 70% hexane 34 t-Bu N 68-0.3 50% 370 FAB B4a, vStN ? 71 EtOAc/ (M+H) + C2b N 50% hexane 35 t-Bu N 159-0.2 50% 370 FAB B4a, \==/\- 161 EtOAc/ (M+H) + C2b 50% hexane 36 t-Bu 183-0.3 30% 403 FAB C2b \/Cl 186 EtOAc/ (M+H) + 70% hexane 98-0. 25 10% 454 FAB C2b 101 EtOAc/ (M+H) + hexane hexane 38 t-Bu 163-0.25 20% 394 FAB Bl, C2b \/166 EtOAc/ (M+H) + 80% hexane 39 t-Bu 0-&SMe 144-0. 3 30% 403 FAB C2b EtOAc/) 70% hexane 40 t-Bu/ 25 10% 454 FAB C2b -J-O-OMc., 57 90% hexane 41 t-Bu 162-0.25 20% 394 FAB B 1, C2b S \/F 164 EtOAc/ (M+H) + 80% hexane 42 t-Bu S Me 149-0.15 15% 382 FAB C2b 150 EtOAc (M+H) + 85% hexane 43 t-Bu N 200-0. 35 50% 354 FAB B3j, 201 EtOAc/ (M+H) + C2b "50% hexane 44 t-Bu Ço i7-0.3 30% 408 (M+) EI B3e, 80 EtOAc/C2b N hexane 45 t-Bu N 162-0.17 40% 354 FAB B3j, 164 EtOAc/ (M+H) + C2b 60% hexane 46 t-Bu n N= 73 0.2 30% 368 (M+) EI B2, C2b --as-\0/76 EtOAc/ 70% hexane 47 t-Bu 185-030 30% 413 FAB C2b S EtOAc (M+H) + 70% hexane 48 t-Bu/\ S B2, C2b 160 (M+H) + 49 t-Bu MeO 73-0. 15 25% 428 FAB B2, C2b 75 75 EtOAc/ (M+H) + 75% OMe hexane 50 t-Bu Me 188-0.25 5% 422 FAB B1, C2b < vEt 190 EtOAc/ (M+H) + et 95% hexane 51 t-Bu 143-0.25 30% 398 FAB B3e, 145 EtOAc/ (M+H) + C2b 70% hexane 52 t-Bu OMe 148-0.25 30% 428 FAB B3e, 151 EtOAc/ (M+H) + C2b OMe 70% hexane 53 t-Bu 0.30 100% 353 FAB B4b, EtOAc (M+H) + C3b 54 t-Bu CFg 172-0.25 10% 420 FAB C2b 174 EtOAc/ (M+H) + 90% hexane 55-Bu t3OvOMe 112269-0.25 30% 412 FAB B3e, 129 EtOAc/ (M+H) + C2b OMe 70% hexane i 56 t-Bu 201-0. 5 10% 396 FAB B3e, 204 204 EtOAc/ (M+H) + C2b, D2 OEt 90% hexane 57 t-Bu N 163-0.30 40% 369 FAB B4a, \/164 EtOAc/ (M+H) + C2b 60% hexane 58 t-Bu 162-0.20 25% 363 (M+) EI C2b 163 EtOAc/ 75% texane 59 t-Bu N 127-0.22 40% 353 FAB B3e \/129 EtOAc/ (M+H) + Step 1, 60% B2, C2b hexane 60 t-Bu N 85-0.20 50% 402 (M+) EI B3e \J EtOAc Step 1, 50% B2, C2b hexane 61 t-Bu MeO 108-0.25 10% 381 EI B3e, 110 EtOAc (M+H) + C2b 90% hexane 62 t-Bu C02Et 153-0.25 30% 424 FAB B3e, 155 155 EtOAc/ (M+H) + C2b 70% hexane 63 t-Bu no<NH 117-0.25 10% 467 FAB B6, C2b \J 120 EtOAc/ (M+H) + t-BuO 90% hexane 64 t-Bu h)/=\ 186-0.25 30% 367 FAB B6, 189 189 EtOAc/ (M+H) + C2b, D6 70% hexane 65 t-Bu 209-0.25 60% 423 FAB B3e, 2 212 EtOAc/ (M+H) + C2b, 2 40% D5b hexane 66 t-Bu 0 221-0.25 60% 409 FAB B3e, e 224 EtOAc/ (M+H) + C2b, 40% D5b hexane 67 t-Bu °ss 114-0.25 60% 409 FAB B3e, 117 EtOAc/ (M+H) + C2b, 40% DSb hexane 68 t-Bu 201-0.25 60% 423 FAB B3e, 203 EtOAc/ (M+H) + C2b, O (, hexane 69 2530%423t-Bu nOnCO Et 145-0. (M+) EI B3e, 147 EtOAc/C2b 70% hexane 70 t-Bu 148-0. 25 20% 370 FAB B3e, 151 EtOAc/ (M+H) + C2b 80% hexane 71 t-Bu AOn 188-0.25 20% 382 FAB B3e, 201 EtOAc/ (M+H) + C2b OMe 80% hexane 72 t-Bu N 134-0.25 20% 367 FAB B3e, wu 136 EtOAc/ (M+H) + C2b 80% hexane I 73 t-Bu nO m 152-0.25 20% 396 FAB B3e, OMe 155 EtOAc/ (M+H) + C2b 80% hexane 74 t-Bu 176-0.25 50% 403 FAB B3e, 178 EtOAc/ (M+H) + C2b N 50% hexane 75 t-Bu 200 0.30 5% 396 FAB B3a dec MeOH/ (M+H) + Step 2, 0.5% C2b AcOH/ 94.5% CH2C12 76 t-Bu O 177-419 FAB B8, eH2 < B2b, i O C2b 77 t-Bu/\ p \/NH 0.60 60% 485 FAB C2b, D3 zozo EtOAc/ (M+H) + CH2 40% hexane 78 t-Bu Et 194-0.24 5% 377 FAB C3a N 195 MeOH/ (M+H) + 95% CH2C12 79 t-Bu H 160-0. 79 75% 381 FAB C3a oye 25% hexane 80 t-Bu 140-0.25 50% 352 (M+) EI B4b, 143 EtOAc/C3b 0- (N 50% CH2C12 81 t-Bu 147-0.25 50% 352 (M+) EI B3f, 150 EtOAc/C3b b- ( 50% N CH2C12 82 t-Bu 166-0. 44 50% 396 FAB C3b < EtOAc/ (M+H) + 0 50% hexane 7 83 t-Bu _ 175 0.05 80% 369 FAB B3k, 180 EtOAc/ (M+H) + C3b, D9 O4O 20% NH hexane 84 t-Bu n 190-0.25 50% 367 FAB B3g, 193 N 193 EtOAc/ (M+H) + C3b 0-\ Me 50% CH2CI2 85 t-Bu < 136-0. 25 50% 367 FAB B4b, 140 EtOAc/ (M+H) + C3b 0-. N 50% CH2CI2 86 t-Bu Me 65-0.25 50% 367 FAB B4b, oOtN 67 EtOAc/ (M+H) + C3b 67 50% CH2C12 87 t-Bu Me 68-0.25 50% 383 FAB B4a, N 72 EtOAc (M+H) + C3b 50% CH2C12 88 t-Bu N 146 0.49 40% 397 FAB B3k, EtOAc EtOAc/ (M+H) + C3b, D9 60% hexane 89 t-Bu N 100 0. 54 40% 411 FAB B3k, EtOAc (M+H) + C3b, D9 60% hexane 90 t-Bu N 100 0.62 40% 411 FAB B3k, ---O EtOAc/ (M+H) + C3b, D9 60% hexane 91 t-Bu Me 164-0. 25 50% 382 (M+) EI B4a, 165 EtOAc/C3b S-N 50% CH2C12 92 t-Bu H2 175-0.25 20% 485 FAB B3e, < EtOAc/ (M+H) + C3b, 80% 80% D5b hexane O 93 I-Bu 94-0.25 20% 390 FAB B5, C3b 97 97 EtOAc/ (M+H) + 80% OEt hexane 0 1 94 t-Bu H 137-0.30 50% (M+) EI C3a, D2 141 141 EtOAc/step 1 50% hexane 95 t-Bu OH 0.15 100% 367 FAB B9, C3a EtOAc EtOAc (M+H) + 96 t-Bu 120-0.25 20% 471 HPLC B3e, 0 122 EtOAc/ (M+H) + ES-MS C3b, -/'0-<\ hexane ru DSb hexane 97 t-Bu Et-NH 168-0.25 50% 423 HPLC B3e, 170 EtOAc/ (M+H) + ES-MS C3b, 50% D5b hexane 98 t-Bu OH 80-0. 25 50% 396 HPLC B1, 85 EtOAc (M+H) + ES-MS C2b, 50%-D10 hexane D10 99 t-Bu 0 73-0.25 30% 501 HPLC B3a Q EtOAc/ (M+H) + ES-MS step 2, nu 70% C2b, hexane D 11 100 t-Bu Br 240, 414. 414 HPLC DEC 95 (M+H) + ES-MS Br 101 t-Bu OH 132-0. 52 40% 383 FAB B3a, 134 EtOAc (M+H) + B1, C3b 60% hexane 103 t-Bu O 0.52 100% 396 HPLC B10, SNH2 EtOAc (M+H) +/ES-B4b, musMS C2b 104 t-Bu 0 107-0.85 100% 410 FAB B10, 'MMe 110 EtOAc (M+H) + B4b, C2b 105 t-Bu 0 0.75 100% 396 HPLC B10, w, EtOAc (M+H) +/ES-B4b, O N MS C2b 106 t-Bu 132-B3d eOç 135 step 2, /\ 0 C3a 107 t-Bu 0.45 100% 369 FAB C2b EtOAc (M+H) + N I F I 108 t-Bu 0.60 100% 365. FAB C2b EtOAc (M+H) + N XN. 109 t-Bu 0.55 40% 410 FAB B3b, \=/U) EtOAc/ (M+H) + C2b, D2 Me 60% Step 1, hexane D8 110 t-Bu 176-B7, C2a N 178 _a CH2 III i-Bu 195-0. 30 25% 397 FAB C2b 197 EtOAc 1 (M+) 75% hexane 112 t-Bu N=\ 179-B3b, N/1 g2 C2a 113 t-Bu Me 78-0.25 10% 379 EI B3e, / 82 EtOAc/ (M+) C3b 90% Me CH2C12 114 t-Bu H2 203-0. 35 10% 340 FAB B8, -Q-C-N J 206 MeOH (M+H) + B2b, 0.5% C2b AcOH/ 89.5% EtOAc 115 t-Bu H 189-0.189-0.30% 351 FAB C2b 191 191 EtOAc/ (M+H) + 70% hexane 116 t-Bu F 0.60 5% 404 FAB B3b acetone/ (M+H) + step 1,2, 95% Cld FCH2C12 117 t-Bu O 234 0. 30 5% 396 FAB B3a OH dec MeOH/ (M+H) + Step 2, 0. 5% C2b AcOH/ 94.5% CH2C12 118 t-Bu tk 135- D 138 MeHN 119 t-Bu 0.13 5% 486 FAB B3b acetone/ (M+H) + step 1,2, Cl 95% Cld CH2C12 121 t-Bu 177-0.20 30% 351 FAB B7, B1, 1 178 EtOAc/ (M+H) + C2b H 70% uN hexane 122 t-Bu n/=\ 0.40 25% 366 FAB B3a, EtOAc/ (M+H) + C2b Me 75% hexane 123 t-Bu n/=\ 150-0.45 25% 380 FAB B3a, O 158 EtOAc/ (M+H) + C2b Me 75% hexane 124 t-Bu 118-0.50 25% 420 FAB B3a 122 EtOAc/ EtOAc/ (M+H) Step 1, Cl 75% B3b hexane Step 2, C2b 125 t-Bu 176-0. 55 25% 366 FAB B3a, 182 EtOAc/ (M+H) + C2b Me 75% hexane 126 t-Bu 176-0.16 5% 386 FAB C2b /\ O \/Cl 177 MeOH/ (M+H) + 95% CH2C12 127 t-Bu H2 195-B8, C2a 198 128 t-Bu/ S 141-0. 63 5% 381 FAB B3b 144 144 acetone/ (M+H) + step 1,2, Me 95% Cld CH2C12 129 t-Bu 145-0.44 5% 369 FAB B3b 148 acetone/ (M+H) + step 1,2, F 95% Cld CH2C12 131 t-Bu 199-0.59 5% 419 FAB Bla 200 acetone (M+) CF3 95% CH2C12 132 t-Bu S Me 200-0.20 20% 280 FAB Clb < 201 EtOAc/ (M+H) + 80% hexane 133 t-Bu 167-374 FAB B3i, B1, \=/\k 169 (M+H) + C2b 134 t-Bu 137-0.62 25% 410 FAB B3a, 141 EtOAc/ (M+H) + C2b, D2 75% hexane 135 t-Bu 0.57 5% 386 FAB B3b acetone/ (M+H) + step 1,2, F 95% Cld CH2C12 136 t-Bu aOç 0.50 5% 366 FAB Bla acetone/ (M+H) + Me 95% CH2C12 Table 2.3-Substituted-5-isoxazolyl Ureas

mp TLC Solvent Mass Synth. Ex. Rl R2 (°C) Rf System Spec. Source Method 137 Me/ 25 5% 324 FAB Clb O acetone/ (M+H) + 95% CH2CI2 138 i-Pr 166-0.54 50% 352 FAB Clb 170 EtOAc (M+H) + 50% pet ether 139 i-Pr CI Cl 148 0.40 5% 313 EI Clb 149 acetone/ (M+) 95% CH2C12 140 i-Pr H2 272 0.21 5% 337 FAB A2, C3a '\==/\ dec MeOH/ (M+H) + 95% CHC13 141 i-Pr 0.25 5% 355 FAB A2, MeOH/ (M+H) + B4a, S- (N 95% C3a CHOC13 142 i-'p OMe. 14 30% 368 FAB A2, EtOAc/ (M+H) + B3a, 70% pet C3a ether 143 i-Pr AO\N 75-0. 22 5% 339 FAB A2, C3a 77 MeOH/ (M+H) + dec 95% CH2C12 144 i-Pr/ SN 112-0.29 5% 355 FAB A2, 117 MeOH/ (M+H) + B4a, 95% C3a CH2C12 145 Cl Cl 171 0. 33 5% 326 FAB Clb acetone/ (M+H) + 95% CH2C12 146 0-<\ : N 351 HPLC C8 (M+H)/ES- + MS 147 < tO t 0.03 50% 401 FAB C8 EtOAc/ (M+H) 50% + hexane + 148 n °11 159-0.22 5% 325 HPLC C4a 160 160 EtOAc/ (M+H)/ES- 95% + MS hexane 149 190-0. 38 50% 350 FAB Clb Me EtOAc/ (M+H) + Me 50% pet ether 150 Me 175-0.43 50% 364 FAB Clb O \/Me 178 EtOAc/ (M+H+) Me 50% pet ether 151 n-Bu Cl Cl 133 0. 37 5% 328 FAB Clb acetone/ (M+H) + 95% CH2C12 152 t-Bu 165 034 40% 366 FAB Clb deyEtOAc (M+H+) 60% pet ether 153 t-Bu Br 188-0.82 5% 338 FAB Clb 189 acetone/ (M+H) + 95% CH2C12 154 t-Bu/ 0 \/182-352 FAB Clb 184 (M+H) + 155 t-Bu ci 0.65 5% 294 FAB C2a MeOH/ (M+H) + 95% CH2CI2 156 t-Bu ACF 0. 25 3% 328 FAB C2a MeOH/ (M+H) + 97% CH2C12 157 t-Bu Cl Cl 0.57 3% 328 FAB C2a MeOH/ (M+H) + 97% CH2CI2 158 t-Bu h) 0.60 5% 274 FAB C2a vMe MeOH/ (M+H) + 95% CH2CI2 159 t-Bu 0.21 5% 369 FAB B4a, S--N MeOH/ (M+H) + C2a 95% CH2CI2 160 t-Bu 0.52 50% 426 FAB B5, C4a EtOAc/ (M+H) + 50% hexane 161 t-Bu n/=\ 0.36 40% 458 FAB B3a, EtOAc/ (M+H) + C2b 60% hexane 162 t-Bu 213 0.05 5% 369 FAB C3a dec acetone/ (M+H) + S-\CN 95% 1 CH2Cl2 163 t-Bu 210 0.05 5% 353 FAB C3a dec acetone/ (M+H) + 95% CH2C12 164 t-Bu AO<OMe 174-0.25 5% 382 FAB C3a 175 acetone/ (M+H) + 95% CH2C12 165 t-Bu 90-0.16 5% 409 FAB C2a N acetone/ (M+H) + O- ( 95% S CH2C12 166 t-Bu N w 221 0. 14 5% 409 FAB C2a dec acetone/ (M+H) + 95% 9C5H% 2C12 167 t-Bu H 182 0.28 40% 380 El A2, C3a N \/Me EtOAc/ (M+) 60% hexane 168 t-Bu N 196-0.17 5% 368 FAB A2, oc 198 MeOH/ (M+H) + B3h, N 95% C3a CH2C12 169 t-Bu 204-0.27 50% 383 FAB A2, AN 206 EtOAc/ (M+H) + B3a, 50% pet C3a ether 170 t-Bu H2 179-351 FAB A2, C3a t3C<N 180 (M+H) + 171 t-Bu A/=\ 0. 33 50% 414 EI A2, LN EtOAc (M+) B4a, 50% pet C3a ether 172 t-Bu \N 0 SMe 188-0.49 50% 399 HPLC A2, 189 189 EtOAc/ (M+H) + ES-B4a, 50% pet MS C3a ether 173 t-Bu 0 179-0.14 5% 395 FAB A2, tNFO 180 MeOH/ (M+H) + B4a, 95% C3a CH2C12 174 t-Bu oO<F 118-0. 19 5% 387 FAB A2, 121 MeOH/ (M+H) + B4a, 95% C3a CH2C12 175 t-Bu 0 N 197-0.08 10% 353 FAB A2, 199 acetone/ (M+H) + B3h, 90% C3a CH2C12 176 t-Bu 208-0. 17 5% 353 FAB C3b 212 MeOH/ (M+H) + 95% CH2C12 177 t-Bu nS<OCF 155-0.57 10% 453 FAB C3b 156 MEOH (M+H) + CH2C12 178 t-Bu < 163 0.21 5% 453 HPLC C3b < 165 MeOH/ (M+H) +/ES- 95% MS CH2CI2 179 t-Bu oSn 109-0.17 5% 369 FAB C3b 112 MeOH/ (M+H) + 95% CH2C12 180 t-Bu N02 199-0.60 5% C3b 202 KOH CH2C12 181 t-Bu 160-0.58 50% 336 CI C3b 162 162 EtOAc/ (M+) 50% pet ether 182 t-Bu 0. 18 50% EtOAc/ 50% pet ether 183 t-Bu p Me 180 C3b me 184 t-Bu eO4Cl 214-_ _ _ C3b 217 185 t-Bu N 0.13 50% 337 CI C3b \/EtOAc/ (M+H) 50% + hexane 186 t-Bu 154-0. 51 50% 336 FAB C3b 156 EtOAc/ (M+H) 50% pet + ether 187 Me 154-0.50 50% 365 EI Clb nfMe 155 EtOAc (M+) Et 50% pet ether 188 Me 215-0.05 5% 383 FAB C3a nome acetone/ (M+H) + Et dec 95% CH2C12 189 Me 0 137-0.25 5% 396 FAB C3a 138 acetone (M+H) + Et 95% CH2C12 190 Me Cl Cl 196-0.58 5% 342 FAB Clb ---Me 199 acetone/ (M+H+) Et 95% CH2C12 191 Me Me 0-&Me 160-0.37 5% 380 FAB Clb 162 acetone/ (M+H+) Et 95% CH2CI2 192 Me N 199-0.33 70% 468 FAB A2, Et 200 EtOAc (M+) + B3e, Et 30% pet C3a ether 193 Me 161-0.28 40% 394 EI A2, C3a Me vN<OMe 162 EtOAc/ (M+) Et 60% hexane 194 Me H2 0.18 5% 364 EI A2, C3a Me/\ CN MeOH/ (M+) Et 95% CHC13 195 Me 90-0.19 30% 232 EI A2, C3a -\-Me-a N 92 EtOAc/ (M+) Et 70% pet ether 196 Me 180-0. 26 30% A2, Me O Cl 1 g 1 EtOAc/C3b Et 70% pet ether 197 Me/'-/'\- 63-410 FAB A2, -5 (M+H) + B3a, Et C3a 198 Me 84 0.16 5% 381 FAB A2, C3a nfMe vO<N MeOH/ (M+H) + Et 95% CHC13 CHC13 199 Me-Et S-\CN 189-0.16 5% 397 HPLC A2, 192 MeOH/ (M+H) + EI-MS B4a, Et 95% C3a CHC13 200 Me H 175-0. 16 5% 379 FAB A2, C3a kEtEt 177 MeOH/ (M+H) + Et 95% CHC13 201 Me 1S9-0.17 5% 397 FAB A2, ---Et 191 MeOH/ (M+H) + B4a, Et S- (N 95% C3a CHC13 202 Mye 67 0.41 5% A2, --Et-aO--&Me MEOH C3b Et 95% CHC13 203 Me 123-414 FAB A2, C3a ---Et-ao-acl 125 (M+H) + Et 204 Me 135-0. 33 5% A2, Et MeOH/C3b Et 95% CHC13 205Me p 178-039 5% 366 FAB Clb Me Me-a 180 acetone/ (M+H+) 95% CH2C12 206 m rm = 200-0.44 5% 380 FAB Clb Me Me/\ 202 acetone/ (M+H) + 95% CH2CI2 207 Cl Cl 150-0.39 5% 342 FAB Clb Me Me 154 acetone/ (M+H) + 95% CH2CI2 208 Ao\ 155-0. 38 50% 377 EI Clb 156 EtOAc/ (M+) 50% pet ether 209 Ph t3OoMe 0.33 5% 386 FAB Clb acetone/ (M+H) + 95% CH2CI2 210 s-aS-\CN 190-0.23 5% 395 FAB A2, 191 MeOH/ (M+H) + B4a, 95% C3a I CH2CI2 211 O </=\ 0.18 5% 379 FAB A2, MeOH/ (M+I+ C3b 95% CHC13 Table 3. N1-Substituted-3-tert-butyl-5-pyrazolyl Ureas mp TLC Solvent Mass Synth. Ex. R'R (°C) Rr System Spec. Source Method 212 H 0.27 50% 351 FAB Clc EtOAc/ (M+H) + 50% hexane 213 H Cl Cl 0.59 50% 327 FAB Clc EtOAc/ (M+H) + 50% hexane 214 H H2 0. 30 60% 350 FAB C4a z acetone (M+H) + /40% CH2C12 215 H tOoMe 204 0.06 5% 364 EI C3b acetone (M+) /95% CH2C12 216 H 110-0.05 5% 408 FAB C3b N acetone (M+H+) 0-JJ/95% S~< CH2C12 217 H 228-0.24 10% 351 EI C3a H _C dec 90% CHC13 218 H Cl 182-0.05 40% 327 FAB A5, 184 EtOAc/ (M+H) + Cle -Cl 60% hexane 219 H 110-326 EI A5, W CF3 112 (M+) Cle 220 0. 07 5% 368 FAB B4a, KOH/ (M+H) + C4a S-4N 95% 1 CHC13 221 H AS2=\N _ 0.18 5% 364 EI B4a, \=/L gM5eO/ooH/ (M+) C4a 95% CHC13 222 H 0 160-408 FAB A5, B6, HO CF3 O 161 (M+H) + C3b Nome sol tex \===/-salt sale 223 H 181-381 FAB C2b o-a 183 (M+H) + I 224 Me 0. 35 70% 382 FAB B4a, acetone (M+H) + C4a /30% CH2C12 225 Me 0. 46 70% 382 FAB C4a, acetone (M+H) + B4a S30% CH2C12 226 Me hN StS 0.47 100% 497 FAB B3c, t (M+H) + C4a N'pu 227 Me n S 0. 46 100% 464 FAB B3c, EtOAc M+H + C4a 228 Me S Ph 0.50 100% 540 FAB B3c, S-C EtOAc (M+H) + C4a N Ph 229 Me CF3 0.52 100% 506 FAB B3c, I EtOAc (M+H) + C4a ç Sw 230 Me CF3 0.51 100% 509 FAB B3c, O \/Ph EtOAc (M+H) + C4a 231 mye 0.75 100% 421 FAB B3c, 2 EtOAc (M+H) + C4a 232 Me 0-aSCF3 0. 50 100% 465 FAB B3c, EtOAc (M+H) + C4a 233 Me Ph 0.50 100% 349 FAB C4a EtOAc (M+H) + 234 Me 0.09 50% 381 FAB C4a EtOAc (M+H) + 50% hexane 235 Mye 0. 60 100% 471 FAB B2, O 236 Me 0. 61 100% 397 FAB B3c, S (M+H) +C4a 237 Me OPr-n 0.42 100% 439 FAB B5, EtOAc (M+H) + C4a 238 Me eSoOBu-n < 0.25 50% 453 FAB B5, EtOAc (M+H) + C4a 50% hexane 239 Me H 0. 65 100% 100% FAB B6, wC <NH EtOAc (M+H) + C4a i-Bu 240 Me H2 0.100% 100% FAB B6, EtOAc (M+H) + C4a t-BuO 241 Me H2 0. 50 100% 100% FAB C4a C (M+H) + I I i 242 Me H2 0.30 100% 557 FAB C4a 4 o pO EtOAc (M+H) + I-IN _] vIe ÇN V t-Bu _ 243 Me Ho 0.33 100% 420 FAB C4a, C EtOAc (M+H) + D3 O Me 244 Me H2 0.60 10% 478 FAB C4a, C water/ (M+H) + D3 90% HO2C CH3CN 245 Me/\ 0. 28 100% 559 FAB C4a EtOAc (M+H) + HN _ Jvte W N t-Bu 246 Me 0.40 100% 436 FAB C4a, =0 EtOAc (M+H) + D3 Et 1 247 Me 0. 46 50% 422 FAB C4a, =° acetone (M+H) + D3 Me/50% CH2CI2 248 Me 0. 50 100% 464 FAB C4a, =0 EtOAc (M+H) + D3 i-Bu 249 Me HZ 0.55 100% 434 FAB C4a, z EtOAc (M+H) + D3 O Et 1 1 250 Me 0.52 100% 380 FAB C4a /- O-\/H2 EtOAc (M+H) + 251 Me 0.25 60% 366 FAB C4a acetone (M+H) (M+H) /40% _ CH2Ct2 252 Me 0. 52 100% 452 FAB C4a, EtOAc (M+H) + D3 Et0 253 Me NH 0. 52 100% 466 FAB =0 EtOAc (M+H) + D3 i-prao 254 Me H 0. 34 60% 396 FAB C4a 2 eS-CtN acetone (M+H) + /40% CH2CI2 255 Me -\ 0.36 60% 396 FAB C4a c-N acetone (M+H) + /40% CH2C12 256 Me 147-365 FAB Cic 149 (M+H) + 257 Me Cl Cl 173-341 FAB Clc t 175 (M+H) + 258 Me CF 185-341 HPLC/Clc 187 (M+H) + ES-MS 259 Me Br 195-429 FAB Clc > 197 (M+H) + Br 260 Me 0-25 50% 373 FAB Cic COZBu-n 50% hexane hexane 261 Me H2 161-0.15 4% 364 FAB C2b C-N 162 MeOH/ (M+H) + 96% CH2C12 262 Me p Me 228 379 FAB C2b dec (M+H) + I 263 Me 0. 30 5% 422 FAB C2b MeOH/ (M+H) + 95% S 33 CH2C12 264 Me CF3 0.32 70% 450 FAB B3b, S\N acetone (M+H) + C4a /30% CH2C12 265 Me HZHZ 0.15 40% 379 FAB B1, B2, c-c: acetone acetone (M+H) C3a N/60% CH2C12 266 Me H2 0.10 20% 380 FAB C4a w O-Ct, N acetone (M+H) + /80% CH2C12 267 Me H 0.20 80% 365 FAB C3a EtOAc/ (M+H) + 20% hexane 268 Me H2H2 r---\ 0.48 30% 378 FAB B1, acetone (M+H) + C3a /70% CH2C12 269-CH2CF3 0.22 30% 433 FAB A3, EtOAc/ (M+H) + Clb 70% hexane 270-CH2CF3 Cl Cl 0 0. 38 409 FAB A3, EtOAc (M+H) + Clb ./70% hexane 271-(CH2) 2CN Cl Cl 0.(CH2) 2CN Cl Cl 0. 53 70% 380 HPLC/A3, EtOAc/ (M+) ES-MS Clb 30% hexane 272- (CH2) 2CN 0.37 70% 404 HPLC/A3, EtOAc/ (M+H) + ES-MS Clb 30% hexane 273-(CH2) 2OH Cl Cl 0.(CH2) 2OH Cl Cl 0. 15 60% 371 FAB A3, EtOAc/ (M+H) + Clb, 40% D4 hexane w274 5 fi5 H2 = 0.49 40% 432 FAB A3, C--N acetone (M+H) + C4a /60% CH2CI2 275-CH2CO2Et Cl Cl 0.44 50% 413 FAB A3, EtOAc/ (M+H) + Clb 50% hexane 276 ci Cl Cl 0. 59 60% 398 FAB A3, ok 2 < acetone (M+H) + Clb, /40%. D5a CH2C12 277 Me-NH 159-508 FAB A5, B6, 0 (M+H) + C2b t-Bii O

Table 4. 5-Substituted-2-thiadiazolyl Ureas mp TLC Solvent Mass Synth. Ex. R R2 (°C) Rf System Spec. Source Method 278 t-Bu Me 243-355 HPLC/Clc zip 244 (M+H) + ES-MS C 279 t-Bu 0--aMe 0. 30 5% 383 FAB Clb acetone (M+H) + /95% CH2C12 280 t-Bu 0.26 5% 370 FAB C3a MeOH/ MeOH/ (M+H) + 95% CH2C12 281 t-Bu 386 FAB B4a, (M+H) + C3a S-N 282 t-Bu eooOMe 0.37 5% 399 FAB B3a, MEOH/ (M+H) + C3a 95% CH2C12 Table 5.5-Substituted-3-thienyl Ureas mp TLC Solvent Mass Synth. Ex. R R2 (°C) Rf System Spec. Source Method 283 t-Bu Ao\ 144-0.68 5% A4b, 145 acetone Cla /95% CH2C12 284 t-Bu N 0. 28 50% 368 HPLC/A4a \/Et20/ (M+H) + ES-MS 50% pet ether 285 t-Bu 57 381 FAB A4a -0--Me (M+H) + 286 t-Bu H2 0.15 50% 365 EI A4a t3CCN EtOAc/ (M+) 50% pet ether 287 t-Bu nO <OH 0. 44 50% 383 FAB A4a EtOAc/ (M+H) + 50% pet ether 288 t-Bu _ 0.36 50% 384 FAB A4a EtOAc/ (M+H) + 50% pet ether 289 t-Bu Cl C1 169-0.57 20% 343 FAB A4c, 170 EtOAc/ (M+H) + Cld 80% hexane 290 t-Bu tOoOEt 155-0. 40 20% 411 FAB D2 156 EtOAc/ (M+H) + 80% hexane 291 t-Bu oO<OPr-i l 65-0.40 20% 425 FAB D2 166 EtOAc/ (M+H) + 80% hexane 292 t-Bu 188-0.45 20% 439 FAB D2 189 EtOAc/ (M+H) + 80% hexane 293 t-Bu nO\N 0.13 50% 368 FAB A4c, EtOAc/ (M+H) + C4c 50% hexane 294 t-Bu AO<OM 0.26 30% 397 HPLC/A4c, \=/t. (M+H) + ES-MS Cld 70% pet ether 295 t-Bu Me 0.52 30% 381 HPLC/A4a t304 Et20/ (M+H) + ES-MS 70% pet ether Table 5. Additional Ureas

mp TLC Solvent Mass Synth. Ex. _ R (°CL Rr System Spec. Source Method 296 161-0.71 20% 367 FAB D1 163 EtOAc/ (M+H) + s 80% N N-p-ci hexane Br H H c ! 297 162-0.52 30% 365 FAB A8, Cld H 164 EtOAc/ (M+H) f ? iT Ti 70% + N N Me hexane H H 298 Br 0.67 5% 388 FAB Clb acetone (M+H) + /95% CH2CI2 N N H H 299 Cl 0.72 90% 380 HPLC/MS EtOAc/ (M+H) ES 0 10% + B4b, A N hexane C4a H H 300 170-0.328 FAB Clb 172 acetone (M+H) + 0/95% NI CH2CI2 O N N CI H H CI 301 179-362 HPLC/C5 181 (M+H) + ES-MS N I I 0 N N H H H 302 155-0.44 5% 380 FAB Clb 157 acetone (M+H+) /95% CH2C12 zou H H H H 302 0.55 90% 443 FAB B10, EtOAc (M+H) + B4b, 0 C2b N'N N IUIN, (A N hexane H H O NMR O'NHMe 303 OEt 230 377 HPLC/C5 dec M+H) + ES-MS O k W N N i H H

BIOLOGICAL EXAMPLES P38 Kinase Assav : The in vitro inhibitory properties of compounds were determined using a p38 kinase inhibition assay. P38 activity was detected using an in vitro kinase assay run in 96- well microtiter plates. Recombinant human p38 (0.5 pg/mL) was mixed with substrate (myelin basic protein, 5 llg/mL) in kinase buffer (25 mM Hepes, 20 mM MgCl2 and 150 mM NaCI) and compound. One µCi/well of 33P-labeled ATP (10 VW was added to a final volume of 100 µL. The reaction was run at 32 °C for 30 min. and stopped with a 1M HCl solution. The amount of radioactivity incorporated into the substrate was determined by trapping the labeled substrate onto negatively charged glass fiber filter paper using a 1% phosphoric acid solution and read with a scintillation counter.

Negative controls include substrate plus ATP alone.

All compounds exemplified displayed p38 ICsos of between 1 nM and 10 lit.

LPS Induced TNF Production in Mice: The in vivo inhibitory properties of selected compounds were determined using a murine LPS induced TNFa production in vivo model. BALB/c mice (Charles River Breeding Laboratories; Kingston, NY) in groups of ten were treated with either vehicle or compound by the route noted. After one hour, endotoxin (E. coli lipopolysaccharide (LPS) 100 pg was administered intraperitoneally (i. p.). After 90 min, animals were euthanized by carbon dioxide asphyxiation and plasma was obtained from individual animals by cardiac puncture ionto heparinized tubes. The samples were clarified by centrifugation at 12,500 x g for 5 min at 4 °C. The supernatants were decanted to new tubes, which were stored as needed at-20 °C.

TNFa levels in sera were measured using a commercial murine TNF ELISA kit (Genzyme).

The preceeding examples can be repeated with similar success by substituting the generically of specifically described reactants and/or operating conditions of this invention for those used in the preceeding examples From the foregoing discussion, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.