CA2315715C - Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas - Google Patents

Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas Download PDF

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Publication number
CA2315715C
CA2315715C CA2315715A CA2315715A CA2315715C CA 2315715 C CA2315715 C CA 2315715C CA 2315715 A CA2315715 A CA 2315715A CA 2315715 A CA2315715 A CA 2315715A CA 2315715 C CA2315715 C CA 2315715C
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Prior art keywords
urea
substituted
halogen
alkyl
methoxyphenyl
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CA2315715A
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French (fr)
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CA2315715A1 (en
Inventor
Scott Miller
Martin Osterhout
Jacques Dumas
Uday Khire
Timothy Bruno Lowinger
Bernd Riedl
William J. Scott
Roger A. Smith
Jill E. Wood
David Gunn
Holia Hatoum-Mokdad
Mareli Rodriguez
Robert Sibley
Ming Wang
Tiffany Turner
Catherine Brennan
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Bayer Healthcare LLC
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Bayer Healthcare LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
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Abstract

This invention relates to the use of a group of aryl ureas in treating cytokine mediated diseases and proteolytic enzyme mediated diseases, and pharmaceutical compositions for use in such therapy.

Description

WO 99/32463 PCT/US98/Z'7265 Inhibition of p38 Kinase Using Symmetrical and Unsymmetrical biphenyl Ureas held of the Inventlgn This invention relates to the use of a group of aryl areas in treating cytokine mediated diseases and proteolytic enzyme mediated diseases, and pharmaceutical compositions for use in such therapy.
Bac ;ground of ate Inyention 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) iQnase 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 (EItK), 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 CSA>Ds, bicyclic pyridinyi imidazoles, have been shown to have cytokine inhibitory activity both in vitro and in vivo. The isolated enzymes, CSBP-1 and -2 (CSAID binding pmtein 1 and 2) have been cloned and expressed. A marine 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
transladonal 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., rwiP-1, ~-3) in vitro and/or in vivo.
Clinical studies have linked TNFa production andlor signaling to a number of diseases including rheumatoid arthritis (Maim. 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 1997, 349, 170), bone resorption (Pacifici et al. J.
Clin. Endocrinol.
Metabol. 1997, 82, 29), 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 1988, 319, 397), endotoxic shock (Beutler et al. Science 1985, 229, 869; Ashkenasi et al. Proc. Nat'L
Acad. Sci. USA
1991, 88, 10535), toxic shock syndrome, (Saha et al. J. Immunol. 1996, 1 S7, 3869; Lina et al. FEMS Immunol. Med Microbiol. 1996, 13, 81), 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 1995, 109, 129) and ulcerative colitis (Masuda et al. J.
Clin. Lab.
Immunol. 1995, 46, 111), Jarisch-Hcncheimcr reactions (Fekade et al. New England J.
Med. 1996, 335, 311), asthma (Amrani et al. Rev. Malad. Respir. 1996, 13, 539), adult respiratory distress syndrome (Roten et al. Am. Rev. Respir. Dis. 1991,143, 590; Suter et al. Am. Rev Respir. Dis. 1992, 145, 1016), acute pulmonary fibrotic diseases (Pan et al.
Pathol. Int. 1996, 46, 91), pulmonary sarcoidosis (Ishioka et al. Sarcoidosis Vasculitis Di,~''use Lung Dis. 1996, 13, 139), allergic respiratory diseases (Casale et al. Am. J.
Respir. Cell Mol. Biol. 1996, 1 S, 35), silicosis (Gossart et al. J. Immunol.
1996, 1 S6, 1540; Vanhee et al. Eur. Respir. J. 1995, 8, 834), coal worker's pneumoconiosis (Borm ..
et al. Am. Rev. Respir. Dis. 1988, 138, 1589}, alveolar injury (Horinouchi et al. Am. J.
Respir. Cell Mol. Biol. 1996,14, 1044), hepatic failure (Gantner et al. J.
Pharmacol. Exp.
T7eerap. 1997, 280, 53), 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. 1989, 112, 49; Taverne et al.
Parasitol.
Today 1996, 12, 290) including Plasmodium falciparum malaria (Perlmann et al.
Infect.
Immunit. 1997, 6S, 116) and cerebral malaria (Rudin et al. Am. J. Pathol.
1997, ISO, 257), non-insulin-dependent diabetes mellitus (N>DDM; Stephens et al. J. Biol.
Chem.
1997, 272, 971; Ofei et al. Diabetes 1996, 45, 881), congestive heart failure (Doyama et al. Int. J. Cardiol. 1996, S4, 217; 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. 1996, 243, 457), 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. 1990, 170, 32), multiple sclerosis (M.S.; Coyle. Adu Neuroimmunol.
1996, 6, 143; Matusevicius et al. J. Neuroimrnunol. 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. 1996, 16, 31), pancreatitis (Exley et al. Gut 1992, 33, 1126) including systemic complications in acute pancreatitis (McKay et al. Br. J. Surg. 1996, 83, 919), impaired wound healing in infection inflammation and cancer (Buck et al. Am. J. Pathol. 1996, 149, 195), myelodysplastic syndromes (Raze et al. Int. J. Hematol. 1996, 63, 263), systemic lupus erythematosus (Maury et al. Arthritis Rheum. 1989, 32, 146), biliary cirrhosis (Miller et al. Am. J. Gasteroenterolog. 1992, 87, 465), bowel necrosis (Sun et al. .l.
Clin. Invest.
1988, 81, 1328), psoriasis (Christophers. Austr. J. Dermatol. 1996, 37, S4}, radiation injury (Redlich et al. J. Immunol. 1996, IS7, 1705), and toxicity following administration of monoclonal antibodies such as OKT3 (Brod et al. Neurology 1996, 46, 1633).
TNFa levels have also been related to host-versus-graft reactions (Piguet et al.
Immunol. Ser.
1992, S6, 409) including ischemia reperfusion injury (Colletti et al. J. Clin.
Invest. 1989, 85,1333) and allograft rejections including those of the kidney (Maury et al.
J. Exp. Med 1987, 166, 1132), liver (Imagawa et al. Transplantation 1990, S0, 219), heart (Boiling et al. Transplantation 1992, 53, 283), 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;
LoCicem 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. 1993, 21, 5423;
Degre.
Biotherapy 1996, 8, 219) including tuberculosis (Rook et al. Med. Malad Infect. 1996, 26, 904), Helicobacter pylori infection during peptic ulcer disease (Beales et al.
Gastroenterology 1997, 112, 136), 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. 1992, 56, 40), 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. 1996, 144, 1 ), and infections from Borrelia burgdorferi (Brandt et al. Infect. Immunol. 1990, 58, 983), Treponema pallidum (Chamberlin et al.
Infect. Immunol. 1989, 57, 2872), cytomegalovirus (CMV; Geist et al. Am. J.
Respir. Cell Mol. Biol. 1997,16, 31); influenza virus (Beutler et al. Clin. Res. 1986, 34, 491a), Sendai virus (Goldfield et al. Proc. Nat'l. Acad Sci. USA 1989, 87, 1490), Theiler's encephalomyelitis virus (Sierra et al. Immunology 1993, 78, 399), and the human immunodeficiency virus (HIV; Poli. Proc. Nat'l. Acad. Sci. USA 1990, 87, 782;
Vyakaram et al. AIDS 1990, 4, 21; 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 mctalloproteinases (TI1VVIPs). These include osteoartbritis (Woessner et al. J. Biol. Chem. 1984, 259, 3633), rheumatoid arthritis (Mullins et al.

WO 99!32463 PCTNS98/Z7265 Biochim. Biophys. Acta 1983, 695, 117; 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. Nat'1. Acad Sci., USA 1986, 83, 9413), periodontal diseases 5 (Overall et al. J. Periodontal Res. 1987, 22, 81), corneal ulceration (Burns et al. Invest.
Opthalmol. Yis. Sci. 1989, 30, 1569), proteinuria (Baricos et al. Biochem. J.
1988, 254, 609), 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. 1991, 81, 233), birth control (Woessner et al. Steroids 1989, 54, 491), 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, S0, 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, marine 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 WO 99/324b3 PCT/US98/27265 replacement surgery. P38 inhibitors will halt or reverse the progression of cartilage loss and obviate or delay surgical intervention.
Several patents have appeared claiming polyarylimidazoies 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 cytochmme P450~,0, (Harris et al. Mo1 Eng. 1995, S, 143, and references therein), causing concern that these compounds may display structure-related toxicity (Howard-Martin et al.
Toxicol. Pathol.
1987,15, 369). Therefore, there remains a need for improv~i p38 inhibitors.
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 pmteolytic 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 (M1VII'-1) and stmmelysin (MIV»'-3).
Accordingly, these compounds are useful therapeutic agents for such acute and chronic inflarrimatory and/or immunomodulatory diseases as rheumatoid arthritis, osteoarthritis, septic arthritis, rheumatic fever, bone resorption, postrncnopausal osteopemsis, 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 (hTIDDM), congestive heart failure, damage following heart disease, athemsclerosis, 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, impaired 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 repeifusion 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 (H>~.
The present invention, therefore, provides compounds generally described as aryl areas, including both aryl and hetemaryl analogues, which inhibit the p38 pathway.
The invention also provides a method for treatment of p38-mediated disease states in humans or mammals, e.g., disease states mediated by one or more cytokines or proteolytic enzymes produced and/or activated by a p38 mediated process. Thus, the invention is directed to compounds and methods for the treatment of diseases mediated by p38 kinase comprising administering a compound of Formula I
I
B-NH NH-A
wherein WO 99!32463 PCT/US98/27265 A is R3, \ R4r N R4' R
or / Ra, / Rs, B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein if B is substituted, it is substituted by one or more substituents selected from the group consisting of halogen, up to per-halo, and Wp, wherein n is 0-3 and each W is independently selected from the group consisting of -CN, -COzR', -C(O)NR'R', -C(O)-R', -N02, -OR', -SR', -NR'R', -NR'C(O)OR', -NR'C(O)R', C,-C,o alkyl, CZ_,o-alkenyl, C,_,o-alkoxy, C3-C,o cycloalkyl, C6-C,4 aryl, C,-Cu alkaryl, C3-CI3 heteroaryl, C; C~ alkheteroaryl, substituted C,-C,a alkyl, substituted CZ_,o-alkenyl, substituted C,_,o-alkoxy, substituted C3-C,o cycloalkyl, substituted C,-C~ alkheteroaryl and Q-Ar;
wherein if W is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -COZR', -C(O)R', -C(O)NR'R', -OR', -SR', -NR'R' , N02, -NR'C(O)R', -NR'C(O)OR' and halogen up to per-halo;
wherein each R' is independently selected from H, C,-C,o alkyl, CZ_,o-alkenyl, C3-C,o cycloalkyl, C6-C" aryl, C3-C,3 hetaryl, C,-Cu alkaryl, C,-C~
alkheteroaryl, up to per-halosubstituted C,-C,o alkyl, up to per-halosubstituted Cs_,o-alkenyl, up to per-halosubstituted C3-C,o cycloalkyl; up to per-halosubsdtuted C~-C14 aryl and up to per-halosubstituted C3-C,3 hetaryl, wherein Q is - O-, -S-, -N(R')-, -(CHI-m, -C(O)-, -CH(OH)-, -(CH~~O-, NR'C(O)NR'R''-, -NR'C(O)-, -C(O)NR'-i (CH~mS-, -(CH~mN(R')-, -O(CH~~ , -CHX', -CX'2-, -S-(CH~~ and -N(R')(CH~m , m = 1-3, and X' is halogen; and Ar is a 5-10 member aromatic structure containing 0-2 members of the group consisting of nitrogen, oxygen and sulfur, which is unsubstituted or substituted by halogen up to per-halo and optionally substituted by Zpl, wherein ", is 0 to 3 and each Z is independently selected from the group consisting of of -CN, -COZR', -C(O)NR'R', -C(O)- NR', -C(O) R',= NOx, -OR', -SR', -NR'R', -NR'C(O)OR', -NR'C(O)R', C,-Clo allryl, C3-C,o cycloalkyl, C6-C" aryl, C3-C13 hetaryl, C~-Cu alkaryl, C,-C~
alkheteroaryl, substituted C,-C,o alkyl, substituted C3-C,o cycloalkyl, substituted C,-Cu alkaryl and substituted C,-C~ alkheteroaryl; wherein the one or more substituents of Z
is selected from the group consisting of -CN, -C02R', -C(O)NR'R', -OR', -SR', -NO2, -NR'R' , -NR'C{O)R' , -NR'C(O)OR', R'', R'' , RS' are each independently H, C,.,o-alkyl, optionally substituted by halogen, up to perhalo, C,_,o alkoxy, optionally substituted by halogen, up to pcrhaloalkoxy, halogen; NOZ or NHZ;
R6' is H, C,-,o alkyl, C,_,o alkoxy, -NHCOR'; -NR'COR'; N02;
N ~r N I
~NH
O ~ ~O
one of R''' , Rs' or R6' can be X-Y, or 2 adjacent R''-R6' can together be an aryl or hetaryl ring with 5-12 atoms, optionally substituted by C,ao-~Yh C~-~o foxy, C,_,o cYcloalkyl, C=.lo alkenyl, C,.,o alkanoyl, C~.l= aryl, C~.12 hetaryl or C~.~~ aralkyl;
R' is C,_,o-alkyl optionally substituted by halogen, up to pcrhalo;
X is -CH2-, -S-, -N(CH,)-, -NHC(O)-, -CHI-S-, -S-CHI-, -C(O~, or -0-; and X is additionally a single bond where Y is pyridyl;
Y is phenyl, pyridyl, naphthyl, pyridone, pyrazine, benzodioxane, benzopyridine, pyrimidine or benzothiazole, each optionally substituted by C,_,o-alkyl, C,.,o-a~oxy, halogen, OH, - SCH, or NOz or, where Y is phenyl, by or a pharmaceutically acceptable salt thereof.
Preferably, the compounds of fo~tula I are of formula Ia R $ R3.
Ia wherein R', R° , RS and R6 are each independently H, halogen, C,.lo- a~Yl optionally substituted by halogen, up to perhalo, C,_,o alkoxy, optionally substituted by at least one hydroxy group or by halogen, up to perhalo; C~.,z aryl, optionally substituted by C,.,o alkoxy or 10 halogen, C,_,z he~'Yh optionally substitued by C,.,o alkyl, C,.,o alkoxy or halogen; NOz , S02F or -SOZCHpX,_p; -COOR'; -OR'CONHR'; NHCOR'; -SR'; phenyl optionally substituted by halo or C,.,o-foxy; NHz; -N(S02R')z, furyloxy, or -OR'CO-~~O
2 adjacent R'-R6 can together form an aryl or hetaryl ring with 5-12 atoms, optionally substituted by C,au-~yh C,.,o-foxy, Cz.,o-cycloalkyl, Cz.,o-alkenyl, C,_,o alkanoyl, C6,z-~5'1 ~ Cs-~z-hetaryl, Cmz-a~'alkyl, Cs.u-~TY~ ~og~~ NR'; NOz; -CF3;

-COOR'; -NHCOR'; -CN; -CONR'R'; -SOzR2; -SORZ; -SR2; in which R' is H or C,_,o-alkyl and R2 is C,_,o-alkyl; optionally substituted by halogen, up to perhalo, with - SO~
optionally incorporated in the aryl or hetaryl ring;
one of R', RS or R6 can be X-Y, R' is C,.,o-alkyl, optionally substituted by halogen, up to perhalo;
p is 0 or 1;
X is -CH2, -S- , N(CH,)-, -NHC(O), CHI-S-, -S-CHz-, -C(O)-, or -0-; and Y is phenyl, pyridyl, naphthyl, pyridone, pyrazine, benzodixane, benzopyridine, pyrimidine or benzothiazole, each optionally substituted by C,_,o-alkyl, C,_,o-alkoxy, halogen or NO~ or, where Y is phenyl, by U
with the proviso that if R' and R6 are both H , one of R° or Rs is not H.
In formula I, suitable hetaryl groups B 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-1-, -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-thiadia2ol-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 -S-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 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-benz-1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, S-, 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, tent-butyl, etc.
Suitable aryl groups include, for example, phenyl and 1- and 2-naphthyl.
The term "cycloalkyl", as used herein, refers to cyclic structures with or without alkyl substitutents such that, for example, "C, cycloakyl" includes methyl substituted cyclopropyl groups as well as cyclobutyl groups. The term "cycloalkyl" also includes saturated heterocyclic groups.
Suitable halogen groups include F, Cl, Br, and/or I, from one to per-substitution (i.e. all H
atoms on a group replaced by a halogen atom) being possible where an alkyl group is substituted by halogen, mixed substitution of halogen atom types also being possible on a given moiety.
Preferred compounds of formula I include those where R' is H, halogen or C,.,o-~yl, optionally substituted by halogen, up to perhalo, NO~, -SOzF, - S02CHF=; or -SOzCF,; R' is H, C,.,o-~yl, C,.,o-alkoxy, halogen or N02; Rs is H, C,ao-~yl optionally substituted by halogen, up to perhalo; R6 is H, hydroxy, C,.,o-alkoxy, optionally substituted by at least one hydroxy group; -COOR'; -OR'CONHR'; -NHCOR'; -SR'; phenyl optionally substituted by halo or C,.,o-alkoxy; NHS; N(SO=R'~, furyloxy, Preferably, R' is Cl, F, C,.s-branched alkyl, -SO~F or -S02CF,; and R6 is hydroxy;
C,.,o-allcoxy optionally substituted by at least one hydroxy group; -COOR'; -OR'CONHR'; NHCOR'; -SR'; phenyl optionally substituted by halo or C,.,o-foxy;
NH2; -N(SOZR')2, furyloxy, More preferably, R6 is t-butyl or CF, and R6 is -0CH,. Preferably, R'' is C,_,o-alkyl or halogen; Rs' is H, C,_,o alkyl, halogen, CF, , halogen, NOz or NH2; and R6~is H, C,_,o-alkyl, halogen, -NHCOCH" -N(CH,)COCH" N02, or N
~NH
O I IO
The invention also relates to compounds per se, of formula II
R3 R~
4 ~ 4' R ~ ~ R
NH ~ / 5. II
'R
R Rs s wherein R', R° , RS and R6 are each independently H, halogen, C,.,o- alkyl optionally substituted by halogen up to perhalo, C,.,o-foxy, optionally substituted by at least one hydroxy group or halogen, up to perhalo; NOZ, SO2F or -SOzCHnX~.~, C,.,o-foxy; -COOR';
-OR'CONHR'; -NHCOR'; -SR'; C~,= aryl, optionally substituted by C,.,o-alkyl, C,_,o alkoxy or halogen, C~.,z hetaryl, optionally substitued by C,_,o alkyl, C,_,o allcoxy or halogen ; NHZ; -N(SO=R')I; furyloxY;
N or -OR'CO- O
i O

2 adjacent R'-R6 can together form an aryl or hetaryl ring with 5-12 atoms, optionally substituted by C,.,o-alkyl, C,.,o-alkoxy, C,.,o-cycloalkyl, C~.,o-alkenyl, C,.,o-alkanoyl, C~.,i-aryl , C~u-hetaryl, C6,2-aralkyl, C~.,z-alkaryl, halogen; -NR'; -N02; -CF,;
-COOR'; -NHCOR'; -CN; -CONR'R'; -SOzR2; -SOR2; -SRS; in which R' is H or C,.,o-alkyl and R2 is Cl_,o-alkyl;
R'' , R'' and RS' are each independently H, C,.,o alkyl, optionally substituted by halogen, up to perhalo; N02 or NHS;
R6' is H, C,.,o-alkyl, halogen, -NHCOR'; -NR'COR'; NOZ;
or ~
fr _ NH
O
to 2 adjacent R''-R6' can together be an aryl or hetaryl ring with 5-12 atoms;
R' is C,.,o alkyl, optionally substituted by halogen, up to perhalo;
n is0orl;
with the provisos that (a) if R' and R6 are both H , one of R' or Rs is not H, and (b) that R6 is phenyl substituted by alkoxy or halogen, allcoxy substituted by hydroxy, -SO~CFZH, -OR'CONHR', -OR'CO- O
O
furyloxy or N(SOZR.')2;
or R6' is or NH
U U

and (c) if R6 is phenyl substituted by alkoxy or halogen, the compounds have a pKa greater than 10, e.g., greater than 12, preferably greater than 15.
Preferred 5-tart-butvlnhenvl areas are:
N-(5-tart-Butyl-2-methoxyphenyl)-N'-(4-phenyloxphenyl)urea;
N-(5-tart-Butyl-2-methoxyphenyl)-N'-(4-(4-methoxyphenyloxy)phenyl)urea;
N-(S-tort-Butyl-2-methoxyphenyl)-N'-(4-(4-pyridinyloxy~henyl)urea;
N-(5-tart-Butyl-2-methoxyphenyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea;
N-(5-tart-Butyl-2-methoxyphenyl)-N'-{4-(4-pyridinylthio~henyl)urea;
10 N-(5-tart-Butyl-2-methoxyphenyl)-N'-(4-(4-(4,7-methano-1H-isoindole-1,3(2H)-dionyl~nethyl~henyl)urea;
N-(5-tart-Butyl-2-phenylphenyl)-N'-(2,3-dichlorophenyl)urea;
N-(5-tart-Butyl-2-(3-thienyl)phenyl)-N'-(2,3-dichlorophenyl)urea;
N-(5-tart-Butyl-2-{N=methylaminocarbonyl)methoxyphenyl)-N'-(2,3-1 S dichlorophenyl)urea;
N-(5-tart-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N'-(1-naphthyl)urea;
N-(5-tart-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N'-(2,3-dichlorophenyl)urea;
N-(5-tart-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl~N'-(1-naphthyl)urea;
N-(5-tart-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)-N'-(2,3-dichlorophenyl)urea;
ana N-(5-tart-Butyl-2-methoxyphenyl)-N'-(4-(3-pyridinyi)methylphenyl)urea.
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-methylphenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-('4-methyl-2-fluorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-fluoro-3-chlorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-{4-methyl-3-chlorophenyl)urea;
N-{5-Trifluoromethyl-2-methoxyphenyl~N'-(4-methyl-3-fluorophenyl)urea;
N-(5-Trifluommethyl-2-methoxyphenyl)-N'-(2,4-difluorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-{4-phenyloxy-3,5-dichlorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-{4-pyridinylmethyl)phenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-{4-(4-pyridinylthio)phenyl)urea;
N-{5-Trifluoromethyl-2-methoxyphenyl~N'-(4-(4-pyridinyloxy~henyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(3-(4-pyridinylthio)phenyl)urea; and N-(5-Trifluoromethyl-2 methoxyphenyl)-N'-(4-(3-(N-methyiaminocarbonyl)-phenyloxy)phenyl)-urea.
N-(5-Fluorosulfonyl)-2-methoxyphenylrN'-(4-methylphenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methyiphenyl)ureaN-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-fluorophenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methyl-2-fluomphenyl)urea;
N-(5-(Diflummethanesulfonyl)-2-methoxyphenyl)-N'-(4-methyl-3-fluomphenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methyl-3-chlorophenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-fluoro-3-chlorophenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-fluoro-3-methylphenyl)urea;
N-(5-{Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(2,3-dimethylphenyl)urea;
and N-(5-(Trifluommethanesulfonyl)-2-methoxphenyl)-N'-(4-methylphenyl)urea.
N-(3-Methoxy-2-naphthyl)-N'-(2-fluorophenyl~ea;
N-(3-Methoxy-2-naphthyl)-N'-(4-methylphenyi)urea;
N-(3-Methoxy-2-naphthyl)-N'-(3-fluorophenyl)urea;
N-(3-Methoxy-2-naphthyl)-N'-(4-methyl-3-fluorophenyl)urea;

WO 99/32463 ~ PCTNS98/27265 N-(3-Methoxy-2-naphthyl)-N'-(2,3-dimethylphenyl)urea;
N-(3-Methoxy-2-naphthyl)-N'-(1-naphthyl)urea;
N-(3-Methoxy-2-naphthyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea;
N-(3-Methoxy-2-naphthyl)-N'-(4-(4-pyridinylthio~henyl)urea;
N-(3-Methoxy-2-naphthyl)-N'-(4-(4-methoxyphenyloxy)phenyl)urea; and N-(3-Methoxy-2-naphthyl)-N'-(4-(4-(4,7-methano-1H-isoindole-1,3(2H~
dionyl)methyl)phenyl)urea.
Ojher~nrefeaed ureas are:
N-(2-Hydmxy-4-nitro-5-chlorophcnyl)-N'-(phenyl)urea; and N-{2-Hydroxy-4-nitco-5-cl~lomphenyl)-N'-(4-(4-pyridinyhnethly)phenyl)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, malefic 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 rations (e.g., Mg''2 , Ca'"~ or Ba+~), the ammonium ration, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium rations, such as those arising from pmtonation or perallcylation 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]under-7-ene (DBLn.
A number of the compounds of Formula I possess asymmetric carbons and can therefore exist in racelnic and optically active forms. Methods of separation of enantiomcric 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.
Several PrejLarative 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 these compounds, with more detailed particular examples being presented in the experimental section describing the working examples.
H21 catalyst (eg. Ni, Pd, Pt) ArNO 1H ~ - ArNH2 M(0) (eg. Fe, Sn, Ca) Scheme I Reduction of Nitroaryls to Aryl Amines Nitroaryls are commonly formed by electrophilic aromatic nitration using 13N0"
or an alternative N02+ source. Nitroaryls may be further elaborated prior to reduction. Thus, nitmaryls substituted with Ar-H '- ArN02 potential leaving groups (eg. F, Cl, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme In or phenoxide.
Nitroaryls may also undergo Unman-type coupling reactions (Scheme In.

02N . ArSH
\
base %~$ Ar 02ND Br-Ar R j SH Cu0 I base Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls Nitroaryls may also undergo transition metal mediated cross coupling reactions.
For example, nitmaryl electmphiles, such as nitroaryl bromides, iodides or triflates, undergo palladium mediated cross coupling reactions with aryl nucleophiles, such as arylboronic acids (Suzuki reactions, exemplified below), aryltins (Stills reactions) or arylzincs (Negishi reaction) to afford the biaryl (5).
02N ArB(OR'~ 02N
\ X Pd(O~ R~ I4r Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl chloride (7) on treatrnent with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source, such as KF then affords sulfonyl fluoride (8). Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, such as tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding trifluoromethylsulfone (9). Alternatively, sulfonyl chloride 7 may be reduced to the arenethiol (10), for example with zinc amalgam. Reaction of thiol 10 with CHC1F~ in the presence of base gives the difluommethyl mercaptam (11), which may be oxidized to the sulfone (12) with any of a variety of oxidants, including CrO,-acetic anhydride (Sedova et al. Zh. Org. Khfra. 1970, 6, 568).

SOZCI

R ---~ \ ; R 7 KF ~ (H9) ~ R 8 ~,l R 10 (Me2N)3S Me~SiFy CHCIFZ
Me3SiCF3 base ~ R 9 ~l R 11 (O]

Scheme III Selected Methods of Fluorinated Aryl Sulfone Synthesis As shown in Scheme N, non-symmetrical urea forniation may involve reaction of an aryl isocyanate (14) with an aryl amine (13). The hetemaryl isocyanate may be 5 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 fiom a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Cuttius-type rearrangement. Thus, reaction of acid derivative 16 with 10 an azide source, followed by rearrangement affords the isocyanate. The corresponding carboxylic acid (1'~ may also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar regent.

Are-NH2 13 H2N_A~ O
ArWNCO Ar~~N~N.A~

O O
Ate ~ X Are ~OH

Scheme IV Selected Methods of Non-Symmetrical Urea Formation Finally, areas may be further manipulated using methods familiar to those skilled in the art.

The invention also includes pharmaceutical compositions including a compound of Formula I, and a physiologically acceptable carrier.
The compounds may be administered orally, topically, parenterally, by inhalation or 10 spray, vaginally, rectally or sublingually 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 15 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 excipicats 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 agarts and suspending agents are exemplified by those already mentioned above.

WO 99/32463 PCT/US98lZ72b5 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.
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 transdeimal 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 Ca-C,a fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated Ca-C,e fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, pmpyl, 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, diisopmpyl sebacate, diisopropyl maleate, or diisopropyl fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, areas 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 C8-C,8 fatty alcohols, saturated or unsaturated C8-C,8 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, areas 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.
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, 5 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 10 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.
For all regimens of use disclosed herein for compounds of Formula I, the daily oral 15 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 mglKg 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 rectal dosage 20 regimen will preferably be from 0.01 to 200 mg/Kg of total body weight. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg. The daily topical dosage regimen will preferably be finm 0.1 to 200 mg administered between one to four times daily. 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 a given patient depends on a variety of factors, including specific activity of the compound administered, 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 combination, and the seventy of the condition undergoing therapy, etc. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt WO 99!32463 PCT/US98/27265 thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatmment tests.
The compounds of Figure I are producible from known compounds (or from starting materials which, in turn, are producible from known compounds), e.g., through the general preparative methods shown above. The activity of a given compound to inhibit raf kinase can be routinely assayed, e.g., according to procedures disclosed below. The following examples are for illustrative purposes only and are not intended, nor should they be construde to limit the invention in any way.

The entire disclosure of all applications, patents and publications cited above and below are hereby incorporated by reference, including provisional application serial number attorney docket number Bayer 10-V1, filed on December 22, 1997 as serial number 08/995,749, and 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.
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 terns 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mmHg.
All temperatures are reported unconnected in degroes Celsius (°C).
Unless otherwise indicated, all parts and percentages are by weight.
Commercial grade reagents and solvents were used without fiirther purification. Thin-layer chromatography (TLC) was performed using Whatrnano pre-coated glass-backed silica gel 60A F-254 250 pm plates. Visualization of plates was effected by one or more of the follow~ag 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 infrared sprectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton ('H) nuclear magnetic resonance (hlMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me,Si (d 0.00) or residual protonat~l solvent (CHCI, 8 7.26; MeOH 8 3.30; DMSO

2.49) as standard. Carbon ("C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC13 8 77.0; MeOD-d,; 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 p.A. 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 or ammonia as the reagent gas (1x10'' torn to 2.Sx10~ tort). The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was tamped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared ( ~l-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 Paclcard 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 are conducted by Robertson Microlit Labs, Madison NJ.
All compounds 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 tent-butoxycarbonyl cone concentrated dec decomposition DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2( 1 H)-pyrimidinone DMF N,N dimethylformamide DMSO dimethylsulfoxide DPPA diphenylphosphoryl azide EtOAc ethyl acetate EtOH ethanol (100%) EtzO diethyl ether Et;N triethylamine m-CPBA 3-chloroperoxybenzoic acid MeOH methanol pet. ether petroleum ether (boiling range 30-60 C) THF tetrahydrofuran TFA trifluoroacedc acid Tf trifluoromethanesulfonyl A. General Methods for Synthesis of Substituted Anilines Al. Synthesis of 2,5-Dioxopyrrolidinylanilines NOz C~~O
Step 1. 4-tent Bntyl-1-(2,5-dioxo-l-pyrrolidinyl~2-nitrobenzene: To a solution of 4-tent-butyl-2-nitroaniline (1.04 g, 5.35 mmol) in xylene (25 mL) was added succinic anhydride (0.0535 g, 5.35 mmol) and triethylamine (0.?5 mL, 5.35 mmol). The reaction mixture was heated at the reflex temp. for 24 h, cooled to room temp. and diluted with Et20 (25 mL). The resulting mixture was sequentially washed with a 10% HCl solution (50 mL), a saturated NH,CI solution (50 mL) and a saturated NaCI solution (50 mL), dried (MgSO,), and concentrated under reduced pressure. The residue was purified by flash cromatography (60% EtOAc/40% hexane) to yield the succinimide as a yellow solid (1.2 g, 86%): mp 135-138 °C; 'H NMR (CHCI,) 8 1.38 (s, 9H), 2.94-2.96 (m, 4H), 7.29-7.31 (m, 1 H), 7.74-7.78 (m, 1 H), 8.18-8.19 (m, 1 H).
NHZ
Ch~O
Step 2. 5-tent Butyl-2-(2,5-dioxo-l-pyrrolidtnyl)aniline: To a solution of 4-tent butyl-1-(2,5-dioxo-1-pyaolidinyl)-2-nitrobenzene (1.1 g, 4.2 mmol) in EtOAc (25 mL) was added a 10% Pd/C (0.1 g). The resulting slurry was placed under a H~
atmosphere using 3 cycles of an evacuate-quench protocol and was allowed to stir under a H2 atmosphere for 8 h. The reaction mixture was filtered through a pad of Celite~ and the residue was washed with CHCl3. The combined filtrate was concentrated under reduced pressure to yield the desired aniline as an off white solid (0.75 g, 78%): mp 208-211 °C; 'H-NMR

(DMSO-d6) 8 1.23 (s, 9H), 2.62-2.76 (m, 4H), 5.10 (br s, 2H), 6.52-6,56 (m, 1H), 6.67-6.70 (m, 2H).
A2. General Method for the Synthesis of Tetrahydrofuranytoxyanilines 5 Step 1.4-tent Butyl-1-{3-tetrahydrofuranylory~2-nitrobenzene: To a solution of 4-tert-butyl-2-nitrophenol (1.05 g, 5.4 mmol) in anh THF (25 mL) was added 3-hydroxytetrahydrofuran (0.47 g, 5.4 mmol) and triphenylphosphine (1.55 g, 5.9 mmol) followed by diethyl azodicarboxylate (0.93 ml, 5.9 mmol) and the mixture was allowed to stir at room temp. for 4 h. The resulting mixture was diluted with EtzO (50 mL) and 10 washed with a saturated NH4Cl solution (50 mL) and a saturated NaCI
solution (50 mL), dried (MgSO,), and concentrated under reduced pressure. The residue was purified by flash cromatography (30% EtOAc/70% hexane) to yield the desired ether as a yellow solid (1.3 g, 91%): 'H-NMR (CHCIs) b 1.30 (s, 9H), 2.18-2.24 (m, 2H), 3.91-4.09 (m, 4H), 5.00-5.02 (m, 1H), 6.93 (d, .l--8.8 Hz, 1H), 7.52 (dd, .x-2.6, 8.8 Hz, 1H), 7.81 (d, 15 ,~2.6 Hz, 1H).

~O
< ~O
Step 2.5-tent Butyl-2-(3-tetrahydrofuranylozy)aniline: To a solution of 4-tert butyl-1-(3-tetrahydrofiiranyloxy)-2-nitrobenzene (1.17 g, 4.4 mmol) in EtOAc (25 mL) was added 10% Pd/C (0.1 ). The resulting slurry was placed under a H~ atmosphere using 3 20 cycles of an evacuate-quench protocol and was allowed to stir under a H2 atmosphere for 8 h. The reaction mixture was filtered through a pad of Celite~ and washed with CHC13..
The combined filtrate was concentrated under reduced pressure to yield of the desired aniline as a yellow solid (0.89 g, 86%): mp 79-82 °C; 'H-NMR (CHCI,) 8 1.30 (s, 9H), 2.16-2.20 (m, 2H), 3.78 (br s, 2H), 3.85-4.10 (m, 4H),4.90 {m, 1H), 6.65-6.82 (m, 3H).
A3. General Method for the Synthesis of Trifluoromethanesulfonylanilines O
N_ Me0 Step 1. 2-Methoxy-5-(tluorosulfonyl)acetanlllde: Acetic anhydride (0.90 mL, 9.6 mmol) was added to a solution of 4-methoxymetanilyl fluoride {1.0 g, 4.8 mmol) in pyridine (15 mL). After being stirred at room temp. for 4 h, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in CHZC12 (25 mL), washed with a saturated . NaHC03 solution (25 mL), dried (NazS04), and concentrated under reduced pressure to give a foam which was triturated with a EtlO/hexane solution to provide the title compound (0.85 g): 'H-NMR (CDCI,) 8 2.13 (s, 3H), 3.98 (s, 3H), 7.36 (d, .~8.5 Hz, 1H), 7.82 (dd, ,~2.6, 8.8 Hz, 1H), 8.79 (d, J=2.2 IS Hz, 1H), 9.62 (brs, 1H).

O
N_ Me0 Step 2.2-Methory-5-(trifluoromethanesnlfonyl)acetanilide: To an ice-cooled suspension of tris(dimethylamino)sulfonium difluorotrimethylsiliconate (0.094 g, 0.34 mmol) in THF (4 mL) was added a solution of {trifluoromethyl)triraethylsiiane (1.0 mL, 6.88 mmol) in THF (3 mL) followed by a solution of 2-methoxy-5-(fluorosulfonyl)acetanilide (0.85 g, 3.44 mmol) in THF (3 mL). The reaction mixture was stin~cd for 2 h on an ice bath, then was allowed to warm to room temp. and was then concentrated under reduced pressure. The resulting residue was dissolved in CHzCl2 (25 mL), washed with water (25 mL), dried (Na2S0,), and concentrated under reduced pressure. The resulting material was purified by flash chromatography (3%
MeOH/97%

CH2Clz) to provide the title compound as a white solid (0.62 g): 'H-NMR
(CDC1,) 8 2.13 (s, 3H) 4.00 (s, 3H), 7.42 (d, .~8.8 Hz, 1H), 7.81 (dd, .t=2.6, 8.8 Hz, 1H), 8.80 (d, .F=2.2 Hz, 1 H), 9.64 (br s, 1 H); FAB-MS mlz 298 ((M+1 )').

Me0 Step 3.2-Methoxy-5-(trifiuoromethanesulfonyl)aniline: A solution of 2-methoxy-(trifluommethanesulfonyl)acetanilide (0.517 g, 1.74 mmol) in EtOH (5 mL) and a HCI solution (5 mL) was heated at the reflux temp. for 4 h and the resulting mixture was concentrated under reduced pressure. The residue was dissolved in CH2C1~ (30 mL), washed with water (30 mL), dried (Na2S0,,), and concentrated under reduced pressure to afford the title compound as a gum (0.33 g): 'H-NMR (CDCI,) b 3.90 (s, 3H) 5.57 (br s, 2H), 7.11-7.27 (m, 3H); FAB-MS m/z 256 ((M+1)+). This material was used in urea formation without further purification.
A4. General Method for Aryl Amine Formation via Phenol Nitration Followed by Ether Formation and Reduction OH
Step 1.2-Nitro-5-tent bntylphenol : A mixture of fuming nitric acid (3.24 g, 77.1 mmol) in glacial HOAc (10 mL) was added dmpwise to a solution of m-tert-butylphenol (11.58 g, 77.1 mmol) in glacial HOAc (15 mL) at 0 °C. The mixh~re was allowed to stir at 0 °C
for 15 min then warmed to room temp. After 1 h the mixture was poured into ice water (100 mL) and extracted with Et~O (2 x 50 mL). The organic layer was washed with a saturated NaCI solution (100 mL), dried (MgSO,) and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc/70% hexane) to give the desired phenol (4.60 g, 31%): 'H-NMR (DMSO-d~ 8 1.23 (s, 9H), 7.00 (dd, .1.84, 8.83 Hz,1H), 7.07 (d, .1.84 Hz, 1H), 7.82 (d, .h-8.83 Hz,1H), 10.74 (s, 1H).

OMe Step 2. 2-Nitro-5-tent-butylanisote: A slurry of 2-vitro-5-tert-butylphenol (3.68 g, 18.9 mmol) and KzC03 (3.26 g, 23.6 mmol) in anh DMF (100 mL) was stirred at room temp with stirring for 15 min then treated with iodomethane (2.80 g, 19.8 mmol) via syringe. The reaction was allowed to stir at room temp for 18 h., then was treated with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCI solution (50 mL), dried (MgSO,,) and concentrated in vacuo to give the desired ether (3.95 g, 100%): 'H-NMR (DMSO-d~ 8 1.29 (s, 9H), 3.92 (s, 3H), 7.10 (dd, .~=1.84, 8.46 Hz,1H), 7.22 (d, .1.84 Hz, 1H), 7.79 (d, ,8.46 Hz,1H).
This material was used in the next step without further purification.
W
NHZ
OMe Step 3. 4-tert-Butyl-2-methoxyaniline: A solution of 2-vitro-5-tert-butylanisole (3.95 g, 18.9 mmol) in MeOH (65 mL) and added to a flask containing 10% Pd/C in MeOH
(0.400 g), then placed under a H~ atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then filtered through a pad of Celite~ and concentrated in vacuo to afford the desired product as a dark sitcky solid (3.40 g, 99%): 'H-NMR
(DMSO~db) 8 1.20 (s, 9H), 3.72 (s, 3H), 4.43 (br s, 2H), 6.51 (d, .8.09 Hz, 1H), 6.64 (dd, .2.21, 8.09 Hz,1H), 6.76 (d, .2:21 Hz,1H).
A5. General Method for Aryl Amine Formation via Carboxylic Acid Esteriflcation Followed by Reduction F F F
NOZ

Step 1. Methyl 2-Nitro-4-(trifluoromethyl)benzoate: To a solution of 2-vitro-4-(trifluoromethyl)benzoic acid (4.0 g, 17.0 mmol) in MeOH (150 mL) at room temp was added conc HZSO, (2.5 mL). The mixture was heated at the reflux temp for 24 h., cooled to room temp and concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCI solution, dried (MgSO,), concentrated in vacuo. The residue was purified by flash chromatography (14% EtOAc/86% hexane) to give the desired ester as a pale yellow oil (4.17 g, 98%): 'H-NMR (DMSO-ds) S 3.87 (s, 3H), 8.09 (d, .7.72 Hz, 1H), 8.25 (dd, ,F-1.11, 8.09 Hz,1H), 8.48 (d, .1.11 Hz, 1H).
' F F F

C02Me Step 2. Methyl 2-Amino-4-(trifluoromethyl)benzoate: A solution of methyl 2-vitro-4-(trifluoromethyl)benzoate (3.90 g, 15.7 mmol) in EtOAc (100 mL) and added to a flask containing 10% Pd/C (0.400 mg) in EtOAc (10 mL), then placed under a H=
atmosphere (balloon). The reaction was allowed to stir for 18 h at room temp, then was filtered through Celite~ and concentrated in vacuo to afford the desired product as a white crystalline solid (3.20 g, 93%): 'H-NMR (DMSO-d~ 8 3.79 (s, 3H), 6.75 (dd, ,1.84, 8.46 Hz, 1H), 6.96 (br s, 2H), 7.11 (d, .~-0.73 Hz, 1H), 7.83 (d, .8.09 Hz, IH).
A6. General Method for Aryl Amine Formation via Ether Formation Followed Ester Saponification, Curtius Rearrangement, and Carbamate Deprotection i C02Me OMe Step 1. Methyl 3-Methory-2-napht6oate: A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and ICzCO, (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temp for 15 min, then treated with iodomeW ane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at mom temp overnight, then was treated with water (200 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated NaCI solution (100 mL), dried (MgSO,), concentrated in vacuo (approximately 0.4 mmHg overnight) to give the desired ether as an amber oil (10.30 g): 'H-NMR (DMSO-ds) 8 2.70 (s, 3H), 2.85 (s, 3H), 7.38 (app t, ,F=8.09 Hz, 1H), 5 7.44 (s, 1H), 7.53 (app t, .8.09 Hz, 1H), 7.84 (d, ,t=8.09 Hz, 1H), 7.90 (s, 1H), 8.21 (s, 1H).
i COZH
OMe Step 2. 3-Methogy-2-naphthoic Acid: A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water (10 mL) in MeOH (100 mL) at room temp was treated 10 with a 1 N NaOH solution (33.4 mL, 33.4 mmol). The mixture was heated at the reflex temp for 3 h, cooling to room temp, and made acidic with a 10% citric acid solution. The resulting solution was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCI solution, dried (MgSO,) and concentrated in vacuo.
The residue was triturated with hexanes and washed several times with hexanes to give 15 the desired carboxylic acid as a white crystalline solid (5.40 g, 92%): 'H-NMR (DMSO-db) 8 3.88 (s, 3H), 7.34-7.41 (m, 2H), 7.49-7.54 (m, 1H), 7.83 (d, ,8.09 Hz, 1H), 7.91 (d, .8.09 Hz, 1 H), 8.19 (s, 1 H), 12.83 (br s, 1 H).
i O
W ~~O ~ W
OMe Step 3. 2-(N-(Carbobenzylory)amino-3-methorynaphthatene: A solution of 3-20 methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et,N (2.59 mL, 18.6 mmol) in anh toluene (70 mL) was stirred at room temp. for 15 min., then treated with a solution of diphenylphosphoryl azide (5.12 g, 18.6 mmol) in toluene (10 mL) via pipette.
The resulting mixture was heated at 80 °C for 2 h. After cooling the mixture to room temp.
benzyl alcohol (2.06 mL, 20 mmol) was added via syringe. The mixture was then warmed 25 to 80 °C overnight. The resulting mixture was cooled to room temp., quenched with a 10% citric acid solution, and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated NaCI solution, dried (MgSO,), and concentrated in vacuo. The residue was purified by flash chromatography (14% EtOAc/86% hexane) to give the benzyl carbamate as a pale yellow oil (5.1 g, 100%): 'H-NMR (DMSO-d6) b 3.89 (s, 3H), 5.17 (s, 2H), 7.27-7.44 (m, 8H), 7.72-7.75 (m, 2H), 8.20 (s, 1H), 8.76 (s, IH).
i OMe Step 4.2-Amino-3-methoxynaphthalene: A slurry of 2-(N (carbobenzyloxy)amino-3-methoxynaphthalene (S.0 g, 16.3 mmol) and 10% Pd/C (0.5 g) in EtOAc (70mL) was maintained under a HZ atmospheric (balloon) at room temp. overnight. The resulting mixture was filtered through Celite~ and concentrated in vacuo to give the desired amine as a pale pink powder (2.40 g, 85%): 'H-NMR (DMSO-d,~ b 3.86 (s, 3H), 6.86 (s, 2H), 7.04-7.16 (m, 2H), 7.43 (d, .~8.0 Hz, 1 H), 7.56 (d, .~8.0 Hz, 1 H); EI-MS m/z 173 (M+}.
A7. General Method for the Synthesis of Aryl Amines via Metal-Mediated Cross 1 S Coupling Followed by Reduction NOZ
OTf Step 1.5-tent Butyl-2-(trlfluoromethanesulfonyl)ory-1-nitrobenzene: To an ice cold solution of 4-tent-butyl-2-nitmphenol (6.14 g, 31.5 mmol) and pyridine (10 mL, mmol) in CH=Cl= (50 mL) was slowly added trifluoromethanesulfonic anhydride (10 g, 35.5 mmol) via syringe. The reaction mixture was stirred for 15 min, then allowed to warm up to room temp. and diluted with CH~CI= (100 mL). The resulting mixture was sequentially washed with a 1M NaOH solution (3 x 100 mL), and a 1M HCl solution (3 x 100 mL), dried (MgSO,), and concentrated under reduced pressure to afford the title compound (8.68 g, 84%): 'H-NMR (CDCI,) 8 1.39 (s, 9H), 7.30-8.20 (m, 3H).

F
Step 2.5-tart Butyl-2-(3-fluorophenyl)-1-nitrobenzene: A mixture of 3-fluorobenzeneboronic acid (3.80 g, 27.5 mmol), KBr (2.43 g, 20.4 mmol), K,PO, (6.1 g, 28.8 mmol), and Pd(PPh3)4 (1.0 g, 0.9 mmol) was added to a solution of 5-tent-butyl-2-(trilluoromethanesulfonyl)oxy-1-nitrobenzene (6.0 g, 18.4 mmol) in dioxane (100 mL).
The reaction mixture was heated at 80 °C for 24 h, at which time TLC
indicated complete reaction. The reaction mixture was treated with a saturated NH4C1 solution (50 mL) and extracted EtOAc (3 x 100 mL). The combined organic layers were dried (MgSO,}
and concentrated under reduced pressure. The residue was purified by flash chromatography (3% EtOAc/97% hexane) to give the title compound (4.07 g, 81%): 'H-NMR (CDCI,) 1.40 (s, 9H), 6.90-7.90 (m, 7H).
W

F
Step 3.5-tart Batyl-2-(3-fluorophenyl)aniline: To a solution of 5-tent-butyl-2-(3-fluorophenyl)-1-nitrobenzenc (3.5 g, 12.8 mmol) and EtOH (24 mL) in EtOAc (96 mL) was added 5% Pd/C (0.350 g) and the resulting slurry was stinr~i under a H2 atmosphere for 24 h, at which time TLC indicated complete consumption of starting material. The reaction mixture was filtered through a pad of Celite~ to give the desired product (2.2 g, 72%): 'H-NMR (CDC13) 8 1.35 (s, 9H), 3.80 (br s, 2H), 6.90-7.50 (m, 7H).
A8. General Method for the Synthesis of Nitroanitines ~I I~

Step 1.4-(4-(2-Propoxycarbonylamino)phenyl)methylanliine: A solution of di-tert-butyl dicarbonate (2.0 g, 9.2 mmol) and 4,4'-methylenedianiline (1.8g, 9.2 mmol) in DMF (100 mL) was heated at the reflux temp, for 2 h, then cooled to room temp.
This mixture was diluted with EtOAc (200 mL) sequentially washed with a saturated NH,CI
(200 mL) and a saturated NaCI solution (100 mL), and dried (MgSO,). The residue was purified by flash chromatography (30% EtOAd70% hexane) to give the desired carbamate (1.3 g, 48%): 'H-NMR (CDCI,) 8 1.51 (s, 9H), 3.82 (s, 2H), 6.60-7.20 (m, 8H).
I~ o o2N " ~N~O~
H
Step 2.4-(4-(2-Propoxycarbonylamino)phenyl)methyl-1-nitrobenzene: To an ice cold solution of 4-(4-(2-propoxycarbonylamino)phenyl)methylaniline (1.05 g, 3.5 mmol) in CHZCh (15 mL) was added m-CPBA (I.2 g, 7.0 mmol). The reaction mixture was slowly allowed to warm to room temp. and was stirred for 45 min, at which time TLC
indicated disappearance of starting material. The resulting mixture was diluted with EtOAc (50 mL), sequentially washed with a 1M NaOH solution (50 mL) and a saturated NaCI
solution (50 mL), and dried (MgSO,). The residue was purified by flash chromatography (20% EtOAc/80% hexane) to give the desired nitrobenzene (0.920 g): FAB-MS mlz (M'").
I
OzN NH2 Step 3.4-(4-Nitrophenyl)methylaniline: To , a solution of 4-(4-(2-propoxycarbonylamino)phenyl~nethyl-1-nitrobenzene (0.920 g, 2.8 mmol) in dioxane (10 mL) was added a cone. HCI solution (4.0 mL) and the resulting mixture was heated at 80 °C for 1 h at which time TLC indicated disappearance of starting material. The reaction mixture was cooled to room temp. The resulting mixture was diluted with EtOAc (50 mL), then washed with a 1M NaOH solution (3 x 50 mL), and dried (MgSO,) to give the desired aniline (0.570 mg, $9%): 'H-NMR (CDCI,) 8 3.70 (br s, 2H), 3.97 (s, WO 99/32463 PCT/US98/272b5 2H), 6.65 (d, .78.5 Hz, 2H), 6.9s {d, .x-8.5 Hz, 2H), 7.32 (d, .~8.8 Hz, 2H), 8.10 (d, ,~=8.8 Hz, 2H).
A9. General Method for Synthesis of Aryl Anilines via Alkylation of a s Nitrophenol Followed by Reduction O
~N~Br OJ
Step 1.4-(a-Bromoacetyl)morpholine: To an ice cold solution of morpholine (2.17 g, 24.9 mmol) and diisopropylethylamine (3.21 g, 24.9 mmol) in CHzCl2 (70 mL) was added a solution of bromoacetyl bromide (s.OS g, 2s mmole) in CH2C1Z (8 mL) via syringe. The resulting solution was kept at 0 °C for 4s min, then was allowed to wane to room temp. The reaction mixture was diluted with EtOAc (500 mL), sequentially washed with a 1M HCl solution (2s0 mL) and a saturated NaCI solution (250 mL), and dried (MgSO,) to give the desired product (3.2 g, 62%): 'H-NMR (DMSO-db) 8 3.40-3.50 (m, 4H), 3.50-3.60 (m, 4H), 4.11 (s, 2H).

~N O
1 s °~J
Step 2.2-(N Morpholinylcarbonyl)methoxy 5-tent butyl-1-nitrobenzene: A slurry of 4-tert-butyl-2-nitrophenol (3.9 g, 20 mmol) and K2C03 (3.31 g, 24 mmol) in DMF
(7s mL) was stirred at mom temp. for 1 s minutes, then a solution of 4-(a-bromoacetylrnoipholine {4.16 g, 20 mmol) in DMF (10 mL) was added. The reaction was allowed to stir at room temp. ovenught, then was diluted with EtOAc (s00 mL) and sequentially washed with a saturated NaCI solution (4 x 200 mL) and a 1M NaOH
solution (400 mL). The residue was purified by flash chromatography (7s%
EtOAc/2s%
hexane) to give the nitrobenzene (2.13 g, 33%): 'H-NMR (DMSO-d~ 8 1.25 (s, 9H), 3.3s-3.4s (m, 4H), 3.50-3.58 (m, 4H), s.00 (s, 2H), 7.12 (d, .~8.8 Hz, 1H), 7.50-7.80 {m, 2s 2H).

~ NH2 ~N O
OJ
Step 3.2-(N Morpholinyicarbonyl)methoay-5-tent butylaniline: To a solution of 2-(N
moipholinyicarbonyl)methoxy-5-tert-butyl-1-nitrobenzene(2.13 g, 6.6 mmol) and EtOH
(10 mL) in EtOAc (40 mL) was added 5% Pd/C (0.215 g). The resulting slurry was 5 stirred under a H2 atmosphere for 6 h, at which time TLC indicated complete consumption of starting material. The reaction mixture was filtered through a pad of Celite~ to give the desired product (1.9 g, 98%): 'H-NMR {DMSO-d~ S 1.18 (s, 9H), 3.40-3.50 (m, 4H), 3.50-3.60 (m, 4H), 4.67 (br s, 2H), 4.69 (s, 2H), 6.40-6.70 (m, 3H).
10 A10. General Method for Aryl Amine Formation via Nitrophenol Alkylation Followed by Reduction HO~O
Step L 5-tert Butyi~2-(2-hydroxyethoxy~l-nitrobenzene: A solution of 4-tert-butyl-2-nitrophenol {30 g, 0.15 moI) and tetra-n-butylammonium fluoride (0.771 g, 3.0 mmol) in 15 ethylene carbonate (10.24 mL. 0.15 mol) was heated at 150 °C for 18 h, then cooled to room temp. and separated between water (50 mL) and CHZCh (50 mL). The organic layer was dried (MgS04) and concentrated under reduced pressure. The residue was purified by column chromatography (20% EtOAc/80% hexane) to afford the desired product as a brown oil (35.1 g, 90%): 'H-NMR (DMSO-ds) 8 1.25 (s, 9H), 3.66-3.69 (m, 20 2H), 4.10-4.14 (t, J'-5.0 Hz, 2H), 4.85 (t, ,~5.0 Hz, 1H), 7.27 (d, ,~8.8 Hz, 1H), 7.60-7.64 (m,1H), 7.75 (d, ,~2.6 Hz, 1H).

Step 2.5-tent-Butyl-Z-(Z-tent butoxycarbonylogy)ethoxyrl-nitrobenzene: A
solution of 5-tent-butyl-2-(2-hydroxyethoxy)-1-nitrobenzene (0.401 g, 1.68 mmol), di-tert-butyl dicarbonate (0.46 mL, 2.0 mmol) and dimethylaminopyridine (0.006 g, 0.05 mmol) in CHZCh (15 mL) was stirred at room temp. for 30 min, at which time TLC
indicated consumption of starting material. The resulting mixture was washed with water (20 mL), dried (MgSO,) and concentrated under reduced pressure. The residue was purified by column chromatography (3% MeOH/97% CHZC1Z) to give the desired product as a yellow oil (0.291 g, 51%):'H-NMR (DMSO-d6) 8 1.25 (s, 9H), 1.38 (s, 9H), 4.31 (br s, 4H), 7.27 (d, .~9.2 Hz, 1H) 7.64 (dd, ,~2.6, 8.8 Hz, 1H) 7.77 (d, J--2.6 Hz, 1H).

Step 3.5-tert-Butyl-Z-(Z-tert butoxycarbonyloxy)etho~cy)aniline: To a mixture of 5-tert-butyl-2-(2-tent-butoxycarbonyloxy)ethoxy)-1-nitrobenzene (0.290 g, 0.86 mmol) and 5% Pd/C (0.058 g) in MeOH (2 mL) was ammonium formate (0.216 g, 3.42 mmol), and the resulting mixture was stirred at room temp, for 12 h, then was filtered through a pad of Celite~ with the aid of EtOH. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (2% MeOH/98% CHzCI~ tp give the desired product as a pale yellow oil (0.232 g, 87%): TLC (20%
EtOAc/80%
hexane) Rf 0.63; 'H-NMR (DMSO-d~ b 1.17 (s, 9H), 1.39 (s, 9H); 4.03-4.06 (m, 2H), 4.30-4.31 (m, 2H), 4.54 (br s, 2H), 6.47 (dd, .~2.2, 8.1 Hz, 1H) 6.64-6.67 (m, 2H).
All. General Method for Substituted Aniline Formation via Hydrogenation of a Nitr~oarene ~ ~N

4-(4-Pyridinylmethyl)aniline: To a solution of 4-(4-nitmbenzyl~yridine (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 Hz atmosphere (50 psi) using a Purr shaker. After 1 h, TLC
and'H-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-db) 8 3.74 (s, 2H), 4.91 (br s, 2H), 6:48 (d, .8.46 Hz, 2H), 6.86 (d, .8.09 Hz, 2H), 7.16 (d, .5.88 Hz, 2H), 8.40 (d, .t=5.88 Hz, 2H); EI-MS m/z 184 (M+), This material was used in urea formation reactions without fiuther purification.
A12. 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 K~CO, in portions (Caution: foaming). The organic layer was washed with a saturated NaCI solution, dried (MgSO,), 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) Rj0.20.
Al3a. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Redaction O2N OMe Step 1. 1-Methoxy-4-(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 HzO, 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 NaHCO, solution (200 mL), and a saturated NaCI solution (200 mL), dried (NazSO,), and concentrated in vacuo.
The residue was triturated (EtzO/hexane) to afford 1-methoxy-4-(4-nitrophenoxy)benzene (12.2 g, 100%): 'H-NMR (CDCI,) b 3.83 (s, 3H), 6.93-7.04 (m, 6H), 8.18 (d, J=9.2 Hz, 2H); EI-MS mlz 245 (M~').
O
H2N OMe Step 2. 4.(4-Methogyphenoxy)aniline: To a solution of 1-methoxy-4-{4-nitrophenoxy)benzene (12.0 g, 49 mmol) in EtOAc (250 mL) was added 5% PdC (1.5 g) and the resulting slurry was shaken under a HZ atmosphere (50 psi) for 18 h.
The reaction mixture was filtered through a pad of Celite~ 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, .~8.8 Hz, 2H), 6.79-6.92 (m, 6H); EI-MS m/z 215 (M+).
Al3b. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction ~ S
I ~N
OzN
Step I. 3-(TrItluoromethyl~.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 i WO 99/32463 ~ PCT/US98/27265 stirred at room temperature and under argon overnight. TLC showed complete reaction.
The nuxture was diluted with EtzO (100 mL) and water (100 mL) and the aqueous layer was back-extracted with EtzO (2 x 100 mL). The organic layers were washed with a saturated NaCI solution (100 mL), dried (MgSO,), and concentrated under reduced pressure. The solid residue was triturated with EtzO to afford the desired product as a tan solid (3.8 g, 54%): TLC (30% EtOAc/70% hexane) Itf 0.06; 'H-NMR (DMSO-d~ 8 7.33 (dd, .~=1.2, 4.2 Hz, 2H), 7.78 (d, .~8.7 Hz, 1H), 8.46 (dd, .~2.4, 8.7Hz, 1H), 8.54-8.56 (m, 3H).

S
/ I ,N

Step 2. 3-(Trltluoromethy>)-4-(4-pyridlnylthio)anlline: 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 EtzO (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 afi'ord the desired product (3.3 g):
TLC (50% EtOAc/50% hexane) R~ 0.10; 'H-NMR (DMSO-d6) 8 6.21 (s, 2H), 6.84-6.87 (m, 3H), 7.10 (d, .1--2.4 Hz, 1H), 7.39 (d, ,~8.4 Hz, 1H), 8.29 (d, .~6.3 Hz, 2H).
Al3c. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophltic Aromatic Substitution, Followed by Reduction W S II S
N /
OZN
Step 1. 4-(2-(4-Phenyl)thiazoly!)tbio-l-nitrobenzene: A solution of 2-mercapto-phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with 1-fluom-4-nitrobenzene (2.3 mL, 21.7 mmoles) followed by KzCO, (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 (MgSO,) and concentrated under reduced pressure.
The 5 solid residue was triturated with a EtZO/hexane solution to afford the desired product (6.1 g): TLC (25% EtOAc/75% hexane) R f 0.49; 'H-NMR (CDCI,) S 7.35-7.47 (m, 3H), 7.58-7.63 (m, 3H), 7.90 (d, .~--6.9 Hz, 2H), 8.19 (d, J--9.0 Hz, 2H).
,~ sues N~

Step 2. 4-(2-(4-Phenyl)thiazolyl)thioaniline: 4-(2-(4-Phenyl)thiazolyl)thio-1-nitro-10 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 (CDCl3) 8 3.89 (br s, 2H), 6.72-6.77 (m, 2H), 7.26-7.53 (m, 6H), 7.85-7.89 (m, 2H).
15 Al3d. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Redaction O N
w ( ~ i OzN
Step 1. 4-(6-Methyl-3-pyridinyloryrl-nitrobenzene: To a solution of 5-hydroxy-20 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 K~CO, (13.0 g, 91.6 aimol) 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 25 a saturated NaCI solution (2 x 100 mL), dried (Na2S0,), and concentrated in vacuo to stirred at room temperature an WO 99/32463 PCT/US98lZ7265 afford the desired product (8.7 g, 83%). The this material was carried to the next step without fiuther purification.
O N
~I I~

Step 2. 4-(6-Methyl-3-pyrldinyloxy)aniline: A solution of 4-(6-methyl-3-pyridinyloxy)-1-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 HZ
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 tan solid (3.2 g, 92%): EI-MS m/z 200 (M~).
Al3e. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromstic Substitution, Followed by Reduction O ~ OMe 02N OMe Step 1. 4-(3,4-Dimethoryphenoxy~l-nitrobenzene: To a solution of 3,4-dimethoxyphenol (1.0 g, 6.4 mmol) and 1-fluoro-4-nitmbenzene (700 pL, 6.4 mmol) in anh DMF (20 mL) was added ICzCO, (1.8 g, 12.9 mmol) in one portion. The mixture was heated at the reflux temp with staring for 18 h and then allowed to cool to mom temp.
The mixture was then poured into water (100 mL) and extracted with EtOAc (3 x mL). The combined organics were sequentially washed with water (3 x 50 mL) and a saturated NaCI solution (2 x 50 mL), dried (NazS04), and concentrated in vacuo to afford the desired product (0.8 g, 54%). The crude pmduct was carried to the next step without fiuther purification.
O ~ OMe I
H2N OMe Step 2. 4-(3,4-Dimethmcyphenoxy)aniline: A solution of 4-(3,4-dimethoxy-phenoxy~
1-nitrobenzene (0.8 g, 3.2 mmol) in EtOAc (50 mL) was added to 10% PdIC (0.100 g) and the resulting mixture was placed under a H~ 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+).
Al3f. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction N
I
OZN O
Step 1. 3-(3-Pyridinylory~l-nitrobenzene: 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 (S.0 g, 34.8 mmol) in anh DMF (SO mL) was added KZCO, {8.0 g, 58.1 mmol) in one portion.
The resulting mixture was heated at the reflex 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 NaCI solution (2 x 100 mL), dried (Na2S0,,), 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.
N
I

Step 2. 3-(3-Pyridinyloxy)anlline: 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 H~ 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 aE'ord the desired product as a red oil (1.6 g, 94%): EI-MS mlz 186 (M').
Al3g. General Method for Substituted Aniline Formation via Nitroarene Formation Throagh Nucleophilic Aromatic Substitntian, Followed by Redaction N
wl wl Step 1. 3-(5-Methyl-3-pyridinyloxy~l-nitrobenzene: To a solution of 3-hydroxy-methylpyridine (5.0 g, 45.8 mmol), 1-bmmo-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 KzCO, (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 NaCI solution (2 x 100 mL), dried (Na~SO,), and concentrated in vacuo . The resulting oil was purified by flash chromatography (30% EtOAc/70% hexane) tQ afford the desired pmduct (1.2 g,13%).
N
I
HZN O
Step 2. 3-(5-Methyl-3-pyridinylozy)-I-nitrobenzene: A solution of 3-(5-methyl-pyridinyloxy)-1-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 Hz atmosphere (balloon) and was allowed to stir for 18 h at mom temp. The mixture was then filtered through a pad of Celite~ and concentrated in vacuo to afford the desired product as a red oil (0.9 g, 86%):
CI-MS mlz 201 ((M+H)+).
Al3h. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nacleophilic Aromatic Substitution, Followed by Reduction O
I ~N
OZN
Step 1. 5-Nitro-2-(4-methylphenory)pyridine: To a solution of 2-chloro-5-nitropyridine (6.34 g, 40 mmol) in DMF (200 mL) were addod of 4-methylph~nol (5.4 g, 50 mmol, 1.25 equiv) and ICzCO, (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) R f 0.79; 'H-NMR (DMSO-d~ S 2.31 (s, 3H), 7.08 (d, .18.46 Hz, 2H), 7.19 (d, .9.20 Hz, 1H), 7.24 (d, .8.09 Hz, 2H), 8.58 (dd, .2.94, 8.82 Hz, 1H), 8.99 (d, .2.95 Hz,1H); FAB-MS m/z (rel abundance) 231 ((M+H)+), 100%).
CI' Step 2. 5-Amino-2-(4-methylphenoxy)pyridine Dihydrochlorlde: A solution 5-nitro-2-(4-methylphenoxy~yridine (6.94 g, 30 mmol, 1 eq) and EtOH (10 mL) in EtOAc (190 mL) was purged with argon then treated with 10% PdIC (0.60 g). The reaction mixture was then placed under a Hz atmosphere and was vigorously stirred for 2.5 h.
The reaction mixture was filtered through a pad of Celite~. A solution of HCl in EtzO 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, .F=8.45 Hz, 2H), 7.04 (d; .8.82 Hz, 1H), 7.19 (d, ,8.09 Hz, 2H), 8.46 (dd, .2.57, 8.46 Hz, 1H), 8.63 (d, J--2.57 Hz, 1H); EI-MS mlz (rel abundance) (M+,100%).
Al3i. General Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitution, Followed by Reduction OzN
Step 1. 4-(3-Thfenylthio)-1-nitrobenzene: 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
HCl 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 1 M NaOH
solution (2 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (MgSO,,), and concentrated in vacuo . The residual oil was purified by MPLC (silica gel;
gradient from 5 10% EtOAc/90% hexane to 5% EtOAc/95% hexane) to afford of the desired product (0.5 g, 34%). GC-MS »tlz 237 (M'~.
~ w S L.../S
HZN
Step 2. 4-(3-Thienylthio)aniline: 4-(3-Thienylthio)-1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B 1.
Al3j. 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 (MgSO,), and concentrated in vacuo. The residular solids were purified by MPLC (50% EtOAc/50% hexanes) to give the desired amine (0.650 g, 38%).
Al3k. Genera! Method for Substituted Aniline Formation via Nitroarene Formation Through Nucleophilic Aromatic Substitntlon, Followed by Rednc~on $1 Br ~ ~ OMe N
Step 1. S-Bromo-2-methorypyrldlne: A mixture of 2,5-dibromopyridine (5.5 g, 23.2 mmol) and NaOMe (3.768, 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 (NazSO,,) and concentrated under reduced pressure to give a pale yellow, volatile oil (4.1g, 95% yield): TLC (10% EtOAc / 90% hexane) RI0.57.
HO ~ ~ OMe N
Step 2. 5-Hydroacy-2-metho~cypyridine: 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%;
appmx.
50 mL). The resulting yellow and slightly turbid reaction mixture was warned 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 ncutralized with a 1N
HCl solution then extracted with EtzO (2 x 100 mL). The combined organic layers were dried (Na~SO,) and concentrated under reduced pressure to give a viscous yellow oil (3.Sg, 60%).
02N N OMe Step 3. 4-(5-(2-Methory)pyrldyl)oyy-1-nitrobenzene: To a stirred slung of NaH
(97%, 1.0 g, 42 mmol) in anh DMF (100 mL) was added a solution of 5-hydroxy-2-methoxypyridine (3.Sg, 28 mmol) in DMF (100 mL). The resulting mixture was allowed to stir at room temp. for 1 h, 4-fluoronitmbenzene (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%).
I
H2N N OMe Step 4. 4-(5-(2-Methoxy)pyridyl)oxyaniline: 4-(5-{2-Methoxy~yridyl)oxy-1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2.
Al4a. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine N
I~ I~

3-(4-Pyridinylthio)aniline: To a solution of 3-aminothiophenol (3.8 mL, 34 mmoles) in anh DMF (90mL) was added 4-chlompyridine hydrochloride (5.4 g, 35.6 mmoles) followed by K~CO, {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 (100mL). 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 roduced 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 EtzO/hexane solution to afford the desired product (4.6 g, 66%): TLC
(100 % ethyl acetate) Rr 0.29; 'H-NMR (DMSO-d~ b 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).
Al4b. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine O
~I I

4-(2-Methyl-4-pyridinylozy)aniline: To a solution of 4-aminophenol (3.6 g, 32.8 mmol) and 4-chlompicoline (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 mL). The combined extracts were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na~S04), 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 mla 201 ((M+H)+).
Al4c. General Method for Substituted Aniline Synthesis via Nucleophffic Aromatic Substitution using a Halopyridine Me 02N ~ / N
N
Step 1. Methyl(4-nftrophenyl~4-pyridylamine: To a suspension of N methyl-4-nitroaniline (2.0 g, 13.2 mmol) and ICzC03 (7.2 g, 52.2 mmol) in DMPIJ (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 (Na~SO,) 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-nitmphenyl)-4-pyridylamine (0.42 g) Me H2N ~ / N
N
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.
A15. General Method of Substituted Aniline Synthesis via Phenol Alkylation Followed by Redaction of a Nitroarene S
I~ I~

Step 1. 4-(4-Bntoxyphenyl)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 stiwed 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 EtZO (2 x 500 mL). The combibed organics were washed with water (2 x 400 mL), dried (MgSO,,), 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) Itf0.75; 'H-NMR (DMSO-d6) 8 0.92 (t, .~ 7.5 Hz, 3H), 1.42 (app hex, ,~7.5 Hz, 2H), 1.70 (m, 2H), 4.01 (t, .~ 6.6 Hz, 2H), 7.08 (d, .~8.7 Hz, 2H), 7.17 (d, .1--9 Hz, 2H), 7.51 (d, .F= 8.7 Hz, 2H), 8.09 (d, .~ 9 Hz, 2H).
S
I

Step 2. 4-(4-Butoxyphenyl)thioanillne: 4-(4-Butoxyphenyl)thio-1-nitrobenzene was reduced to the aniline in a manner analagous to that used in the preparation of 3-(trifluoromethyl)-4-(4-pyridinylthio)aniline (Method 83b, Step 2): TLC (33%
EtOAc/77% hexane) Rf0.38.
A16. General Method for Synthesis of Substituted Anilines by the Acylat~on of Diaminoarenes O
H2N~ I ~ N~O
H

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 5 methylenedianiline. Additional di-tert-butyl dicarbonate (0.664 g, 3.03 mmol, 0.02 equiv) was added and the reaction stirred at the reflex temp. for 16 h. The resulting mixture was diluted with EtzO (200 mL), sequentially washed with a saturated NaHCO, solution (100 ml), water (100 mL) and a saturated NaCI solution {50 mL), dried (MgS04), and concentrated under reduced pressure. The resulting white solid was IO 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) Rr 0.45; 'H-NMR (DMSO_d~ 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, .~8.I Hz, 2H), 7:00 (d, .~8.4 Hz, 2H), 7.28 (d, .t=8.1 Hz, 2H), 9.18 (br s, 1H); FAB-MS m/z 298 (M~.
A17. General Method for the Synthesis of Aryl Amines via Electrophilic Nitration Followed by Redaction OzN
Step 1. 3-(4-Nitrobenzyl)pyridine: 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 1N NaOH solution, then extracted with EtzO (4 x mL). The combined extracts were sequentially washes with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (Na2S0,), 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 mla 214 (M').
I

Step 2. 3-(4-Pyridinyl)methylaniline: 3-(4-Nitrobenzyl)pyridine was reduced to the aniline in a manner analogous to that described in Method B1.
A18. General Method for Synthesis of Aryl Amines via Substitution with Nitrobenzyl Halides Followed by Reduction ~I

Step 1. 4-(1-Imidazolylmethylrl-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 KzCO, (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 m1z 203 (M'").
~I ~~

Step Z. 4-(1-Imidazolylmethyl)aniline: 4-(1-Imidazolylinethyl)-1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B2.
A19. Formation of Substituted Hydroxymethylanilines by Oxidation of Nitrobenzyl Compounds Followed by Reduction OH
~1 ~ ~ ~N
OZN
Step 1. 4-(1-Hydrory-1-(4-pyridyl)methyl-1-nitrobenzene: To a stirred solution of 3-(4-nitrobenzyl~yridine (6.0 g, 28 mmol) in CH~CI= (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% NaHSO, solution (50 mL), a saturated ICzC03 solution (50 mL) and a saturated NaCI solution (50 mL), dried (MgSO,) 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 NH, 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 CHZC12 (50 mL). The organic layer was dried (MgSO,), concentrated under reduced pressure, and purified by column chromatography (80% EtOAc/ 20% hexane) to afford the desired pmduct as a white solid. (0.53 g, 8%):
mp 110-118 °C; TLC (80% EtOAc/20% hexane) R~, 0.12; FAB-MS m/z 367 ((M+H)+, 100%).
OH
~1 H I / ~N

Step 2. 4-(1-Hydrogy-1-(4-pyridyl)methylaniline: 4-(1-Hydroxy-1-(4-pyridyl~methyl-1-nitrobenzene was reduced to the aniline in a manner analogous to that described in Method B3d, Step2.
AZO. Formation of 2-(N methylcarbamoyl)pyrld~nes vIa the Menisci reaction O
CI ~ NHZ
I ~N
Step 1. 2-(N methylcarbamoyl~4-chloropyridine. (Cannon: 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 addal conc. HMSO, (3.55 mL) (exotherm). To this was added HzOz (17 mL, 30% wt in H20) followed by FeS04 7H20 (0.55 g) to pmduce 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 NaCI solution (3 x 150 mlL. 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 bmwn 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) Its 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, IH, J = 2.4, 5.4 Hz, C1CHCN), 3.04 (d, 3H, J = 5.1 Hz, methyl); CI-MS m/z 171 ((M+Hr').
A21. Generalmethod for the Synthesis of urSulfonylphenyl Anilines O
~ I I

Step 1. 4-(4-Methylsulfonylphenory)-1-nitrobenzene: To a solution of 4-(4-methylthiophenoxy)-1-ntirobenzene (2 g, 7.66 mmol) in CHZCIZ (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 NaCI solution {25 mL), dried (MgSO~}, and concentrated under reduced pressurc to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene as a solid (2.1 g).
Step 2. 4-(4-Methylsulfonylphenoxyrl-aniline: 4-(4-Methylsulfonylphenoxy)-1-nitrobenzene was reduced to the aniline in a manner anaologous to that described in Method B3d, step 2.
A22. General Method for Synthesis of co-Alkogy-w-carboxyphenyl Anilines O
O OMe 02N OMe Step 1. 4-(3-Methorycarbonyl-4-methoxyphenoxyrl-nitrobenzene: To a solution of -(3-carboxy-4-hydroxyphenoxy)-1-nitrobenzene (prepared in a manner analogous to that described in Method B3a, step 1, 12 mmol) in acetone (50 mL) was added KZCO, (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 Celite~. The resulting solution was concentmated under reduced pressure, absorbed onto silica gel, and purified by column chromatography (50% EtOAc / 50% hexane) to give 4-(3-methoxycarbonyl-4-methoxyphenoxy)-1-nitrobenzene as a yellow powder (3 g):
mp 115 118 °C.
O
O OH
~ i 02N OMe Step 2. 4-(3-Carboxy-4-methoxyphenory)-1-nitrobenzene: 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 HCl solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgSO,) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy~l-nitrobenzene (1.04 8)~
B. General Methods of Urea Formation Bla. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate O
~i 'N N
O H H

N (5-tart-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)-N =(4-methylphenyl)urea: To a solution of S-tent-butyl-2-(3-tetrahydrofuranyloxy)aniline (0.078 g, 0.33 mmol) in toluene (2.0 mL) was added p-tolyl isocyanate (0.048 g, 0.36 mmol) and the resulting mixture was allowed to stir at room temp. for 8 h to produce a precipitate. The reaction mixture 5 was filtered and the residue was sequentially washed with toluene and hexanes to give the desired urea as a white solid (0.091 g, 75%): mp 229-231 °C; 'H-NMR
(DMSO-d~ 8 1.30 (s, 9H), 1.99-2.03 (m, IH), 2.19-2.23 (m, 4H), 3.69-3.76 (m, 1H), 3.86-3.93 (m, 3H), 4.98-5.01 (m, 1H), 6.81-6.90 (m, 2H), 7.06 (d, .8.09 Hz, 2H, 7.32 (d, .8.09 Hz, 2H), 7.84 (s, 1 H), 8.22 (d, .2.21 Hz, 1 H), 9.26 (s, 1 H).
Bib. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate O=S=O
O ~ ~ CH3 ~N N
H H
N (2-Methoxy-5-(trifluoromethanesulfonyl)phenyl~N'(4-methylphenyl)urea: p-Tolyl isocyanate (0.19 mL, I.55 mmol) was added to a solution of 2-methoxy-5-(triffuoromethanesulfonyl)aniline (0.330 g, 1.29 mmol) in EtOAc (5 mL), and the reaction mixture was stirred at mom temp. for 18 h. The resulting precipitate was collected by filtration and washed with EtzO to give a white solid (0.28 g).
This material was then purified by HPLC (C-18 column, 50% CH,CN/50% Hz0) and the resulting solids were triturated with Et~O to provide the title compound (0.198 g): 'H-NMR
(CDCI,) 8 7.08 (d, .~-8.5 Hz, 2H), 7.33 (d, .h~8.5 Hz, 2H), 7.40 (d, .~8:8 Hz, 1H), 7.71 (dd, .~2.6, 8.8 Hz, 1H), 8.66 (s, 1H), 8.90 (d, J=2.6 Hz, 1H), 9.36 (s, 1H);
FAB-MS m/z 389 ((M+1)'~.
Blc. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate O=S=O

Jl ~ I
~N N
MeO H H
N (2-Methoxy-5-(difluoromethanesulfonyl)phenyl)-N =(4-methylphenyl)urea: p-Tolyl isocyanate (0.058 mL, 0.46 mmol) was added to a solution of 2-methoxy-5-(difluoromethanesulfonyl)aniline (0.100 g, 0.42 mmol) in EtOAc (0.5 mL) and the resulting mixture was stirred at room temp. for 3 d. The resulting precipitate was filtered and washed with EtzO to provide the title compound as a white solid (0.092 g):
'H-NMR
(CDCI,) 8 2.22 (s, 3H) 4.01 {s, 3H), 7.02-7.36 {m, 6H), 7.54 (dd, .~2.4, 8.6 Hz, 1H), 8.57 (s, 1H), 8.79 (d, .~2.6 Hz, 1H), 9.33 (s, 1H); EI-MS m/z 370 (M').
Bld. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate Me0 / O , CH3 I ~l ~I
~N N
Me0 H H
N (2,4-Dimethoxy-5-(trifluoromethyl)phenyl)-N'-(4-methylphenyl)area: p-Tolyl isocyanate (0.16 mL, 1.24 mmol) was added to a solution of 2,4-dimethoxy-5-(trifluoromethyl)aruline (0.25 g, 1.13 mmol) in EtOAc (3 mL) and the resulting mixture was stirred at room temp. for 18 h. A resulting precipitate was washed with EtzO to give the title compound as a white solid (0.36 g): 'H-NMR (CDCI,) 8 2.21 (s, 3H).
3.97 (s, 3H), 3.86 (s, 3H), 6.88 (s, 1H), 7.05 (d, .~8.5 Hz, 2H), 7.29 (d, .~8.5 Hz, 2H), 8.13 (s, 1H), 8.33 (s,1H), 9.09 (s,1H); FAB-MS m/z 355 {(M+1)''~.
Bie. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate I\ i' i w I ~ w ( OMe H H

N {3-Methory-2-naphthyl~N'-(1-naphthyl)urea: To a solution of 2-amino-3-methoxynaphthalene (0.253 g, 1.50 mmol) in CH~CIz (3 mL) at room temp. was added a solution of 1-naphthyl isocyanate (0.247 g, 1.50 mmol) in CHZC12 (2 mL) and the resulting mixture was allowed to stir overnight. The resulting precipitate was separated S and washed with CHZCI= to give the desired urea as a white powder (0.450 g, 90%): mp 235-236 °C; 'H-NMR (DMSO-d~ 8 4.04 (s, 3H), 7.28-7.32 (m, 2H), 7.38 (s, 1H), 7.44-7.72 (m, 6H), 7.90-7.93 (m, 1H), 8.05-8.08 (m, 1H), 8.21-8.24 (m, 1H), 8.64 (s,1H), 9.03 (s, 1H), 9.44 (s, 1H); FAB-MS mlz 343 ((M+H)').
Blf. General Method for the Reaction of an Aryl Amine with an Aryl Isocyanate ~ I_ ~ ~ I
~ '~ H H
~O~O~O
N (5-tert Butyl-2-(2-tent butorycarbonyloxy)ethory)phenyl~N'-(4-methylphenyl)urea: A mixture of 5-tent-butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)aniline (Method A10, 0.232 g, 0.75 mmol) and p-tolyl isocyanate (0.099 mL, 0.79 mmol) in EtOAc (1 mL) was stirred at room temp. for 3 d to produce a solid, which was separated. The filtrate was purified by column chromatography (100% CH2C1~) and the residue was triturated (EtzO/hexane) to give the desired product (0.262 g, 79%): mp 155-156 °C; TLC (20% EtOAc/80%
hexane) Rf0.49;
'H-NMR (DMSO-d6) b 1.22 (s, 9H), 1.37 (s, 9H), 2.21 (s, 3H), 4.22-4.23 (m, 2H), 4.33-4.35 {m, 2H), 6.89-7.00 (m, 4H), 7.06 (d, .~8.5 Hz, 2H), 7.32 (d, .~8.1 Hz, 2H), 7.96 (s, 1H); 8.22 (d, .~1.5 Hz, 1H), 9.22 (s, 1H); FAB-MS m/z (rel abundance) 443 ((M+I~+, 6%).
B2a. General Method for Reaction of an Aryl Amine with Phosgene Followed by Addition of a Second Aryl Amine O ~ I /~N
N~N ~ S ~~
Me0 H H
N (2-Methoxy-5-(trifluoromethyl)phenyl~N'-(3-(4-pyridinylthio)phenyl)urea: To a solution of pyridine (0.61 mL, 7.5 mmol, 3.0 equiv) and phosgene (20% in toluene; 2.65 mL, 5.0 mmol, 2.0 equiv) in CH~CIs (20 mL) was added 2-methoxy-5-(trifluoromethyl)aniline (0.48 g, 2.5 mmol) at 0 °C. The resulting mixture was allowed warm to room temp. stirred for 3 h, then treated with anh. toluene (100 mL) and concentrated under reduced pressure. The residue was suspended in a mixture of CHZCIz (10 mL) and anh. pyridine (10 mL) and treated with 3-(4-pyridinylthio)aniline (0.61 g, 2.5 mmol, 1.0 equiv). The mixture was stirred overnight at room temp., then poured into water (50 mL) and extracted with CHzCIz (3 x 25 mL). The combined organic layers were dried (MgS04) and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CHZC12 and treated with pet. ether to give the desired product as a white precipitate {0.74 g, 70%): mp 202 °C; TLC (5% acetone/95% CH,CIz) R f 0.09; 'H-NMR (DMSO-d~ S 7.06 (d, .~5.5 Hz, 2H), 7.18 (dd, .Y-2.4, 4.6 Hz, 2H), 7.31 (dd, .F=
2.2, 9.2 Hz, 1H), 7.44 (d, .~5.7 Hz, 1H), 7.45 {s, 1H), 7.79 {d, .~2.2 Hz, 1H), 8.37 (s, 2H), 8.50 (dd, .~2.2, 9.2 Hz, 2H), 9.63 (s, 1H), 9.84 (s, 1H); FAB-MS m/z 420 ((M+H)+, 70%).
B2b. General Method for Reaction of an Aryl Amine with Phosgene Followed by Addition of a Second Aryl Amine CFA
W O ~ S
\~N
~N N
M~ H H
N-(2-Methoxy-5-(tritluoromet6yl)phenyl}-N'-(4-(4-pyridinylthio)phenyl)urea: To a solution of pyridine {0.61 mL, 7.5 mmol, 3.0 equiv) and phosgene (20% in toluene; 2.65 mL, 5.0 mmol, 2.0 equiv) in CH~Ch (20 mL) was added 4-(4-pyridinylthio)aniline (0.506 g, 2.5 mmol) at 0 °C. After stirring for 3 h at room temp., the mixture was treated with anh. toluene (100 mL) then concentrated under reduced pressure. The residue was suspended in a mixture of CHZC1Z (10 mL) and anh. pyridine (10 mL) and treated with 2-methoxy-5-(trifluoromethyl)aniline (0.50 g, 2.5 mmol, 1.0 equiv). After stirring the mixture overnight at room temp., it was poured into a 1 N NaOH solution (50 mL) and extracted with CHsCl2 (3 x 25 mL). The combined organic layers were dried (MgSO,) and concentrated under reduced pressure to give the desired urea (0.74 g, 71%): mp 215 °C; TLC (5% acetone/95% CH2C1~ R f 0.08; 'H-NMR {DMSO-d~ 8 3.96 (s, 3H), 6.94 (dd, .F=1.1, 4.8 Hz, 2H), 7.19 (d, .F=8.4 Hz, 1H), 7.32 (dd, .~2.2, 9.3 Hz, 1H), 7.50 (d, .~8.8 Hz, 2H), 7.62 (d, .~8.8 Hz, 2H), 8.32 (d, .~5.1 Hz, 2H), 8.53 (d, J~.7 Hz, 1H), 8.58 (s,1H), 9.70 (s,1H); FAB-MS m/z 420 ((M+H)+).
B3a. General Method for the Reaction of an Aryl Amine with Phosgene with Isolation of the Isocyanate, Followed by Reaction with a Second Aryl Amine NCO
Me0 Step 1. 5-(Difluoromethanesulfonyl)-2-methoxyphenyl isocyanate: To a solution of phosgene (1.95 M in toluene; 3.0 mL, 5.9 mmol) in CH2C12 (40 mL) at 0 °C was added a solution of 5-(difluoromethanesulfonyl~2-methoxyaniline (0.70 g, 2.95 mmol) and pyridine (0.44 mL, 8.85 mmol) in CHzCh (10 mL) dropwise. After being stirred at 0 °C
for 30 min and at room temp. for 3 h, the reaction mixture was concentrated under reduced pressure, then treated with toluene (50 mL). The resulting mixture was concentrated under reduced pressure, then was treated with EtrO (50 mL) to produce a precipitate (pyridinium hydrochloride). The Iesulting filtrate was concentrated under reduced pressure to provide the title compound as a white solid (0.33 g). This material was used in the next step without further purification.

O=S=O

N N
Me0 H H F
Step 2. N (2-Methoxy-5-(difluoromethanesulfonyl)phenyl)-N =(2-fiuoro-4-methylphenyl)urea: 2-Fluoro-4-methylaniline (0.022 mL, 0.19 mmol) was added to a solution of 5-(difluoromethanesulfonyl)-2-methoxyphenyl isocyanate (0.046 g, 0.17 5 mmol) in EtOAc (1 mL). The reaction mixture was stirred at mom temp. for 3 d. The resulting precipitate was washed with Et?O to provide the title compound as a white solid (0.055 g): 'H-NMR (CDCI,) 8 2.24 (s, 3H), 4.01 (s, 3H), 6.93 (d, .~8.5 Hz, 1H), 7.01-7.36 (m, 3H), 7.56 (dd, .F=2.4, 8.6 Hz, 1H), 7.98 (app t, .t=8.6 Hz, 1H), 8.79 (d, .T--2.2 Hz, 1H), 9.07 (s,1H), 9.26 (s, 1H); FAB-MS m/z 389 ((M+1)+).
B3b. General Method for the Reaction of an Aryl Amine with Phosgene with Isolation of the Isocyanate, Followed by Reaction with a Second Aryl Amine NCO
Me0 Step 1. 2-Methoxy-5-triflaoromethylphenyl Isocyanate: To a solution of phosgene (1.93 M in toluene; 16 mL, 31.4 mmol) in CHzCh (120 mL) at 0 °C was added a solution of 2-methoxy-5-(triffuoromethyl)aniline (3.0 g, 15.7 mmol) and pyridine (2.3 mL, 47.1 mmol) in CHZCIZ (30 mL) dropwise. The resulting mixture was stirred at 0 °C for 30 min and at room temp for 3 h, then concentrated under reduced pressure. The residue was diluted with toluene (30 mL), concentrated under reduced pressure, and treated with EtzO.
The resulting precipitate (pyridinium hydrochloride) was removed and the filtrate was concentrated under redeuced pressure to give the title compound as a yellow oil (3.0 g) which crystallizcd upon standing at room temp. for a few days.

F
~N N
M~ H H

Step 2. N (2-Methozy-S-(tritluoromethyl)phenyl)- N'-(4-fluorophenyl)urea: 4-Fluoroaniline (0.24 mL, 2.53 mmol) was added to a solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.50 g, 2.30 mmol) in EtOAc (6 mL) and the reaction mixture was stirred at room temp. for 3 d. The resulting precipitate was washed with EtzO to give the title compound as a white solid (0.60 g): NMR: 3.94 (s, 3H). 7.13-7.18 (m, 3H), 7.30 (dd, .~1.5, 8.4 Hz, 1H), 7.44 (m, 2H), 8.45 (s, 1H), 8.52 (d, .F=2.2 Hz, 1H), 9.42 (s, 1H); FAB-MS mla 329 ((M+1)+).
B4. General Method for Urea Formation via Curtius Rearrangement, Followed by Trapping with an Amine i ~N N
OMe H H
N-(3-Methoxy-2-naphthyl)-N'-(4-methylphenyl)urea: To a solution of 3-methoxy-2-naphthoic acid (Method A6, Step 2; 0.762 g, 3.80 mmol) and Et,N (0.588 mL, 4.2 mmol) in anh toluene (20 mL) at room temp. was added a solution of diphenylphosphoryl azide I S (1.16 g, 4.2 mmol) in toluene (5 mL). The resulting mixture was heated to 80 °C for 2 h, cooled to room temp., and p-toluidine (0.455 g, 4.1 mmol) was added. The mixture was heated at 80 °C overnight, cooled to room temp., quenched with a 10%
citric acid solution, and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with a saturated NaCI solution (25 mL), dried (MgSO,), and concentrated in vacuo. The residue was triturated with CHZCIz to give the desired urea as white powder (0.700 g, 61%): mp 171-172 °C;'H-NMR (DMSO-d~ 8 2.22 (s, 3H), 3.99 (s, 3H), 7.07 (d,.~8.49 Hz, 2H), 7.27-7.36 (m, SH), 7.67-7.72 (m, 2H), 8.43 (s, 1H), 8.57 (s, 1H), 9.33 (s,1H); FAB-MS m/z 307 ((M+I-~+).
B5. General Method for the Reaction of Substituted Aniline with N,N =
Carbonyldiimidazole Followed by Reaction with a Second Amine CI
ON

O
'N N
HO H H
N (5-Chloro-2-hydroxy-4-nitrophenyl) N'-(4-(4-pyridinylmethyl)phenyl)urea: A
solution of 4-(4-pyridinylinethyl)aruline (0.300 g, 1.63 mmol) and N,N =
carbonyldiimidazole (0.268 g, 1.65 mmol) in CH=C12 (10 mL) was stirred at room temp.
for 1 h at which time TLC analysis indicated no starting aniline. The reaction mixture was then treated with 2-amino-4-chloro-5-nitrophenol (0.318 g, 1.65 mmoi) and stirred at 40-45 °C for 48 h. The resulting mixture was cooled to room temp. and diluted with EtOAc (25 mL). The resulting precipitate was separated to give the desired product (0.416 g, 64%): TLC (50% acetone/50% CH~C12) Rf 0.40; 'H-NMR (DMSO-d6) 8 3.90 (s, 2H), 7.18 (d, .~8.4 Hz, 2H), 7.21 (d, J~ Hz, 2H), 7.3 8 (d, .~8.4 Hz, 2H), 7.54 (s, 1 H), 8.43-8.45 (m, 3H), 8.78 (s, 1H), 9.56 (s, IH), 11.8 (br s, 1H); FAB-MS mlz (rel abundance) 399 ((M+H)+,10%).
B6. General Method for the Synthesis of Symmetrical biphenyl Ureas as Side-I S Products of Urea Forming reactions CI ~ ~ CI
FaC H H CFa Bis(4-chloro-3-(trIfluoromethyl)phenyl)urea: To a solution of 5-amino-3-tert-butylisoxazole (0.100 g) in anh toluene (5 mL) was added 4-chloro-3-(trifluoromethyl~henyl isocyanate (0.395 g). The reaction vessel was sealed, heated at 85 °C for 24 h, and cooled to room temp. The reaction mixture was added to a slurry of Dowex~ SOWXZ-100 resin (0.5 g) in CHxCIZ (40 mL), and the resulting mixture was stirred vigorously for 72 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (gradient form 100% CHZC12 to 5% MeOH/95% CHsCI~ to give bis(4-chlom-3-(trifluoromethyl~henyl)unea followed by N (3-tent-butyl-5-isoxazolyl)-N =(4-chloro-3-(trifluoromethyl~henyl)urea. The residue from the symmetrical urea fractions was triturated (EtzO/hexanc) to give the urea as a white solid (0.110 g): TLC (3%
MeOH/97%
CHZCI~ Rf0.55; FAB-MS m/z 4I7 ((M+H)+).
C. Urea Interconversions and Misc. Reactions Cl. General Method for Alkylation of Hydroxyphenyl Ureas W
~N N
OH H H
Step 1.N (2-Hydroxy-5-(trifluoromethylthio)phenyl) N'-(4-methylphenyl)urea: p-Tolyl isocyanate (0.066 mL, 0.52 mmol) was added to a solution of 2-hydroxy-5-(trifluoromethylthio)aniline (0.100 g, 0.48 mmol) in EtOAc (2 mL) and the reaction mixture was stirred at room temp. for 2 d. The resulting precipitate was washed with EtOAc to provide the title compound (0.13 g): 'H-NMR (CDCI,) 8 2.24 (s, 3H).
7.44-7.03 (m, 6H), 8.46 (s, 1 H), 8.60 (d, .~ 1. 8 Hz, 1 H), 9.16 (s, 1 H), 10.41 (s, 1 H); FAB-MS
mlz 343 ((M+1)'). This material was used in the next step without purification.

'N N
Me0 H H
Step 2.N (2-Methory-5-(trlfluoromethylthio)phenyl) N'-(4-methylphenyl)urea: A
solution of N (2-hydroxy-5-(trifluoromethylthio~henyl)-N'-(4-methylphenyl)urea (0.125 g, 0.36 mmol), iodomethane (0.045 mL, 0.73 mmol), and ICzCO, (100 mg, 0.73 mmol) in acetone (2 mL) was heated at the reflux temp. for 6 h, then was cooled to room temp. and concentrated under reduced pressure. The residue was dissolved in a minimal amount of MeOH, absorbed onto silica gel, and then purified by flash chromatograpy (3%
EtzO/97% CH~CI~ to provide the title compound as a white solid (68 mg): 'H-NMR
(CDCI,) 8 2.22 (s, 3H), 3.92 (s, 3H), 7.05-7.32 (m, 6H), 8.37 (s, 1H), 8.52 (d, .~2.2 Hz, 1H), 9.27 (s,1H); FAB-MS m/z 357 ((M+1)'~.

C2. General Method for the Reduction of NItro-Contafning Ureas ~I_~ ~I
Me0 H H H N
N (5-tert-Bntyl-2-methoyyphenyl~N =(2-amilno-4-methylphenyl)urea: A solution of N (5-tert-butyl-2-methoxyphenyl)-N'-(2-nitro-4-methylphenyl)urea (prepared in a manner analogous to Method B 1 a; 4.0 g, 11.2 mmol) in EtOH ( 100 mL) was added to a slurry of 10% Pd/C (0.40 g) in EtOH (10 mL), and the resulting mixture was stirred under an atmosphere of H~ (balloon) at room temp. for 18 h. The mixture was filtered through a pad of Celite~ and concentrated in vacuo to afford the desired product (3.42 g, 94%) as a powder: mp 165-166 °C; 'H-NMR (DMSO-db) 8 1.30 (s, 9H), 2.26 (s, 3H), 3.50 (br s, 2H), 3.71 (s, 3H), 6.39 (br s, 1H), 6.62 (s, 1H), 6.73 (d, .8.46 Hz, 1H), 6.99 (dd, .2.21, 8.46 Hz, 1H), 7.05 (d, .18.46 Hz, 1H), 7.29 (s, 1H), 8.22 (d, .2.57 Hz, 1H);
FAB-MS
mla 328 ((M+H)+).
C3. General Method of Thiourea Formation by Reaction with a Thioisocyanate I~
S
~ I NON ~ I
M~ H H
N-(5-tent Butyl-2-methoryphenyt}-N'-(1-naphthyl)thiourea: To a solution of 5-tert-butyl-2-methoxyaniline (0.372 g, 2.07 mmol) in toluene (5 mL) was added 1-naphthyl thioisocyanate (0.384 g, 2.07 mmol) and the resulting mixture was allowed to stir at room temp. for 8 h to produce a precipitate. The solids were separated and sequentially washed with toluene and hexane to give the desired product as an off white pwoder (0.364 g, 48%): mp 158-160 °C;'H-NMR (DMSO-d~ 8 1.31 (s, 9H), 3.59 (s, 3H), 6.74 (d, .8.46 Hz, 1H), 7.13 (dd, .2.21, 8.46 Hz, 1H), 7.53-7.62 (m, 4H), 7.88-7.95 (m, 4H), 8.06-8.08 (m, 1H), 8.09 (br s,1H); FAB-MS m/z 365 ((M+H)'').

C4. General Method for Deprotection of tert-Butyl Carbonate-Containing Ureas O
~N N
O H H
HO~
N-(5-tent-Butyl-2-(2-hydroxyethoxy)phenyn-N'-(4-methylphenyl)urea: A solution of N (5-tert-butyl-2-(2-tert-butoxycarbonyloxy)ethoxy)phenyl)-N'-(4-methylphenyl)urea 5 (Method B 1 f; 0.237 g, 0.54 mmol) and TFA (0.21 mL, 2.7 mmol) in CHzCh (2 mL) was stirred at room temp for 18 h, then was washed with a saturated NaHCO, solution (2 mL).
The organic layer was dried by passing through 1PS filter paper (VVhatman~ and concentrated under reduced pressure. The resulting white 'foam was triturated (EtzO/hexane), then recrystallized (EtZO) to give the desired product (3.7 mg): TLC (50%
10 EtOAc/50% hexane} RI 0.62; 'H-NMR (DMSO-d~ S 1.22 (s, 9H), 3.75-3.76 (m, 2H}, 4.00-4.03 (m, 2H), 4.80 (t, ,~5.0 Hz, 1H), 6.88-6.89 (m, 4H), 7.06 (d, .F=8.5 Hz, 2H), 7.33 (d, .T--8.1 Hz, 2H), 7.97 (s, 1H), 8.20 br s, 1H), 9.14 (s, 1H); FAB-MS
mlz (rel abundance) 343 ((M+H)+, 100~/0).
The following compounds have been synthesized according to the General Methods listed above:
Table 1. 2-Substituted-5-tert butylphenyl Ureas ~.N.~
Rt ~ H
mp TLC SolventMass Symh.

le R' R= C S ec. Soarce Method 1 OH 0.54 2% 299 FAB Bld ~Me MeOH (M+~+
/

98%

2 OMe _ 313 FAB Bld Me 200 (M+H}~+

3 OMe 208- 390 EI Bld O~ 209 (M+) 4 OMe HZ 192- 389 FAB B l d C-~N 194 (M+H~

OMe CI 0.5850% 347 FAB B36 EZOAc (M+H~
/

---~-Me 50%

hexane 6 OMe CI 0.62SO% 351 FAB B3b EtOAc (M+H~
/

~F 50%
-~-hexane 7 OMe F 0.7150% 331 FAB Bld EtOAc (M+H~
/

~M~ SOYo hexane 8 OMe U.74SO% 331 FAB B3b ~F EtOAc (M+H~+
/

Me 50%
hexaae 9 OMe 0.6620% 327 FAB Bld ~M~ EtOAc (M+H~
/

Me 88'/0 hexaae OMe 0.6220% 331 FAB Bld ~Me EtOAc (M+H~
/

F 80%

hexane 11 OMe F 0.4213% 335 FAB Bld / EtOAc (M+H~+
~ /

F $7%

hexane 12 OMe M~ 0.522% 327 FAB Bld MeOH (M+H~
/

Me 98%
13 OMe 0.562% 335 FAB Bld ~F MeOH (M+H~
/

F 98%

CH2Cl2 14 OMe 0.482% 351 FAB Bld ~F MeOH (M+H~
/

Cl 98%

OMe M 0.50~ ~+ FAB Bld ~ ~H ~
~ /

98%

16 OMe H2 N 201- 390 FAB 82a -~-C ~ / 202 (M+H~

SUBSTITUTE SHEET (RULE 26) 17 OMe H= N 199- 390 FAB B2a --~-C- \ , 200 (M+H~
I8 OMe ~Et 198- 0.45 25% Bls 199 EtOAc 75%
hexane 19 OMe H= 181- 389 CI B2a --~-C-~ 182 (1N+H)+
20 OMe 181- 390 EI Bla 183 (I~'1+) 21 OMe OiT1 175- 358 FAB Bla ~Ma 17T (M+1~+' 22 OMe Me 219- 358 FAB Bla 220 (M+Hr' NOZ
23 OMe HIN 165- 328 FAB C2 ~Ma 166 (M+H?+' 24 OMe ~Ma 102- 2y1 FAH C2 104 (M+H~+
~x 25 OMe 236- 349 FAB Bls 238 (M+H~
26 OMe ~ 192- 367 FAB Bla 194 (M+H~

27 OMe ~ 137- 550 FAB B2a 140 (M+H~
N O
O
28 OMe HI 197- 434 G1 A8, B2a w~-C-~>-NO= 199 (M+H~
29 OMe $t 212- 416 FAB B2a N 215 (M+H)+
30 OMe ~Ma 195 405 FAB Ble (M+H~
31 OMe ~S~N I10 0.07 5% / ~ ~ FAB B2b 95%
CH2C>Z
32 OMe 185 0.67 5% 425 FAB B2a ~0~~ / (M+i~+
95%
CH2C>Z
SUBSTITUTE SHEET (RULE 26) 33 OMe N 214-0.54S% 448 FAB B2a '~-O-'< ~ 215 aceta~e(M+I~+
S l ~o~

34 OMe 180 0.565% 421 FAB B2s ~~OMe acetone(M+H~+
J /

95%

CHZCu 35 -01 ~Ma 0.6750% 343 FAB A10, EtOAc (M+H~ Blf, / G

OH 50%

hexaae 36 # 0.45506 340 FAB Bld ~O ~Me EtOAc (M+H~
/

Me hexme 37 Ne 222- 354 ES Blc _ ~Me 223 (M+I~+
O

Me 38 M~- FAB BId ~ ZOS ~+~
'N

39 O 230- 367 FAB Bld ,Nk -~-Me ~2 ~+Hr.

v 40 -O~ 197- 406 FAB A9, BIa 198 (M+H~+
O NH

Me 41 -O~ F 204- 392 FAB A9, Bla ~F 205 (M+H~
O NH

Me 42 -00~~ - 217- 424 FAB A9, Bla 218 (M+H~

Me 43 =p~ Me 187- 370 FAB A9, BIa 188 (M+H~

O NH

Me '0 118- 462 FAB A9, Bls O_ 120 (M+H~
J

CO' \O I~ ,fig FAB A9, Bla O_ ~ 148 (M+H)+
J F

COJ

sues~r~nv~ sH~r cRU~ zs~

46 'O 110- 480 FAB A9, Bla ~ 113 (M+H?+

CO' 47 ~ ~Ma 1~ ~+~ FAB A9, ~ 81a H
N
'OH

48 'O 107- 398 FAB A9, Bla O ~& 110 (MfH~
~Me NHMe 4S1 ' FAB A9, Bla O~ ~a ~ ~+~

Me NHMe 50 'p ~F 217- 388 FA8 A9,Bla O~Me 219 (M+H)+

NHMe 51 'O 116- 420 FAB A9,Bla O IZO (M+H~
~Me NHMe 52 'O F 100 406 FA8 A9, . B 1 a O~Me ---~F 105 (M+H~

NHMe 53 ' ~ 103- 438 FA8 A9, O~ 105 (M+H)+ Bla ~

Ma Cl C>
NHMe 54 'O --~-.M 118- 384 FA8 A9, Bla p e Izo (M+H~+
~Me NHMe 55 ~Et 125- 394 FAB Al, Bla ~ 128 (M+Hy+

36 ~ FAB Al, Bla ~ ~Q ~+~

~1 1~ 434 FA8 Al,Bla 156 (M+H~+
d Q

38_ ' - F ;~ ~~ FAB A2,Bla ~~~I..~~..ll~

O

suesTn~u~ sHSer tau~ zs~

59 ~ ~ 157- 423 FAB A2, Bla 159 (tut+HN' O
3~ F~ ,~~ Bla ~"Me 231 (M+H)+
61 _ ~~ 2~ 4~ FA8 B2a 104 (M+H?+
187- - ~8 FAB B2a 188 (1~'t+H~' C1 C!
204- 413 FAB Bla 206 (M+Ii~+

M ~ -~~-Me 192- 389 FAB A7, Bla 194 (M+H~
O
183- 425 FAB A7, Bla 185 (M+H~
O
159- 443 FAB A7, Bla 160 (M+H~

67 ~ F 179- 411 FAB A7, Bla ~F 180 (M+H~
-~'O
6g F ~N~ 0.06 ~Ac / 408 H FAB A7, Bla 90'/0 hexaae 69 ~ ~Ma 227- 377 FAB A7, Bls 229 (M+I~+
7p ~ ~F 216~ 381 FAB A7, Bls 217 (M+H~
71 ~ ~ 213- 431 FAB A7, BIa Z14 (M+H)+
CI CI _ 72 F 200- 399 FAB A7, Bla ~F 201 (M+H)+
73 ~g 134- 443 EI A7, Bla 136 (M+1 suesmvTE sHE~r (RUB zs~

74 ~S ~ 185. 459 FAB A7, Bla 186 (1~+I~+
S-~N

75 ~S ~ 207- 419 FAB A7, Bls 208 (M+li~+

suesTn~urs sH~r ~u~ zs~

Table 2. 2-Substituted- C trlflnoromethyl)phenyl Ureas H

mp TL SolventMau gyp, Exrmple R' R=
(G~ C Symm Spec. SourceMethod 76 OMe -~-.Me 185- 325 FAB Bld 186 +H

T1 OMe --~-F 0 20%

. 329 FAB B3b 2 EtOAc (M+H)+
/

hexane 78 OMe F 0.4206 343 FAB $3b -~--Me 9 EtOAc (M+H~+
/

80~O

bexaae 79 OMe F 0.320% 343 FAB B3b ''~( Me 2 EtOAc (M+H~+
/

80%

bexaae 80 OMe ~ 03 20'r6 359 FAB B3b '-~-Me 7 EtOAc (M+H~+
/

l 81 OMe ~ 0.420'X. 363 FAB B3b F

4 EtOAc (M+Hr.
/

80%

ixxane OMe ~Me 0,650'Xo 339 FAB Bld Me 8 EtOAc (M+1~+
/

50%

sues~n~rurs gHEET (RULE 26~

hacane 83 OMe Me 0.6SO% 343 '~( FAB
Bld F 8 EtOAc (M+,H~
/

50%
luxme 84 OMe ~ 0.650% 347 F FAB
Bld 0 EtOAc (M+H~+.
/

50%

85 OMe M~ O.s2% 339 FAB
~..N Bld ~~

~/ 3 MeOH (M+H~+
/

98%

CH2C>Z

_ 86 OMe ~F 0.22% 347 FAB H 1 d ~( F 9 MeOH (M+Hr.
/

98%

CH2C>Z

87 OMe F 0.22% 363 FAB Bld ~( CI 7 MeOH (M+1~+
/

98%

CH2Cl?

88 OMe ~Ma 0.42% 359 FAB Bid ''~( ~ s MeOH (M+H~+.
/

98~6 89 OMe ~H~ lg,~ 401 FA8 B2a ~../

Iss +

90 OMe --~-~ 176 4 ' 02 ~ B1a (M+) 91 OMe Z31- 361 FA8 Bla 233 (A,t+~

92 OMe ~ 192- 379 FAH Bla CI CI 194 ( M+~, 93 OMe --~-O~Me 198 4 17 FAB Ble +H

suesmurs sH~.r ~u~ 2a~

I' OMe --~-O~~ 106 0 S%

. 437 FAB B2a 8 acetone(M+H~
/

95%

--.- C'H2C12 95 OMe ~O S~ 98.990 . S%
'~i' 0 acetone /

95%

G~i2CJ2 OMe -~--O~~e 190 0 . 5S6 95%

CHZCI?
97 OMe -~--S~N~ l~

0.75% 464 FAB B2t 6 / (M+H~

95%

H
98 OMe Z10- 0 CH1CI2 ~C~N 0 . 5% 402 FAB B2a ~../

211 7 sceoone(M+H~
/

93%

CHZ~
OMe ~ 102 5% 410 FA8 B2a 0.0 acetone /
(M+H~

95%

OMe --~~-g~N 215 . F,,B
5%
4=0 /
CM+I~+

95%

CHZa2 101 OMe --~-.~N 206 , FAB B2a 5%

/
(M+~+

95%

CiitQ2 102 OMe FAB la O 0.7 B
5%

G'1 acerone /
(M+~+

95%

suesnTUTE sHEEr ~au~ ash WO 99/32463 PCT/US9$/Z7Z65 $0 103 OMe M~ 471 FAS Bia O-~

+H

104 OMe F~ 487 FAH Bla S~

+H

105 -~~ -~~-Mc 0.620% 352 FAB Bld Me 3 EtOAc (M+I~+
/

80%

-~--OMe Me 159- 03 25% 353 FAB A5, Bla 160 3 EtOAc (M+~+
/

75%
hexane 107 ~O -~

152- 0.325% 339 FAB A5, Bla OMe 153 5 EtOAc (M+~+
/

75%

108 SMe 246- 0.325% 377 FAB B1a 247 0 EtOAc (M+H~
/

75%

hexane 109 SMe -~--F 210- 0.325% 345 Q Bla 211 5 EtOAc (M+H~.
l 75%

haca~e 110 SMe -~-Me 195- 0.325% 314 FAB Bla 196 S EtOAc (M+~+
/

75'6 hexane 111 SMe 196- 0.425% 395 FAB Bla tOAc (M+Ii}+
/

75%
hexane suesT~TUrs sHEEr ~u~ Zs~

WO 99/324b3 PCT/11598/27265 Table 3. S-Snbstitnted 2-Methory-5-suUonylphenyt Uresa O S.Rs ~ N~N-~
Ms0 H H
mp TLC SolventMaa Sy>uh.

ie R= R' C) Svmm S Sore Method 112 -~-Me F 205- 339 HPLC B1d 207 + ES-MS

113 --~~-Me Cfff= 195- 370 EI Bid (M+) 114 ~F CHF= 0.46s0% 389 FAB B3a '~

cMe EtOAc (M+I~+
/

hexaae 115 C1 CI~~ 0.2150% 40s FAB B3s --- ~~-Me EtOAc (M+H~
/

50%
I~ne 116 Ci CIA= 0.2320% 409 FAB B3a ~ EtOAc (M+H~
-~--F /

hexaae 11? M~ Cfff= 0.405036 389 FAB B3s ---~-F EtOAc (M+H)+
/

50x hexane 118 -~--F CHF= 0.5350% 37s FA8 83a EtOAc (M+I~+
/

sos6 i suesTrruTE sHe~ tAU~ ~

119 F CFffl O.s8sOaYe 389 FAB Blc ---~-Me EtOAc (M+H~
/

>~e 120 Me CHF= 0.48s0% 389 FAB Bld ~

'' EtOAc (M+H)+
(F /

sfl%

here 121 ~ CFff= 0.44306 393 FAB Blc F EtOAc (M+H}+
/

SO%

122 M CFff= 0.33s% 38s FAB Blc ~ MeOH (M+H~
M /

95%

123 F CHF= 393 FAB Blc ' ~F (M+H

124 F CT3F= 409 FAB Blc +H~

125 ~Me CFff= 405 FAB Blc '' (Q (1~+~

126 Me Cfff= 0.56s0% 385 FAB Blc EtOAc (M+H~
/

so~c b~

127 --~--Me CF, 0.56s0% 389 FA8 A3, Bid , EtOAc (M+H~+
/

50%
hexes suesTwu~ sH~r tRU~ z~

WO 99/32463 PCT/US98/Z72b5 Table 4. 3-Snb:tituted-2~napbthyl Ureai i w NJI~.t~
Rt H H
mp TI,CSolventMau Synth.

le R~ R= (Cl Svmm S SourceMethod 128 OMe --~-Me 171-0.402s% 307 FAB B4 In Etowc (M+H~+
/

7s%

i~

129 OMe ~Me 197-0.4014% 325 FAB B4 '~

CF 199 EtOAc (M+H)+
/

8b%

hexane 130 OMe 235-0.4s2s% 343 FAB A6, Bls 236 EtOAc (M+H~
/

7s%

131 OMe -~-F 236-0.452s% 311 FAB A6, Bia 237 EtOAc (M+~+
/

75%

132 OMe ~ 209- 311 FAB A6, Bla 133 OMe ~ 22s- 321 FAB Ab, B1a Me Ma Z26 (M+~+

134 OMe ~Cl 199- 395 FAB Ab, '~ Bla (CF3 200 (M+H~

I3s OMe ~CI 227- 361 FAB A6, '~ Bla (Cl 228 (M+

suesTrrurs sH~r tRU~ zs~

136 OMc ~ 207- 327 FAB A6, Bls 208 (M+H~

137 OMe ~ ~ 234- 361 FAB A6, Bla 235 (M+H~

138 OMe ~ 228- 352 FAB A6, Bla Me NO= 229 ~M+~' 139 OMe ~~ 190- 323 FAB A6, Bls ig5 MH

140 OMe ~ 203- 310 FAB A6, Bla F 205 (M+

141 OMe ~ 209- 307 FAB A6, Bla Me 210 S+H?~

142 OMe -~OMe 200- 323 FAB A6, Bla 201 +H

143 OMe C~ 201- 307 FAB A6, BIs 202 +H

144 OMe --~-O-~ 216- 385 FAB A6, B1a 218 +H
+

145 OMe -~~-CF3 181- 361 FAB A6, Bla 182 +H

146 OMe --y-S-~N 238- 0.2525x 402 FAB B4 239 EtOAc (M+H)+
I

fuxaae 147 OMe ~H~N 199 0.202586 384 FAB B4 200 EtOAc (M+H~+
/

>~x~me 148 OMe --~-Et 175- 32I FAB A6, Bla 176 M+H
+

suesmu~ sHe~r tRU~ zs~

WO 99/32463 PCTlUS98/27265 i49 OMe -~-CHZ I64- 544 FAB A6, Bla i66 ~M+H?+
N O
O
150 OMe -y-S--~--NOZ 206. 446 FAB A6, Bla 209 +H
151 OMe N 234- 410 FAB 82a 237 (M+H}+
152 OMe -~-Q-~--OMe 209- 0.40 25'J~6 414 (M+) EI H4 211 EtOAc 75'Yo suesTnvrs sH~r ~u~ z~

Table 5. Miac. Urea mp TLC Solvent Ma:: Symh.
k R° Svatera S~u~ce Method Is3 183- 327 FAB Bid O i 184 (M+H~
I Nil ~ ~
H
154 Is6- 312 (M+ El Bld H
Ms0 lss C~ 0.46 50~~fo 291 FAB Bld w I w ( EtOAc l (M+H~
Me0 ~ ~ 50%
hexane ~N w I N~ w ~
HO
ls7 ~ 0.40 s0% 399 FAB Bs w ( ~. ~ I I acetone / (M+H~
HO ~ ~ s0%

is8 ~ 219- 336 FAB B1d ' ( ~ I21 (1~+H)'+' is9 a , 2W- 30s FAB Bid 20s (M+H)+
160 N~ Z08- 302 FAB Bld 110 (M+H~.
suesTrturs sH~r tRU~ zs~

F' u6. 355 FAB Bld w ~ ~ w ~ Z28 (M+Hy+
162 \ ~ ~ \ ~ 160- 328 FAB Bla 162 (M~
0.85 50% 291 FAB Blb EtOAc / (M+H)+
50%
1~ 225- O.bO 25% 367 FAB A4, Bla 226 EsOAc / (M+H)+
~ a a C~ G 75%
hexane 165 G ' ~ o \ ( G 0.55 3% 417 FAB 86 F~ t~~~ CFA MeOH / (M+H~
CH2Ci?
1~ G -I ~ / I C ( ' 1~- 407 FAB Bla F~ w ~ 171 (M+~
as \ ( \ I 160 (M+H)+
E~8.I~iao~sssv:
The in vitro intu'bitory pmpercies of compounds were determined usiag a p38 lcinase ialubition assay. P38 activity was detxted using an is vitro ltinase assay run in 96-well miccotiter plates. Ra;ombinant homes p38 (0.5 pgfmL) was mixod with substrate (myelin basic protein, 5 ~gfmL) in ldnase buffer (25 mM Hepes, 20 mM MgCiz and 150 mM
NaCI) and compound. One pCilwell of "P-labelod ATP (10 ~ was added to a foist SUBSTITUTE SHEET (RULE 2~

volume of 100 ~.L.. The reaction was run at 32 °C for 30 min. and stopped with a 1M HC1 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 ICs of between 1 nM and 10 E.iM.
t PS Induced TNFa Prodyction in Mice:
The in vivo inhibitory properties of selected compounds were determined using a marine LPS induced TNFa production in vivo model. BALB/c mice (Charles River Breeding Laboratories; Kingston, N~ in groups of ten were treated with either vehicle or compound by the mute noted. After one hour, endotoxin (E. coli lipopolysaccharide (LPS) 100 wg) 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 marine TNF ELISA kit (Genzyme).
The proceeding 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 proceeding 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.

Claims (22)

WHAT IS CLAIMED IS:
1. A method of treating a disease, other than cancer, mediated by p-38, comprising administering a compound of formula I
wherein A is B is a substituted or unsubstituted, up to tricyclic aryl or heteroaryl moiety of up to 30 carbon atoms with at least one 6-member aromatic structure containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein if B is substituted, it is substituted by one or more substituents selected from the group consisting of halogen, up to per-halo, and Wo, wherein n is 0-3 and each W is independently selected from the group consisting of -CN, -CO2R7, -C(O)NR7R7, -C(O)-R7, -NO2, -OR7, - SR7, -NR7R7, -NR7C(O)OR7; -NR7C(O)R7, C1-C10 alkyl, C1-10-alkenyl, C1-10 alkoxy, C3-C10 cycloalkyl, C6-C14 aryl, C7-C24 alkaryl, C3-C13 heteroaryl, C4-C23 alkheteroaryl, substituted C1-C10 alkyl, substituted C2-10-alkenyl, substituted C1-10-alkoxy, substituted C3-C10 cycloalkyl, substituted C4-C23 alkheteroaryl and Q-Ar;

wherein if W is a substituted group, it is substituted by one or more substituents independently selected from the group consisting of -CN, -CO2R7, -C(O)R7, -C(O)NR7R7, -OR7, -SR7, -NR7R7 , NO2, -NR7C(O)R7, -NR7C(O)OR7 and halogen up to per-halo;
wherein each R7 is independently selected from H, C1-C10 alkyl, C2-10 alkenyl, C3-C10 cycloalkyl, C6-C14 aryl, C3-C13 hetaryl, C4-C24 alkaryl, C4-C23 alkheteroaryl, up to per-halosubstituted C1-C10 alkyl, up to per-halosubstituted C2-10 alkenyl, up to per-halosubstituted C3-C10 cycloalkyl, up to per-halosubstituted C6-C14 aryl and up to per-halosubstituted C3-C13 hetaryl, wherein Q is -O-, -S-, -N(R7)-, -(CH2)-m, -C(O)-, -CH(OH)-, -(CH2)m O-, -NR7C(O)NR7R7-, -NR7C(O)-, -C(O)NR7-, -(CH2)m S-, -(CH2)m N(R7)-, -O(CH2)m, -CHX a, -CX a2, -S-(CH2)m and -N(R7)(CH2)m, m = 1-3, and X a is halogen; and Ar is a 5-10 member aromatic structure containing 0-2 members of the group consisting of nitrogen, oxygen and sulfur, which is unsubstituted or substituted by halogen up to per-halo and substituted or unsubstituted by Z n1, wherein n1 is 0 to 3 and each Z is independently selected from the group consisting of of -CN, -CO2R7, C(O)NR7R7, -C(O)- NR7, -COR7, -NO2, -OR7, - SR7, - NR7R7, -NR7C(O)OR7, -NR7C(O)R7, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C14 aryl, C3-C13 hetaryl, C7-C24, alkaryl, C4-C23 alkheteroaryl, substituted C1-C10 alkyl, substituted C3-C10 cycloalkyl, substituted C7-C24 alkaryl and substituted C4-C23 alkheteroaryl; wherein the one or more substituents of Z is selected from the group consisting of -CN, -CO2R7, -C(O)NR7R7, -OR7, -SR7, -NO2, -NR7R7 , -NR7C(O)R7 , -NR7C(O)OR7, R3, R4, R5 are each independently H, C1-10 alkyl, substituted or unsubstituted by halogen, up to perhalo, C1-10 alkoxy, substituted or unsubstituted by halogen, up to perhaloalkoxy, halogen; NO2 or NH2;
R6' is H, C1-10 alkyl, C1-10 alkoxy, -NHCOR1; -NR1COR1; NO2;

one of R4', R5' or R6' can be -X-Y, or 2 adjacent R4'-R6' when taken together form an aryl or hetaryl ring with 5-atoms, substituted or unsubstituted by C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl, C2-10 alkenyl, C1-10 alkanoyl, C6-12 aryl, C5-12 hetaryl or C6-12 aralkyl;
R1 is C1-10 alkyl substituted or unsubstituted by halogen, up to perhalo;
X is -CH2-, -S-, -N(CH3)-, -NHC(O)-, -CH2-S-, -S-CH2-, -C(O)-, or -O-; and X is additionally a single bond where Y is pyridyl;
Y is phenyl, pyridyl, naphthyl, pyridone, pyrazine, benzodioxane, benzopyridine, pyrimidine or benzothiazole, each substituted or unsubstituted by C1-10 alkyl, C1-10 alkoxy, halogen, OH, - SCH3 or NO2 or, where Y is phenyl, by or a pharmaceutically acceptable salt thereof.
2. A method according to claim 1, comprising administering a compound of formula Ia wherein R3, R4, R5, and R6 are each independently H; halogen; C1-10 alkyl substituted or unsubstituted by halogen up to perhalo; C1-10-alkoxy substituted or unsubstituted by at least one hydroxy group or halogen up to perhalo, C6-12 aryl, substituted or unsubstituted by C1-10 alkoxy or halogen, C5-12 hetaryl, substituted or unsubstituted by C1-10 alkyl, C1-10 alkoxy or halogen; NO2 ; SO2F; -SO2CH p X3-P; -COOR1; -OR1CONHR1; -NHCOR1; -SR1;
NH2; -N(SO2R1)2; furyloxy;
2 adjacent R3-R6 can together form an aryl or hetaryl ring with 5-12 atoms, substituted or unsubstituted by C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl, C2-10 alkenyl, C1-10 alkanoyl, C6-12 aryl , C5-12-hetaryl, C6-12-aralkyl, C6-12-alkaryl, halogen; -NR1; -NO2; -CF3;
-COOR1; -NHCOR1; -CN; -CONR1R1; -SO2R2; -SOR2; -SR2; in which R1 is H or C1-10 alkyl and R2 is C1-10 alkyl substituted or unsubstituted by halogen, up to perhalo, with -SO2- or no -SO2- or group incorporated in the aryl or hetaryl ring;
p is 0 or 1;
one of R3, R4, R5 or R6 can be -X-Y, with the proviso that if R3 and R6 are both H , one of R4 or R5 is not H, and R3' - R6' are as defined in claim 1.
3. A method according to claim 2, wherein R3 is H; halogen; C1-10-alkyl substituted or unsubstituted by halogen, up to perhalo, NO2, -SO2F or -SO2CF3;
R4 is H, C1-10 alkyl, C1-10 alkoxy, halogen or NO2;
R5 is H, C1-10 alkyl substituted or unsubstituted by halogen, up to perhalo;
R6 is H, hydroxy, C1-10 alkoxy substituted or unsubstituted by at least one hydroxy group;

-COOR1; -OR'CONHR1; -NHCOR1; -SR1; phenyl substituted or unsubstituted by halo or C1-10 alkoxy; NH2; -N(SO2R1)2, furyloxy, thiophene, pyrole or methyl substituted pyrole,
4. A method according to claim 2, wherein R3 is C1, F, C4-5-branched alkyl, SO2F or -SO2CF3; and R6 is hydroxy; C1-10 alkoxy substituted or unsubstituted by at least one hydroxy group; -COOR1; -OR1 CONHR1; -NHCOR1; -SR1; phenyl substituted or unsubstituted by halo or C1-10 alkoxy; NH2; -N(SO2R1)2, furyloxy,
5. A method according to claim 2, wherein R4 is C1-10 alkyl or halogen;
R5' is H, C1-10 alkyl, halogen, CF3, halogen, NO2 or NH2; and R6' is H, C1-10 alkyl, halogen, -NHCOCH3, -N(CH3)COCH3, NO2,
6. A method according to claim 2, wherein R5' is C1-10 alkyl, halogen, CF3, halogen, NO2 or NH2.
7. A method according to claim 2, wherein R6' is C1-10-alkyl, halogen, -NHCOCH3, -N(CH3)COCH3, NO2,
8. A method according to claim 4, wherein R3 is t-butyl or CF3 and R6 is -OCH3.
9. A method according to claim 2, wherein the disease is mediated by a cytokine or protease regulated by p38.
10. A method according to claim 2, wherein the disease is mediated by TNF.alpha., MMP-1, MMP-3, IL-1, IL-6 or IL-8.
11. A method according to claim 2, wherein the disease is an inflammatory or immunomodulatory disease.
12. A method according to claim 2, wherein the disease is osteoarthritis, rheumatoid arthritis, osteoporosis, asthma, septic shock, inflammatory bowel disease, or the result of host-versus-graft reactions.
13. A method according to claim 1, wherein the compound of formula I is N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-phenyloxphenyl)urea;
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-(4-methoxyphenyloxy)phenyl)urea;
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-(4-pyridinyloxy)phenyl)urea;
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea;
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-(4-pyridinylthio)phenyl)urea;
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-(4-(4,7-methano-1H-isoindole-1,3(2H)-dionyl)methyl)phenyl)urea;
N-(5-tert-Butyl-2-phenylphenyl)-N'-(2,3-dichlorophenyl)urea;
N-(5-tert-Butyl-2-(3-thienyl)phenyl)-N'-(2,3-dichlorophenyl)urea;
N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N'-(2,3-dichlorophenyl)urea;
N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N'-(1-naphthyl)urea;
N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N'-(2,3-dichlorophenyl)urea;
N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N'-(1-naphthyl)urea;
N-(5-tert-Butyl-2-methoxyphenyl)-N'-(4-(3-pyridinyl)methylphenyl)urea;
N-(5-tert-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)-N'-(2,3-dichlorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-methylphenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-methyl-2-fluorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-fluoro-3-chlorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-methyl-3-chlorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-methyl-3-fluorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(2,4-difluorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-phenyloxy-3,5-dichlorophenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-(4-pyridinylinethyl)phenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-(4-pyridinylthio)phenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-(4-pyridinyloxy)phenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(3-(4-pyridinylthio)phenyl)urea;
N-(5-Trifluoromethyl-2-methoxyphenyl)-N'-(4-(3-(N-methylaminocarbonyl)-phenyloxy)phenyl)-urea;
N-(5-Fluorosulfonyl)-2-methoxyphenyl)-N'-(4-methylphenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methylphenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N-(4-fluorophenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methyl-2-fluorophenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methyl-3-fluorophenyl)urea;
N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methyl-3-chlorophenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-fluoro-3-chlorophenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-fluoro-3-methylphenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(2,3-dimethylphenyl)urea;
N-(5-(Trifluoromethanesulfonyl)-2-methoxphenyl)-N'-(4-methylphenyl)urea;
N-(3-methoxy-2-naphthyl)-N'-(2-fluorophenyl)urea);
N-(3-Methoxy-2-naphthyl)-N'-(4-methylphenyl)urea;
N-(3-Methoxy-2-naphthyl)-N'-(3-fluorophenyl)urea;
N-(3-Methoxy-2-naphthyl)-N'-(4-methyl-3-fluorophenyl)urea;
N-(3-Methoxy-2-naphthyl)-N'-(2,3-dimethylphenyl)urea;
N-(3-Methoxy-2-naphthyl)-N'-(1-naphthyl)urea;
N-(3-Methoxy-2-naphthyl)-N'-(4-(4-pyridinylmethyl)phenyl)urea;
N-(3-Methoxy-2-naphthyl)-N'-(4-(4-pyridinylthio)phenyl)urea;
N-(3-Methoxy-2-naphthyl)-N'-(4-(4-methoxyphenyloxy)phenyl)urea; and N-(3-Methoxy-2-naphthyl)-N'-(4-(4-(4,7-methano-1H-isoindole-1,3(2H)-dionyl)methyl)phenyl)urea.
N-(2-Hydroxy-4-nitro-5-chlorophenyl)-N'-(phenyl)urea; or N-(2-Hydroxy-4-nitro-5-chlorophenyl)-N'-(4-(4-pyridinylmethly)phenyl)urea.
14. A compound of formula II
wherein R3, R4, R5, and R6 are each independently H; halogen; C1-10 alkyl substituted or unsubstituted by halogen up to perhalo; C1-10 alkoxy substituted or unsubstituted by at least one hydroxy group; NO2; SO2F; -SO2CH n X3-n; -COOR1; -OR1CONHR1; -NHCOR1;
-SR1; C6-12 aryl, substituted or unsubstituted by C1-10 alkyl, C1-10 alkoxy or halogen, C5-12 hetaryl, substituted or unsubstituted by C1-10 alkyl, C1-10 alkoxy or halogen;
NH2;
-N(SO2R1)2; furyloxy;
2 adjacent R3-R6 can together form an aryl or hetaryl ring with 5-12 atoms, substituted or unsubstituted by C1-10 alkyl, C1-10 alkoxy, C3-10 cycloalkyl, C2-10 alkenyl, C1-10 alkanoyl, C6-12-aryl, C5-12 hetaryl, C6-12-aralkyl, C6-12-alkaryl, halogen; NR1R1, NO2;
-CF3; -COOR1; -NHCOR1; -CN; -CONR1R1; -SO2R2; -SOR2; -SR2; in which R1 is H or C1-10 alkyl and R2 is C1-10 alkyl; C1-10 alkoxy, substituted or unsubstituted by halogen up to perhaloalkoxy, R3', R4' and R5' are each independently H, C1-10 alkyl, substituted or unsubstituted by halogen, up to perhalo; halogen; NO2 or NH2;

R6' is H, C1-10 alkyl, halogen, -NHCOR1-; -NR1COR-; NO2;
or 2 adjacent R4'-R6' can together be an aryl or hetaryl ring with 5-12 atoms;

R1 is C1-10-alkyl;
n is 0 or 1;
X is -CH2-, -S-, N(CH3)-, -NHC(O), CH2-S-, -S-CH2-, -C(O)-, or -O-; and Y is phenyl, pyridyl, naphthyl, pyridone, pyrazine, benzodixane, benzopyridine, pyrimidine or benzothiazole, each substituted or unsubstituted by C1-10 alkyl, C1-10 alkoxy, halogen or NO2 or, where Y is phenyl, by or a pharmaceutically acceptable salt thereof, with the provisos that (a) if R3 and R6 are both H, one of R4 or R5 is not H, (b) R6 is phenyl substituted by halogen, alkoxy substituted by hydroxy, -SO2CF2H, -OR1CONHR1, furyloxy or -N(SO2R1)2; or R6' is and (c) the compounds have a pKa greater than 10.
15. A compound according to claim 14, wherein R3 is H, halogen or C1-10 alkyl substituted or unsubstituted by halogen, up to perhalo, NO2, -SO2F or -SO2CF3;
R4 is H, C1-10 alkyl, C1-10 alkoxy, halogen or NO2;
R5 is H, C1-10 substituted or unsubstituted by halogen, up to perhalo;
R6 is H, hydroxy, C1-10 alkoxy substituted or unsubstituted by at least one hydroxy group;
-COOR1; -OR1CONHR1; -NHCOR1; -SR1; phenyl substituted or unsubstituted by halo or C1-10 alkoxy; NH2; -N(SO2R2)2, furyloxy,
16. A compound according to claim 14, wherein R3 is Cl, F, C4-5-branched alkyl, -SO2F or -SO2CF3; and R6 is hydroxy; C1-10-alkoxy substituted or unsubstituted by at least one hydroxy group; -COOR1; -OR1CONHR1; -NHCOR1; -SR1; phenyl substituted or unsubstituted by halo or C1-10-alkoxy; NH2; -N(SO2R1)2, furyloxy,
17. A compound according to claim 14, wherein R4' is C1-10-alkyl or halogen;
R5' is H, C1-10-alkyl, halogen, CF3, halogen, NO2 or NH2; and R6' is H, C1-10-alkyl, halogen, -NHCOCH3, -N(CH3)COCH3, NO2,
18. A compound according to claim 14, wherein R3 is t-butyl or CF3 and R6 is
19. A compound according to claim 14, which is N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N'-(2,3-dichlorophenyl)urea;
N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N'-(1-naphthyl)urea;
N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N'-(2,3-dichlorophenyl)urea;
N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N'-(1-naphthyl)urea;
N-(5-tert-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)-N'-(2,3-dichlorophenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methylphenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-fluorophenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methyl-2-fluorophenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methyl-3-fluorophenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-methyl-3-chlorophenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-fluoro-3-chlorophenyl)urea;
N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(4-fluoro-3-methylphenyl)urea;

N-(5-(Difluromethanesulfonyl)-2-methoxyphenyl)-N'-(2,3-dimethylphenyl)urea;
or N-(5-(Trifluoromethanesulfonyl)-2-methoxphenyl)-N'-(4-methylphenyl)urea.
20. A compound of formula II
wherein R3, R4, R5, and R6 are each independently H; halogen; C1-10- alkyl substituted or unsubstituted by halogen up to perhalo; C1-10-alkoxy substituted or unsubstituted by at least one hydroxy group; NO2; SO2F; -SO2CH n X3-n; -COOR1; -OR1CONHR1; -NHCOR1;
-SR1; phenyl substituted or unsubstituted by halogen or C1-10 alkoxy; NH2; -N(SO2R1)2;
furyloxy;
2 adjacent R3-R6 can together form an aryl or hetaryl ring with 5-12 atoms, substituted or unsubstituted by C1-10 alkyl, C1-10-alkoxy, C3-10-cycloalkyl, C2-10-alkenyl, C1-10-alkanoyl, C6-12-aryl, C5-12-hetaryl, C6-12-aralkyl, C6-12-alkaryl, halogen; -NR1; -NO2;
-CF3; -COOR1; -NHCOR1; -CN; -CONR1R1; -SO2R2; -SOR2; -SR2; in which R1 is H or C1-10-alkyl and R2 is C1-10 alkyl;
R3', R4' and R5' are each independently H, C1-10-alkyl, substituted or unsubstituted by halogen, up to perhalo; halogen; NO2 or NH2;
R6' is H, C1-10-alkyl, halogen, -NHCOR1; -NR1COR1; NO2;
R1 is C1-10-alkyl;
n is 0 or 1;
X is -CH2-, -S- or -O-; and Y is phenyl, pyridyl, naphthyl or benzothiazole, each substituted or unsubstituted by C1-10-alkyl, C1-10-alkoxy, halogen or NO2 or, where Y is phenyl, by or a pharmaceutically acceptable salt thereof with the provisos that (a) if R3 and R6 are both H, one of R4 or R5 is not H, and (b) R6 is alkoxy substituted by hydroxy, -SO2CF2H, -OR1CONHR1, furyloxy or -N(SO2R1)2; or R6' is
21. A pharmaceutical composition comprising a compound of claim 14, and a physiologically acceptable carrier.
22. A pharmaceutical composition comprising a compound of claim 20, and a physiologically acceptable carrier.
CA2315715A 1997-12-22 1998-12-22 Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas Expired - Lifetime CA2315715C (en)

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Families Citing this family (164)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6696475B2 (en) 1997-04-22 2004-02-24 Neurosearch A/S Substituted phenyl derivatives, their preparation and use
US7329670B1 (en) 1997-12-22 2008-02-12 Bayer Pharmaceuticals Corporation Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas
US7517880B2 (en) 1997-12-22 2009-04-14 Bayer Pharmaceuticals Corporation Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas
CA2315646C (en) * 1997-12-22 2010-02-09 Bayer Corporation Inhibition of raf kinase using symmetrical and unsymmetrical substituted diphenyl ureas
ATE286021T1 (en) 1998-10-22 2005-01-15 Neurosearch As SUBSTITUTED PHENYL DERIVATIVES, THEIR PRODUCTION AND USE
SI1140840T1 (en) * 1999-01-13 2006-06-30 Bayer Pharmaceuticals Corp -g(v)-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
RU2319693C9 (en) 1999-01-13 2008-08-20 Байер Копэрейшн Derivatives of urea (variants), pharmaceutical composition (variants) and method for treatment of diseases associated with cancer cells growth (variants)
EP1140840B1 (en) 1999-01-13 2006-03-22 Bayer Pharmaceuticals Corp. -g(v)-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
AU2004200566B2 (en) * 1999-01-13 2006-08-17 Bayer Pharmaceuticals Corporation Omega-carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US20020065296A1 (en) * 1999-01-13 2002-05-30 Bayer Corporation Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors
ATE538794T1 (en) * 1999-01-13 2012-01-15 Bayer Healthcare Llc GAMMA CARBOXYARYL SUBSTITUTED DIPHENYL UREA COMPOUNDS AS P38 KINASE INHIBITORS
UA73492C2 (en) 1999-01-19 2005-08-15 Aromatic heterocyclic compounds as antiinflammatory agents
JP2002537397A (en) 1999-02-22 2002-11-05 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド Polycyclic heterocyclic derivatives as anti-inflammatory agents
HUP0202248A3 (en) 1999-03-12 2006-06-28 Boehringer Ingelheim Pharma Compounds useful as anti-inflammatory agents
EP1163236B1 (en) 1999-03-12 2005-11-09 Boehringer Ingelheim Pharmaceuticals Inc. Aromatic heterocyclic compounds as anti-inflammatory agents
US6337418B1 (en) * 1999-04-09 2002-01-08 Eastman Chemical Co. Preparation of C1-C5 alkyl esters of nitro or thioether substituted aromatic carboxylic acids
WO2001004115A2 (en) 1999-07-09 2001-01-18 Boehringer Ingelheim Pharmaceuticals, Inc. Novel process for synthesis of heteroaryl-substituted urea compounds
US7030109B2 (en) 1999-07-19 2006-04-18 Pharmacia & Upjohn Company 1,2,3,4,5,6-Hexahydroazepino[4,5-b]indoles containing arylsulfones at the 9-position
MY122278A (en) 1999-07-19 2006-04-29 Upjohn Co 1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles containing arylsulfones at the 9-position
CA2389360C (en) 1999-11-16 2008-06-03 Steffen Breitfelder Urea derivatives as anti-inflammatory agents
AU3003701A (en) * 1999-11-19 2001-05-30 Axxima Pharmaceuticals Ag Inhibitors of helicobacter pylori induced gastrointestinal diseases
US6525046B1 (en) 2000-01-18 2003-02-25 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as antiinflammatory agents
US6608052B2 (en) 2000-02-16 2003-08-19 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
GB0010757D0 (en) 2000-05-05 2000-06-28 Astrazeneca Ab Chemical compounds
US7001911B2 (en) 2000-06-28 2006-02-21 Bristol-Myers Squibb Company Fused cyclic modulators of nuclear hormone receptor function
US20040077605A1 (en) 2001-06-20 2004-04-22 Salvati Mark E. Fused heterocyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
US6960474B2 (en) 2000-06-28 2005-11-01 Bristol-Myers Squibb Company Method for the treatment of a condition remediable by administration of a selective androgen receptor modulator
US6645990B2 (en) 2000-08-15 2003-11-11 Amgen Inc. Thiazolyl urea compounds and methods of uses
PE20020506A1 (en) 2000-08-22 2002-07-09 Glaxo Group Ltd PIRAZOLE DERIVATIVES FUSED AS PROTEIN KINASE INHIBITORS
US6849409B2 (en) 2000-10-16 2005-02-01 Axxima Pharmaceuticals Ag Cellular kinases involved in Cytomegalovirus infection and their inhibition
JP2004517080A (en) 2000-11-29 2004-06-10 グラクソ グループ リミテッド Benzimidazole derivatives useful as inhibitors of TIE-2 and / or VEGFR-2
US7235576B1 (en) * 2001-01-12 2007-06-26 Bayer Pharmaceuticals Corporation Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
DE10109204A1 (en) * 2001-02-26 2002-09-19 4Sc Ag Use of new and known diphenylurea compounds for the preparation of a medicament for the inhibition of intracellular protein-degradation pathway
EP1395548A1 (en) 2001-02-26 2004-03-10 4Sc Ag Derivatives of diphenylurea, diphenyloxalic acid diamide and diphenylsulfuric acid diamide and their use as medicaments
US20040087548A1 (en) * 2001-02-27 2004-05-06 Salvati Mark E. Fused cyclic succinimide compounds and analogs thereof, modulators of nuclear hormone receptor function
UA76977C2 (en) 2001-03-02 2006-10-16 Icos Corp Aryl- and heteroaryl substituted chk1 inhibitors and their use as radiosensitizers and chemosensitizers
JP2004528311A (en) * 2001-03-07 2004-09-16 テリック，インコーポレイテッド Substituted diaryl ureas as stimulators of Fas-mediated apoptosis
US6525091B2 (en) * 2001-03-07 2003-02-25 Telik, Inc. Substituted diarylureas as stimulators for Fas-mediated apoptosis
MXPA03009361A (en) * 2001-04-13 2004-01-29 Boehringer Ingelheim Pharma Compounds useful as anti-inflammatory agents.
US7371763B2 (en) 2001-04-20 2008-05-13 Bayer Pharmaceuticals Corporation Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas
EP1392661A1 (en) 2001-05-16 2004-03-03 Boehringer Ingelheim Pharmaceuticals Inc. Diarylurea derivatives useful as anti-inflammatory agents
MXPA03010724A (en) 2001-05-25 2004-03-02 Boehringer Ingelheim Pharma Carbamate and oxamide compounds as inhibitors of cytokine production.
WO2002098869A2 (en) 2001-06-05 2002-12-12 Boehringer Ingelheim Pharmaceuticals, Inc. 1,4-disubstituted benzo-fused cycloalkyl urea compounds
CA2453147A1 (en) 2001-07-11 2003-01-23 Boehringer Ingelheim Pharmaceuticals, Inc. Methods of treating cytokine mediated diseases
EP1709965A3 (en) 2001-07-11 2006-12-27 Boehringer Ingelheim Pharmaceuticals, Inc. Methods of treating cytokine mediate diseases
GB0121941D0 (en) 2001-09-11 2001-10-31 Astrazeneca Ab Chemical compounds
GB0124941D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124934D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124938D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124936D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124939D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124933D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124931D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
CA2462441A1 (en) * 2001-10-18 2003-04-24 Pier F. Cirillo 1,4-disubstituted benzo-fused urea compounds as cytokine inhibitors
WO2003053358A2 (en) 2001-12-19 2003-07-03 Bristol-Myers Squibb Company Fused heterocyclic compounds and analogs thereof: modulators of nuclear hormone receptor function
PE20030701A1 (en) 2001-12-20 2003-08-21 Schering Corp COMPOUNDS FOR THE TREATMENT OF INFLAMMATORY DISORDERS
US20040072237A1 (en) * 2001-12-26 2004-04-15 Barry Schweitzer Use of cytokines secreted by dendritic cells
AU2003210969A1 (en) * 2002-02-11 2003-09-04 Bayer Corporation Aryl ureas with raf kinase and angiogenesis inhibiting activity
SI1580188T1 (en) 2002-02-11 2012-02-29 Bayer Healthcare Llc Aryl ureas as kinase inhibitors
DK1478358T3 (en) 2002-02-11 2013-10-07 Bayer Healthcare Llc Sorafenibtosylate for the treatment of diseases characterized by abnormal angiogenesis
US10653684B2 (en) 2002-02-11 2020-05-19 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
SI1864975T1 (en) 2002-02-12 2011-01-31 Glaxosmithkline Llc Nicotinamide derivates useful as P38 inhibitors
AU2003213806A1 (en) 2002-02-25 2003-09-09 Boehringer Ingelheim Pharmaceuticals, Inc. 1,4-disubstituted benzofused cycloalkyl urea compounds useful in treating cytokine mediated diseases
KR20030080509A (en) * 2002-04-09 2003-10-17 주식회사 엘지생명과학 Antibacterial Compositions Containing Urea, Thiourea and Sulfamide Derivatives
RU2369605C2 (en) * 2002-05-29 2009-10-10 Новартис Аг Diaryl urea derivatives used for treatment of protein kinase dependent illnesses
AR037647A1 (en) 2002-05-29 2004-12-01 Novartis Ag USED DIARILUREA DERIVATIVES FOR THE TREATMENT OF DEPENDENT DISEASES OF THE PROTEIN KINase
EP1707205A2 (en) 2002-07-09 2006-10-04 Boehringer Ingelheim Pharma GmbH & Co. KG Pharmaceutical compositions of anticholinergics and p38 kinase inhibitors in the treatment of respiratory diseases
GB0217757D0 (en) 2002-07-31 2002-09-11 Glaxo Group Ltd Novel compounds
CA2494824A1 (en) * 2002-08-08 2004-02-19 Boehringer Ingelheim Pharmaceuticals, Inc. Fluorinated phenyl-naphthalenyl-urea compounds as inhibitors of cytokines involved in inflammatory processes
CA2497240A1 (en) 2002-08-29 2004-03-11 Andrew Asher Protter Methods of promoting osteogenesis
AU2003303678A1 (en) 2003-01-03 2004-08-10 Genzyme Corporation Urea derivatives and their use as anti-inflammatory agents
CA2511970C (en) * 2003-01-14 2012-06-26 Cytokinetics, Inc. Urea derivatives useful in the treatment of heart failure
CA2516931C (en) 2003-02-28 2014-09-09 Bayer Pharmaceuticals Corporation Novel bicyclic urea derivatives useful in the treatment of cancer and other disorders
US7078419B2 (en) * 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
GB0308185D0 (en) 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
GB0308201D0 (en) 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
GB0308186D0 (en) 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
US20070010529A1 (en) * 2003-05-19 2007-01-11 Kanji Takahashi Nitrogenous heterocyclic compounds and medical use thereof
US20070020704A1 (en) 2003-05-20 2007-01-25 Scott Wilhelm Diaryl ureas with kinase inhibiting activity
US7297709B2 (en) 2003-05-22 2007-11-20 Abbott Laboratories Indazole, benzisoxazole, and benzisothiazole kinase inhibitors
DE602004000260T2 (en) 2003-07-22 2006-08-24 Arena Pharmaceuticals, Inc., San Diego DIARYL AND ARYLHETEROARYL DRUG DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR SUITABLE FOR THE PROPHYLAXIS AND TREATMENT OF RELATED DISEASES THEREOF
US8637553B2 (en) 2003-07-23 2014-01-28 Bayer Healthcare Llc Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
GB0318814D0 (en) 2003-08-11 2003-09-10 Smithkline Beecham Corp Novel compounds
EP1670787B1 (en) 2003-09-11 2012-05-30 iTherX Pharma, Inc. Cytokine inhibitors
US7244441B2 (en) 2003-09-25 2007-07-17 Scios, Inc. Stents and intra-luminal prostheses containing map kinase inhibitors
CA2545711A1 (en) 2003-11-13 2005-06-02 Ambit Biosciences Corporation Urea derivatives as kinase modulators
KR20060110307A (en) * 2003-11-28 2006-10-24 노파르티스 아게 Diaryl Urea Derivatives in the Treatment of Protein Kinase Dependent Diseases
AU2005211448A1 (en) * 2004-01-30 2005-08-18 Merck Patent Gmbh Bisarylurea derivatives
TW200530236A (en) 2004-02-23 2005-09-16 Chugai Pharmaceutical Co Ltd Heteroaryl phenylurea
WO2005103011A1 (en) 2004-03-23 2005-11-03 Arena Pharmaceuticals, Inc. Processes for preparing substituted n-aryl-n’-[3-(1h-pyrazol-5-yl) phenyl] ureas and intermediates thereof
CN1926098A (en) * 2004-03-29 2007-03-07 神经研究公司 Novel urea derivatives and their medical use
US7838524B2 (en) 2004-04-30 2010-11-23 Bayer Healthcare Llc Substituted pyrazolyl urea derivatives useful in the treatment of cancer
US7550499B2 (en) 2004-05-12 2009-06-23 Bristol-Myers Squibb Company Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
HRP20141048T1 (en) 2004-06-17 2015-01-02 Cytokinetics, Inc. Compounds, compositions and methods
JP2008504283A (en) * 2004-06-25 2008-02-14 イコス・コーポレイション Bisarylurea derivatives useful for inhibition of CHK1
US20060035893A1 (en) 2004-08-07 2006-02-16 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders
EP2578226B1 (en) 2004-08-23 2017-10-25 Yeda Research And Development Co., Ltd. Peptide for treating amyotrophic lateral sclerosis
WO2006040056A1 (en) * 2004-10-13 2006-04-20 Merck Patent Gmbh Heterocyclic substituted bisarylurea derivatives as kinase inhibitors
ES2365858T3 (en) * 2004-10-13 2011-10-11 Merck Patent Gmbh FENILUREA DERIVATIVES AS INHIBITING SUBSTANCE OF TYROSINE-KINASES FOR THE TREATMENT OF TUMOR DISEASES.
SA05260357B1 (en) 2004-11-19 2008-09-08 ارينا فارماسيتو تيكالز ، أنك 3-phenyle-pyrazole derivatives as modulators of the 5-ht 2a serotonin receptor useful for the treatment of disorders related thereto
WO2006062982A2 (en) 2004-12-07 2006-06-15 Locus Pharmaceuticals, Inc. Urea inhibitors of map kinases
EP1824843A2 (en) 2004-12-07 2007-08-29 Locus Pharmaceuticals, Inc. Inhibitors of protein kinases
PE20060777A1 (en) 2004-12-24 2006-10-06 Boehringer Ingelheim Int INDOLINONE DERIVATIVES FOR THE TREATMENT OR PREVENTION OF FIBROTIC DISEASES
EP1676574A3 (en) 2004-12-30 2006-07-26 Johnson &amp; Johnson Vision Care, Inc. Methods for promoting survival of transplanted tissues and cells
ATE499370T1 (en) 2005-01-19 2011-03-15 Bristol Myers Squibb Co 2-PHENOXY-N-(1,3,4-THIADIZOL-2-YL)PYRIDINE-3-AMINE DERIVATIVES AND RELATED COMPOUNDS AS P2Y1 RECEPTOR INHIBITORS FOR THE TREATMENT OF THROMBOEMBOLIC DISEASES
WO2006094626A1 (en) 2005-03-07 2006-09-14 Bayer Healthcare Ag Pharmaceutical composition comprising an omega- carboxyaryl substituted diphenyl urea for the treatment of cancer
US7816382B2 (en) 2005-06-27 2010-10-19 Bristol-Myers Squibb Company Linear urea mimics antagonists of P2Y1 receptor useful in the treatment of thrombotic condition
US7714002B2 (en) 2005-06-27 2010-05-11 Bristol-Myers Squibb Company Carbocycle and heterocycle antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
WO2007002635A2 (en) 2005-06-27 2007-01-04 Bristol-Myers Squibb Company C-linked cyclic antagonists of p2y1 receptor useful in the treatment of thrombotic conditions
US7728008B2 (en) 2005-06-27 2010-06-01 Bristol-Myers Squibb Company N-linked heterocyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
US7538223B2 (en) 2005-08-04 2009-05-26 Cytokinetics, Inc. Compounds, compositions and methods
ES2380236T3 (en) 2005-10-28 2012-05-09 Takeda Pharmaceutical Company Limited Heterocyclic amide compound and use thereof
ES2419007T3 (en) 2005-12-15 2013-08-19 Cytokinetics, Inc. Certain chemical entities, compositions and procedures
US7825120B2 (en) 2005-12-15 2010-11-02 Cytokinetics, Inc. Certain substituted ((piperazin-1-ylmethyl)benzyl)ureas
EP1959962A2 (en) 2005-12-16 2008-08-27 Cytokinetics, Inc. Certain chemical entities, compositions, and methods
US7989455B2 (en) 2005-12-19 2011-08-02 Cytokinetics, Inc. Compounds, compositions and methods
JP5406018B2 (en) 2006-05-18 2014-02-05 アリーナ ファーマシューティカルズ， インコーポレイテッド Primary amines as modulators of 5-HT2A serotonin receptors useful for the treatment of disorders associated with 5-HT2A serotonin receptors, and derivatives thereof
EA016675B1 (en) 2006-05-18 2012-06-29 Арена Фармасьютикалз, Инк. Processes for the preparation of phenyl-pyrazoles and a crystalline form of phenyl-pyrazole derivative
US8148418B2 (en) 2006-05-18 2012-04-03 Arena Pharmaceuticals, Inc. Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
EP2338488A1 (en) 2006-05-26 2011-06-29 Bayer HealthCare, LLC Drug combinations with substituted diaryl ureas for the treatment of cancer
US20080076770A1 (en) * 2006-09-25 2008-03-27 Arete Therapeutics, Inc. Soluble epoxide hydrolase inhibitors
TWI415845B (en) 2006-10-03 2013-11-21 Arena Pharm Inc Pyrazole derivatives as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto
US7960569B2 (en) 2006-10-17 2011-06-14 Bristol-Myers Squibb Company Indole antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
ES2371723T3 (en) 2006-12-20 2012-01-09 Bayer Healthcare, Llc 4- {4 - [({3-TERC-BUTIL-1- [3- (HYDROXIMETHYL) PHENYL] -1H-PIRAZOL-5-IL} CARBAMOIL) AMINO] -3-CHLOROPHENOXY} -N-METHYLPIRIDINE-2-CARBOXAMIDE AS A VEGFR KINASE INHIBITOR FOR TREATMENT AGAINST CANCER.
EP1992344A1 (en) 2007-05-18 2008-11-19 Institut Curie P38 alpha as a therapeutic target in pathologies linked to FGFR3 mutation
WO2009023253A2 (en) 2007-08-15 2009-02-19 Arena Pharmaceuticals Inc. IMIDAZO[L,2-α]PYRIDINE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
WO2009123714A2 (en) 2008-04-02 2009-10-08 Arena Pharmaceuticals, Inc. Processes for the preparation of pyrazole derivatives useful as modulators of the 5-ht2a serotonin receptor
BRPI0917411A2 (en) 2008-08-15 2015-12-01 Univ Georgetown dansyl carbazole compound, method for treating cancer in a subject, method for reducing dna menthyltransferase activity in a cell, method for increasing expression of family domain 1a (rassf1a) association in a cell, cell identification methods Method of determining whether one or more cells of a subject are cancer cells, pharmaceutical composition and kit.
CA2741731A1 (en) 2008-10-28 2010-06-03 Arena Pharmaceuticals, Inc. Compositions of a 5-ht2a serotonin receptor modulator useful for the treatment of disorders related thereto
US9126946B2 (en) 2008-10-28 2015-09-08 Arena Pharmaceuticals, Inc. Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea and crystalline forms related thereto
AU2009333259B2 (en) 2008-12-17 2015-02-26 The Scripps Research Institute Generation and maintenance of stem cells
EP2406389B1 (en) 2009-03-13 2019-05-08 Agios Pharmaceuticals, Inc. Methods and compositions for cell-proliferation-related disorders
TWI691493B (en) 2009-06-29 2020-04-21 美商阿吉歐斯製藥公司 Therapeutic compounds and compositions
JP2013503170A (en) * 2009-08-28 2013-01-31 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー Compounds and methods
PT2484661T (en) 2009-09-30 2017-06-05 Toray Industries 2,3-dihydro-1h-indene-2-ylurea derivative and pharmaceutical application of same
WO2011050210A1 (en) 2009-10-21 2011-04-28 Agios Pharmaceuticals, Inc. Methods and compositions for cell-proliferation-related disorders
US8980891B2 (en) 2009-12-18 2015-03-17 Arena Pharmaceuticals, Inc. Crystalline forms of certain 3-phenyl-pyrazole derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto
JP2013531067A (en) 2010-07-19 2013-08-01 バイエル ヘルスケア リミティド ライアビリティ カンパニー Combinations using fluoro-substituted omega-carboxyaryl diphenylureas for the treatment and prevention of diseases and conditions
SMT202400081T1 (en) 2011-05-03 2024-03-13 Agios Pharmaceuticals Inc Pyruvate kinase activators for use in therapy
EP2715350B1 (en) 2011-05-23 2017-09-27 Yeda Research and Development Co. Ltd. Use of akt phosphorylation as a biomarker for prognosing neurodegenerative diseases and treating same
CN102827170A (en) 2011-06-17 2012-12-19 安吉奥斯医药品有限公司 Active treatment compositions and use method thereof
CN102827073A (en) 2011-06-17 2012-12-19 安吉奥斯医药品有限公司 Therapeutically active compositions and application methods thereof
US9474779B2 (en) 2012-01-19 2016-10-25 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
WO2013162027A1 (en) 2012-04-27 2013-10-31 学校法人 慶應義塾 Neuronal differentiation promoter
CN104822373B (en) * 2012-10-15 2018-08-28 安吉奥斯医药品有限公司 Therapeutic compound and composition
EP2975938A4 (en) * 2013-03-15 2017-02-15 Ohio State Innovation Foundation Inhibitors of prmt5 and methods of their use
US10376510B2 (en) 2013-07-11 2019-08-13 Agios Pharmaceuticals, Inc. 2,4- or 4,6-diaminopyrimidine compounds as IDH2 mutants inhibitors for the treatment of cancer
WO2015003360A2 (en) 2013-07-11 2015-01-15 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US9579324B2 (en) 2013-07-11 2017-02-28 Agios Pharmaceuticals, Inc Therapeutically active compounds and their methods of use
WO2015003355A2 (en) 2013-07-11 2015-01-15 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US20150031627A1 (en) 2013-07-25 2015-01-29 Agios Pharmaceuticals, Inc Therapeutically active compounds and their methods of use
GB201404372D0 (en) * 2014-03-12 2014-04-23 Univ Warwick Assay and treatment
UA121211C2 (en) 2014-03-14 2020-04-27 Аджіос Фармасьютикалз, Інк. Pharmaceutical compositions of therapeutically active compounds
US9638690B2 (en) 2014-11-07 2017-05-02 The University Of British Columbia Compounds and compositions for use as alkylating agent sensors and methods of use thereof
PL3307271T3 (en) 2015-06-11 2024-02-05 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators
RU2017145976A (en) 2015-06-12 2019-07-15 Аксовант Сайенсиз Гмбх Diaryl- and arylheteroarylurea derivatives applicable for the prevention and treatment of behavioral disturbances during the REM phase of sleep
US11053255B2 (en) 2015-06-22 2021-07-06 Georgetown University Synthesis of mahanine and related compounds
TW201720439A (en) 2015-07-15 2017-06-16 Axovant Sciences Gmbh Diaryl and arylheteroaryl urea derivatives as 5-HT2A serotonin receptors for the prevention and treatment of hallucinations associated with neurodegenerative diseases
ES2981538T3 (en) 2015-10-15 2024-10-09 Servier Lab Combination therapy comprising ivosidenib, cytarabine, and daunorubicin or idarubicin for the treatment of acute myelogenous leukemia
MX386735B (en) 2015-10-15 2025-03-19 Servier Lab COMBINATION THERAPY TO TREAT MALIGNANT TUMORS.
MX2019011023A (en) 2017-05-12 2020-01-30 Rti Int Diarylureas as cb1 allosteric modulators.
US10980788B2 (en) 2018-06-08 2021-04-20 Agios Pharmaceuticals, Inc. Therapy for treating malignancies
CN109824560B (en) * 2019-03-11 2022-03-01 利尔化学股份有限公司 Preparation method of 1-cyclopropyl-3- (2-methylthio-4-trifluoromethylphenyl) propane-1, 3-dione

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB828231A (en) * 1955-10-20 1960-02-17 Geigy Ag J R Improvements relating to insecticidal compounds and their use
NL254871A (en) * 1959-08-14
BE616734A (en) * 1961-04-21
US3200035A (en) * 1962-06-01 1965-08-10 Ciba Ltd Treatment of synthetic products, especially synthetic fibers
DE2928485A1 (en) * 1979-07-14 1981-01-29 Bayer Ag USE OF UREA DERIVATIVES AS A MEDICINAL PRODUCT IN THE TREATMENT OF FATTY METABOLISM DISORDERS
CA2290520C (en) * 1997-05-23 2009-01-27 Bayer Corporation Inhibition of p38 kinase activity by aryl ureas

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