AU2004200566A1 - Omega-carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors - Google Patents

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Our Ref: 12224001 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Bayer Corporation 100 Bayer Road Pittsburgh Pennsylvania 15205-9741 United States of America Address for Service: Invention Title: DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street Sydney, New South Wales, Australia, 2000 w-carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors The following statement is a full description of this invention, including the best method of performing it known to me:- 5951 WO 00/41698 PCT/USOO/00768 c)-CARBOXY ARYL SUBSTITUTED DIPHENYL UREAS AS p38 KINASE INHIBITORS Cross-Reference to Related Applications This is a continuation-in-part of Serial No. 09/257,265 filed February 1999 and a continuation-in-part of Serial No. 60/115,878 filed January 13, 1999.

Field of the Invention 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.

Background of the Invention Two classes of effector molecules which are critical for the progression of rheumatoid arthritis are pro-inflammatory cytokines and tissue degrading proteases.

Recently, a family.ofkinases was described which is instrumental incgntrolling the transcription and translation of the structural genes coding for these effector molecules.

The mitogen-activated protein (MAP) kinase family is made up of a series of structurally related proline-directed serine/threonine kinases which are activated either by growth factors (such as EGF) and phorbol esters (ERK), or by IL-1, TNFac 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 WO 00/41698 PCT/US00/00768 cytokine production. A pair of novel protein kinases involved in the regulation of cytokine synthesis was recently described by a group from SmithKline Beecham (Lee et al. Nature 1994, 372, 739). These enzymes were isolated based on their affinity to bond to a class of compounds, named CSAIDSs (cytokine suppressive anti-inflammatory drugs) by SKB. The CSAIDs, bicyclic pyridinyl imidazoles, have been shown to have cytokine inhibitory activity both in vitro and in vivo. The isolated enzymes, CSBP-1 and -2 (CSAID binding protein 1 and 2) have been cloned and expressed. A murine homologue for CSBP-2, p38, has also been reported (Han et al. Science 1994, 265, 808).

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

Clinical studies have linked TNFao production and/or signaling to a number of diseases including rheumatoid arthritis (Maini. J. Royal Coll. Physicians London 1996, 30, 344). In addition, excessive levels of TNFa have been implicated in a wide variety of inflammatory and/or immunomodulatory diseases, including acute rheumatic fever (Yegin et al. Lancet 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, 11, 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,J19, 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, 157, 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. 107; van Dullemen et al.

Gastroenterology 1995, 109, 129) and ulcerative colitis (Masuda et al. J. Clin. Lab.

PCTfUSOO/00768 WO 00/41698 Immunol. 1995, 46, 111), Jarisch-Herxheimer 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 Diffuse Lung Dis. 1996, 13, 139), allergic respiratory diseases (Casale et al. Am. J. Respir. Cell Mol. Biol. 1996, 15, 35), silicosis (Gossart et al. J Immunol. 1996, 156, 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), 0 hepatic failure (Gantner et al. J. Pharmacol. Exp. Therap. 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; Taveme et al. Parasitol. Today 1996, 12, 290) including Plasmodium falciparum malaria (Perlmann et al. Infect. Immunit.

1997, 65, 116) and cerebral malaria (Rudin et al. Am. J. Pathol. 1997, 150, 257), non-insulin-dependent diabetes mellitus (NIDDM; 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, 54, 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 Coyle. Adv. Neuroimmunol. 1996, 6, 143; Matusevicius et al. J.

Neuroimmunol. 1996, 66, 115) including demyelation and oligiodendrocyte loss in multiple sclerosis (Brosnan et al. Brain Pathol. 1996, 6, 243), advanced cancer (MucWierzgon et al. J. Biol. Regulators Homeostatic Agents 1996, 10, lymphoid malignancies (Levy et al. Crit. Rev. Immunol. 1996, 16, 31), pancreatitis WO 00/41698 PCT/USOO/00768 (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 (Raza et al. Int. J. Hematol. 1996, 63, 265), systemic lupus erythematosus (Maury et al. Arthritis Rheum. 1989, 32, 146), biliary cirrhosis (Miller et al. Am. J. Gasteroenterolog. 1992, 87, 465), bowel necrosis (Sun et al. J.

Clin. Invest. 1988, 81, 1328), psoriasis (Christophers. Austr. J. Dermatol. 1996, 37, S4), radiation injury (Redlich et al. J. Immunol. 1996, 157, 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-versusgraft reactions (Piguet et al. Immunol. Ser. 1992, 56, 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, 50, 219), heart (Bolling 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; LoCicero et al. J. Thorac. Cardiovasc. Surg. 1990, 99, 1059), as well as complications due to total hip replacement (Cirino et al. Life Sci. 1996, 59, 86).

TNFa has also been linked to infectious diseases (review: Beutler et al. Crit. Care Med. 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, and infections from Borrelia burgdorferi (Brandt et al. Infect. Immunol. 1990, 58, 983), Treponema pallidum (Chamberlin et WO 00/41698 PCT/US00/00768 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 metalloproteinases (TIMPs). These include osteoarthritis (Woessner et al. J. Biol. Chem. 1984, 259, 3633), rheumatoid arthritis (Mullins et al. 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'l. Acad. Sci., USA 1986, 83, 9413), periodontal diseases (Overall et al. J. Periodontal Res. 1987, 22, 81), corneal ulceration (Bums et al. Invest. Opthalmol. Vis. 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.-c-artilage loss following traumatic joint injury, osteopenias mediated by MMP activity, tempero mandibular joint disease, and demyelating diseases of the nervous system (Chantry et al. J. Neurochem. 1988, 50, 688).

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

WO 00/41698 PCT/US00/00768 Inhibitors of p38 are active in animal models of TNFa production, including a muirne lipopolysaccharide (LPS) model of TNFa production. Inhibitors of p38 are active in a number of standard animal models of inflammatory diseases, including carrageenan-induced edema in the rat paw, arachadonic acid-induced edema in the rat paw, arachadonic acid-induced peritonitis in the mouse, fetal rat long bone resorption, murine type II collagen-induced arthritis, and Fruend's adjuvant-induced arthritis in the rat. Thus, inhibitors of p38 will be useful in treating diseases mediated by one or more of the above-mentioned cytokines and/or proteolytic enzymes.

The need for new therapies is especially important in the case of arthritic 0 diseases. The primary disabling effect of osteoarthritis, rheumatoid arthritis and septic arthritis is the progressive loss of articular cartilage and thereby normal joint function. No marketed pharmaceutical agent is able to prevent or slow this cartilage loss, although nonsteroidal antiinflammatory drugs (NSAIDs) have been given to control pain and swelling. The end result of these diseases is total loss of joint function which is only treatable by joint replacement surgery. P38 inhibitors will halt or reverse the progression of cartilage loss and obviate or delay surgical intervention.

Several patents have appeared claiming polyarylimidazoles and/or compounds containing polyarylimidazoles as inhibitors of p38 (for example, Lee et al. WO 95/07922; Adams et al. WO 95/02591; Adams et al. WO 95/13067; Adams et al. WO 95/31451). It has been reported that arylimidazoles complex to the ferric form of cytochrome P450cam (Harris et al. Mol. Eng. 1995, 5, 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 improved p3 8 inhibitors.

Summary of the Invention This invention provides compounds, generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit p38 mediated events and WO 00/41698 PCT/USOO/00768 thus inhibit the production- of cytokines (such as TNFca, IL-1 and IL-8) and proteolytic enzymes (such as MMP-1 and MMP-3). The invention also provides a method of treating a cytokine mediated disease state in humans or mammals, wherein the cytokine is one whose production is affected by p38. Examples of such cytokines include, but are not limited to TNFa, IL-1 and IL-8. The invention also provides a method of treating a protease mediated disease state in humans or mammals, wherein the protease is one whose production is affected by p38.

Examples of such proteases include, but are not limited to collagenase (MMP-1) and stromelysin (MMP-3).

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

I

WO 00/41698 PCT/USOO/00768 liver, heart, and skin allograft rejections, lung allograft rejection including chronic lung allograft rejection (obliterative bronchitis) as well as complications due to total hip replacement, and infectious diseases including tuberculosis, Helicobacter pylori infection during peptic ulcer disease, Chaga's disease resulting from Trypanosoma cruzi infection, effects of Shiga-like toxin resulting from E. coli infection, effects of enterotoxin A resulting from Staphylococcus infection, meningococcal infection, and infections from Borrelia burgdorferi, Treponema pallidum, cytomegalovirus, influenza virus, Theiler's encephalomyelitis virus, and the human immunodeficiency virus (HIV).

10 The present invention, therefore, provides compounds generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit the p38 pathway. The invention also provides a method for treatment of p38-mediated disease states in humans or mammals, 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, compositions and methods for the. treatment of diseases mediated by p38 kinase wherein a compound of Formula I is administered or a pharmaceutically acceptable salt thereof.

A-D-B (I) In formula I, D is -NH-C(O)-NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: L' )q where L is a 5 or 6 membered cyclic structure bound directly to D, L' comprises a substituted'cyclic moiety having at least 5 members, M'i9a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L i contains 0-4 members of the group consisting of nitrogen, oxygen and.

sulfur, and 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 cyclic structure bound WO 00/41698 PCT/USOO/00768 directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L' is substituted by at least one substituent selected from the group consisting of-SO 2 Rx, -C(O)Rx and -C(NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally halosubstituted, up to per halo, Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; Rx is Rz or NRaRb where Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally 0 substituted by halogen, or -OSi(Rf) 3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0 substituted by halogen, WO 00/41698 PCTIUSOO/00768 hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or c) one of R. or Rb is a Ci-C 5 divalent alkylene group or a substituted CI-Cs divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted Ci-C divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; where B is substituted, L is substituted or L' is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of CN, -COzR 7

-C(O)NR

7

R

7

-C(O)-R

7

-NO

2

-OR

7

-SR

7

-NR

7

R

7

-NR

7

C(O)OR

7

NRTC(O)R

7 -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents independently selected from the group consisting of -CN,

CO

2

R

7

-C(O)R

7

-C(O)NR'R

7

-OR

7

-SR

7

-NR

7

-NO

2

-NR

7 C(0)R 7

NR

7

C(O)OR

7 and halogen up to per-halo; with each R 7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, wherein Q is -N(R 7

-(CH

2

-(CH

2

(CH

2

-(CH

2

)N(R

7

-O(CH

2 )m CHX'-, -CX 2

-S-(CH

2 and N(R )(CH 2 where m= 1-3, and Xa is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, WO 00141698 WO 0041698PCTIUSOO/00768 C0R,- 7

-C(O)NR

7

R

7

-NO

2 -OR 7

-SR

7

-NIR

7

R

7 -NR 7 C(O) R 7 NR 7

C(O)R

7 and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents selected from the group consisting of -CN, -C0 2 R -COR

C(O)NR

7

R

7 -OR 7

-SR

7

-NR

7

R

7

-NIR

7

C(O)R

7 and -NR 7 C(0O0R 7 with R' as defined above.

In formula 1, suitable hetaryl groups include, but are not limited to, 5-12 carbon-atom aromatic rings or ring systems containing 1-3 rings, at least one of which is aromatic, in which one or more, 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, 2- or 3-pyrrolyl, 4- or 5-imidazolyl, 4- or 5-pyrazolyl, 4- or oxaz Iolyl, 4- or 5-isoxazolyl, 4- or 5-thiazolyl, 4- or 5-isothiazolyl, 3or 4-pyridyl, 5- or 6-pyrimidinyl, l,2,3-triazol- or -5-yl, 1,2,4-triazolor 5 -yI, I or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, l,2,4-oxadiazol-3- or 1 ,3,4-thiadiazol-2- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, I ,3,4-thiadiazol-2- or 1 ,3,4-thiadiazol-3- or -5-yl, 1 ,2,3-thiadiazol-4- or -5-yI, 5- or 6- 2H-thiopyranyl, 3- or 4-4H-thiopyranyl, or 4-pyridazinyl, pyrazinyl, 4-; 6- or 7-benzofuryl, 6- or 7-benzothienyl, 6- or 7indolyl, 4- or 5-benzimidazolyl, 1 6- or 7-benzopyrazolyl, 4-, 6- or 7-benzoxazolyl, 5- 6- or 7-benzisoxazolyl, 6- or 7- O benzothiazolyl, 6- or 7-benzisothiazolyl, 2- 6- or 7-benz-1,3oxadiazolyl, 7- or 8-quinolinyl, -8isoquinolinyl, 4- or 9-carbazolyl, 8ori'9-acridinyl, or 7- or 8-quinazolinyl, or additionally optionally substituted phenyl, 2- or 3-thienyl, 1,3,4-thiadiazolyl, 3-pyrryl, 3-pyrazolyl, 2-thiazolyl or etc. For example, -B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2thienyl, I -methyl-3-pyrryl, I -methyl-3 -pyrazolyl, 5-methyl-2-thiazolyl or 1 ,2,4-thiadiazol-2-yl.

P:\WPDOCS\REQ\7621140claims.doc- 1/02/04 Suitable alkyl groups and alkyl portions of groups, e. alkoxy, etc. throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.

Suitable aryl groups which do not contain heteroatoms include, for example, phenyl and 1-and 2-naphthyl.

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

Suitable halogen groups include F, Cl, Br, and/orl, from one to persubstitution 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.

The invention also relates to compounds per se, of formulal.

The present invention is also directed to pharmaceutically acceptable salts of formulal. 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, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid, 1naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid,maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and mandelic acid. In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations Li+ Na+ orK+), alkaline earth cations g.,Mg+2, Ca+2 orBa+2), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation or peralkylation of triethylamine, N, N-diethylamine, N, Ndicyclohexylamine, lysine, pyridine,NN-dimethylaminopyridine (DMAP), 1,4 WO 00/41698 PCT/USOO/00768 diazabiclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene

(DBU).

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

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

General Preparative Methods The compounds of Formula I may be prepared by use of known chemical reactions and procedures, some from starting materials which are commercially available. Nevertheless, the following general preparative methods are presented to aid one of skill in the art in synthesizing these compounds, with more detailed particular examples being presented in the experimental section describing the working examples.

Substituted anilines may be generated using standard methods (March.

Advanced Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985). Larock.

Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H 2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAIH 4 (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3 d Ed.; John Wiley: New York (1985). Larock.

Comprehensive Organic Transformations; VCH Publishers: New York (1989)).

I

WO 00/41698 PCT/US00/00768 Substituted anilines may be generated using standard methods (March. Advanced Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985). Larock.

Comprehensive Organic Transformations; VCH Publishers: New York (1989)). As shown in Scheme I, aryl amines are commonly synthesized by reduction of nitroaryls using a metal catalyst, such as Ni, Pd, or Pt, and H 2 or a hydride transfer agent, such as formate, cyclohexadiene, or a borohydride (Rylander. Hydrogenation.

Methods; Academic Press: London, UK (1985)). Nitroaryls may also be directly reduced using a strong hydride source, such as LiAlH 4 (Seyden-Penne. Reductions by the Alumino- and Borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a zero valent metal, such as Fe, Sn or Ca, often in acidic media. Many methods exist for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3 rd Ed.; John Wiley: New York (1985). Larock.

Comprehensive Organic Transformations; VCH Publishers: New York (1989)).

H

2 catalyst (eg. Ni, Pd, Pt) ArNO 2

IH

ArNH 2 M(0) (eg. Fe, Sn, Ca) Scheme I Reduction of Nitroaryls to Aryl Amines Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO 3 or an alternative NO 2 s6otice. Nitroaryls may be further elaborated priorto reduction.

Thus, nitroaryls substituted with

HNO

3 Ar-H ArNO 2 potential leaving groups (eg. F, Cl, Br, etc.) may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or WO 00/41698 PCT/USOO/00768 phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme

II).

0 2 N- ArSH R/ F R base 1 0 2N Br-Ar

SH

R CuO base 2 N 2 S-Ar 2 0 Scheme II Selected Nucleophilic Aromatic Substitution using Nitroaryls Nitroaryls may also undergo transition metal mediated cross coupling reactions. For example, nitroaryl electrophiles, 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 (Stille reactions) or arylzincs (Negishi reaction) to afford the biaryl 0 0 2

N~

ArB(OR') 2 Pd(0) 0 2 N Ar Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl chloride on treatment with chlorosulfonic acid. Reaction of the sulfonyl chloride with a fluoride source, such as KF then affords sulfonyl fluoride 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 Alternatively, sulfonyl chloride 7 may be reduced to the

I

WO 00/41698 WO 00/1 698PCTfUSOO/00'768 arenethiol for example with zinc amalgum. Reaction of thiol 10 with CHCIF 2 in the presence of base gives the difluoromethyl mercaptam which may be oxidized to the sulfone (12) with any of a variety of oxidants, including CrO 3 -acetic anhydride (Sedova et al. Zh. Org. Khiin. 1970, 6, 568), CIS0 3 H 6

C

R 7 6 KF \ZnQ-Ig) S0 2 F

SH

R 8 -R 1 0 (Me 2

N)

3 S Me 3 SiF 2

CCF

Me 3 SiCF 3 base1F

SO

2

CF

3

SCH

2 -R 9 1 S0 2

CHF

2 0 12 Scheme H1 Selected Methods of Fluorinated Aryl Sulfone Synthesis As shown in Scheme IV, non-symmetrical urea formation may involve reaction of an aryl isocyanate (14) with an aryl amine The heteroaryl isocyanate may be synthesized from a heteroaryl amnine by treatment with phosgene or a phosgene equivalent, such as trichioromethyl chioroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or NN'-carbonyldiimidazole (CDI).

WO 00/41698 PCT/USOO/00768 The isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an -ester, an acid halide or an anhydride by a Curtius-type rearrangement.

Thus, reaction of acid derivative 16 with an azide source, followed by rearrangement affords the isocyanate. The corresponding carboxylic acid (17) may also be subjected to Curtius-type rearrangements using diphenylphosphoryl azide (DPPA) or a similar reagent.

Arl-NH 2 13 COCl 2 I H2N-Ar 2 0 Ar'-NCO Ar-- N. Ar2 14 H H N3/ \DPPA 0 0 Ar X Ar' OH 16 17 Scheme IV Selected Methods of Non-Symmetrical Urea Formation Finally, ureas may be further manipulated using methods familiar to those 10 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 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 WO 00/41698 PCT/US00/00768 more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.

Compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.

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

Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used.

Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example' polyoxyethylene WO 00/41698 PCT/USOO/00768 stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products-of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.

Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.

The compounds may also be in the form of non-aqueous liquid formulations, 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 antioxidant 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 WO 00/41698 PCT/US00/00768 can be formulated following known procedures into dosage forms. In addition, on treatment with emulsifying agents and water, a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.

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

Suitable penetration enhancing materials for transdermal delivery system are known to those skilled in the art, and include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated Cs-C 1 s fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated Cs-Cg fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl isobutyl tertbutyl or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropyl sebacate, diisopropyl maleate, or diisopropyl -fumarate. Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether. Suitable penetration enhancing formulations may also include mixtures of one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated

C

8 -C 8 fatty alcohols, saturated or unsaturated C 8

-C

18 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 WO 00/41698 PCT/US00/00768 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.

Suitable binding materials for transdermal delivery systems are known to those skilled in the art and include polyacrylates, silicones, polyurethanes, block polymers, styrenebutadiene coploymers, and natural and synthetic rubbers.

Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added -to increase the viscosity of the matrix.

Pharmaceutical compositions of the invention may also be in the form of oilin-water emulsions. The oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.

Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

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

The compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is sodat 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 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 P:\WPDOCS\REQ\7621l40claims.doc-11/02/04 techniques will preferably be from 0.01 to 200 mg/Kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.

The daily rectal dosage 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 from 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 severity of the condition undergoing therapy, etc. It will be further appreciated by one skilled in the art that the optimal course of treatment, i. the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment tests.

The compounds of Formula I are producible from known compounds (or from starting materials which, in turn, are producible from known compounds), e. through the general preparative methods shown above. The activity of a given compound to inhibit raf kinase can be routinely assayed, e. according to procedures disclosed below. The following examples are for illustrative purposes only and are not intended, nor should they be construed to limit the invention in any way.

WO 00/41698 PCT/USOO/00768 The entire disclosure of all applications, patents and publications cited above and below are hereby incorporated by reference, including non-provisional application Serial No. 09/257,265 filed February 25, 1999 and provisional application serial number 60/115,878, filed on January 13, 1999.

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

EXAMPLES

All reactions were performed in flame-dried or oven-dried glassware under a positive pressure of dry argon or dry nitrogen, and were stirred magnetically unless otherwise indicated. Sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Unless otherwise stated, the term 'concentration under reduced pressure' refers to use of a Buchi rotary evaporator at approximately 15 mmHg. Unless otherwise stated, the term 'under high vacuum' refers to a vacuum of 0.4 1.0 mmHg.

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

Commercial grade reagents and solvents were used without further purification. Ncyclohexyl-N'-(methylpolystyrene)carbodiimide was purchased from Calbiochem- Novabiochem Corp. 3-tert-Butylaniline, 5-tert-butyl-2-methoxyaniline, 4-bromo-3- (trifluoromethyl)aniline, 4-chloro-3-(trifluoromethyl)aniline (trifluoromethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4chloro-3-(trifluoromethyl)phenyl isocyanate were purchased and used without further purification. Syntheses of 3-amino-2-methoxyquinoline Cho et al. WO 98/00402; A. Cordi et al. EP 542,609; IBID Bioorg. Med. Chem.. 3, 1995, 129), 4- (3-carbamoylphenoxy)-l-nitrobenzene Ikawa Yakugaku Zasshi 79, 1959, 760; Chem. Abstr. 53, 1959, 12761b), 3-tert-butylphenyl isocyanate Rohr et al. DE WO 00/41698 PCT/US00/00768 2,436,108) and 2-methoxy-5-(trifluoromethyl)phenyl isocyanate Inukai et al. JP 42,025,067; IBID Kogyo Kagaku Zasshi 70, 1967, 491) have previously been described.

Thin-layer chromatography (TLC) was performed using Whatman® pre-coated glass-backed silica gel 60A F-254 250 gm plates. Visualization of plates was effected by one or more of the following techniques: ultraviolet illumination, (b) exposure to iodine vapor, immersion of the, plate in a 10% solution of phosphomolybdic acid ir ethanol followed by heating, immersion of the plate in io a cerium sulfate solution followed by heating, and/or 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 spectra were obtained using a Mattson 4020 Galaxy Series spectrophotometer. Proton 1 H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me 4 Si (5 0.00) or residual protonated solvent (CHC1 3 8 7.26; MeOH 8 3.30; DMSO 8 2.49) as standard. Carbon 3 C) NMR spectra were measured with a General Electric GN-Omega 300 (75 MHz) spectrometer with solvent (CDC1 3 77.0; MeOD-d 3 8 490; DMSO-d 6 5 39.5) as standard. Low resoluti6Tinass 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 oC. Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 gA. Liquid-cesium secondary ion mass spectra (FAB-MS), an updated version WO 00/41698 PCT/US00/00768 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 (Ixl0 4 torr to 2.5x10 4 torr). The direct insertion desorption chemical ionization (DCI) probe (Vaccumetrics, Inc.) was ramped from 0-1.5 amps in 10 sec and held at 10 amps until all traces of the sample disappeared -1-2 min). Spectra were scanned from 50-800 amu at 2 sec per scan. HPLC electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a C-18 column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Spectra were scanned from 120- 800 amu using a variable ion time according to the number of ions in the source.

Gas chromatography ion selective mass spectra (GC-MS) were obtained with a Hewlett Packard 5890 gas chromatograph equipped with an HP-1 methyl silicone column (0.33 mM coating; 25 m x 0.2 mm) and a Hewlett Packard 5971 Mass Selective Detector (ionization energy 70 eV). Elemental analyses are conducted by Robertson Microlit Labs, Madison NJ.

All compounds displayed NMR spectra, LRMS and either elemental analysis or HRMS consistent with assigned structures.

List of Abbreviations and Acronyms: AcOH acetic acid anh anhydrous atm atmosphere(s) BOC tert-butoxycarbonyl CDI 1,1'-carbonyl diimidazole cone concentrated d day(s) dec decomposition DMAC N,N-dimethylacetamide WO 0041698PCT/1JSOO100768 WO 00/41698

DMPU

DMF

DMSO

DPPA

EDCI

EtOAc EtOH Et 2

O

Et 3

N

1 h

HOBT

ni-CPBA MeOH pet. ether temp.

THE

TFA

Tf 1 ,3-dimethyl-3 ,4,5 ,6-tetrahydro-2( I H)-pyrimidinone N,N-dimethylfor-mamide dimethylsulfoxide diphenyiphosphoryl azide 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide ethyl acetate ethanol (100%) diethyl ether triethylamine hour(s) 1 -hydroxybenzotriazole 3-chloroperoxybenzoic acid methanol petroleum ether (boiling range 30-60 'C) temperature tetrahydrofuran trifluoroAcOll trifluoromethanesulfoflyl 0 WO 00/41698 PCT/USOO/00768 A. General Methods for Synthesis of Substituted Anilines Al. General Method for Aryl Amine Formation via Ether Formation Followed by Ester Saponification, Curtius Rearrangement, and Carbamate Deprotection. Synthesis of 2-Amino-3methoxynaphthalene.

CO

2 Me OMe Step 1. Methyl 3-methoxy-2-naphthoate A slurry of methyl 3-hydroxy-2-naphthoate (10.1 g, 50.1 mmol) and K 2

CO

3 (7.96 g, 57.6 mmol) in DMF (200 mL) was stirred at room temp. for 15 min., then treated with iodomethane (3.43 mL, 55.1 mmol). The mixture was allowed to stir at room 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 NaCl solution (100 mL), dried (MgSO 4 concentrated under reduced pressure (approximately 0.4 mmHg overnight) to give methyl 3-methoxy-2naphthoate as an amber oil (10.30 'H-NMR (DMSO-d 6 8 2.70 3H), 2.85 (s, 3H), 7.38 (app t, J=8.09 Hz, 1H), 7.44 1H), 7.53 (app t, J=8.09 Hz, 1H), 7.84 (d, J=8.09 Hz, 1H), 7.90 1H), 8.21 1H).

C0 2

H

OMe Step 2. 3-Methoxy-2-naphthoic acid A solution of methyl 3-methoxy-2-naphthoate (6.28 g, 29.10 mmol) and water mL) in MeOH (100 mL) at room temp. was treated with a 1 N NaOH solution (33.4 mL, 33.4 mmol). The mixture was heated at the reflux temp. for 3 h, cooled 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 WO 00/41698 PCT/USOO/00768 with a saturated NaCI solution, dried (MgSO 4 and concentrated under reduced pressure. The residue was triturated with hexane then washed several times with hexane to give 3-methoxy-2-naphthoic acid as a white solid (5.40 g, 'H-NMR (DMSO-d 6 5 3.88 3H), 7.34-7.41 2H), 7.49-7.54 1H), 7.83 J=8.09 Hz, 1H), 7.91 J=8.09 Hz, 1H), 8.19 1H), 12.83 (brs, 1H).

0 N O OMe H S Step 3. 2-(N-(Carbobenzyloxy)amino-3-methoxynaphthalene A solution of 3-methoxy-2-naphthoic acid (3.36 g, 16.6 mmol) and Et 3 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 DPPA (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 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 4 and concentrated under reduced pressure. The residue was purified by column chromatography (14% EtOAc/86% hexane) to give 2-(N- (carbobenzyloxy)amino-3-methoxynaphthalene as a pale yellow oil (5.1 g, 100%): 'H-NMR (DMSO-d 6 8 3.89 3H), 5.17 2H), 7.27-7.44 8H), 7.72-7.75 (m, 2H), 8.20 1H), 8.76(s, 1H).

4NH2 OMe Step 4. 2-Amino-3-methoxynaphthalene A slurry of 2-(N-(carbobenzyloxy)amino-3-methoxynaphthalene (5.0 g, 16.3 mmol) and 10% Pd/C (0.5 g) in EtOAc (70 mL) was maintained under a H 2 atm (balloon) WO 00/41698 PCT/USOO/00768 at room temp. overnight. The resulting mixture was filtered through Celite and concentrated under reduced pressure to give 2-amino-3-methoxynaphthalene as a pale pink powder (2.40 g, 'H-NMR (DMSO-d 6 5 3.86 3H), 6.86 2H), 7.04-7.16 2H), 7.43 J.=8.0 Hz, 1H), 7.56 J=8.0 Hz, 1H); EI-MS m/z 173 A2. Synthesis of co-Carbamyl Anilines via Formation of a Carbamylpyridine Followed by Nucleophilic Coupling with an Aryl Amine. Synthesis of 4-(2-N-Methylcarbamyl-4pyridyloxy)aniline 0 CI NHMe Step la. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide via the Menisci reaction Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temp. was added conc. H 2

SO

4 (3.55 mL) to generate an exotherm. To this mixture was added H 2 0 2 (30% wt in H 2 0, 17 mL) followed by FeSO 4 -7H20 (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over 4 h to 45 When bubblinghad subsided, the reaction was heated at 60 °C for 16 h. The resulting opaque brown solution was diluted with H 2 0 (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The organic phases were washed separately with a saturated NaCl solution (3 x 150 mL), then they were combined, dried (MgSO 4 and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow WO 00/41698 PCT/USOO/00768 oil crystallized at 0 oC over 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, TLC (50% EtOAc/50% hexane) Rf 0.50; 'H NMR (CDC1 3 6 3.04 J=5.1 Hz, 3H), 7.43 (dd, J=5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 1H), 8.44 J-5.1 Hz, 1 CI-MS m/z 171 0 CI C I -N HCI Step lb. Synthesis of 4-chloropyridine-2-carbonyl chloride HCI salt via picolinic acid Anhydrous DMF (6.0 mL) was slowly added to SOC1 2 (180 mL) between 400 and 50 The solution was stirred in that temperature range for 10 min. then picolinic acid (60.0 g, 487 mmol) was added in portions over 30 min. The resulting solution was heated at 72 °C (vigorous SO 2 evolution) for 16 h to generate a yellow solid precipitate. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered and the solids were washed with toluene (2 x 200 mL) and dried under high vacuum for 4 h to afford 4-chloropyridine-2-carbonyl chloride HCI salt as a yellow-orange solid (92.0 g, 89%).

*0 SC" OMe .IN HCI Step 2. Synthesis of methyl 4-chloropyridine-2-carboxylate HCI salt Anh DMF (10.0 mL) was slowly added to SOC12 (300 mL) at 40-48 oC. The solution was stirred at that temp. range for 10 min., then picolinic acid (100 g, 812 mmol) was added over 30 min. The resulting solution was heated at 72 °C (vigorous SO02 evolution) for 16 h to generate a yellow solid. The resulting mixture was cooled to room temp., diluted with toluene (500 mL) and concentrated to 200 mL. The toluene addition/concentration process was repeated twice. The resulting nearly dry residue was filtered, and the solids were washed with toluene (50 mL) WO 00/41698 PCT/USOO/00768 and dried under high vacuum for 4 hours to afford 4-chloropyridine-2-carbonyl chloride HC1 salt as an off-white solid (27.2 g, This material was set aside.

The red filtrate was added to MeOH (200 mL) at a rate which kept the internal temperature below 55 The contents were stirred at room temp. for 45 min., cooled to 5 °C and treated with Et20 (200 mL) dropwise. The resulting solids were filtered, washed with Et 2 0 (200 mL) and dried under reduced pressure at 35 °C to provide methyl 4-chloropyridine-2-carboxylate HC1 salt as a white solid (110 g, mp 108-112 'H-NMR (DMSO-d 6 5 3.88 3H); 7.82 (dd, J=5.5, 2.2 Hz, 1H); 8.08 J-=2.2 Hz, 1H); 8.68 J=5.5 Hz, 1H); 10.68 (br s, 1H); HPLC ES-MS m/z 172 0 cI NHMe Step 3a. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl 4-chloropyridine-2-carboxylate A suspension of methyl 4-chloropyridine-2-carboxylate HCI salt (89.0 g, 428 mmol) in MeOH (75 mL) at 0 °C was treated with a 2.0 M methylamine solution in THF (1 L) at a rate which kept the internal temp. below 5 The resulting mixture was stored at 3 °C for 5 h, then concentrated under reduced pressure. The resulting solids were suspended in EtOAc (1 L) and filtered. The filtrate was washed with a saturated NaCl solution (500 mL), dried (Na 2

SO

4 and concentrated under reduced pressure to afford 4-chloro-N-methyl-2-pyridinecarboxamide as pale-yellow crystals (71.2 g, mp 41-43 OC; 'H-NMR (DMSO-d 6 5 2.81 3H), 7.74 (dd, J=5.1, 2.2 Hz, 1H), 8.00 J=2.2, 1H), 8.61 J=5.1 Hz, 1H), 8.85 (br d, 1H); CI-MS m/z 171 CI." NHMe WO 00/41698 PCT/USOO/00768 Step 3b. Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from 4chloropyridine-2-carbonyl chloride 4-Chloropyridine-2-carbonyl chloride HCI salt (7.0 g, 32.95 mmol) was added in portions to a mixture of a 2.0 M methylamine solution in THF (100 mL) and MeOH (20 mL) at 0 The resulting mixture was stored at 3 °C for 4 h, then concentrated under reduced pressure. The resulting nearly dry solids were suspended in EtOAc (100 mL) and filtered. The filtrate was washed with a saturated NaCl solution (2 x 100 mL), dried (Na 2

SO

4 and concentrated under reduced pressure to provide 4chloro-N-methyl-2-pyridinecarboxamide as a yellow, crystalline solid (4.95 g, 10 mp 37-40 °C.

*0 2 I O NHMe

H

2 N N Step 4. Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at room temp. for 2 h. The contents were treated with 4-chloro- N-methyl-2-pyridinecarboxamide (15.0 g, 87.9 mmol) and K 2 C0 3 (6.50 g, 47.0 mmol) and then heated at 80 °C for 8 h. The mixture was cooled to room temp. and separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCI solution (4 x 1000 mL), dried (Na 2

SO

4 and concentrated under reduced pressure. The resulting solids were- dried under reduced pressure at 35 °C for 3 h to afford 4-(2-(N-methylcarbamoyl)-4pyridyloxy)aniline as a light-brown solid 17.9 g, 'H-NMR (DMSO-d 6 8 2.77 J=4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA'BB' quartet, .J=8.4 Hz, 4H), 7.06 (dd, 2.5 Hz, 1H), 7.33 J=2.5 Hz, 1H), 8.44 .J=5.5 Hz, 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 A3. General Method for the Synthesis of Anilines by Nucleophilic WO 00/41698 PCT/USOO/00768 Aromatic Addition Followed by Nitroarene Reduction. Synthesis of 5-(4- Aminophenoxy)isoindoline-l,3-dione 0 HO NH

HOO

0 Step 1. Synthesis of 5-hydroxyisoindoline-1,3-dione To a mixture of ammonium carbonate (5.28 g, 54.9 mmol) in conc. AcOH (25 mL) was slowly added 4-hydroxyphthalic acid (5.0 g, 27.45 mmol). The resulting mixture was heated at 120 °C for 45 min., then the clear, bright yellow mixture was heated at 160 °C for 2 h. The resulting mixture was maintained at 160 °C and was concentrated to approximately 15 mL, then was cooled to room temp. and adjusted pH 10 with a IN NaOH solution. This mixture was cooled to 0 °C and slowly acidified to pH 5 using a IN HCI solution. The resultant precipitate was collected by filtration and dried under reduced pressure to yield 5-hydroxyisoindoline-1,3dione as a pale yellow powder as product (3.24 g, 'H NMR (DMSO-d 6 7.00-7.03 2H), 7.56 J=9.3Hz, 1H).

0 2 N 0

NH

0 Step 2. Synthesisof 5-(4-nitrophenoxy)isoindoline-1,3-dione.

To a stirring slurry of NaH (1.1 g, 44.9 mmol) in DMF (40 mL) at 0 °C was added a solution of 5-hydroxyisoindoline-l,3-dione (3.2 g, 19.6 mmol) in DMF (40 mL) dropwise. The bright yellow-green mixture was allowed to return to room temp.

and was stirred for 1 h, then 1-fluoro-4-nitrobenzene (2.67 g, 18.7 mmol) was added via syringe in 3-4 portions. The resulting mixture was heated at 70 °C overnight, then cooled to room temp. and diluted slowly with water (150 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried (MgSO 4 and WO 00/41698 PCT[USOO/00768 concentrated under reduced pressure to give 5-(4-nitrophenoxy)isoindolifle- 1,3dione as a yellow solid (3.3 g, TLC (30% EtOAc/70% hexane) Rj 0.28; 1H NMR (DMSO-d 6 5 7.32 J1=12 Hz, 2H), 7.52-7.57 (in, 2H), 7.89(d, J=7.8 Hz, I1H), 8.29 .1=9 Hz, 2H), 11.43 (br s, I Cl-MS ni/z 285 4 100%).

H

2 Na 0

NH

0 Step 3. Synthesis of 5-(4-aminophenoxy)isoifldolife-l ,3-dione A solution of 5-(4-nitrophenoxy)isoindoline-1 ,3-dione (0.6 g, 2.11 mmol) in conc.

AcOH (12 mL) and water (0.1 mL) was stirred under stream of argon while iron powder (0.59 g, 55.9 mmol) was added slowly. This mixture stirred at room temp.

for 72 h, then was diluted with water (25 mL) and extracted with EtOAc (3 x mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give aminophenoxy)i soindoline- 1,3 -di one as a brownish solid g, 75 TLC (5 0% EtOAc/5 0% hexane) Rf 0.7; 'H NMR (DMSO-d 6 5.14 (br s, 2H), 6.62 .1=8.7 Hz, 2H), 6.84 J=8.7 Hz, 2H), 7.03 J=2.1 Hz, 1H), 7.23 (dd, 1H), 7.75 .1=8.4 Hz, 111), 11.02 IIH); HPLC ES-MS m/z 255 100%).

A4. General Method for the Synthesis of Pyrrolylanilines. Synthesis of 5,-tert-Butyl-2-(2,5-dimethylpyrroIyl)aIniliile *N0 2

N

Step 1. Synthesis of I -(4-tert-butyl-2-n itroph To a stirring solution of 2-nitro-4-tert-butylaniline g, 2.57 inmol) in cyclohexane (10 mL) was added AcOH (0.l1mL) and acetonylacetone (0.299 g, 2.63 WO 00/41698 PCT/USOO/00768 mmol) via syringe. The reaction mixture was heated at 120 °C for 72 h with azeotropic removal of volatiles. The reaction mixture was cooled to room temp., diluted with CH 2

C

2 (10 mL) and sequentially washed with a 1N HCI solution mL), a IN NaOH solution (15 mL) and a saturated NaCI solution (15mL), dried MgSO 4 and concentrated under reduced pressure. The resulting orange-brown solids were purified via column chromatography (60 g SiO 2 gradient from 6% EtOAc/94% hexane to 25% EtOAc/75% hexane) to give 1-(4-tert-butyl-2as an orange-yellow solid (0.34 g, TLC EtOAc/85% hexane) Rf0.67; 'H NMR (CDC13) d 1.34 9H), 1.89 6H), 5.84 2H), 7.19-7.24 1H), 7.62 (dd, 1H), 7.88 J=2.4 Hz, 1H); CI-MS m/z 273 WO 00/41698 PCT/USOO/00768 NH2

N

Step 2. Synthesis of 5-tert--Butyl-2-(2,5-dimethylpyrrolyl)aniline A slurry of 1-(4-tert-butyl-2-nitrophenyl)-2,5-dimethylpyrrole (0.341 g, 1.25 mmol), 10%Pd/C (0.056 g) and EtOAc (50 mL) under an H 2 atmosphere (balloon) was stirred for 72 h, then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give 5-tert--butyl-2-(2,5-dimethylpyrrolyl)aniline as yellowish solids (0.30 g, TLC (10% EtOAc/90% hexane) Rf 0.43; 'H NMR (CDC13) 5 1.28 9H), 1.87-1.91 (mi, 8H), 5.85 (br s, 2H), 6.73-6.96 3H), 7.28 (br s, 1H).

General Method for the Synthesis of Anilines from Anilines by Nucleophilic Aromatic Substitution. Synthesis of Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline HCI Salt 0 H2 O NHMe

SH

2 N HC Me A solution of 4-amino-3-methylphenol (5.45 g, 44.25 ,mol) in dry dimethylacetamide (75 mL) was treated with potassium tert-butoxide (10.86 g, 96.77 mmol) and the black mixture was stirred at room temp. until the flask had reached room temp. The contents were then treated with 4-chloro-N-methyl- 2 pyridinecarboxamide (Method A2, Step 3b; 7.52 g, 44.2 mmol) and heated at 110 °C for 8 h. The mixture was cooled to room temp. and diluted with water (75 mL).

The organic layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with a saturated NaCI solution (200 mL), dried (MgS0 4 and concentrated under reduced pressure. The residual black oil was treated with mL) and sonicated. The solution was then treated with HCI (I M in Et20; 100 mL) and stirred at room temp. for 5 min. The resulting dark pink solid (7.04 g, 24.1 mmol) was removed by filtration from solution and stored under anaerobic conditions at 0 °C prior to use: 1H NMR (DMSO-d 6 8 2.41 3H), 2.78 J=4,4.

Hz, 3H), 4.93 (br s, 2H), 7.19 (dd, J=8.5, 2.6 Hz, 1H), 7.23 (dd, 2.6 Hz, 1H), 7.26 J=2.6 Hz, 1H), 7.55 J=2.6 Hz, 1H), 7.64 J=8.8 Hz, 1H), 8.55 (d, J=5.9 Hz, 1H), 8.99 J=4.8 Hz, 1H).

9 10 A6. General Method for the Synthesis of Anilines from Hydroxyanilines by N-Protection, Nucleophilic Aromatic Substitution and Deprotection. Synthesis of 4- (2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline O OH

F

3 C N H Cl Step 1: Synthesis of 3-Chloro-4-(2,2,2-trifluoroacetylamino)phenol Iron (3.24 g, 58.00 mmol) was added to stirring TFA (200 mL). To this slurry was added 2-chloro-4-nitrophenol (10.0 g, 58.0 mmol) and trifluoroacetic anhydride mL). This gray slurry was stirred at room temp. for 6 d. The iron was filtered from Ssolution and the remaining material was concentrated under reduced pressure. The resulting gray solid was dissolved in water (20 mL). To the resulting yellow solution was added- a- saturated NaHCO 3 solution (50 mL). IThesolid which precipitated from solution was removed. The filtrate was slowly quenched with the sodium bicarbonate solution until the product visibly separated from solution (determined was using a mini work-up vial). The slightly cloudy yellow solution was extracted with EtOAc (3 x 125 mL). The combined organic layers were washed with a saturated NaCI solution (125 mL), dried (MgSO 4 and concentrated under reduced pressure. The 'H NMR (DMSO-d 6 indicated a 1:1 ratio of the nitrophenol starting material and the intended product 3-chloro-4-(2,2,2- WO 00/41698 PCT/USOO/00768 trifluoroacetylamino)phenol. The crude material was taken on to the next step without further purification.

0 0 NHMe

F

3 C N NHMe H Cl Step 2: Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)- 2 chlorophenyl (222-trifluoro)acetamide A solution of crude 3-chloro-4-(2,2,2-trifluoroacetylamino)phenol (5.62 g, 23.46 mmol) in dry dimethylacetamide (50 mL) was treated with potassium tert-butoxide (5.16 g, 45.98 mmol) and the-brownish black mixture was stirred at room temp.

until the flask had cooled to room temp. The resulting mixture was treated with 4chloro-N-methyl-2-pyridinecarboxamide (Method A2, Step 3b; 1.99 g, 11.7 mmol) and heated at 100 °C under argon for 4 d. The black reaction mixture was cooled to room temp. and then poured into cold water (100 mL). The mixture was extracted with EtOAc (3 x 75 mL) and the combined organic layers were concentrated under reduced pressure. The residual brown oil was purified by column chromatography (gradient from 20% EtOAc/pet. ether to 40% EtOAc/pet. ether) to yield Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide as a yellow solid (8.59 g, 23.0 mmol).

0 f:0 N H M e

H

2 N J CI, Step 3. Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)- 2 chloroaniline A solution of crude 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222trifluoro)acetamide (8.59 g, 23.0 mmol) in dry 4-dioxane (20 mL) was treated with a IN NaOH solution (20 mL). This brown solution was allowed to stir for 8 h. To this solution was added EtOAc (40 mL). The green organic layer was extracted with EtOAc (3 x 40 mL) and the solvent was concentrated to yield' Methylcarbamoy)-4-pyridylox y)2chi oroaniline as a green oil that solidified upon standing (2.86 g, 10.30 mmol): 'H NMR (DMSO-d 6 5 2.77 J=4.8 Hz, 3H), 5.51 2H1), 6.60 (dd, J=8.5, 2.6 Hz, 1H), 6.76 J=2-6 Hz, IH), 7.03 J=.8.5 Hz, 1H), 7.07 (dd, J=5.5, 2.6, Hz, 111), 7.27 J=2.6 Hiz, 1H), 8.46 J=5.5 Hz, 1H), 8.75 (q,.1=4.82 1H).

A7. General Method for the Deprotection of an Acylated Aniline.

Synthe: jis of -4-Chloro-2-meth

CF

3

C!

NH

2 OMe A suspension of 3-chloro-6-(N-acetyl)-4-(trfluoromhethyI)3fl1sole (4.00 g, 14.95 rnol) in a 6M HCI solution (24 rnL) was heated at the reflux temp.

for 1 h- The resulting solution was allowed to cool to room temp. during which time it -olidified slightly. The resulting mixture was diluted with water (20 mL) then treated with a combination of solid NaO}I and a saturated NaHCO 3 solution until the solution was basic. The organic layer was extracted with CH 2

CI

2 (3 x 50 mL). The combined organics were dried (MgSO4) and concentrated under reduced pressure to yield 4-chloro-2as a brown oil (3.20 g, 14.2 mmol): 'H NMvR (DMSO-d 6 5 3.84 3H), 5.30 2E1), 7.01 2H).

A8. General Method for Synthesis of W-AMkoxy-w-carboxyphenyl Anilines.

Synthesis of 4- (N-Methylcarbamoyl)-4-methoxyphenoxy) aniline.

0 *0 2 N' oMeM Step 1. 4-(3-Metboxycarbol-l4meth~oxyphenoxy)-l-nitrob enzene: To a solution of 4-(3-carboxy-4-hydroxyphenoxy)-l-nitrobenzene (prepared from acid in a manner analogous to that described in Method A13, Step 1, 12 mmol) in acetone (50 mL) was added K 2 C0 3 (5 g) and dimethyl sulfate mL). The resulting mixture was heated at the reflux temp. overnight, then cooled to room temp. and filtered through a pad of Celite®. The resulting solution, was concentrated under reduced pressure, absorbed onto SiO 2 and purified by column chromatography (50% EtOAc 50% hexane) to give 4-(3-methoxycarbonyl- 4-methoxyphenoxy)-l-nitrobenzene as a yellow powder (3 mp 115-118 °C.

Step 2. 4-(3-Carboxy-4-methoxyphenoxy)-l-nitrobenzene: A mixture of 4-(3-methoxycarbonyl-4-methoxyphenoxy)-l-nitrobenzene (1.2 g), KOH (0.33 g) and water (5 mL) in MeOH (45 mL) was stirred at room temp.

overnight and then heated at the reflux temp. for 4 h. The resulting mixture was cooled to room temp. and concentrated under reduced pressure. The residue was dissolved in water (50 mL), and the aqueous mixture was made acidic with a 1N HC1 solution. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was dried (MgS04) and concentrated under reduced pressure to give 4-(3-carboxy-4-methoxyphenoxy)-1 -nitrobenzene (1.04 g).

0 2 N v Me Step 3. 4-(3-(N-Methylcarbamoyl)-4-methoxyphenoxy)-l-nitrobenzene: To a solution of 4-(3-carboxy-4-methoxyphenoxy)-l-nitrobenzene (0.50 g, 1.75 mmol) in CH 2 C1 2 (12 mL) was added SOC12 (0.64 mL, 8.77 mmol) in portions. The resulting solution was heated at the reflux temp. for 18 h, cooled to room temp., and concentrated under reduced pressure. The resulting yellow solids were dissolved in

CH

2 C1 2 (3 mL) then the resulting solution was treated with a methylamine solution M in THF, 3.5 mL, 7.02 mmol) in portions (CAUTION: gas evolution), and Stirred at room temp. for 4 h. The resulting mixture was treated with a IN NaGH solution, then extracted with CH 2

CI

2 (25 mL). The organic layer was dried (Na 2

SO

4 and concentrated under reduced pressure to give 4 3 -(N-methylcarbamoyl)-4methooxyphenoxy)-l-nitrobenzene as a yellow solid (0.50 g, 0 0" NHMe

H

2 N OMe Step 4. 4-3(-ehlabml)4mtoyhnx~nlie A slurry of 4-3(Vmthlabm1y mtoypeoy--nitrobenzene (0.78 g, 2.60 mimol) and 10% Pd/C (0.20 g) in EtOH (55 mL) was stirred under I atm of H 2 (balloon) for 2.5 d, then was .filtered through a pad of Celite®. The resulting Solution was concentrated under reduced pressure to afford methylcarbamoly)-4-methoxyphenoxy)afliline as an off-white solid (0.68 g, 96%): TLC Et 3 N/99.9% EtOAc) Rf 0.36.

A9. General Method for Preparation of co-Alkylphthalimidecontaining Anilin es. Synthesis of 5-(4-Amin ophen oxy)-2methylisoindoline-i ,3-dione 0 J* N-Me 0 2 N0 Step 1. Synthesis of 5-(4.-Nitrophenoxy)-2-fllethylisoindoline!-1 ,3-dione: A slurry of 5-(4-nitrophenoxy)isoifldoline-1,3-dione (A3 Step 2; 1.0 g, 3.52 minol) and NaH (0.13 g, 5.27 mmol) in DMYf (15 mL) was stirred at room temp. for 1 h, then treated with methyl iodide (0.3 mL, 4.57 mniol). The resulting mixture was stirred at room temp. overnight, then was cooled to 0 C and treated with water niL). The resulting so .lids were collected and dried under reduced pressure to give 5-(4-nitrophenoxy)-2-methylisoindolifle-l ,3-dione as a bright yellow solid (0.87 g, TLC (35% EtOAc/65% hexane) Rf 0.61.

I

WO 00/41698 WO 0041698PCTIUSOO/00768 Step 2. Synthesis of 5-(4-A min op hen oxy)-2-methylisoin doli ne-I ,3-dion e: A slurry of nitrophenoxy)-2-methylisoindoline-1,3-dione (0.87 g, 2.78 mmol) anid, Pd/C 10 g) in MeOH was stirred under I atm of H 2 (balloon) overnight. The resulting mixture was filtered through a pad of Celiteg and concentrated under reduced pressure. The resulting yellow solids were dissolved in EtQAc (3 mL) and filtered through a plug Of SiO 2 (60% EtOAc/40% hexane) to afford 5-(4aminophenoxy)-2-methylisoindoline-1,3-dione as a yellow solid (0.67 g, 86%): TLC (40% EtOAc/60% hexane) Rf 0.27.

Al 0. General Method for Synthesis of o-Carbamoylaryl Anilinies Through Reaction of co-Alkoxycarbonylaryl Precursors with Amines. Synthesis of 4-(2-(N-(2-morpholin-4ylethyl)carbamoyl)pyridyloxy)aniline 0 Step 1. Synthesis of 4-Chloro-2-(N-(2-morpholil-4ylethyl)carbamoyl)pyridine To a solution of methyl 4-chloropyridine-2-carboxylate HCl salt (Method A2, Step 2; 1.01 g, 4.86 rmnol)in-TH-F (20 mL) was added 4-(2-aminoethyl.)merrpholine (2.55 mL, 19.4 mmol) dropwise and the resulting solution was heated at the relflux temnp.

for 20 h, cooled to room temp., and treated with water (50 mL). The resulting' mixture was extracted with EtOAc (50 mL). The organic layer was dried (M\4S 04) and concentrated under reduced pressure to -afford 4-chloro-2-(N-(2-morpholin-4ylethyl) carbamoyl)pyridine as a yellow oil (1.25 g, TLC (10% EtOAc) Rf 0.50.

WO 00/41698 PCT/USOO/00768 0

H

2 N N 0 Step 2. Synthesis of 4-(2-(N-(2-Morpholin-4ylethyl)carbamoyl)pyridyloxy)aniline.

A solution of 4-aminophenol (0.49 g, 4.52 mmol) and potassium tert-butoxide (0.53 g, 4.75 mol) in DMF (8 mL) was stirred at room temp. for 2 h, then was sequentially treated with 4-chloro-2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridine (1.22 g, 4.52 mmol) and K 2

CO

3 (0.31 g, 2.26 mmol). The resulting mixture was heated at 75 °C overnight, cooled to room temp., and separated between EtOAc (25 mL) and a saturated NaCl solution (25 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were washed with a saturated NaCI solution (3 x 25 mL) and concentrated under reduced pressure. The resulting brown solids were purified by column chromatography (58 g; gradient from 100% EtOAc to 25% MeOH/75% EtOAc) to afford 4-(2-(N-(2-morpholin-4ylethyl)carbamoyl)pyridyloxy)aniline (1.0 g, TLC (10% MeOH/90% EtOAc) Rf 0.32.

All. General Method for the Reduction of Nitroarenes to Arylamines.

Synthesis of 4-(3-Carboxyphenoxy)aniline.

0 H02 O

OH

H

2

N

A slurry of 4-(3-carboxyphenoxy)-l-nitrobenzene (5.38 g, 20.7 mmol) and Pd/C (0.50 g) in MeOH (120 mL) was stirred under an H 2 atmosphere (balloon) for 2 d. The resulting mixture was filtered through a pad of Celite®, then concentrated under reduced pressure to afford 4-(3-carboxyphenoxy)aniline as a brown solid (2.26 g, TLC (10% MeOH/90% CH 2 C1 2 Rf 0.44 (streaking).

WO 00/41698 PCT/USOO/00768 A12. General Method for the Synthesis of Isoindolinone-Containing Anilines. Synthesis of 4-(1-Oxoisoindolin-5-yloxy)aniline.

HO'

I H NH 0 Step 1. Synthesis of To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux temp. for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 Kg SiO 2 gradient from EtOAc/40% hexane to 25% MeOH/75% EtOAc) to give (3.77 TLC (100% EtOAc) Rf 0.17; HPLC ES-MS m/z 150 0 O NH 0 2

N

0 Step 2. Synthesis of 4-(1-isoindolinon-5-yloxy)-l-nitrobenzene To a slurry of NaH (0.39 g, 16.1 mmol) in DMF at 0 °C was added hydroxyisoindolin-1-one (2.0 g, 13.4 mmol) in portions. The resulting slurry was allowed to warm to room temp. and was stirred for 45 min., then 4-fluoro-1nitrobenzene was added and then mixture was heated at 70 °C for 3 h. The mixture was cooled to 0 °C and treated with water dropwise until a precipitate formed. The resulting solids were collected to give 4-(1-isoindolinon-5-yloxy)-l-nitrobenzene as a dark yellow solid (3.23 g, TLC (100% EtOAc) Rf0.35.

H

2 N "O N 0 Step 3. Synthesis of 4-(1-oxoisoindolin-5-yloxy)aniline A slurry of 4-(1-isoindolinon-5-yloxy)-l-nitrobenzene (2.12 g, 7.8 mmol) and Pd/C (0.20 g) in EtOH (50 mL) was stirred under an H 2 atmosphere (balloon) for 4 h, then filtered through a pad of Celite®. The filtrate was concentrated under WO 00/41698 PCT/USOO/00768 reduced pressure to afford 4-(1-oxoisoindolin-5-yloxy)aniline as a dark yellow solid: TLC (100% EtOAc) Rf0.15.

A13. General Method for the Synthesis of o-Carbamoyl Anilines via EDCI-Mediated Amide Formation Followed by Nitroarene Reduction. Synthesis of 4-(3-N- Methylcarbamoylphenoxy)aniline.

0 OEt 0 2 N ci' Step 1. Synthesis of 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene A mixture of 4-fluoro-l-nitrobenzene (16 mL, 150 mmol), ethyl 3-hydroxybenzoate g, 150 mmol) and K 2 CO3 (41 g, 300 mmol) in DMF (125 mL) was heated at the reflux temp. overnight, cooled to room temp. and treated with water (250 mL). The resulting mixture was extracted with EtOAc (3 x 150 mL). The combined organic phases were sequentially washed with water (3 x 100 mL) and a saturated NaCI solution (2 x 100 mL), dried (NazSO 4 and concentrated under reduced pressure.

The residue was purified by column chromatography (10% EtOAc/90% hexane) to afford 4-(3-ethoxycarbonylphenoxy)-1-nitrobenzene as an oil (38 g).

0 0 OH Step 2. Synthesis of 4-(3-carboxyphenoxy)-l-nitrobenzene To a vigorously stirred mixture of 4-(3-ethoxycarbonylphenoxy)-l-nitrobenzene (5.14 g, 17.9 mmol) in a 3:1 THF/water solution (75 mL) was added a solution LiOH-H 2 0 (1.50 g, 35.8 mmol) in water (36 mL). The resulting mixture was heated at 50 °C overnight, then cooled to room temp., concentrated under reduced pressure, and adjusted to pH 2 with a 1M HCI solution. The resulting bright yellow solids were removed by filtration and washed with hexane to give 4-(3-carboxyphenoxy)- 1-nitrobenzene (4.40 g, WO 00/41698 PCT/USOO/00768 0 0~ NHMe 0 2

N

Step 3. Synthesis of 4-(3-(N-methylcarbamoyl)pheloxy)4litrobeflzene A mixture of 4-(3-carboxyphenoxy)-l-flitrobeflzene (3.72 g, 14.4 mmol), EDCIPHCl (3.63 g, 18.6 mmol), N-methylmorpholifle (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CH 2 C1 2 (45 mnL) was stirred at room temp. for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc mnL) and the resulting mixture was extracted with a 1M HC1 solution (50 mL).

The aqueous layer was back-extracted with lEtOAc (2 x 50 mL). The combined organic phases were washed with a saturated NaCI solution (50 mL), dried l0 (Na 2

SO

4 and* concentrated under reduced pressure to give methylearbamoy)phenoxy)-l-ntroben~zene as an oil (1.89 g).

0 NHMe

H

2

N

Step 4. Synthesis of 4-(3-(N-methylcarb amoyl)phenoxy)aniline A slurry of 4-(3-(N-methylcarbamoyl)phenoxy)-l -nitrobenzene (1.89 g, 6.95 mniol) and 5% Pd/C (0.24 g) in EtOAc (20 mL) was stirred u nder an H 2 atmi (balloon) overnight. The resulting mixture was filtered through a pad of Celite(&> and concentrated under lrieduced pressure. The residue was purified-by column chromatography MeOH/95% CH 2

CI

2 The resulting oil solidified under vacuum overnight to give 4-(3-(N-methylcarbamoyl)phenoxy)aflile -as a yellow solid (0.95 g, 56%).

A14. General Method for the Synthesis of co-Carbamoyl Auiines via -EDCI-Mediated Amide Formation Followed by Nitroarene Reduction.

Synthesis of 4-3-(5-Methylcarbanoyl)pyridy1oxy)afliliile WO 00/41698. PCT/IUSOO/00768 0 0~ OMe 0 2 N'

N

Step 1. Synthesis of 4-(3-(5-methoxycarboflyl)pyridyIoxy)nitrobenzene To a slurry of NaI- (0.63 g, 26.1 mmol) in DMF (20 mL) was added a solution of methyl 5-hydroxynicotinate (2.0 g, 13.1 mmol) in DMF (10 The resulting mixture was added to a solution of 4-fluoronitrobenzene (1.4 mL, 13.1 mmol) in DMF (10 mL) and the resulting mixture was heated at 70 'C overnight, cooled to room temp., and treated with MeOH (5 mL) followed by water (50 mL). The resulting mixture was extracted with EtOAc (100 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (30% iEtOAc/70% hexane) to afford methoxycarbonyl)pyridyloxy)-l1-nitrobenzene (0.60 g).

0 OMe

H

2 N

N

Step 2. Synthesis of 4-(3-(5-methoxycarbol)pyridy1oxy)afulifle A slurry of 4-(3.-(5-methoxycarbonyl)pyridyloxy)-l-ntrobenzene (0.60 g, 2.20 mmol) and 10% PdIC in MeOHJEtOAc was stirred under an H 2 atmosphere (balloon) for 72 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography .(grddietnt from 10% EtOAc/90% hexane to 309/a-EtOAc/70% 2o hexane to 50% EtOAcI5O% hexane) to afford methoxycarbonyl)pyridyloxy)afliline (0.28 g, 'H NMR (CDC1 3 8 3.92 (s, 3H), 6.71 2H), 6.89 2H), 7.73 8.51 1H), 8.87 1H).

Synthesis of an Aniline via Electrophilic Nitration Followed by Reduction. Synthesis of 4-(37Methylsulfamoylph eoxy) anlinle.

WO 00/41698 PCT/USOO/00768 Br S NHMe Step. 1. Synthesis of N-methyl-3-bromobenzenesulfonamide To a solution of 3-bromobenzenesulfonyl chloride (2.5 g, 11.2 mmol) in THF mL) at 0 °C was added methylamine (2.0 M in THF; 28 mL, 56 mmol). The resulting solution was allowed to warm to room temp. and was stirred at room temp.

overnight. The resulting mixture was separated between EtOAc (25 mL) and a 1 M HCI solution (25 mL). The aqueous phase was back-extracted with EtOAc (2 x mL). The combined organic phases were sequentially washed with water (2 x 0 mL) and a saturated NaCl solution (25 mL), dried (MgSO 4 and concentrated under reduced pressure to give N-methyl-3-bromobenzenesulfonamide as a white solid (2.8 g, 99%).

0o0 0 S- NHMe Step 2. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene To a slurry of phenol (1.9 g, 20 mmol), K 2

CO

3 (6.0 g, 40 mmol), and Cul (4 g, mmol) in DMF _(25 mL) was added N-methyl-3-bromobenzenesulfonamide (2.5 g, and the resulting mixture was stirred at the reflux temp. overnight, cooled to room temp., and separated between EtOAc (50 mL) and a 1 N HCI solution mL). The aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic phases were sequentially washed with water (2 x 50 mL) and a saturated NaCI soluti6ff'(50 mL), dried (MgSO 4 and concentratedP ier reduced pressure. The residual oil was purified by column chromatography hexane) to give 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g).

-~2~SNHMe Step 3. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene Step 3. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)-l-nitrobenzene WO 00/41698 PCT/USOO/00768 To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at -10 0 C was added NaNO 2 (0.097 g, 1.14 mmol) in portions over min. The resulting solution was stirred at -10 °C for 1 h, then was allowed to warm to room temp., and was concentrated under reduced pressure. The residue was separated between EtOAc (10 mL) and water (10 mL). The organic phase was.

sequentially washed with. water (10 mL) and a saturated NaC1 solution (10 mL), dried (MgSO 4 and concentrated under reduced pressure to give methylsulfamoyl)phenyloxy)-l-nitrobenzene (0.20 This material carried on to the next step without further purification.

0'0 00 S. NHMe

H

2

N

Step 4. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)aniline A slurry of 4 -(3-(N-methylsulfamoyl)phenyloxy)-l-nitrobenzene (0.30 g) and Pd/C (0.030 g) in EtOAc (20 mL) was stirred under an H 2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (30% EtOAc/70% hexane) to give methylsulfamoyl)phenyloxy)aniline (0.070 g).

A16. Modification of co-ketones. Synthesis of methoxy)iminoethyl)phenoxyaniline HCI salt.

HCI

NO

H

2 No To a slurry of 4-(4-acetylphenoxy)aniline HCI salt (prepared in a manner analogous to Method A13, step 4; 1.0 g, 3.89 mmol) in a mixture of EtOH (10 mL) and pyridine (1.0 mL) was added O-methylhydroxylamine HCI salt (0.65 g, 7.78 mmol, 2.0 equiv.). The resulting solution was heated at the reflux temperature for 30 min, cooled to room temperature and concentrated under reduced pressure. The resulting WO 00/41698 PCTIUSOO/00768 solids were triturated with water (10 mL) and washed w ith water to give methoxy)iminoethyl) phenoxyaniline HCI salt as a yellow solid (0.85 TLC pet. ether) RJ 0.78; 'H NMR (DMSO-d 6 563.90 3H), 5.70 3H); HPLC-MS in/z 257 Al 7. Synthesis of N-(co-Silyloxyalkyl)amnides. Synthesis of 2 -Triisopropysilyloxy,)ethylearbamoyl)pyridyloxyaniline.

0 Cl~ -N~ 0

SI-

Step 1. 4 -Chloro-N-(2-triisopropylsiyloxy)ethylpyridine2carboxamide To a solution of 4-chloro-N-(2-hydroxyethyl)pyridie2carboxamide (prepared in a manner analogous to Method A2, Step 3b; 1.5 g, 7.4 mmol) in anh DMF (7 mL) was added triisopropylsilyl chloride (1.59 g, 8.2 mmol, 1.1 equiv.) and imidazole (1.12 g, 16.4 mmol, 2.2 equiv.). The resulting yellow solution was stirred for 3 h at room temp, then was concentrated under reduced pressure. -The residue was separated between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried (MgSO 4 and concentrated under reduced pressure to afford 4-chloro-2-(N-(2triisopropylsily loxy)ethyl)pyridinecarboxamide as an orange oil (2.32 g, This material was used in the next step withoutfurther purification.

H

2 N7 Step 2. 4(-2(-2 Triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline To a solution of 4-hydroxyaniline (0.70 g, 6.0 mmol) in anh DMF (8 mL) was added potassium tert-butoxide (0.67 g, 6.0 mmol, 1.0 equiv.) in one portion causing an exotherm. When this mixture had cooled to room temperature, a solution of 4choo2(-2tispoysllx~ty~yiieabxmd (2.32 g, 6 mmol, 1 WO 00/41698 PCT/US00/00768 equiv.) in DMF (4 mL) was added followed by K 2 CO3 (0.42 g, 3.0 mmol, 0.50 equiv.). The resulting mixture was heated at 80 °C overnight. An additional portion of potassium tert-butoxide (0.34 g, 3 mmol, 0.5 equiv.) was then added and the mixture was stirred at 80 °C an additional 4 h. The mixture was cooled to 0 °C with an ice/water bath, then water (approx. 1 mL) was slowly added dropwise. The organic layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with a saturated NaCI solution (20 mL), dried (MgSO 4 and concentrated under reduced pressure. The brown oily residue was purified by column chromatography (SiO 2 30% EtOAc/ 70% pet ether) to afford 10 triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline as a clear light brown oil (0.99 g, 38%).

A18. Synthesis of 2-Pryidinecarboxylate Esters via Oxidation of 2- Methylpyridines. Synthesis of methoxycarbonyl)pyridyloxy)aniline.

Step 1. 4-(5-(2-Methyl)pyridyloxy)-l-nitrobenzene.

A mixture of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol), 1-fluoro-4nitrobenzene (9.8 mL, 91.6 mmol, 1.0 equiv.), K 2 C0 3 (25 g, 183 mmol, 2.0 equiv.) 0 20 in DMF (100 mL) was heated at the reflux temperature overnight. The resulting mixture was cooled to room temperature, treated with water (200 mL), and extracted with EtOAc (3 x 100 mL). The combined organic layers were sequ etilly washed with water (2 x 100 mL) and a saturated NaCI solution ((100 mL), dried (MgS0 4 and concentrated under reduced pressure to give 4-(5-(2-methyl)pyridyloxy)-lnitrobenzene as a brown solid (12.3 g).

WO 00/41698 PCT/USOO/00768 Step 2. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)-lnitrobenzene.

A mixture of 4-(5-(2-methyl)pyridyloxy)-l-nitrobenzene (1.70 g, 7.39 mmol) and selenium dioxide (2.50 g, 22.2 mmol, 3.0 equiv.) in pyridine (20 mL) was heated at the reflux temperature for 5 h, then cooled to room temperature. The resulting slurry was filtered then concentrated under reduced pressure. The residue was dissolved in MeOH (100 mL). The solution was treated with a cone HC1 solution (7 mL), then heated at the reflux temperature for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was separated between EtOAc (50 mL) and a 1N NaOH solution (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were sequentially washed with water (2 x 50 mL) and a saturated NaCl solution (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 50% EtOAc/50% hexane) to afford methoxycarbonyl)pyridyloxy)-1-nitrobenzene (0.70 g).

OMe

H

2 N O N O 0 Step 3. Synthesis of 4-(5-(2-Methoxycarbonyl)pyridyloxy)aniline.

A slurry of 4-(5-(2-methoxycarbonyl)pyridyloxy)-l-nitrobenzene (0.50 g) and Pd/C (0.050 g) in a mixture of EtOAc (20 mL) and MeOH (5 mL) was placed under a H 2 atmosphere (balloon) overnight. The resulting mixture was filtered through a pad of Celite®, and-the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 70% EtOAc/30% hexane) to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline (0.40 g).

A19. Synthesis of <a-Sulfonylphenyl Anilines. Synthesis of 4-(4- Methylsulfonylphenyoxy)aniline.

WO 00/41 698 PCT/USOO/00768 0 0 2 N 00\ Step 1. 4-(4-Methylsulfonylpheloxy)-l-flitrobeflzefe: To a solution of 4-(4methylthiophenoxy)-l-litrobelzefe (2.0 g, 7.7 mmol) in CH 2 C1 2 (75 mL) at 0 0

C

was slowly added m-CPBA (57-86%, 4.0 and the reaction mixture was stirred at, room temperature for 5 h. The reaction mixture was treated with a IN NaOH solution (25 miL). The organic layer was sequentially washed with a IN NaOH solution (25 mnL), water (25 mL) and a saturated NaCI solution (25 mL), dried (MgSO 4 and concentrated under reduced pressure to give 4-(4miethylsulfonylphenoxy)-l-nitrobenzene as a solid (2.1 g).

Step 2. 4-(4-Methylsulfonylpheloxy)-1.aulile: 4-(4-Methylsulfonylphenoxy)-l nitrobenzene was reduced to the aniline in a manner analogous to that described in Method Al18, step 3.

B. Synthesis of Urea Precursors' BI. General Method for the Synthesis of Isocyanates from Anilines Using CDI. Synthesis of 4-Bronio-3-(trifluoromethyl)phenyI Isocyaflate.

CF

3 Br

SNH

2 -HC1 Step 1. Synthesis of 4-bromo-3-(trifluoromfethyl)aflilifle HC1 salt To a solution of 4-bromo-3-(trifluoromethyl)anilifle (64 g, 267 mmol) in Et 2 O (500 mL) was added an HCI solution (1 M in Et 2 O; 300 mL) dropwise and the resulting, mixture was stirred at room temp. for 16 h. The resulting pink-white precipitate was removed by filtration and washed with Et 2 O (50 mL) and to afford 4-bromo-3-.

(trifluoromethyl)aniline HCl salt (73 g 98%).

WO 00/41 698 PCT/USOO/00768

CF

3 Br,

NCO

Step 2. Synthesis of 4-brom0-3-(trifluorQImethyl)phenII~ isocyanate A suspension of 4-bromo-3-(trifluoromethyl)alhlifle HCI salt (36.8 g, 133 mmol) in toluene (278 mL) was treated with trichioromethyl chioroformate dropwise and the resulting mixture was heated at the reflux temp. for 18 h. The resulting mixture was concentrated under reduced pressure. The residue was treated with toluene (500 mL), then concentrated under reduced pressure. The residue was treated with

CH

2

CI

2 (500 then concentrated under reduced pressure. The CH 2 C1 2 treatment/concentration protocol was repeated and resulting amber oil was stored at -20 cC for 16 h, to afford 4-bromo-3-(trifluoromethyl)phelyl isocyanate as a tan solid (35.1 g, GC-MS rn/z 265 C. Methods of Urea Formation Cla. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3- (trifluoromethyl)phenyl)N'(4-(2-(Nmethylcarbamoyl) 4 pyridyloxy)phenyl) Urea

CF

3 0 C1 0 NHMe N N* H H A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (14.60 gj, 65 .90 mmol) in CH 2 Cl 2 (35 mL) was added dropwise to a suspension of methylcarbamoyl)-4-pyridyloxy)anilifle (Method A2, Step 4; 16.0 g, 65.77 mniol) in

CH

2

CI

2 (35 mL) at 0 The resulting mixture was stirred at room temp. for 22 h.

The resulting yellow solids were removed by filtration, then washed with CH 2 C1 2 (2 x 30 mL) and dried under reduced pressure (approximately 1 mmil-g) to afford NV-(4chloro-3-(trifluoromethyl)phenyl)-N -(N-methylcarbamoyl)-4pyridyloxy)phenyl) urea as an off-white solid (28.5- g, mp 207-209 'H- WO 00/41 698 PCT/USOO/00768 NMR (DMSO-d 6 5 2.77 1=4.8 Hz, 3H), 7.16 (in, 3H), 7.37 J 25 Hz, lH), 7.62 (in, 4H), 8 .11 1=2.5 Hz, 1 8.49 1=5.5 Hz, IlH), 8.77 (br d, I1H), 8.99 1H), 9.21 1H); HPLC ES-MS m/lz 465 Cib. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Bromno-3- (trifll oromethyI)pheny)-N'-(4-(2-(N-methyIcarbamoyl).

4 pyridyloxy)phenyl) Urea

CF

3 .0 Br 0 NHMe N NJY1T H, H A solution of 4-bromo-3-(trifluoromethy1)phelyl isocyanate (Method BI, Step 2; g, 30.1 inmol) in CH 2

CI

2 (80 mL) was added dropwise to a solution of methylcarbamoyl)-4-pyridyloxy)alhlifle (Method A2, Step 4; 7.0 g, 28.8 mmcd) in

CH

2

CI

2 (40 mL) at 0 TC. The resulting mixture was stirred at room temp. for 16 h.

The resulting yellow solids were removed by filtration, then washed with CH 2 Cl 2 (2 x 50 mL) and dried under reduced pressure (approximately 1 mmi~g) at 40 'C to afford N-(4-bromo-3-(rfurmty hey)N-4(-Nmehlabmy)4 pyridyloxy)phenyl) urea as a pale-yellow solid (13.2 g, mp 203-205 'H- NMR (DMS0-cl 6 5 2.77 .1=4.8 Hz, 3H), 7.16 (in, 3H), 7.37 J125 Hz, 1 H), 7.58 (in, 3H), 7.77 J=8.8 Hz, lH), 8.1 1 J12.5 Hz, 1H), 8.49 J=5.5 Hz, 1 8.77 (br d, I1H), 8.99 I 9.21 I1H); IHPLC ES-MS m/z 509 Cic. General Method-for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3- (trifluoromethyl)ph enyl)-N'-(2-methyl-4-(2-(NmethylcarbamoyI)(4-pyridyloxy))phenyl) Urea WO 00/41698 PcTUSOO/00768

CF

3 0 C1 11 j NHMe N N 1

N

H HqM A solution of 2-ehl4(-Nmtycramy)4pnyoy)nln (Method 0. 11 g, 0.45 mmol) in CIH 2

C

2 (1 mL) was treated with Et 3 N 16 mL) and 4-, chloro-3-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.45 mmol). The resulting brown solution was stirred at room temp. for 6 d, then was treated with water mL). The aqueous layer was back-extracted with EtOAc (3 x 5 mL). The combined organic layers were dried (MgSO 4 and concentrated under reduced pressure to 0 yield N-(4-chloro-3-(tnifluoromethyl)phenyl)-N '-(2-methyl-4-(2-(Nmethylcarbamoyl)(4-pyridyloxy))phenyl) urea as a brown oil 11. g, 0.22 mmol): 'HNMR (DMSO-d 6 5 2.27 3H), 2.77 J1=4.8 Hz, 3H), 7.03 (dd, J=8.5, 2.6 Hz, 1H), 7.11 J=2.9 Hz, 1H), 7.15 (dd, J= 5.5, 2.6, Hz, 1H), 7.38 .1=2.6 Hz, 1H), 7.62 (aPP d, J=2.6 Hz, 2H), 7.84 .1=8.8 Hz, 1H), 8.12 1H), 8.17. 1H); 8.50 J1=5.5 Hz, 1H), 8.78 J1=5.2, lH), 9.52 1H); HPLC ES-MS m/z 479 CId. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3- (triflu oromethyl)phenyl)-N'-(4-amiophelyl) Urea

CF

3 N 'kN H H To a solution of 4-chloro-3-(trifluoromethyl)phenyl isocyanate (2.27 g, 10.3 mmol) in CH 2

CI

2 (308 mL) was added p-phenylenediamnine (3.32 g, 30.7 mmol) in one part. The resulting mixture was stirred at room temp. for I h, treated with CH1 2 C1 2 (100 mL), and concentrated under reduced pressure. The resulting pink solids were dissolved in a mixture of EtOAc (110 mL) and MeOR (1 5mL), and the clear solution was washed with a, 0.05 N HCI solution. The organic layer was WO 00/41698 PCT/USOO/00768 concentrated under reduced pressure to afford impure N-(4-chloro-3- (trifluoromethyl)pheflyl)-N'-(4-amilophenyl) urea (3.3 TLC (100% EtOAc) Rf 0.72.

C1le. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3- (trifluoromethyl)pheny)-N-(4ethoxyCarbollph enyl) Urea

CF

3 0 CI0 O -Et N 'kN H H- To a solution of ethyl 4-isocyanatobenzoate (3.14 g, 16.4 mmol) in CH 2 Cl 2 (30 mL) was added 4-chloro-3-(trifluoromethyl)auiline (3.21 g, 16.4 mmol), and the so lution was stirred at room temp. overnight. The resulting'slurry was diluted with CH 2

CI

2 mL) and filtered to afford N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-( 4 ethoxycarbonylphenyl) urea as a white solid (5.93 g, TLC (40% hexane) Rf 0.44.

CIfL General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of N-(4-Chloro-3- (trifluoromethyl)phenyl)-N-(3-CarboxyphenyI) Urea

CF

3 0 C1 0 0 OH N ,kN H H To a solution of 4-chloro-3-(trifluoromethyl)phelyl isocyanate (1.21g, 5.46 mmol) in CH 2 C1 2 (8 mL) was added 4-(3-carbox yphenoxy)aniline (Method All1; 0.81 g, 5.76 n-mol) and the resulting mixture was stirred at room. temp. overnight, then treated with MeOIH (8 inL), and stirred an additional 2 h. The resulting mixture was concentrated under reduced pressure. The resulting brown solids were triturated with a 1: 1 EtOAc/hexane solution to give N-(4-chloro-3-(trifluoromethyl)phenyl)- N'-(3-carboxyphenyl) urea as an off-white solid (1.21 g, 76%).

WO 00/41698 PCT/USOO/00768 C2a. General Method for Urea Synthesis by Reaction of an Aniline with N,N'-Carbonyl Diimidazole Followed by Addition of a Second Aniline. Synthesis of (trifluoromethyl)phenyl)-N'(4-(2-(N-methylcarbamoyl)4pyridyloxy)phenyl) Urea

CF

3 0 S N 0 NHMe OMe To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH 2 C1 2 mL) at 0 °C was added CDI (0.13 The resulting solution was allowed to warm to room temp. over 1 h, was stirred at room temp. for 16 h, then was treated with 4- (2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 The resulting yellow solution was stirred at room temp. for 72 h, then was treated with H 2 0 (125 mL).

The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organics were washed with a saturated NaCl solution (100 mL), dried (MgSO 4 and concentrated under reduced pressure. The residue was triturated EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc. The filtrate was concentrated under reduced pressure and the residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give (trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl) urea as a light tan solid (Q,098 g, TLC (100% EtOAc) Rf 0.62; 1 H NMR (DMSOd 6 8 2.76 J=4.8 Hz, 3H),-3.96 3H), 7.1-7.6 and 8.4-8.6 11H), 8.75 (d, J=4.8 Hz, 1H), 9.55 1 FAB-MS m/z 461 C2b. General Method for Urea Synthesis by Reaction of an Aniline with N,N'-Carbonyl Diimidazole Followed by Addition of a Second Aniline. Symmetrical Urea's as Side Products of a N,N'- Carbonyl Diimidazole Reaction Procedure. Synthesis of Bis(4-(2- (N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea WO 00/41698 PCT/USOO/00768 0 0 MeHN O O NHMe N N

N

H H To a stirring solution of 3-amino-2-methoxyquinoline (0.14 g) in anhydrous CH 2 Cl 2 mL) at 0 C was added CDI (0.13 The resulting solution was allowed to warm to room temp. over 1 h then was stirred at room temp. for 16 h. The resulting mixture was treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g).

The resulting yellow solution stirred at room temp. for 72 h, then was treated with water (125 mL). The resulting aqueous mixture was extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with a saturated NaCI solution (100 ml), dried (MgSO 4 and concentrated under reduced pressure. The residue was triturated (90% EtOAc/10% hexane). The resulting white solids were collected by filtration and washed with EtOAc to give bis(4-(2-(N-methylcarbamoyl)- 4 pyridyloxy)phenyl) urea (0.081 g, TLC (100% EtOAc) Rf 0.50; 'H NMR (DMSO-d 6 8 2.76 J=5.1 Hz, 6H), 7.1-7.6 (mn, 12H), 8.48 J=5.4 Hz, 1H), 8.75 J=4.8 Hz, 2H), 8.86 2H); HPLC ES-MS m/z 513 C2c. General Method for the Synthesis of Ureas by Reaction of an Isocyanate with an Aniline. Synthesis of (trifluoromethyl)phenyl-N'-(4-(1,3-dioxoisoindolin-5yloxy)phenyl) Urea

CF

3 N N O OMe H H NH 0 To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol) in CH 2 C1 2 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-1,3dione (Method A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then was treated with CH 2 C1 2 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a IN HC1 solution (15 mL) and a WO 00/41698 PCT/USOO/00768 saturated NaCi solution (15 mL), dried (MgSO 4 and concentrated under reduced pressure to afford N-(2-methoxy-5 -(trifluoromethyl)phenyl-N'-(4-( 1,3urea as a white solid (0.2 g, TLC hexane) Rf 0.50; 'H NMR (DMSO-d 6 5 3.95 3H), 7.31-7.10 (in, 6H), 7.57 J=9.3Hz, 2H), 7.80 J=8.7 Hz, 1H), 8.53 (br s, 2H), 9.5 7 IlH), 11.27 (hr s, 1H4); HPLC ES-M .S 472.0 100%).

C2d. General Method for Urea Synthesis by Reaction of an Aniline with NN'-Carbonyl Diimnidazole Followed by Addition of a 10 Second Anilin e. Synthesis of N-(5-(tert-Butyl)-2-(2,5dimethylpyrrolyl)ph enyl)-N '-(4-(2-(N-methylcarbamoyl)-4pyridyloxy)phenyl) Urea 0 S 0 HMe N"U N 01 N H H To a stirring solution of CDI (0.21ig, 1.30 minol) in CH 2 Cl 2 (2 mL) was added (tert-butyl)-2-(2,5-dimethylpyrrolyl)aniline (Method A4, Step 2; 0.30 g, 1.24 minol) in one portion. The resulting mixture was stirred at room temp. for 4 h. then 4-(2- (N-methylcarbamoyl)-4-pyridyloxy)aniline (0.065 g, 0.267mmo1) was then added in one portion. The resulting mixture was heated at 36 00 overnight, then cooled to rom ep.ad iilte it tOc(5 mL). The resultinfg-Inixture was sequentially washed with water (15 mnL) and a 1N HCI solution (l5mL), dried (MgSO4), and filtered through a pad of silica gel (50 g) to afford N-(5-(tert-butyl)-2- '-(4-(2-(N-inethylcarbamoyl)-4-pyridyloxy)phenyl) urea as a yellowish solid (0.033 g, TLC (40% EtOAc/60% hexane) Rf 0.24; 11H NMR (acetone-d 6 8 1.37 9H), 1.89 6H), 2.89 .14.8Hz, 3H), 5.83 (s, 2H),.6.87-7.20 (in, 6H), 7.17 (dd, 11H), 7.51-7.58 (in, 3H), 8.43 Jk5.4Hz, 1H), 8.57 (d,J=2.lHz, 1H), 8.80 (hrs, 1H); HPLC ES-MS 512 100%).

WO 00/41698 PCT/USOO/00768 C3. Combinatorial Method for the Synthesis of Diphenyl Ureas Using Triphosgene One of the anilines to be coupled was dissolved in dichloroethane (0.10 This solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a bis(trichloromethyl) carbonate solution (0.12 M in dichloroethane, 0.2 mL, 0.4 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The vial was capped and heat at 80 'C for 5 h, then allowed to cool to room temp for approximately 10 h. The second aniline was added (0.10 M in dichloroethane, 0.5 mL, 1.0 equiv.), followed by diisopropylethylamine (0.35 M in dichloroethane, 0.2 mL, 1.2 equiv.). The resulting mixture was heated at 80 °C for 4 h, cooled to room temperature and treated with MeOH (0.5 mL). The resulting mixture was concentrated under reduced pressure and the products were purified by reverse phase HPLC.

I

WO 00/41698 PCT/USOO/00768 C4. General Method for Urea Synthesis by Reaction of an Aniline with Phosgene Followed by Addition of a Second Aniline.

Synthesis of N-(2-Methoxy-5-(trifluoromethyl)phenyl)-N'-(4-( 2 (N-methylcarbamoyl)-4-pyridyloxy)phenyl) Urea

CF

3 0 N0 N°NHMe N N OMeH

H

To a stirring solution of phosgene (1.9 M in toluene; 2.07 mL0.21g, 1.30 mmol) in

CH

2 C1 2 (20 mL) at 0 0 C was added anh pyridine (0.32 mL) followed by 2-methoxy- (0.75 The yellow solution was allowed to warm to room temp during which a precipitate formed. The yellow mixture was stirred for 1 h, then concentrated under reduced pressure. The resulting solids were treated with anh toluene (20 mL) followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (prepared as described in Method A2; 0.30 g) and the resulting suspension was heated at 80 °C for 20 h, then allowed to cool to room temp. The resulting mixture was diluted with water (100 mL), then was made basic with a saturated NaHCO 3 solution (2-3 mL). The basic solution was extracted with EtOAc (2 x 250 mL). The organic layers were separately washed with a saturated NaCl solution, combined, dried (MgSO 4 and concentrated under reduced pressure. The resulting pink-brown residue was dissolved in MeOH and absorbed onto SiO 2 (100 Column chromatography (300 g SiO 2 gradient from 1% Et 3 N/33% EtOAc/66% hexane to 1% Et 3 N/99% EtOAc to 1% Et 3 N/20% MeOH/79% EtOAc) followed by concentration under reduced pressure at 45 °C gave a warm concentrated EtOAc solution, which was treated with hexane (10 mL) to slowly form crystals of N-(2methoxy-5-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methylcarbamoyl)-4pyridyloxy)phenyl) urea (0.44 TLC Et 3 N/99% EtOAc) Rf0.40.

WO 00/41 698 PCT/USOO/00768 D. Interconversion of Ureas Dia. Conversion of co-Aminophenyl Ureas into co-(Aroylamino)phenyI Ureas. Synthesis of N-(4-Chloro-3-((triflu oromethyl)phenyl)-N'- (4-(3-methoxycarboflphel)carboxyamin ophenyl) Urea

CF

3

H

CI N Y OMe 0 0 N N H H To a solution of N-(4-chloro-3 -((trifluoromethyl)pheflyl)-N '-(4-aminophenyl) urea (Method Cid; 0.050 g, 1.52 mmol), mnono-methyl isophthalate (0.25 g, 1.38 mrnol),

HOBT-H

2 O (0.41 g, 3.03 mmol) and N-methylmorpholifle (0.33 rnL, 3.03 mmol) in DMF (8 mL) was added EDGI *FICI (0.29 g, 1.52 mmol). The resulting mixture was stirred at room temp. overnight, diluted with EtOAc (25 mnL) and sequentially washed with water (25 mL). and a saturated NaHCO3 solution (25 mL). The organic layer was dried (Na 2

SO

4 and concentrated under reduced pressure. The resulting solids were triturated with an EtOAc solution (80% EtOAc/20% hexane) to -give N- (4-chloro-3-((trifluoromethy1)pheflyl)-N methoxycarbonylphenyl)carboxyaminophenyl) urea (0.27 g, mp 121-122; TLC (80% EtOAc/20% hexane) Rf,-0.75.

Dib. Conversion of co-Carboxyphenyl Ureas into o (Arylcarbamoyl)phel Ureas. Synthesis of N-(4-Chloro-3- ((triflurwomethyl)pheflyl)-N'-( 4 3 methylcarbamoylphelyl)CarbamoyIphenyl) Urea

CF

3 0 CI 0N NHMe N Ne H H To a solution of N-(4-chloro-3-((trifluoromethyl)phenyl)-N methylcarbamoylphenyl) carboxyaminophenyl) urea (0.14 g, 0.48 numol), 3- 25 inethylcarbamoylaniline (0.080 g, 0.53 rnol), HOBT-H 2 O (0.14 g, 1.07 mmol), WO 00/41698 PTUO/06 PCT/USOO/00768 and N-methylmorpholine (.5mL, 1.07 mmol) in DMF (3 mL) at 0 'C was .added EDCI*HCI (0.10 g, 0.53 mmol). The resulting mixtr was allowed to warm to room temp. and was stirred ovemight. The resulting mixture was treated with water (1 OmL), and extracted with EtOAc (25 mL). The organic phase was concentrated under reduced pressure. The resulting yellow solids were dissolved in EtOAc (3 mL) then filtered through a pad of silica gel (17 g, gradient from 70% hexane to 10% MeOH/90% EtOAc) to give N-(4-chloro-3- ((trifluoromethyl)phenyl)-N '-(4-(3-methylcarbamoylphenyl) carbamnoylphenyl) urea As a white solid (0.097 g, 4 mp 225-229; TLC (100% EtOAc) Rf 0.23.

D1ic. Combinatorial Appro ach to the Conversion of cw-Carboxyphenyl Ureas into co-(Arylcarbamoyl)phenyI Ureas. Synthesis of N-(4- Chloro-3-((trifluoromethyl)phenyl) pyridyl)carb amoyl)phenyl)carb amoyt)phenyl) Urea

CF

3 0 H CI

N

0 N 0 N Ne H H A mixture of N-(4-chloro-3J-((trifluoromethyl)pheny1)-N'-(3 -carboxyphenyl) urea (Method C I4f 0.03 0 g, 0.067 mmol) and N-cyclohexyl-N'- (methylpolystyrene)carbodiimide (55 mg) in 1 ,2-dichloroethane (1 m-L) was treated 2 0 with a solution of 3-arninopyridine in CH 2 Cl 2 (1 M; 0.074 mL, 0.074 mmol). (In cases of insolubility orvturbidity, a small amount of DMSO was alsq-alded.) The resulting mixture was heated at 36 0 C overnight. Turbid reactions were then treated with THF (I mL) and heating was continued for 18 h. The resulting mixtures were treated with poly(4-(isocyanatomethyl)styrene) (0.040 g) and the resulting mixture ,was stirred at 36 'C for 72 h, then cooled to room temp. and filtered. The resulting solution was filtered through a plug of silica gel (1 Concentration under reduced pressure afforded N-(4-chloro-3 -((trifluoromethyl)phenyl)-N WO 0/41 698 pCTiUSOO/0O768 pyridyl)carbamoyl)Phelyl)carbamoyl)phenyl) urea (0.024 g, TLC hexane) Rf 0. 12.

D2. Conversion of (o-Carboalkxyaryl Ureas into o-Carbanioylaryl U reas. Synthesis of N-(4-Ch loro-3-((triflIIoromethyI)pheIIyl)-N"- 4 -(3-InethyIearbamoylpheflyl)carboxyamiilophenyI) Urea

CF

3

H

N '0 N NHMe N~N0 0 H H To a sample of N-(4-chloro-3((trfluoromethyl)phenyl)N-( 4 3 carbomethoxypheflyl) carboxyamninopheflyl) urea (0.17 g, 0.34 mmol) was added I0 methylamine (2 M in THE; I rnL, 1.7 nimol) and the resulting mixture was stirred at room temp. overnight, then concentrated under reduced pressure to give N-(4chloro-3-((trifiuoromethy1)phel-N methylcarbamoylPheflYl)carboxYaminophenYl) urea as a white solid: mp 247; TLC (100% EtOAc) R 1 0.35.

D3I Conversion of co-Carboalkoxyaryl Ureas into co-Carboxyaryl Ureas. Synthesis of N-(4-Chloro-3-((trifluoro!UethyI)phenyl)-N' (4-carboxyphely) Urea

CF

3 0 CI 0 OH N Ne H H To a slurry of N-(4-chloro-3-((trifluoromethyl)phenyl)-N-'(4-ethoxycarbonylphe1yl) urea (Method Cle; 5.93 g, 15.3 mmol) in MeOH (75 mL) was added an aqueous KOH solution (2.5 N, 10 mL, 23 rnmol). The resulting mixture was heated at the reflux temp. for 12 h, cooled to room temp., and concentrated under reduced pressure. The residue was diluted with water (50 mL), then treated with a 1 N HCI solution to adjust the pH to 2 to 3. The resulting solids were collected and dried WO 00/41 698 PCTUSOO/00768 under reduced pressure to give N-(4-chloro-3.-((trifluoromethyl)phefl)-N-( 4 carboxyphenyl) urea as a white solid (5.05 g, 92%).

WO 00/41 698 PCT/USOO/00768 D4. General Method for the Conversion of o-Alkoxy Esters into.cD- Alkyl Amides. Synthesis of N-(4-Chloro-3- ((triflu oro methyl)p hen 4 3 5 2 dimethyla min oeth vl)ca rb amoyl)pyridyl)oxyph enyl) Urea

CF

3 0

C

N N N H H Step 1. Synthesis of N-(4-Chloro-3-(trifluoromethyl)pIIenyl)-N'-((4-(3-(5carboxypyridyl) oxyphenyl) Urea N-(4-Chloro-3-(trifluoromethyl)phel)-N -methoxycarbonylpyridyl) oxyphenyl) urea was synthesized from 4-chloro-3-(trifluorome thyl)phenyl isocyanate and .4-(3-(5-methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous to Method Cla. A suspension of N-(4-chloro-3- (trifluoromethyl)phenyl)-N '-((4-(3-(5-methoxycarbonylpyridyl)oxyphelyl) urea (0.26 g, 0.56 mmol) in MeOH (10 mL) was treated with a solution of KOH (0.14 g, mrnol) in water (1 mL) and was stirred at room temp. for 1 h. The resulting mixture was adjusted to pH 5 with a I N HCI solution. The resulting precipitate was removed by filtration and washed with water. The resulting solids were dissolve d in EtOH (10 mL) and the resulting solution was concentrated under reduced pressure. The EtOH/concentration procedure was repeated twice to give N- (4-chloro-3-(trifluoromethyl)phenyl)-N '-((4-(3-(5-carboxypyridyl) oxyphenyl) urea 18 g, 71%)

CF

3 0 N H H H Step 2. Synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-((4-(3-( 5 (2~imehy~minethI~crba~y1pyrdyIO~yhe~l)urea A mixture of N-(4-chloro-3-(trifluoromethyl)phenyl)-N -((4-(3-(5-carboxypyridyl) oxyphenyl) urea (0.050 g, 0.011 mmol), NN-dimethylethylenediamine (0.22 mg, WO 00/41698 PCTIUSOO/00768 0.17 mmol), HOBT (0.028 g, 0.17 mmol), N-methylmorpholine (0.035 g, 0.28 mmol), and EDCI-HCI (0.032 g, 0.17 mmol) in DMF (2.5 mL) was stirred at room temp. overnight. The resulting solution was separated between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (35 mL), dried (MgSO 4 and concentrated under reduced pressure. The residue was dissolved in a minimal amount of CH 2 Cl 2 (approximately 2 mL). The resulting solution was treated with Et 2 O dropwise to give N-(4-chloro-3-(trifluoromet hyl)phenyl)-N dimethylaminoethyl)carbamoyl) pyrfidyl)oxyphenyl) urea as a white precipitate (0.48 g, 84%: 1 H NMR (DMSO-d 6 8 2. 10 s, 6H), 3.26 7.03 2H), 7.52 (d, 2H), 7.60 (in, 3H),.8.05 IH), 8.43 1H), 8.58 1H), 8.69 lH), 8.90 1H), 9.14 1H); HPLC ES-MS m/z 522 General Method for the Deprotection of N-(o- Silyloxyalkyl)amides. Synthesis of N-(4-Chloro-3- ((trill uoromethyl)ph efyl)-N'-( 4 4 2 (NV(2 hydroxy)ethylarbamoyl)pyridyloxypheDyI) Urea.

CF

3 0 C1 0~ 0- r N K 0

OSI

H H To. a solution of N-(4-chloro-3 -((trifluoromethy1)phenyl)-N triisopropylsilyloxy) ethvlcarbamoyl)pyridyloxypheflyl) urea (prepared in a manmer analogous to Method1 Cla; 0.25 g, 0.37 mnmol) in anh THE. (2 mL) was tetrabutylammonium fluoride (1.0 M in THE; 2 mL). The m ixture was stirred at room temperature for 5 min, then was treated with water (10 mL). The aqueous mixture was extracted with EtOAc: (3 x 10 mL). The combined organic layers were dried (MgS 04) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2 gradient from 100% hexane to 40% hexane) to give N-(4-chloro-3-((trifluoroinethyl)phenyl)-N'-(4-(4-(2-(N-(2hydroxy)ethylcarbamoyl) pyridyloxyphenyl) urea as a white solid (0.019 g, WO 00/41698 PCTJUSOO/00768 Listed below are compounds listed in the Tables below which have been synthesized according to the Detailed Experimental Procedures given above: Syntheses of Exemplified Compounds (see Tables for compound characterization) Entry 1: 4-(3-N-Methylcarbamoyiphenoxy)aflilifle was prepared according to Method A13. According to Method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl)carbonate followed by 4-(3 -N-Methylcarb amoylphenoxy)aniline O 1 to afford the urea.

Entry 2: 4.Fluoro-l-nitrobenzene and p-hydroxyacetophelone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-l-litrobelzene.

4-(4-Acetylphenoxy)-l-nitrobenizefe was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)ani lne. According to Method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4acetylphenoxy)aniline to afford the urea.

Entry 3: According to Method C2d, 3-tert-butylaniline was treated with CDJ, followed by 4-3Nmtycraol--ehxpeoyaiie which had been prepared according to Method AS, to afford the urea.

Entry 4: 5-ter-t-Butyl-2-methoxyaniline was converted to ~$rt-buty1-2methoxyphenyl isocyanate according to Method B 1. 4-(3-N- Methylcarbamoylphenoxy)alhline, prepared according to Method A13, was reacted with the isocyanate according to Method Ci1a to afford the urea.

Entry 5: According to Method C2d, 5-tey-t-butyl-2-methoxyanilifle was reacted with CDI followed by 4-(3-N-methylcarbamoyl)-4methoxyphenoxy)aniine, which had' been prepared according to Method A8, to afford the urea.

WO 00/41698 PCTIUSOOIOO768 Entry 6: 5 -(4-Aminophenoxy)i soifdolile- 13 -di one was prepared according to Method A3. According to Method 2d, 5-tert-butyl-2-methoxyaflilifle was reacted with CDl followed by 5-(4-aminophenoxy)isoifldohine-l ,3-dione to afford the urea.

Entry 7: 4-(l-Oxoisoindolin-5-yloxy)anilifle was synthesized according to Method A12. According to Method 2d, 5-tert-butyl-2-methoxyanilifle was reacted with CDI followed by 4-(l-oxoisoindolin-5 -yloxy) anilinle to afford the urea.

io Entry 8: 4-(3-N-Methylcarbamoylphenoxy)aflilifle was synthesized according to Method A13. According to Method C2a, 2-methoxy-5-(trfluoromethy1)an1iine was reacted with CDI followed by 4-(3-N-rnethylcarbamoylphefloxy)afilifle to afford the urea.

Entry 9: 4-Hydroxyacetophelone was reacted with 2-chloro-5-nitropyridine to give 4-(4-acetylphenoxy)-5-flitropyridine according to Method A3, Step 2. According to Method A8, Step 4, 4-(4-acetylpheloxy)-5-flitropyridifle was reduced to 2-Methoxy-5-(triflUioromethyl)5flilifle was converted to 2-rnethoxy-5-(trifluoromethyl)pheflyl isocyanate according to 'Method BI. The isocyanate was reacted with 4-(4-acetylphenoxy)-5-amilopyridine according to Method C Ia to afford the urea.

Entry 10: 4-Fliioro4--nitrobenzefle and p-hydroxyacetophenone~ywere reacted according to Method Al13, Step 1 to afford the 4-(4-acetylphenoxy)-l1-nitrobenzene.

4-(4-Acetylphenoxy)--ni2trobeflzefe was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)anilifle. According to Method C3, 2-methoxybutylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea.

WO 00/41698 PCTIUSOO/00768 Entry 11: 4-Chloro-N-methyl-2-pyridilecarboxamide, which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give rnethylcarbamoy)-4-pyridyloxy)aniline. According to Method C4, (trifluoromethyl)aniline was reacted with phosgene followed by methylcarbamoy)-4-pyridyloxy) aniline to afford the urea.

Entry 12: 4-Chloropyridine-2-carboflyl chloride HCl salt was reacted with ammonia according, to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4io1 ChlOo-2-py-ridinecarboxamide was reacted with 3-aminophenol according to W Method A2, Step 4 using DMAC in place of DMF to give 3-(2-carbamoy]-4pyridyloxy)aniline. According to Method C2a, (trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-carbamoyl-4pyridyloxy)aniline to afford the urea.

Entry 13: 4-hooNmty--yiieabxmd was synthesized according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-amninophenol according to Method A2, Step 4 using DMLAC in place of DMF to give 4-(2-(N-methylcarbamnoyl)-4-pyridyloxy)aniline. According to Method C2a, 2- 20 methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed by 4-(24-Qmethylcarbanoyl) 4-pyridyoxy)anilifle to afford the urea.

Entry 14: 4-Chloropyricline-2-carbonyl chloride HCl salt was reacted wt ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxanmide. 4- Chloro-2-pyridinecarboxamide was reacted with 4-amninophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-carbamoyl-4- Spyridyloxy)aniline. According to Method C4, was reacted with phosgene followed by 4-(2-carbamoyl-4-pyridyloxy)aflilifle to afford the urea.

Entry 15: According to Method C2d, 5-.(trifluoromethYl)-2-.methoxyaniline was reacted with CDI followed by 4-.(3-.N-methylcarbam~oyl)- 4 methoxyphenoxy)arnline, which had been prepared according to Method A8, to afford the urea.

Entry 16: 4-.(2-(N-.Methylcarbamoyl)4-pyridyIoxy- 2 -methylaniline was, synthesized according to Method A5. 5-.(Trifluoromethyl)-2-methoxyaflilifle was converted into 5-(trifiuoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. The isocyanate was reacted with 4-(2-(N-methylcarbanmoyl)-4pyridyloxy)-2-methylaflilne according to Method C I c to afford the urea.

Entry 17: 4-.(2-(N-.Methylcarbamoyl)-4-pyr dyloxy) 2 chloro aniline was synthesized -according to Method A6. 5-.(Trifluoromrethyl)-2-methoxyafliline was converted into 5-.(trifiuoroxnethyl)-.2-.methoxypheflyI isocyanate according to Method B I. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4- (2-.(N-.methycarbamoy)4-pyridyloxy)- 2 -chloroaniline according to Method C Ia to afford the urea.

Entry 18: According to Method- A-1, Step 4, 5-amnino-2-methylphenol was reacted with 4-.chloro-.N-.methyl-.2-pyrdiflecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-.(N-.methyIcarbamoyl)-4-pyrdyloxy)- 4-inethylaniline. 5-(Trifluorornethyl)-.2-.methoxyalliline was converted into (trifluoronethyl)-;-methoxypheflyl isocyanate according to Method B 1. (Trifluoromethyl)-2-nethoxypheflyl isocyanate was reacted wit h rnethylcarbanoyl)-4-pyrdyloxy)-4.methylaniline according to Method Cia to afford the urea.

Entry 19: 4-.Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2pyridinecarboxamide was reacted with 4-arninophenol according to Method A2, WO 00/41698 WO 0041698PCT!USOO/00768 Step 4 to give 4-.(2-(N-ethylcarbamoyl)-4-pyridyloxy)alilifle. 2-methoxyani line was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-.(N-.ethylcarbarnoyl)-4-pyridyloxy)fhlifle according to Method C Ia to afford the urea.

Entry 20: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridYloxy)- 3-chioroaniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method BI. (Tnifluoromethyl)-2-methoxyphenyl isocyanate was reacted with methylcarbamoyl)-4-pyridyloxy)-3-chloroafliline according to Method C1ia to afford the urea.

Entry 21: 4-(4-Methylthiophenoxy)-l1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4-.(4-.methylsulfonylphenoxy)-l-nitrobenzene. The nitrobenizene was reduced according to Method A19, Step 2 to give 4-(4methylsulfonyiphenoxy)- 1 -aniline. According to Method Cia, 2-methoxyphenyl isocyanate was reacted with 4-(4-methylsulfonylphenoxy)-1aniline to afford the urea.

Entry 22: 4-(3-carbarnoylphenoxy)-l-nitrobenzene was reduced to 4-(3carbamnoylphenoxy)aniline according to Method A15, Step 4. Ac'cording-do Method C Ia, 5-(trifluoromethyl)-2 -methoxyphenyl isocyanate was reacted with 4-(3carbamoylphenoxy)aniline to afford the urea.

Entry 23; 5-(4-Aminophenoxy)isoindoline- 1,3-dione was synthesized according to Method A3. 5-(Trifluoromethyl)-2-methoxyaniline was converted into (trifluoromethyl)-2-methoxyphenyl isocyanate .according to Method B 1. WO 00/41698 PTUO/06 PCTIUSOO/00768 (Trifluoromethy])-2-methoxyphenyl isocyanate was reacted with 5-(4aminophenoxy)isoindoline-1,3-dione according to Method Cl a to afford the urea.

Entry 24: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-NN-dimethyl-2pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(NN-dimethylcarbamoyl)-4-pyidy1oxy)alinfe. (Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2methoxyphenyl isocyanate according to Method Bi. 5-(Trifluoromethyl)-2methoxyphenyl isocyanate was reacted with 4-(2-(NN-dimethylcarbamfoyl)-4pyridyloxy) aniline according to Method C Ia to afford the urea.

Entry 25: 1-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. 5-(Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4- (I -oxoisoindolin-5-yloxy)aniline according to Method C2d to afford the urea.

Entry 26: 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenizene was reduced according to Method A13, Step 4 to afford 4-(4acetylphenoxy) aniline, which was converted to the methoxy)iminoethyl)phenoxyaniline HCI salt according* to Method A16. (Trifluoromethyl)-2-methoxyanilinie was converted into _5-(trifluoromethyl)-2methoxyphenyl isocyamate. according to Method Bi. 5-(Trifloomethyl)-2methoxyphenyl isocyanate was reacted with -4l(N methoxy)iminoethyl)phenoxyaniline HCl salt to Method C Ia to afford the urea.

Entry 27: 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A'2, Step 3b. The chioropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give methylearbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was WO 00/41698 PCT[USOOIOO768 converted into 5-(tri fluoromethyl)-2-methoxyphenYl isocyanate accordinga to Method B 1. 5-(Trifluoromethyl)-2-methoxyphelyl isocyanate was reacted with 4.- 2.(N-methylcarbarnoyl)pheflylthio)aflilifle according to Method Cia to afford the urea.

Entry 28: 5 .(4..Aminophenoxy)-2-methylisoifldolifle-1I,3-dione was synthesized according to Method A9. 5..(Trifluoromethyl)-2-methoxyanilifle was converted into 5..(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. (Trifluoromethyl)-2-methoxyphenyl isocy anate was reacted. with 5-(4io aminophenoxy)-2..methylisoifldoline-l, 3 -diofle according to Method Cla to afford the urea.

Entry 29: 4..Chloro..N.methylpyridiflecarboxamide was synthesized as described in Method A2, Step 3b. The chioropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give methylcarbamoyl)phenylthio)anilifle. 5..(Triflu-oromethyl).2methoxyalhlife was converted into 5..(trifluoromethyl).2-methoxyphenyl isocyanate according to Method B 1. 5..(Trifluoromethyl).2methoxyphenyl isocyanate was reacted with 3-I (4.(2-(N-methylcarbamoyl)phenylthio)anilifle according to Method Cla to afford the urea.

Entry 30: 4..Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2pyridinecarboxamide was reacted with 4-aminophenol according to--Method A2, Step 4 to give 4..(2..(N.isopropylcarbamoyI)..4.pyridylo xy)nline. (Trifluoromethyl)-2-methoxyaflilifle was converted into 5-(trifluoromethyl)-2methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2methoxyphenyl isocyanate was reacted with 4..(2-(N-isopropylcarbamoyl)#4 pyridyloxy)aniline according to Method C Ia to afford the urea.

WO 00/41698 PCTIUSOO/00768 Entry 31: 4-(3D-(5-Methoxycarbonyl)pyrldoxy)anilifle was synthesized according t o Method A14. 5-(Trifluoromhethyl)-2-methoxyaflilifle was converted into (trifluoromethyl)-2-methoxyphelYl isocyanate according to Method BI. (Trifluoromethyl)-2-methoxyphelyl isocyanate was reacted with Inethoxycarbonyl)pyidyloxy)aflilifle according to Method CI a to afford the urea.

N-(5-(Trifluoromnethyl)-2-methoxyphenyl)-N'-(4-(3-(5methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4-(2-aminoethyl)xnorpholine to afford the amide according to Method D4, Step 2.

Entry 32: 4-(3-(5-MethoxycarbonyI)pyndyloxy)aflilifle was synthesized according to Method A14. .5-(Trifluoromethyl)-2-methoxyaniline was converted into (trifluor omethyl)-2-methoxyphelyl isocyanate according to Method Bl. (Trifluoromethyl)-2-methoxyphelyl isocyanate was reacted with is methoxycarbonylpyridyloxy)aniline according to Method Cia to afford the urea..

N-(5-(Trifluoromethyl)-2-Ifethoxypheflyl)-N'-(4-(3-(5methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamnine according to Method D4, Step 2 to afford the amide.

Entry 33: 4-(3-(5-Methoxyarbonyl)PYridyloxy)aline was synthesized according to Method A14. 5-(Trifluoronmethyl)-2-flethoxyamnile was converted into (trifluoromethyl)-2-methoxyphenyl isocyanate according to Method El. (Trifluoromethy)-2-methoxyphenyl isocyanate was reacted Xfth according to Method Cia to afford the urea.

-etoyhnl methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with NN-dimethyiethylenediamine according to Method, D4, Step 2 to afford the amide.

WO 00/41 698 PCT/USOO/00768 Entry 34: 4-(3-Carboxyphenoxy)anilifle was synthesized according to Method'Al 1.

-(Tri fluoromethy1)-2 -methoxyali linle was converted into 5-(tri'fluoromethyl)-2methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethy1)-2-methoxyphelyl isocyanate according to Method Cl f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N carboxyphenyl) urea, which was coupled with 3-aminopyridine according to..

Method Di1c.

Entry 35: 4-(3-Carboxyphenoxy)anilifle was synthesized according to Method Al 1.

5-(Trifluoromethyl)-2-methoxyaline was converted into 5-(trifluoromethyl)-2- W methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)a-niline was reacted with 5-(trifluoromethyl)-2-methoxyphenyI isocyanate according to Method Cl f to afford N-(5-(trifluoromethyl)-2-methoxypheflyl)-N'-(3carboxyphenyl) urea, which was coupled with N-(4-fluorophenyl)piperazifle according to Method D Ic.

Entry 36: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All1.

5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2methoxyphenyl, isocyanate according to Method BD1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxypheflyl isocyanate according to Method Ci f to afford N-(5-(trifluoromethy1)-2-methoxyphenyl)WN'-( 3 carboxyphenyl) urea, which was coupled with 4-fluoroaniline according to Method Dic.

Entr y 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method AllI.

5-(Trifluoromethyl)-2 -methoxyani line was converted into 5-(trifluoromethyl)-2methoxyphenyl isocyanate according to Method BI1. 4-(3-Carboxyphenoxy)anilifle was reacted with 5-(trifluoromethyl)-2-methoxypheflyI isocyanate according to Method C If to -afford N-(5-(trifluoromethy1)-2-methoxyphenyl)-N'-(3- WO 00/41698 PTUO/06 PCTIUSOO/00768 carboxyphenyl) urea, which was coupled with 4-(dimethylamino)ani line according to Method D Ic.

Entry 38: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al. 1.

5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-.

methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method Cl f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3carboxyphenyl) urea, which was coupled with 5-amino-2-methoxypyridine according to Method DIec.

Entry 39: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1.

5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(tifluoromethyl)-2methoxyphenyl isocyanate according to Method B 1. 4-(3-Carboxyphenoxy)aniiine was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C If to afford- N-(5-(trifluoromethyl)-2-methoxyphenyl)-N'-(3carboxyphenyl) urea, which was coupled with 4-morpholinoaniline according to Method Di1e.

Entry 40: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1.

5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2inethoxyphenyl isocyanate according to Method B I. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(tifluoromethyl)-2-methoxypheny isocyanate according to Method Cif to afford N-(5-(trifluoromethyi)-2-methoxyphenyl)-N'-(3carboxyphenyl) urea, which was coupled with N-(2-pyridyl)piperazine according to Method DIec.

Entry 41: 4-(3-(N-Methylcarbamoyl)phenoxy)aniline was synthesized according to Method Al13. According to Method C3, 4-chloro-3-(trifluoromethyl)aniline was

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WO 00/41 698 PCT/UJSOO/00768 converted to the isocyanate, then reacted with Methylcarb amoyl)phenoxy)ani linle to afford the urea.

Entry 42: 4-(2-N-Methylcarbamyl-4-pyrdyloxy)alhlifle was synthesized according to Method A2. 4-Chloro-3-(trifluoromethyl)phenyI isocyanate, was reacted with 4-.

(2-N-methylcarbamy1-4-pyridyloxy)ali line according to Method Cia to afford the urea.

Entry 43: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4- WChloro-2-pyridinecarboxamide was reacted with 4-amino phenol according to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method Cia, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacte d with 4-(2carbamoyl-4-pyridyloxy)aniline to afford the urea.

Entry 44: 4-Chloropyridine-2-carbonyl chloride HCI salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-- Chlorp-2-pyridinecarboxamide was reacted with 3-amninophenol according to Method A2, Step 4 to form 3-(2-carbanioyl-4-pyridyloxy)aniline. According to Method Cia, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2carbamoyl-4-pyridyloxy)aniline to afford the urea.

Entry 45: 4-Chloro-N..-methyl-2-pyridinecarboxamide, which w ,sntsie according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(N-methylcarbainoy1)-4-pyridyioxy)aniline.

According to Method Cia, 4-chioro-3-(trifluoromethyi)phenyl isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyoxy)alhline to afford-the urea.

Entry 46: 5-(4-Aminophenoxy)isoindoline-1 ,3-dione was synthesized according to Method A3. According to Method Cia, 4-chloro-3-(trifluoromethyl)phenyI WO 00/41698 PCT/US0010076 8 isocyanate was reacted with 5-( 4 -aminophenoxy)isoindone1, 3 dione to afford the urea.

Entry 47: 4-(2(NMethylcarbamoyU)4pyriyJ/y--mtyailn a synthesized according to Method A5. According to.Method Cl c, 4-chloro-3- (trifluoromethyl)p heyl isocyanate was reacted with aminophenoxy)isoifdoline1, 3 -dione to afford the urea.

Entry 48: 4 3 -N-Methylsulfamoyl)phenyloxy)aniline was synthesized according to Method A15. According to Method Cia, 4 -chloro-3-(trifluoromethyl)phenyI isocyanate was reacted with 4-(3 -N-methylsulfamoy)phenyloxy)aniline to afford the urea.

Entry 49: 4-(2(NMethylcrbamoyl)4prdyfloy)--horaiin a synthesized according to Method A6. According to Method Cia, 4-chloro-3- (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(Nmethylcrbroyl)- 4 pyridyloxy)-2-chloro aniline to afford the urea.

Entry 50: According to Method A2, Step 4, 5-amnino-2-methylphenol was reacted with 4-hooNmty--prdncroaie which had been synthesized according to Method A2, Step 3b, to give 3 -(2-(N-methylcarbamlY)4-pyridyloxy)- 4-methylalhline. According to Method Cla, 4-chioro-3-(trifluoromethyl)phenyI isocyanate was .,reacted with 3 -(2-(N-methylcarbamoyl)}t-yridyloxy- 4 methylaniline to afford the urea.

Entry 51: 4-Chloropyridine-2-CarbOnyl chloride was reacted with ethylanhine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl- 2 pyridinecarboxamnide was reacted with 4-amninophenol according to Method A2, Step 4 to give 4 2 -(Nethylcarbamoyl)4-pyrdyloxy) ailine. According to Method WO 00/41698 PCTIUSOO/0 0 7 68 Cia, 4-chloro-3-(trifluoromfethylDphenyI isocyanate was reacted with ethylcarbamoyl)-4-pyrdyloxy)aniline to afford the urea.

Entry 52: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted with 4 -chloro-N-methyl-2-pyridinecarboxamTide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyrdyloxy)- 3-chioroaniline. According to Method Cia, 4-chloro-3-(trfluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)A4pyrdyloxy)- 3 chioroaniline to afford the urea.

010 KEntry 53: 4 4 -Methylthiophenoxy)lflitrobenzene 'was oxidized according to Method A19, Step I to give 4 4 -methylsulfonylphenoxy)lnitrobentzene. The nitrobenzene was reduced according to Method Al19, Step 2 to give 4-(4methylsulfonylphenoxy)- 1 -aniline. According to Method Cia, 4-chloro-3- (trifluoromethyl)phelyl isocyanate was reacted with 4-(4-methylsulfonllphenoxy)- 1 -aniline to afford the urea.

Entry 54: 4-Bromobenzenesulfoflyl chloride was reacted with methylainine according to Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide.

N-Methyl-4bromobeflzenesulfoniide was coupled with phenol according to 9 Method A15, Step 2 to afford 4 4 -(Nmethylsulfamoyl)phenoxy)benzene. Methylsulfamoyl)pheloxy)benzene was converted into 4(-N inethylsulfamoyl)phe'1oxy)lnitrobenzene according to Method A1. 5,._tep 3. 4-(4- (N-Methylsulfarnoyl)phefo)l-Yitrobenzene was reduced to 4-(4-Nxethylsulfamoyl)phenyIoxy)aniline according to Method A15, Step 4. According to Method Cla, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4- (3-N-methylsulfamoy)pheIyloxy)aniline to afford the urea.

Entry 55: 5-Hydroxy-2-methy1pyridiine was coupled with 1 -fluoro-4-nitrobeflzene according to Meth od A18, Step 1 to give 4 (5-(2-Methyl)pyridyloxy)-l

I

WO 00/41698 WO 0041698PCTJUSOO/00768 nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method Al18, -Step 2 to give methoxycarbonyl)pyridyloxy)- 1 -nitrobenzene. The nitrobenzene was reduced according the Method Al18, Step 3 'to give methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-37.

(trifluoromethyl)phenyl isocyanate according to Method C1ia to afford the urea.

Entry 56: 5-Hydroxy-2-methylpyri dine was coupled with 1 -fluoro-4-nitrobenzene according to Method Al18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-l- 1 nitrobenzene. The methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method Al 8, Step 2 to give methoxycarbonyl)pyridyloxy)-l1-nitrobenzene. The nitrobenzene was reduced according the Method Al 8, Step 3 to give methoxycarbonyl)pyridyloxy)aniline. The aniline was reacted with 4-chloro-3- (trifluoromethyl)phenyl isocyanate according to Method Cia to give N-(4-chloro-3- (trifluoromethyl)phenyl)-N '-(4-(2-(methoxycarbonyl)-5-pyridyloxy)phenyl) urea.

The methyl ester was reacted with methylamine according to Method D2 to afford N-(4-chloro-3 -(trifluoroniethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)-5pyridyloxy)phenyl) urea.

Entry 57: N-(4-Chloro-3-(trifluoromethyl)phenyl-N '-(4-aminophenyl) urea was prepared according to Method Cl d. N-(4-Chloro-3-(trifluoro methyl)phenyl-N'-(4aminophenyl) urea was- coupled with mono-methyl isophthalate..,according to Method DlI a to afford the urea.

Entry 58: N-(4-Chloro-3-(trifluoromethyl)phenyl-N-(4-aminophenyl) urea was prepared according to Method Cld. N-(4-Chloro-3-(trifluoromethyl)phenyl-N-(4-, aminophenyl) urea was coupled with mono-methyl isophithalate according to Method Dl a to afford N-(4-chloro-3-(trifluoromethyl)phenyl-N'-(4-(3methoxycarbonylphenyl)carboxyaminophenyl) urea. According to Method -D2, N- WO 00/41698 PCT/USOO100768 (4-chloro-3-(trifluoromethiyl)phefl-N methoxycarbonylphenyl)carboxyamilophelyl) urea was reacted with methylamine to afford the corresponding methyl amide.

Entry 59: 4-Chloropyridine-2-carbolyl chloride was reacted with dimethylamnine.

according to Method A2, Step 3b. The resulting 4-chloro-NN-dimethyl-2pyridinecarboxamide was reacted -with 4-aminophenol according to Method A2, Step 4 to give 4-2(,Vdmtycraoy)4prdlx)aie 'According to Method Cla, .4-chloro-3-(trifluoromethy)phenyl isocyanate was reacted with 4-(2- (NN-dimethylcarb amoyl)-4-pyridyloxy) aniline to afford the urea.

Entry 60: 4-IHydroxyacetophienone was reacted with 4-fluoronitrobenzene according to Method A 13, Step 1 to give 4-(4-acetylphenoxy)nitrobenzene. The nitrobenzene was reduced according to Method 13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was converted to the 4-(4-(1-(N-methoxy)inlinoethyl) phenoxyaniline HCI salt according to Method Al16. According to Method Cla, 4-chloro-3- (trifluoromethyl)phenyl isocyanate was reacted with 4-(4-acetylphenoxy) aniline toafford the urea.

Entry 61: 4-(3-Carboxyphenoxy)-l -nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-l-nitrobenzene was coupled with 4- (2-aminoethyl)morpholine according to Method A13, Step 3 to give morpholinylethyl)carbamoyl)phenoxy)-l1-nitrobenzene. According t~i, .eod Al13 Step 4, 4-(3-(N-(2-morpholinylethyl)crbanoy)phenoxy) 1 -nitrobenzene was reduced to 4-(3-(N-(2-morpholiflylethyl)carbamoy1)phefloxy)aniline. According to Method Cia, 4-chloro-3-(trifluoromethyl)phenyI isocyanate was reacted with 4-(3- (N-(2-morpholinylethyl)carbamoyl)pheloxy)afliline to afford the urea.

Entry 62: 4-(3-Carboxyphenoxy)-l -nitrobenzene was synthesized according to Method A13,. Step 2. 4-(3-Carboxyphenoxy)-l-nitrobeflzene was coupled with 1- WO 00/41 698 PCTIUSOO/00768 (2-aminoethyl)piperidine according to Method A13, S tep 3 to. give piperidylethyl)carbanoyl)pheloxy)- 1 -nitrobenzene. According to Method Al13 Step 4, 4-(3-(N-(2-piperidylethyl)carbamoy1)pheloxy)- 1-nitrobenzene was reduced to 4-(3-(N-(2-pi.peridylethy1)Carbamoyl)pheloxy)afliline. According to Method Cia, 4-chloro-3-(trifluoromethyl)Phelyl isocyanate was reacted with piperidylethyl)carb amoyl)phenoxy) anilinle to afford the urea..

Entry 63: 4-(3-Carboxyphenoxy)-1-flitrobenzefle was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-flitrobeflzefe was coupled with tetrahydrofurfurylainlife according to -Method A13, Step 3 to give W (tetrahydrofurylmethyl)carbamoYl)pheloxy)-l1-nitrobenzene. According to Method Al13 Step 4, 4-(3-(N-(tetrahydrofurylmethyl)carbamnoyl)pheloxy)- 1 -nitrobenzene was reduced to 4-(3 -(N-(tetrahydrofurylmethy)carbamoyl)Pheloxy)ailine.

According to Method Cia, 4-chloro-3-(trifluoromethy)phelyl isocyanate was reacted with 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl) phenoxy)aniline to afford the urea.

Entry 64: 4-(3-Carboxyphenoxy)-1 -nitrobenzene was synthesized, according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-litrobelzene was coupled with 2aminomethyl-l-ethylpyrrolidifle according to Method A13, Step 3 to give -methylpyrrolidinyl)methyl)carbanoy)Phenoxy)-l1-nitrobenzene. According to Method Al13 Step 4, methylpyrrolidiny1)methyl)carbamoyl)pheloxy)-l nitrobenzene w--as reduced to 4(-N(I methylpyrrolidinyl)methyl)carbamoyl)pheIoxy)aniline. According to Method Cia, 4-.chloro-3-(trifluoromethyl)phelyl isocyanate was reacted with methylpyrrolidinyl)methyl)carbamoyl)phenoxy)anilifle to afford the urea.

Entry 65: 4-Chloro-N-methylpyridinecarboxamnide was synthesized as described in Method A2, Step 3b. The chioropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give WO 00/41698 PCTIUSOO/00768 methylcarbamoyl)phelylthio)ani line. According to Method Cia, 4-chloro-3- (trifluoromethyl)phelyl isocyanate was reacted with methylcarbamoyl)pheflylthio)afliline to afford the urea.

Entr 66: 4-Chloropyridile-2-carboflyl chloride was reacted with isoprop ylane according to Method A2, Step 3b, The resulting 4-chloro-N-isopropyI- 2 pyridinecarboxamide was reacted with 4-aminopheflol according to Method A2, Step 4 to give 4-2(-spoycraol--yiyoyaiie According to Method Cla, 4-chloro-3-(trifluoromfethyl)phenyI isocyanate was reacted with 4-(2- 9 10 (N-isopropylcarb amoyl)-4-pyridyloxy) iline to afford the urea.

Entry 67: N-(4-Chloro-3 -(trifluoromethyl)pheflyl-N-'(4-ethoxycarbonylphelyl) urea was synthesized according to Method Cl e. N-(4-Chloro-3 (trifluoromethyl)phelYl-N '-(4-ethoxycarbonylphe1yl) urea was saponified according to Method D3 to give N-(4-chloro-3-(trfluoromethyl)pheflyl-N'-l4 ~carboxyphenyl) urea. N-(4-Chioro-3 -(trifluoromethyl)pheflyl-N'-(4-carboxypheflyl) urea was coupled with 3-methylcarbamoylaflilifle according to Method DIb to give N-(4-chloro.-3-(trifluoromethyl)phenyl-N methylcarbamoylphelyl)c arbamnoylPhenyl) urea.

Entry 68: 5-(4-Aminophenoxy)-2-methylisoindoline- 1,3-dione was synthesized according to Method A9. According to Method Cia, 4-chloro-3- (trifluoromethyl)pheflyl ,.,isocyanate was reacted with 5-4a~_Whnx)2 methylisoindoline-I ,3-dione to afford the urea.

Entry 69: 4-Chloro-N-methylpyridifecarboxamide was synthesized as described in Method A2, Step 3b The chioropyridine was reacted with 3-aminothiophellol according to Method A2, Step 4 to give methylcarbamoyl)phenylthio)aluline. According to Method Cia, 4-chloro-3- WO 00/41698 PCTIUSOO/00768 (trifluoromethyl)phenyl isocyanate was react ed with methylcarbamoylphelylthio)aflilifle to afford the urea.

Entry ,70: 4-2(-2Mrhln4yehlcraolprdlx~nln was synthesized according to Method AlO. According to Method Cia, 4-chloro-3- (trifluoromethyl)phenYl isocyanate was reacted with 4-(2-(N-(2-morpholin-4ylethyl)carbamoyl)pYridyloxy)aflilifle.to afford the urea.

Entry 71: 4-(3-(5-Methoxycarbolyl)pyrldYoxy)anilifle was synthesized. according to Method A14. 4-Chloro-3-(trifluoromethyl)-2methoxyphenyI isocyanate was W reacted with 4-(3-(5-methoxycarbolyl)pyrdyloX.y)allifle according to Method Cia to afford the urea. N-(4-Chloro-3-(t rifluoromethy1)phenyl)-N methoxycarbonylpyridyl) oxy)phenyl) urea was saponified according to MethodD4 Step 1, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide.

Entry 72: 4-(3-(5-Methoxycarbolyl)pyridyloxy)aniline was synthesized according* to Method A14. 4-Chloro-3-(trifluoromethy1)phelyl isocyanate was reacted with 4according to Method C Ia to afford. the urea. N-(5-(Trifluoromethyl)-2-methoxyphenl)-N 4 3 9 methoxycarbonylpyridyl)oxy)Phelyl) urea, was saponified according to Method D4, Step 1, and the corresponding acid was coupled with rhethylainine according to Method D4, Step 2 toafford the amide.

Entry 73: 4-(3-(5-Methoxycarbonyl)pyrdyloxy)alhlifle was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyI isocyanate was reacted with 4according to Method Cia to afford the urea. N-(5 -(Trifiuoromethyl)-2-methoxyphenyl)-N methoxycarbonylpyridyl)oxy)phelyl) urea was saponified according to Method D4,

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WO 00/41698 PCT/USOO/00768 Step 1, and the corresponding acid was coupled with N, N-dimethylethylenediamine according to Method D4, Step 2 to afford the amide.

Entry 74: 4-Chloropyridine-2-carbolyl chloride HC] salt was reacted with 2hydroxyethylamine according to Method A2, Step 3b to form 4.-chloro-N-(2triisopropylsilyloxy)ethylpyridine-2carboxamide. 4-Chloro-N-(2.triisopropylsilyloxy)ethylpyridie2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form (2-triisopropylsilylo:y)ethylcarbamoyl)pyridyloxyaniline. According to Method Cia, 4-chloro-3-(trifluoromethyl)Phenyl isocyanate was reacted with Vtriisopropylsilylox y)ethylcarbamoyl) pyridyloxyaniline to afford N-(4-chloro-3- ((trifluoromethyl)phenyl)-N '-(4-(4-(2-(N-(2-triisopropylsilyloXY) ethylcarbamoyl)pyridyloxyphelyl) urea.

Entry 75: 4-(3-Carboxyphenoxy)anilifle was synthesized according to Method Al 1.

4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with methoxycarbonyl)pyridyloxy)aniline according to Method Cif to afford the urea, which was coupled with 3-aminopyridine according to Method D Ic.

Entry 76: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All1.

4-Chloro-3-(trifluoromethyl)pheflyl isocyanate was reacted with 4-(3carboxyphenoxy)aniline according to Method Cif to afford the urea, which was coupled with N-(4-ap.ktylphenyl)piperazine according to Method DlI c.

Entry 77: 4-(3-Carboxyphenoxy)anilifle was synthesized according to Method Al 1.

4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3carboxyphenoxy)aniline according to Method Cif to afford the urea, which was coupled with 4-fluoroaniline according to Method DlI c.

WO 00/41698 PCT/US00/00768 Entry 78: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All.

4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 4-(dimethylamino)aniline according to Method Dic.

Entry 79: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method All1.

4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N-phenylethylenediamine according to Method Dic.

Entry 80: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1.

4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 2-methoxyethylamine according to Method D1 c.

Entry 81: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al l.

4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with 5-amino-2-methoxypyridine according to Method Dlc.

Entry 82: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1.

4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3carboxyphenoxy)aniline ,according to Method Clf to afford the urt, which was coupled with 4-morpholinoaniline according to Method Dlc.

Entry 83: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method Al 1.

4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3carboxyphenoxy)aniline according to Method Clf to afford the urea, which was coupled with N-(2-pyridyl)piperazine according to Method Dlc.

WO 00/41698 PCT/USOO/007 6 8 Entry 84: 4-Chloropyridine-2-carboflyl chloride HCl salt was reacted with 2hydroxyethylamnife according to Method A2, Step 3b to formn 4-chloro-N-(2triisopropylsilyloxy)ethylpyridife2carboxamide. 4-Chloro-N-(2trisopropysilyloxy)ethylpyridie2caboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method Al17 to form 2 -triisopropylsilyloxy)ethylcarbamoylDpyridyloxyaniline. According to Method C1ia, 4-chloro-3-(trifluoromethyl)pheflyI isocyanate was reacted with triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline to give N-(4-chloro-3- ((trifluoromethyl)phenyl)-N -4(-2(-2trlorpliyox~tycrao pyridyloxyphenyl) urea. The urea was deprotected according to.Method D5 to afford N-(4-chloro-3-((trifluoromethyl)phenyl).N hydroxy)ethylcarbamoyl)pyridyloxyphenyl) urea.

Entry 85: 4-2(-ehlabmy)4prdlx~nln was synthesized according to Method A2. 4-Bromo-3-(trifluoromethyl)arnline was converted to 4bromo-3-(trifluoromethyl)pheflyl isocyanate according to Method B 1. According to Method Cla, 4-bromo-3-(trifluoromnethyI)phelyI isocyanate was reacted with 4-(2- (N-methylcarbamoyl)-4-pyridyloxy) aniline to afford the urea.

Entry 86: 4-2(-ehlabmy)4pyiyoy--hoonln was synthesized according to Method A6. 4-Bromo-3-(trifluoromethyl)afliline was converted into 4- bromo-3-(trifluoromethyl)phenyI isocyanate according to Method BI. According to Method Cla, 4-rm--tilooehy~hnlA~ynt was reacted with 4-2(-etycraoy)4prdyloxy)-2-chloroaniline to afford the urea.

Entry 87: According to Method A2, Step 4, 4-amino-2-chl orophenol was reacted with 4-hooNmty--yiieabx'ie which had been synthesized according to Method A2, Step 3b, to give 4-2(-ehlabmy)4prdlx) 3-chioroaniline. 4-Bromo-3-(trifluoromethy1)afline was converted into 4-bromo-3- WO 00/41698 PcTIUSOO/00768 (trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method Cia, 4-bromo-3-(trifluoromethy)phelyl isocyanate was reacted with methylcarbamoyl)-4-pyldyloxy)- 3 -chioroani line to afford the urea.

Entry 8 8: 4-Chloropyridine-2-carboflyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2pyridinecarboxamide was reacted with 4-aminophenol according to Method A-7, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)anilifle. 4-Bromo-3- (trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl ft 1 isocyanate according to Method BI1. According to Method Cia, 4-bromo-3- W (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)- 4 pyridyloxy)ani line to afford the urea.

Entry 8 9: 4-hooNmty--prdncroaie which was synthesized according to Method A2, Step 3a, was reacted with 3-amninophenol. according to Method A2, Step 4 to form 3-(-2-(N-methylcarbamoyI)-4-pyridyloxy)aniline. 4- Bromo-3-(trifluoromethyl)afliline was converted into 4-bromo-3- (trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method Cia, 4-bromo-3-(trifluoronethyl)phenyl isocyanate was reacted with methylcarbamoyl)-4-pyri dyloxy)anilifle to afford the urea.

Entry 90: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-hooNmthl2prdncroaie which had .bee -syntesized according to Method A2, Step 3b, to give 3-2(-ehlabmy)4prdlx) 4-methylaniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo- 3-(trifluoromethyl)phenyl isocyanate according to Method B 1. According to Method Cia, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2- (Nmtycraol--yidlx)4mtyaiiet afford the urea.

WO 00/41698 PCT/USOO/00768 Entry 91: 4-Chloropyridine-2-carboflyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-NN-dimethy1-2pyridinecarboxamide was reacted with 4-amninophenol according to Method A2, Step 4 to give 4-2(Ndmtycraol--yiyoyaiie 4-Bromo-3- (tri fluoromethyl)ani linle was converted into 4-bromo-3-(trifluoromethyl)phenyI isocyanate according to Method BE1 According to Method Cia, 4-bromo-3- (trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(NN-dimethylcarbamoyl).

4-pyridyloxy)aniline to afford the urea.

10 Entry 92: 4-Chloro-N-methylpyn'dinecarboxamide was synthesized as described in Method A2, Step 3b. The chioropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give methylcarbamoyl)phenylthio)afliline. 4-Bromo-3-(trifluoromethyl)anilifle was converted into 4-bromo-3-(trifluoromethyl)phelyI isocyanate according to Method, Bi. According to Method Cla, 4-bromo-3-(trifluoromethyl)phenyI isocyanate was reacted with 4-(4-(2-(Nmethylcarbamoyl)phenylthio)alhline to afford the urea.

Entry 93: 4-Chloro-]N-methylpyridiflecarboxamide was synthesized as described in Method A2, Step 3b. The chioropyridine was reacted. with 3-aminothiophenol according to Method A2, Step 4 to give 9methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate. according to Method Bi. According to-Method Cia,4-rm--tilooehlpe~l, ynt was reacted with 3-(4-(2-(Nmethylcarbamnoyl)pheflylthio)anilile to afford the urea.

Entry 94: 4-2(-2Mrhln4yehlcraolpndlx~nln was synthesized according to Method A10. 4-Bromo-3-(trifluoromethyl) aniline was converted into 4-bromo-73-(trifluoromethyl)phenyl isocyanate according to Method Bi. According to Method Cia, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was WO 00/41698 PCT/USOO/00768 reacted With 4-(2 -(-2Mrh i--lt lcabmy~yiyoy nln to afford the urea.

Entry 95: 4-2(-ehlabmy)4prdlx~nln was synthesized according to Method A2. 4-hoo2mtoy5(rfurmty~nln was synthesized according to Method A7. 4-Chloro-2-methoxy-5- (trifluoromethyl)anilifle was converted into 4-chloro-2-methoxy-S- (trifluoromethyl)phenyl isocyanate according to Method BI1. According to Method Cia, 4-hoo2mtoy5(tilooehlpey isocyanate was reacted with 4- (2-(N-methylcarbamoy1)-4-pyridyloxy)afliline to afford the urea.

Entry 96: 4-2(-ehlabmy)4pyiyoy--hoonln was synthesized according to Method A6. 4-Chloro-2-methoxy-5- S(trifluoromethyl)aniline was synthesized according to Method AT 4-Chloro-2methoxy-5-(trifluoromethyl)aflhline was converted into 4-chloro-2-methoxy-5- (trifluoromethyl)phenyl isocyanate according to Method BL1 According to Method Cia, 4-hoo2mtoy5(tilooehlpey isocyanate was reacted with 4- (2(-ehlabrol--yiyoy--hoonln afford the urea.

Entry 97: According to Method A2, Step 4, 4-amino-2-chlorophenol was reacted 9with 4-hooNmty--prdncroaie which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N-methylcarbamoy)-4-pyrdyloxy)- 3-chloroaniline. 4-C-~oo2mtoy5(rfurmty~nln w.,;s4synthesized according to Method A7. 4-hoo2mtoy5(rfurmty~nln was converted into 4-hoo2mtoy5(rfuriehlpey isocyanate according to Method Bi. According to Method Cia, 4-chloro-2-methoxy- 5 (trifluoromethyl)phenyl isocyanate 'was reacted with 4-(2-(N-methylcarbamoyl)- 4 pyridyloxy)-3-chloroaniline to afford the urea.

WO 00/41698 PCT/IJSOO/00768 Entry 98: 4-hooNmty--prdncroaie which was synthesized according to Method A2, Step 3a, was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(-2-(N-methylcarbamoyI)-4-pyidyloxy)afliline. 4- Chloro-2-methoxy- 5 (trifluoromethylani line was synthesized according to Method A7. 4-hoo2-ehx- (r looehl nln was converted into 4-chloro-2,isocyanate according to Method Bi1. According to Method Cia, 4-hoo2mtoy5(tilooehlpey isocyanate as was reacted with 3 2-N ehlabmyl--yiyoyailn to afford the urea.

Entry 99: 4-Chloropyridine-2-carboflyl chloride was reacted with ethylarmine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-2(-tycraol-4prdlx)aiie 4-Chloro-2-methoxywas synthesized according to Method A7. 4-Chloro-2methoxy-5-(trifluoromiethyl)aniline was converted into 4-chloro-2-methoxy-5- (trifluoromethyl)pheflyl isocyanate according to Method B 1. According to Method Cla, 4-hoo2mtoy5(tilooehlpey isocyanate was reacted with 4- (2-(N-ethylcarbamoyl)-4-pyridyloxy)anilifle to afford the urea.

Entry 100: 4-Chloropyridine-2-carboflyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-NN-diniethyl- 2 pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give -iehlabmy)4prdlx~nl~,.,-hoo2 was synthesized according to Method A7. 4- Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2methoxy-5-(trifluoromethy1)phenyl isocyanate according to Method B 1. According to Method Cla, 4-hoo2mtoy5(tilooehlpey isocyanate was reacted with 4-2(Ndmtycraoy)4prdlx~nln to afford the urea.

Entry 10 1: 2-According to Method C3, 2-amino-3-methoxynaphthalene was reacted with bis(trichloromethyl) carbonate followed by an aniline to form the urea.

Entry 102: 4-(2-(NMethylcrbamoyI)-4-pyridyloxy)aniline was synthesized io -according to Method A2. 5-tert-Butyl-2-(2,5-dimethylpyrro1yl)alhlife .was synthesized according to Method A4. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)anilifle was reacted with -CDI followed by 4-(2-(N-mcthylcarbamoyl)-4-pydyoxy)afliline according to Method C2d to afford the urea.

Entry 103: 4-hooNmty--yiieabxmd was synthesized according to Method A2, Step 3b. 4-Chloro-iN-methyl-2-pyridinecarboxamnide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMIF to give 4-2(-ehlabmy)4prdyoyaiie According to Method C2b, reaction of 3-amino-2-methoxyquilolie with .CDI followed by rnethylcarbamoyl)-4-pyfldyloxy)aniline afforded bis(4-(2-(N-methylcarbamloyl)-4 pyridlyoxy)phenyl)urea.

Tables The compounds listed in Tables 1-6 below were synthesized according to the general methods shown above, and the more detailed exemplary procedures are in the entry listings above and characterizations are indicated in the tables.

Table 1. 3-tert-Butylpheflyl Ureas PCT/USOO/00768 WO 00/41698 TLC Mass mp HPLC TLC Solvent Spec. Synith.

nryRj('C) (min) Rf System [Source] Method Enr -R 1 0 0.22 50% 418 A13 N.H EtOAc C3 Me /50% (HPLC Shexane

ES-MS)

2 o0.58 50% 403 A13 0 EtOAc C3 Me /50% (IHPLC hexane EIS-MS) 3 0 133- 0.68 100% 448

AS

N.H 135 EtOAc C2d Me

(FAB)

e Table 2. 5-tert-ButyI-2-meth0xyph enyl Ureas TLC Miassmp, HPLC TL Solvent Spec. Synth.

Entry R (OC) C Rf Systemil-Pource] Method 4 0 5.93 1448 A13 N.H B1 Me (HPLC Cla -0 0- 0120- 0.67 100% 478 A8 N.H 122 EtOAc C2d e (FAB) 0C OMe PCTIUSOO/00768 WO 00/41698 0.40 50% 460 A3 EtOAc C2d

(HPLC

hexane ES-MS) 0.79 50% 446 A12 EtOAc C2d

(HPLC

hexane ES-MS) PCTIUSOO/00768 WO 00/41698 Table 3.

5-(TrifluoromethIl)-2-flethoxvphenYI Ureas FF F 0 RN

N

H H e Entry mp 0 0~

HPLC

(min.)

TLC

TLC

Solvent System Mass Spec.

[Source] Synth.

Method

S

91 12

R

0 N *H Me \N 0 0 Me 0e O-eMe 0 eNH2

INH

250 (dec) 206- 208

(FAB)

0.54 06.33 0.20 0.27 46 f /1 MeOH/ CH2CI2 5T 0%.

EtOAc! pet ether 2% Et3NI 98% EtOAc

TO%

Et3NI 99% EtOAc-,- 100% EtOAc 1% Et3N/ 99%, EtOAc

?HPLC

ES-MS)

445

(HPLC

461

(HPLC

ES-MS)

47

(HPLC

ES-MS)

461

(FAB)

C2a A3 step AS step 4,

BI,

A13 C3 A2 C4 C4 7 A2 C2a 0 6 13

N.H

-e Me 00

N,

0 114-

NH

2 117 07 \N 0.40 447 A2 C4

(FAB)

WO 00/41 698 PCT/USOO/00 768 16 17

S

0 N 'H Me 0--&OMe 0 Me

N.H

D-0-e Me .0 cl

NH

Me O- lN 0 .0 /N 0

NH

Et 0 cI

NH

Me

C\N

232- 23 5 210- 213 187- 188 0.54 0.29 0.17 0O.48 1000%1 EtOAc 5% MeGH! 45% EtOAc! pet ether 50% EtOAc! 50% pet ether 100% EtOAc 490

(FAB)

475 (1-PLC

ES-MS)

495 tA6 18 19

(HPLC

ES-MS)

475

(HPLC

ES-MS)

AS

C2cl B I CIc A2 step 4,

BI

Cla Cla I .L r 194- 196 214- 216 0.25 0.30 0.30 0 .50 0 211 *1 Me 208- 210 188- 190 MeOH/ 45% EtOAc! pet ether 5% MeGH/ 45% EtOAc! pet ether 50% EtOAc/ 50% hexane 70% EtOAc! hexane 70% EtOAc! 30% hexane

(HPLC

ES-MS)

495

(HPLC

ES-MS)

481-

ILC

ES-MS)

447

(HPLC

IES-MS)

Cia A2 Cla Al19 C2a Al step 4,' Cla A3 B I Cla 221 0

NH

2 .23 0\ 0

NH

0 WO 00/41'698 PCT/USOO/00768 24 0 Me 02o

NH

26 MeO

N

27 0

NH

Me 0 S- elN 203- 205

S

169- 171 218- 219 212-, 214 0.13 0.09 0.67 0.40 0.30 0O.33 75% EtOAc! 25% hexane 50% EtOAc! pet ether 50% EtOAc! 50% pet ether 40% EtOAc! 60% hexane 50% EtOAc! 50% pet ether EtOAc 100% 479

(HPLC

ES-MS)

458 (H7PLC

ES-MS)

474

(HPLC

ES-MS)

477

(HPLC

iES-MS) AX2

BI

Cla A12 C2d A13 step I, A13 step 4, A16,

BI

Cia A2 step 3b, A2 step 4,

BI,

Cia A9

BI

Cia A2 step 3b, A2 step 4,

BI,

Cla A2 B I Cia A14

BI

Cia D4 28 0' NMe 0 I I I 0

NH

Me S-e 474 (M-iH)+

(HPLC

ES-MS)

0

NH

0 -N Pr-i 2 1 0- 211 31 0

NH

NN

N -0 210- 204 0.43 10% MeOHI/ CH2C12

I

PCT/USOO/00768 WO 00/41 698 r 1 T I 10% 32 33 247- 249 1 0.57 MeGH! CH2CI2 A14

BI

Cla D4 1* 0.07 A14

-&I

NH

N-Me 217- 219 0.07 10% MeOH/ CH2Cl2

BI

C11 a D4 0.11 70% All -NH EtOAc!

BI

70%an All 'No 0.38 EtOAc! hex ane

BI

Cif Dic

N

N

0 36 F H0.77 70% All F NHEtOAc/

BI

Cif Shexane Dic 37 Me\ 0.58 70% All /N NH EtOAc/ B I me -0 30% Cif IN~,hexane Dic 38 N~ 0.58 70% All MeG ,N NH EtOAc!

BI

0 30% Cif a hexane D Ic 39 0.17 70% All 0 NH EtOAc! B I 030% CIf.

hexane Dic pCTIUSOO/00768 WO 00/41698 Table 4.

3-(Trifluoro methvl)-4-chloropheflyl Ureas

F

F F 0

RK

N N H H

TLC

Solvent System M- ass Spec. Snh [Source] Mto Synth.

Method *1* A13 EtOAc/ pet ether EtOAcI pet ether EtOAc! pet ether EtOAa&, pet ether EtOAc/ pet ether EtOAc/ hexane 464 (1{PLC

ES-MS)

465

(HPLC

ES-MS)

451

(HPLC

ES-MS)

451

(HPLC

ES-MS)

(HPLC

ES-MS)

476

(FAB)

C3 A2 -Cla A2 C.1a A2 Cla Ci a A3 Cla WO 00/41698 WO 0041698PCTIUSOO/00768

S

47 0 0.29 5% 478 Me N.H MeOH/ Cic Me 45% (HPLC N EtOAc/ ES-MS) 50% pet etherA 48 o.P206- ~S-N.H 209 Cia Me 49 0 147- 0.22 50% 499 A6 NI NH 151 iEtOAcI- Cia Me 50% pet (HPLC e \N ether ES-MS) 50 0 0.54 100% 479 A2 ~Me N.H EtOAc C Ia Me (HPLC 0\N ES-MS) 51 0 187- 0.33 5% 479 A2 N H 189 MeGH/ Cla Et 45% (K-PLC 1 NEtOAc!

ES-MS)

pet ether 52 0 219 0.18 5% 499 A2 CI N *H MeOHI Cia -e N me 45% (HPLC ,,NEtOAc!

ES-MS)

pet ______ether 53 -0246- 0.30 50% 485 A19, /248 EtOAc/ Cla Me 50% ,,.(HPLC hexane 54 196- 0.30 70% 502 0 o 200 -EtOAc/ Cla NH 30%

(HPLC

Me hexane) ES-MS) 0 228- 0.30 30% 466 0 230 EtOAc! Me 70% (HPLC 1 lN CH2C12 ES-MS) WO 00/41698 pCT/USOO/00768 56 57 58 59 N 0

NH

Me 0 0 H 0 -Me 0

N.H

H 0 Me

NI-N

0 Me

N

Me0O

N

&O C Me 238- 245 221- 222 0.75, 80% EtOAc/ 20% hexane 492

(FAB)

Cid Dla 1 O I 247 19-8- 200 158- 160 0.35 To-09 EtOAc 100%/1 EtOAc EtOAc! pet ether 479

(HPLC

ES-MS)

Dia D2 A2 Cia 0.64 i i .L I 0 62 0 0 195- 197 170- 172 0.39 0.52

I

10% MeOH/ CH2CI 2 10% MeOH/ CH2CI 2

NH

(D

0l A13 Cia A13 Cia A13 Cla A 1* 03 10% NH 0 171106- 1 I 10.35 NH N 0- 176- 177 i 1 0.35 MeOHI CH-2C1, 2 f 1 MeOH/ CH-2C1, 2

I

-4 i--f t A2 0

N.H

Me

S-N

130- 133 487

(HPLC

ES-MS)

I

BI

Cia t WO 0041698PCTIUSOO/00768 66 67 68 69 71 0

NH

Pr-i 0 N 0

NH

$H Me N-NLe 0

NH

Me 0

-NH

*0 \N N 00

NH

N

N

0

NH

-a Me

NH

0 N-M/ N Me I I 225- 229 234- 236 0.29 0.48 0.46 100% Et7OAc 40% EtOAc/ hexane 50% EtOAc! 50% pet ether 5% MeOH/ 95% CH2CI2 10% MeOH/ CH2CI 2 10% MeOH/ CH2CI 2 50% MeOH/A CH2CI 2 155 481

(HPLC

ES-MS)

564

(HPLC

ES-MS)

A2 Cia Cle D3 Dib A9 Cla

S

199- 201 235- 237 145- 148 0.55 0.21 -10.50 Al 0 Cla A14 Cia D4 A14, Cia D4 A14 Cia D4 73 0

NH

/OSi(Pr-i) 3

N

L-

PCT/USOO/00768 WO 00/41698 mm~. 1~ VT IUYo

I

I1I 1

N

NH

00

I

IU.IL'

EtOAc/ hexane

(HPLC

ES-MS)

Cif Dic I T All 76 0 Me- No

N

0 I 1 10-18 1 70% EtOAc! hex ane Dic 77 0.74 70% All F77 F NH EtOAcI Cif, 030% Dic 0, hexane 78 Me, 0.58 70% All 'N "NH EtOAc/ Cif Me -030% DIc 0 hexane 79 0 0.47 70% 569 All NH EtOAc! Cif (HPLC Dic 0 /NH hexane ES-MS) 0 0.18 70% 508 All ~NH EtOAc/,,. Cl f Q\ 30% (HJPLC Dic /OMe hexane 81 N 0.58 70% 557 All MeO /\NH EtOAc/ Cif 030% (HPLC Dic o:exane

ES-MS)

WO 00/41698 PCTLJSOOIOO768 82 0 N&

NH

0 83

N

N

0 0 -1 84 0 N 0 e\N OH 06.37 0.19 7 0%/ EtOAc/ hexane 70% EtOAc! 30% hexane 611

(HPLC

ES-MS)

All Cif Dic All Ci f Dic A2 A17 Cia 179- Table 5.

3-(Trifluoromethyl)-4-bromophenyI Ureas FF F ~Br RN

N

H .H ~Enfty-R_

HPLC

mp

TLC

TLC

Solvent System Mass Spec.

[Source] Synth.

Method (O509 851 0 N H -e Me

N

186-1 0.13 0.31 50% EtOAc! 50% pet ether 50% EtOAc/ 50% pet ether

(IIPLC

ES-MS)

545

(HIPLC

ES-MS)

A2 B I Cia A6 B I Cla 86 0 150- IN.H 152 0 Me pCTIUSOO/00768 WO 00/41698 0 CI N H Me

\N

217- 219 0.16 50% EtOAc/ 50% pet ether 545

(HPLC

ES-MS)

A2

BI

ICla 88 0 183- 0.31. 50% 525 A2 N 'H 184 EtOAc! B I 0- Et 50% pet (HPLC Cla Nether

ES-MS)

89 0 0.21 50% 511 A2 NH EtOAc! B 1 'Me 50% pet (HPLC Cia o- N ether ES-MS) 0 0.28 50% 525 A2 ~M e N H EtOAc! B 1 Me 50% pet (HPLC Cia 0 N ether 91 0 'Me 214- 0.28 50% 522 A2 N. 216 EtOAc! BI 0 Me 50% pet (HPLC Cia e ether 92 0 0.47 50% 527 A2 step -N.H EtOAc! 3b, Me 50% pet (HPLC A2 step e\ N ether ES-MS) 4,

BI,

Cla 93 0 0.46 50% 527 A2 step N H EtOAc! 3b, me 50%/opet (HPLC A2 step S /Nether ES-MS) 4, Bi, Cla 94 4.145- 0.41 5

AIO

NH 150 MeOH-/ BI \95% Cia -&OeN CH2CI2 WO 00/41698 WO 0041698PCTIUSOO/00768 Table 6.

lireas 5-(Trifluoromethy'l)-4-chloro-2-methoxypheflyI

F

F F 0

C

RN N H H OMe TLC Mass mp HPLC TLC Solvent Spec. Synth.

Entry R (IC) (min.) Rf Sys tem [Source] Method 0140- 0.29 5% 495 A2 N.H 144 MeOHI A7 Me 45% (HPLC BI 0 N EtOAc! ES-MS) Cia pet ether 96 0 244- 0.39 5% 529 A6 CI N.H 245 MeOH/ A7 0 NMe 45% (HPLC BI 0 N EtOAc! ES-MS) Cia pet ether 97 0 220- 0.25 5% 529 A2 CI N.H 221 MeOH/ -A7 0 NMe 45% (HPLC BI1 0 N -EtOAc! ES-MS) Cla pet ether 98 NH 0.27 5% 45 A MeOR! A7 Me 45% (HPLC B I 0 EtOAcT 'S-MS) Cia pet 99 0 180- 0.52 5% 509 A-9 N H 181 MeOH/ A7 Et 45% (IILC B1 N EtOAc! ES-MS) Cla, pet ____ether WO 00/41698 WO 00/1 698PCT[USOO/00768 100 0 162- A2 N H 165 A7 Pr-i BI 0- Cla PCTTJSOO/00768 WO 00/41698 Table 7.

Additional Ureas

S

TLC Mass mp HPLC TLC Solvent Spec. Synth.

Entry R (OC) (min.) RJ. System [Source] Method 101 0 162-

A

00 i. H165

A

IN 11) Me C3.

OH H 102 00.10 50%, 442 A2 00 N EtOAc! A4, 0 II50% (HPLC C2d N) NaN M hexane ES-MS) H H Me N e 103 0 125- 0.24 40% 512 A HN NH 13 0 EtOAc! C2b

(FAB)

hexane 0 0 NH-Me Me-NH Wo 00/41698 PCT/USOO/00768 BIOLOGICAL EXAMPLES P38 Kinase Assay: The in vitro .inhibitory properties of compounds were determined using a p38 kinase inhibition assay. P38 activity was detected using an in vitro kinase assay run in 96-well microtiter plates. Recombinant human p38 (0.5 jg/mL) was mixed with substrate (myelin basic protein, 5 p.g/mL) in kinase buffer (25 mM Hepes, mM MgC12 and 150 mM NaCl) and compound. One pCi/well of 33 P-labeled ATP pM) was added to a final volume of 100 pL. The reaction was run at 32 °C for min. and stopped with a IM HCI 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 IC 50 s of between 1 nM and RtM.

LPS Induced TNFa Production in Mice: The in vivo inhibitory properties of selected compounds were determined using a murine LPS induced TNFac production in vivo model. BALB/c mice (Charles River Breeding Laboratories; Kingston, NY) in groups of ten were treated with either vehicle or compound by the route noted. After one hour, endotoxin (E.

coli lipopolysaccharide (LPS) 100 pg) was administered intraperitoneally After 90 min, animals were euthanized by carbon dioxide asphyxiafi 6'and plasma was obtained from individual animals by cardiac puncture into heparinized tubes.

The samples were clarified by centrifugation at 12,500 x g for 5 min at 4 The supernatants were decanted to new tubes, which were stored as needed at -20 °C.

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

WO 00/41698 PCT/USOO/00768 The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding 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 (36)

1. A method of treating a disease mediated by p38 within a host, said method comprising administering to said host a compound of Formula I: A-D-B (I) or pharmaceutically acceptable salt or isolated stereoisomer thereof, wherein D is -NH-C(O)-NH- A is a substituted moiety of up to 40 carbon atoms of the formula: L' where L is a 5 or 6 membered cyclic structure bound directly to D, L' comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L' contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and 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 cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L' is substituted by at least one substituent selected from the group consisting of -SO 2 Rx,C(0)Rx and -C(NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally halosubstituted, up to per halo; Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which WO 00/41698 PCT/USOO/00768 optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; Rx is Rz or NRaRb where Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen, or -OSi(Rf) 3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0 substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or c) one of Ra or Rb is a CI-C 5 divalent alkylei group or a substituted Ci-C 5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted CI-C divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; WO 00/41698 pCTIUS00/00768 where B is substituted, L is substituted or L' is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of CN, -CO 2 R 7 -C(O)NRR, -C(O)-R 7 -NO 2 -OR 7 -SR 7 -NR 7 R, -NRC(0)OR 7 NR'C(O)R 7 -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents independently selected from the group consisting of -CN, CO 2 R 7 -C(O)R 7 -C(O)NR 7 R 7 -OR 7 -SR 7 -NR 7 R 7 -NO 2 -NR 7 C(O)R 7 NR'C(O)OR 7 and halogen up to per-halo; with each R 7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, wherein Q is -N(R 7 -(CH 2 -(CH 2 (CH 2 -(CH 2 )mN(R 7 -O(CH 2 CHX a -CXa 2 -S-(CH 2 and N(R 7 )(CH 2 )m where m= 1-3, and Xa is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, CO 2 R 7 -C(O)R 7 -C(O)NRR 7 -NO 2 -OR 7 SR 7 -NR 7 R 7 -NR 7 C(O)OR 7 NR 7 C(O)R 7 and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms-selected from N, S and 0 and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO2R 7 -COR 7 C(O)NR 7 R 7 -OR 7 -SR 7 -NO 2 -NR7R 7 -NR 7 C(O)R 7 and -NR 7 C(O)OR 7 with R 7 as defined above.

2. A method as in claim 1 for the treatment of a cancerous cell growth mediated by p38 kinase.

3. A method as in claim 1 for the treatment ,of a disease other than cancer.

4. A method as in claim I wherein the condition within a host treated by administering a compound of formula I is rheumatoid arthritis, osteoarthritis, septic arthritis, tumor metastasis, periodontal disease, corneal ulceration, proteinuria, coronary thrombosis from atherosclerotic plaque, aneurysmal aortic, birth control, dystrophobic epiderrnolysis bullosa, degenerative cartilage loss following traumatic joint injury, osteopenias mediated by MMP activity, tempero mandibular joint disease or demyelating disease of the nervous system. A method as in claim I wherein the condition within a host treated by administering a compound of formula I is rheumatic fever, bone resorption, postmenopausal osteoperosis, sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, systemic inflammatory response syndrome, inflammatory bowel disease (Crohn's disease and ulcerative colitis), Jarisch- Herxheimer reaction, asthma, adult respiratory distress syndrome, acute pulmonary fibrotic disease, pulmonary sarcoidosis, allergic respiratory disease, silicosis, coal worker's pneumoconiosis, alveolar injury, hepatic failure, liver disease during acute inflammation, severe alcoholic hepatitis, malaria (Plasmodium falciparum malaria and cerebral malaria), non-insulin-dependent diabetes mellitus (NIDDM), congestive heart failure, damage following heart disease, atherosclerosis, Alzheimer's disease, acute encephalitis, brain injury, multiple sclerosis (demyelation and oligiodendrocyte loss in multiple sclerosis), advanced cancer, lymphoid malignancy, pancreatitis, impaired wound healing in infection, inflammation and cancer, myelodysplastic syndromes, systemic lupus erythematosus, biliary eirrhosis, bowel necrosis, psoriasis, radiationinj".ry/ toxicity following administration of monoclonal antibodies, host-versus-graft reaction (ischemia reperfusion injury and allograft rejections of kidney, liver, heart, and skin), lung allograft rejection (obliterative bronchitis) or complications due to total hip replacement.

6. A method as in claim 1 wherein the condition within a host treated by administering a compound of formula I is an, infectious disease selected from WO 00/41698 PCT/USOO/00768 the group consisting of tuberculosis, Helicobacter pylori infection during peptic ulcer disease, Chaga's disease resulting from Trypanosoma cruzi infection, effects of Shiga-like toxin resulting from E. coli infection, effects of enterotoxin A resulting from Staphylococcus infection, meningococcal infection, and infections from Borrelia burgdorferi, Treponema pallidum, cytomegalovirus, influenza virus, Theiler's encephalomyelitis virus, and the human immunodeficiency virus (HIV).

7. A method as in claim 1 wherein M is one or more bridging groups selected from the group consisting of-0-, -N(R 7 -(CH 2 -CH(OH)- -(CH 2 -(CH 2 -(CH 2 )mN(R 7 -O(CH 2 CHX a -CXa 2 -S-(CH 2 and -N(R 7 )(CH 2 where m= 1-3, Xa is halogen and R 7 is as defined in claim 1.

8. A method as in claim 7, wherein said substituted cyclic moiety L' is phenyl,.pyridyl or pyrimidinyl.

9. A method of claim 1 wherein L' is substituted by -C(O)Rx or -SO 2 Rx, wherein Rx is NRaRb. A method of treating a disease mediated by p38 within a host, said method comprising administering to said host a compound of Formula I: A-D-B (I) or a pharmaceutically acceptable salt thereof, wherein D is -NH-C(O)-NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: L' where L is a 6 membered aryl moiety or a 6 membered hetaryl moiety bound directly to D, L 1 comprises a substituted cyclic moiety having at least 5 members, M is a bridging group having at least one atom, q is an integer of from 1-3; and each cyclic structure of L and L' contains 0-4 members of the group consisting of nitrogen, oxygen and sulfur, and WO 00/41698 PCT/USOO/00768 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 cyclic structure bound directly to D containing 0-4 members of the group consisting of nitrogen, oxygen and sulfur, wherein L' is substituted by at least one substituent selected from the group. consisting of -SO 2 Rx, and -C(NRy) Rz, Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally halosubstituted, up to per halo; Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; Rx is Rz or NRaRb where Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen, or -OSi(Rf)3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or WO 00/41698 PCT/USOO/00768 b) Ra and Rb together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0 substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or c) one of Ra or Rb is a CI-C5 divalent alkylene group or a substituted Ci-C 5 divalent alkylene group bound to the moiety L to form a cyclic structure with at least 5 members, wherein the substituents of the substituted Ci-Cs divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; where B is substituted, L is substituted or L 1 is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of -CN, -CO2R 7 -C(O)NR 7 R 7 -C(O)-R 7 -NO 2 -OR 7 -SR 7 -NR 7 R -NRC(o)OR 7 NR 7 C(O)R 7 -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents independently selected from the group consisting of -CN, CO 2 R 7 -C(O)R 7 -C(O)NR 7 R 7 -OR 7 -SR 7 -NRR 7 -NO 2 -NR 7 C(O)R 7 NR 7 C(O)OR 7 and haligen up to per-halo; with each R 7 independently-selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, wherein Q is -N(R 7 -(CH 2 -(CH 2 (CH 2 -(CH 2 )mN(R 7 -O(CH 2 CHX a -CXa 2 -S-(CH2)m- and N(R 7 )(CH 2 )m where m- 1-3, and Xa is halogen; WO 00/41698 PCT/US00O/00768 Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zni, wherein nl is 0 to 3 and each Z is independently selected from the group consisting of -CN, CO 2 R 7 -C(O)R 7 -C(O)NR 7 R 7 -NO 2 -OR 7 SR 7 -NR 7 R 7 -NR 7 C(O)OR 7 NR 7 C(O)R 7 and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO 2 R 7 -COR 7 C(O)NR'R 7 -OR 7 -SR 7 -NO 2 -NR 7 R 7 -NR 7 C(O)R 7 and -NR 7 C(0)OR 7 and wherein M is one or more bridging groups selected from the group consisting of -0- -N(R 7 -(CH 2 -(CH 2 -(CH 2 -(CH 2 )mN(R 7 O(CH 2 CHX a -CXa 2 -S-(CH 2 and -N(R 7 )(CH 2 where m= 1-3, X a is halogen and R 7 is as defined above.

11. A method of treating a disease mediated by p38 within a host, said method comprising administering to said host a compound of Formula I: A-D-B (I) or a pharmaceutically acceptable salt thereof, wherein D is -NH-C(O)-NH-, A is a substituted moiety of up to 40 carbon atoms of the formula: L' where L is a substituted or unsubstituted phenyl or pyridine moiety bound directly to D, L l comniises a substituted phenyl, pyridine or pyrimidtiil moiety, M is a bridging group having at least one atom, q is an integer of from 1-3; and B is a substituted or unsubstituted phenyl or pyridine group bound directly to D, wherein L' is substituted by at least one substituent selected from the group consisting of-SO 2 Rx, -C(O)Rx and -C(NRy) Rz, WO 00/41698 PCT/USOO/00768 Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally halosubstituted, up to per halo; Rz is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by" halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; Rx is Rz or NRaRb where Ra and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen, or -OSi(Rf)3 where Rf is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or b) Ra andk Rtogether form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0 substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; or c) one of Ra or Rb is a Ci-C 5 divalent alkylene group or a substituted Ci-C 5 divalent alkylene group. bound to the moiety L to form a cyclic I WO 00/41698 PCT/USOO/00768 structure with at least 5 members, wherein the substituents of the substituted divalent alkylene group are selected from the group consisting of halogen, hydroxy, and carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and 0 and are optionally substituted by halogen; where B is substituted, L is substituted or L' is additionally substituted, the substituents are selected from the group consisting of halogen, up to per-halo, and Wn, where n is 0-3; wherein each W is independently selected from the group consisting of-CN, -C0 2 R 7 -C(O)NR 7 R 7 -C(O)-R 7 -NO 2 -OR 7 -SR 7 -NR 7 R 7 -NR 7 C(O)OR 7 NR7C(O)R 7 -Q-Ar, and carbon based moieties of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents independently selected from the group consisting of -CN, C0 2 R 7 -C(O)R 7 -C(O)NR 7 R 7 -OR 7 -SR 7 -NR 7 R 7 -NO 2 -NR 7 C(O)R 7 NR 7 C(O)OR 7 and halogen up to per-halo; with each R 7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, wherein Q is -N(R 7 -(CH 2 -(CH 2 (CH 2 -(CH 2 )mN(R 7 -O(CH 2 CHX a -CXa2-, -S-(CH 2 and N(R 7 )(CH 2 where m= 1-3, and X a is halogen; Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up to per-halo, and optionally substituted by Zni, wherein ni is 0 to 3 and each Z is independently selected from the group consisting of -CN, CO 2 R 7 -C(O)R 7 -C(O)NR 7 R 7 -NO 2 -OR 7 SR 7 -NR 7 R 7 -NR 7 C(O)OR 7 NR 7 C(O)R 7 and a carbon based moiety of up to 24 carbon atoms, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by one or more substituents selected from the group consisting of -CN, -CO 2 R 7 -COR 7 C(O)NR 7 R -OR 7 -SR 7 -NO 2 -NR 7 R 7 -NR 7 C(O)R 7 and -NR 7 C(O)OR 7 with R 7 is as defined above; and I WO 00/41 698 PCT/USOO/00768 wherein M is one or more brid Iging groups selected from the group consisting of -0- -N(R 7 -(CH 2 -(CH 2 -(CH 2 -(CH 2 )nN(R 7 O(CH 2 CHXa2-, cxa 2 -S-CH 2 and -N(R 7 )(CH 2 where m= 1-3, X- is halogen and R 7 is as defined above.

12. A method for the treatment of a disease mediated by p38 kinase other than cancer which comprises administering a compound selected from the group consisting of the 3-tert butyl phenyl ureas: N-(3-tert-butylphenyl)-N -(N-methylcarbamoyl)pheloxy)phely1 urea and N-(3-tert-butylphenyl)-N '-(4-(4-acetylphenoxy)phenyI urea; the 5-tert-butyl-2-methoxyphenyl ureas: N-(5-tert-butyl-2-methoxyphefl)lN 1,3-dioxoisoindolin-5- yloxy)phenyl) urea, N-(5-tert-butyl-2-methoxyphenyl)-N '-(4-(l1-oxoisoindolin-5-yloxy)phenyl) urea, N-(5-tert-butyl-2-methoxypheny1)-N '-(4-(4-methoxy-3-(N- methylcarbamoyl)phenoxy)Phenyl) urea and N-(5-tert-butyl-2-methoxyphenyl)-N methylcarbamoyl)phenoxy)phenyl) urea; the 2-methoxy-5-trifluoromethyl)phenyl ureas: -(trifluoromethyl)pheny1)-N'-(3-(2-carbaimoylA4 pyridyloxy)phenyl) urea, (-2(-ehlabmy)4 pyridyloxy)phenyl) urea, N-2mtoy5(rfurmty~pey)N-4(-ab~ol4 pyridyloxy)phenyl) urea, WO 00/41698 PCTLJSOO/00768 -(trifluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl) urea, fluoromethyl)phenyl)-N '-(4-(2-(N-methylcarbamoyl)-4- pyridylthio)phenyl) urea, -(trifluoromethyl)phenyl)-N '-(2-chloro-4-(2-(N- methylcarbamoyl(4-pyridyloxy))pheflyl) urea and -(trifluoromethyl)phenyl)-N '-(3-chloro-4-(2-(N- methylcarbamoyl)(4-pyridyloxy))pheflyl) urea; the 4-chloro-3-(trifluoromethyl)pheflyl ureas: N-(4-chloro-3-(trifluorometbyl)phefl)-N '-(3-(2-carbamoyl-4- pyridyloxy)phenyl) urea, N-(4-chloro-3-(trifluoromethyl)pheflyl)-N '-(3-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl) urea, N-(4-chloro-3-(trifluoronmethy)phenlY)-N'-(4(2-carbaml- 4 pyridyloxy)phenyl) urea and N-(4-chloro-3-(trifluoromethy1)phenfl)-N '-(4-(2-(N-methylcarbamoyl)- 4 pyridyloxy)phenyl) urea; the 4-bromo-3-(trifluoromethyl)pheflyl ureas: N-(4-bromho-3-(trifluoromethy1)pheflyl)-N'-(3-(2-(N-methylcarbamoyl)-4- -pyridyloxy)phenyl) urea, N-(4-bromo-3-(trifluoromethyl)pheflyl)-N '-(4-(2-(N-methylcarbamoyl)-4- pyridyloxy)phenyl) urea, N-(4-bromo-3-(trifluoromethyl)pheflYl)-N '-(3-(2-(N-methylcarbamoyl)-4- pyridylthio)phenyl) urea, N-(4-bromo-3-(trifluoromrethylpheflyl)-N'-(2-chloro-4-(2-(N- methylcarbamoyl)(4-pyridyloxy))phelyl) urea and N-(4-bromo-3-(trifluoromethylpheflyl)-N '-(3-chloro-4-(2-(N- methylcarbamoyl)(4-pyridyloxy))phelyl) urea; and from the group consistiag of tuberculosis, Helicobacter pylori infection during peptic ulcer disease, Chaga's disease resulting from Tryparosoma cruzi infection, effects Of Shiga-like tox~in resulting from E. coli infection, effects of enterotoxin. A resulting fromn staphylococcus infection, meningococcal infection, and infections from Borrelia burgdorferi. Trepontma pallidum,. cylomegalovinus. iunluenza virus, Theilers encephalomyclifis virus, and the human immunodeficiency virus (MlV).

13. A Method for the treatment of a discase me4iaWe by p38 comprising admninistrinng a compound selected firm the group consisting of' N-(5-ger,-butyl-2-methoxyphenyl)-N '-(4-(4-methoxy-3 methylcarbamoyl)phenoxy)phenyl) urea. N-(2-xnetboxy--(iluormethylpenyl)-N-(4-(2-(N-mthylcubamoyl)-4- pyridyloxy)phenyl) urea, NV-N4coro-3-ziluoreThy)peyl)-N'-(4-(2-carbanoyl-4- pynidyloxy)phenyl) Urea, N-(4-chlr3-(tifluoroehyl)phyl)-N-(4.(2(N-mhylcarbnoy;-4 pyridyltwy~phenyl) urea: N-(2-rnethoxy-4-cbloro-5.(tnifluoromethy)pbenyUlN-(3.(24(N- 0 uiethylcarbamoyl)-4-pyrndyloxy)phenyl) urea and their pbarmaccutically acceptable

14. A mecthod as in claimi1 3 1,-omprising administering: N-(S-Tern-buryl-2-methoxyphenyl)-V-(4-{4-methoxy-3-{N-nrethyI carbamoyl~phenoxy~phenyI) urea or a pharmnaceutically acceptable salt treof. A method as in claim 1 3 comprising administering: N-{2-methoxy-5-mluoromethyl)phenyl)-Nf'-{4-(2.(N-mecthylcurbanoyl)-4- pyridyloxy)phenyl) urea or a pharmaceutically acceptable salt thereof 125

16. A, method as in claim 13 comprising administering: N-(4-cloro3(rfluoromethyl)pbfnlY)-N-(4-( 2 rboyl-4- pyridyloxy)phcnyl) area or a pharmaceuttically acceptable salt thereof.

17. A method as in claim 1 I 3 comprising administering: N-(4-chloro-3(riuromfctyl)phehyl)-N '-(4.(2-(N-methylcarbamoyl)-4- pyriclyloxy)phenyl) urea or a pharmaceically acceptable salt thereof.

18. A melhod as in claim 1 3cOnlpriIMg administcriuz N-(2methoxycbloro--tifuoroethyl)pbheflN- 3 rchylcabamoyl)-4-pyridyoxy)pholyl) Ltrea or a pharmaceutically acceptable salt thereof~ 0 0

19. salt. salt.

21. S41.

22. salt.

23. salt.

24. salt. group A method 4s in claim 15 where the compound administered is a iosylate A method as in claim 16 where the compound administered is a tosylatte A method as in claim 1 7 wheTre the compound administered is a tosylate A method as in claim 1 8where the compound administered is a tosylate A Method as in claim 3 where the comnpound admainistered is a rosylave A method as in claim 14 where The compound administered is a vosylate A method for a rreatment of the disems within a host selected from the consisting of rheumTnoid urrbritis, osteozmriiis. septic arthritis, tLuznor 126 metastasis, periodontal. disease, corneal, u.lceration, proteinhwia, coronary thrombosis from aTherosclerotic plaque, aneurysmnal aortic, birth control, dystrophobic epidermolysis bullosa, degenerative cartilage loss following traumatic joint injury, osteopenias mediated by MWP activity, teinpero n~dibular joint diseas or demyelaiing disease of the nervous system said method comnipri sing administering to a host a compound selected from the group consisting of, utyl-2-methoxyphenyl)-N-(4-(4-methoxy-3 methylcarbamoyl)phenoxy)phe'yl) urea, N-(2-incrhoxy-5-(trifluoromethylpheuyl)-NV'-(4-(2-(N- methylcarbamoyl)-4-pyridyloxy)phenyl) urea, Juoromehyt)plienyU)-N-(4-(2r=bamoy-4-pyridyloxy)pllenyl) urea, N-(+.cbloro-3-(rritluoromerbyl)phcuyl)-N-(4-{2-(N- methylcarbamoyl)-4-pyridyloxy)phenyl) urea; N-(2-mcthoxy-4-chloco-5-(urituoromethyl)phenyl)-N'-(3-(72-{N- methYlcarbarnoyD)-4-pyridyloxy)phenyl) urea, and their pharmaceutically acceptable salts.

26. A method for a treaunent of' the condition within a host selected from The goup consisting of rheumatic fever, bone resorption, postnenopausal osteoperosis, 4ePsis, gi-aM negative secpsis, septic shock, endotoxic shock, toxic shock syndrome, systemic inflammratory response syndrome. inflannatory bowel disease (Crohn's disease and ulcerative colitis), Jarisch-flerxlwiier reaction., asthmia, adult respiratory distress syndrome, acute pulmonary fibrotic disease, pulmonary sarcoidosis, allergic resp iratory disease, silicosis, coal workes Prneumoconiosis, alveolar injury, hiepatic failure, liver disease during acute inflammxation, severe alcoholic hepatitis, najania (Plasmnodium falciparumn malaria and cerebral malaria), non-insulin-dependent diabetes mnellitus (NTDDMJ, congestive heart f~ilure, d=Age following bearn disease, atherosclerosis, Alzbeimner's disease, acute encephalitis, brain injwy, multiple sclerosis (deinyelation and oligiodcldrocyte loss in multiple sclerosis), lymaphoid malignanicy, pancreatitis, impaired wound healing in infection, inyelodysplastic Syndromes, systemic lipus erythernatosls, bili 'ary cirrhosis, bowel necrosis, pscriasis, radiation injury/ roxicity following adxninistration of inonoclonal antibodies, host- versus-graft reactin (ischemia reperfitsion injury and allogralt rejections of kidney, 127 liver. heart, and skin). lung allogrft rejection (obliterative bronchitis) or complicavions due To total hip replacement said method comprising administering to a host a compound selected from the group consisting of: N-(5-ier-butyl-2-rethoxyphnyl)-'-(4-(4-methoxy3-(N- mthylcarbamoyl)Pbenoxy)pbenyI) urea, N-(2-meihoxy -5-(wriflLoromethyl)phenyl)-N'-(4-(2-(NV-methylcarbamoyl)-4- pyridyloxy)phenyl) urea. N-chloro-3-(tluormethyl)phenyl)-N'-(42-carbanoyl.4- pyridyloxy)phenyl) urea, N-(4-chloro-3-(rritluoromethyl)phenyl)-N-(4-(2-(N-methylcarb~moyl)-4- pyridyloxy)phenyl) ure; N-(2-mutoxy-hlorS-(trifluoroetyl)phenyl)-N'-(3-(2-(N- methylcarhamoyl)-4- pyridyloxcy)phenyl) ureat and their pharmceutically acceptable salts.

27. A method for treating an infeTious disease within a host selected firom the group consisting of Tuberculosis, Helicobacter pylor infection during peptic ulcer disease, Chiaga's disease resulting from Tzypaosoma cruzi infcction, effects of Shipa- like toxin resulting from coli infection, effects of enterotoxin A resulting from Stephylococcus infection, meningococcal infection, and infections f=o4 Borrlia btirgdorferi, Treponerna palliduzn. vyromegalovimts. intluonza virus, Theilers encephalomyclitis virus, and the human inmmiodeficiency virus MWJ) said miethod comprisng administering to 4 host a compound selected from The group consisting of: N-5tr-uy--e~oyhey)N-4(-ebx--N met1hylcarbamroyl)phenoxy)phenyl) urea. N-(2-rneloxy-S-(Uifluoromethyl)phcnyl)-N'-(4-(2-(N-methylcarbamoyl-4 pyridyloxy)phenyl) Urea, N-(4-cloro-3-(riuoronehyl)phenyl)-N'-{4(2-carbAmuoyl- pyridyloxy)pheiiyl) uirea, N-(4-chloro-3-(trifluorometliyl)phenyl)-N'-(4-(2-(Ar-methylcarbamoyl)-4- pyridyloxy)phenyl) urea; N-(2-methoxy-4-C1IorO-5-(UOOMtYI)PhelYl)-N methylcarbamoyl)-4-pyriyloxY)pheflyl) urea, and their pharmaceutically acceptable salts

28. A mie"lo of mrating 4 disease mediated by p38 within a host, said method comprising admninistering to said host a compounid of Formula L; A-fl-f (1) or a pharmaceutically acceptable salt or isolated steroisomcr tereof wherein D is -NH-C(O)-NHi-, wherein L' is A is a substituted moiety of The formula: where L. is 4 5 or 6 mnembered cyclic stracture bound directly to Di. L' comprises a cyclic moiety having, at leas 5 members substituted by at leant one substituent selected from, the group coinssting of -SOzR.. and R. q is an integer of from 1-3; Wherein M is one or more bridging groups selected from the group consisting of N(R 7 -(CH~ 2 -CHOi)QU} -CH 2 -(Cli 2 )znS- (CH2N(R 7 Q(CH). CUX'-, and -N(R 7 XCIHi)m, Whiere m72- 1-3, X'0j halogen and R 7 iS as defined below. and B, L and L' am~ independently selected from substituted or unsubstitued pheayl, substituted or unsabstituted a naphrbyl, substituted or wisubstituted heteroary) selected from the group consisting of 2- fury!, 3-futryl, 2-thieny), 3-thienyl, 2-triazinyl, 4-niazinyL, 1-pyrnoly!, 2-pyrrolyl, 3- pyrrolyl. l-iinidazolyl 2-iznidazolyl, 4-iraidazaly]. S-imidazoly], 1-pyrazolyL, 3- pyrazolyl, 4-pyrazoly), 5-pymuolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxa2olyl, 2- oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-oxazolyl. 2-thiazolyi, 4-diiazolyl, 5-Ihiazolyl, 3- isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2 -pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidinyl, 4-pyrirnidinyl. 5-pyriinidinyl, 6-pyrinmidinyl, 1 ,2,3-iriazol-1-yl, 1,2,3- triazol-4-yl, 1,3-riazol-5-yl, 1 ,2,4-triazol-l -yl. I ,2,3-rriazol-3-yl, I ,2,3-triazol-5-yi, 129 I-retrazolyl, 5-tetrazolyl, 1 ,2,3-oxadiazol-4-yl, I ,2.3o0xaclazol-5-yl, 1 ,2,4-oxadiaUoI- 3-yI, 1,2,4-oxadiazol-5-yI. I ,3,4-!hiadiazoI-2-YI, 1,3.4-aiLiadiazol-5-yI, 1,3,4- Uhadiazol-3-yl, 1.2,3-thiadiazol-4-YI, 1,2,3-hia4iazoI-5-y], 3-pyri"Aziyl-. 4- pynidaziuyl, 2-pyrazinyl and 3-pyrazinyl or a substitured or unsubstituted bicyclic hcraroarYl group selected from The group consisting of 6- and 7-benofuryl, 6- and 7- benzothienyl. 6- and 7-indolyl, 6- or 7-isoindoly], I-, 4- and 5-beuzilnidazolYi, 6- and 7-judazaly) (benzopyrazolyl), 4-, 6- and 7-benzoxazolyl, 5- 6- and 7-benziswcazolyl, 6- and 7- benzorbiaolyl, 6- and 7-benzisohiazolyl, 6- and 7-banz-1.3- oxadiazolyl, 7- and 8-quinolinyl, 8- isoquizzoliny), and 7-and g-quinazolinyl- 8 is selected from the group consisting of 2-pyridyL, 3-pyt-idyl, 4-pyuidyl, 2- pyrimidinyl, 4-pyrinidinyl. .5-pyrimnidinyl. 6-pyrimidiziy), I ,2,3-Oxadizol-4-yI, 1,2,3- l,2,4-oxadiazol-3-yI, 1.2,4-oxadiazol-5-yI. 1,3,4-thiaclimzl-2-yl, 1 ,3,4-thiadiazol-5-yl, I ,3,4-thiadiazol-3-yl, 1,2,3-rbiaiazol+yI, 1,2,3-tiidiazol-5- yI. 3-pyzridazinyl-, 4-pyridazinyL, 2-pymzinyl and 3-pyruinyl or 4 substituted or unsbstituteci bicyclic hewvraryl group selecTed from the group consisting of 6- and 7-bcnzofTryl, 6- and 7- benzolhienyl, and 7-itidolyl, 6-or 7-isoindolyl, 1-, 4- and 5-benzirnidazolYl, 4-i 6- and 7-induzolyl (betizpyrozolyI), 6- and 7-bCnzOxazolyl, 5- 6- aid 7-benzIsoxazlYL, 6- aud 7- S ~benzothiazolyl, 6- and 7-betizisotbWioyl, 6- and 7-benz-1.3- oxadiazolyl, 7- and 8-quipolinyl, 8- isoquinolinyl, anqd 7- and 8-quinazolinyl. Ry is hydrogen or a carbon based moiety of up to 24 carbon atoms selected from the group consisting of Cr-CI alkcyl, Ci-Cio Allcoxy, C.. 1 cycloalkyl having 0-3 heero atoms, selected from N. S and 0, C 2 1 0 alkeMyl CI- 0 alkenOYI, C&1 4 WYL C 3 1 betaryl having 1-3 heteroaroms selected from 0, N and S, C7-24 arIlcYl, C7-C 2 4 alkary). 130 optionally containing heter=Oatos selected from N. S and 0 and optionally halosubstiuted, up to per halo; is hydrogen or a carbon based moiety of up to 30 carbon atoms selected from the group consisting of CI-Clo alkyl, CI-Clo alkoxy, C3-ID cycloalkyl having 0-3 herero atoms selected from N. S and 0. C 2 1 o alkenyL, C1.1 ankeoyl, C 6 aryl, c 3 .17 hetaryl having 1-3 heteroaronls selected from 0, N anid S, C 7 .,24 arakYl, C 7 -C 24 opionally containing heteroatoms selected from N, S and 0 and optionally substituted boy halogen and hydroxy; R.is Ror NP where R. and 4 ,are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms selected from the group consisting of CI-Cla alkyL, CI-Clo alicoxy, C.1- 0 cycloaLyl having 0-3 betera atoms; selected trom N. S and 0- C2-10 alkonyl- CR-0 alk&noyl, C&14 arYl C 3 12 hetayI having 1-3 beteroAtoms selected from 0, N and S, C 7 24 aralkyl, Cr-C24 alkaxyl optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen and hydroxy, or b) R. and R 1 together forrm a 5-7 member heterocyclic structure of 1-3 hereroators selected from N, S and 0. or a substituted 5-7 member heterocyclic structure of 1-3 heteroaroms selected from N, S and 0 suibstituted by halogen hydroxy or carbon based substizernts of up to 24 carbon atoms, selected from The group consisting of CI-Clo alkyl, CI-CIO alkoxy. C3-io cYcloalcyl having 0-3 hetero AM= selected front N. S aud 0. C 210 ailcenyl, C1.10 alkenoy), C6. 4 aTYl, C 3 12 hetaryl. having 1-3 hereroatoms selected from 0, N arid S. C 7 24 aralky, Cr-CZ a1CM7yL -which optionally contain heteroaroms selected from N. S and 0 and are optionally substituted by halogen; or c) one of R. or &b is a CI-Cs divalent alkylene group Or 4 substituted C,-Cs divalent alkylene group bound to the moiety L' to form at cyclic stcture with at least 5 members, wherein the substiruents of the substituted CI-Cs divalent alkylene group are selected from the group consisting of halogen, hydroxy, 131 and catbon based substituents of UP to 24 carbon atoms, selected from the group consisting of C 1 -C 10 alkcyl, C 1 -C 10 alkoxy, c 3 .10o cycloalcyl having 0-3 botero atoms selected from N, S and 0, C2-to alkeyl, C 1 1 0 ZlkenOYl, C6. 1 4 aryl, CJ-2 heWayI hIAVing 1-3 heteoatoms selected from 0, N and S, C 7 .2q U4t1ky, C 7 -C 2 4 alkaryl. which Optionally contain heteroatozns sclected from N, S and 0 and are optionally substituted by halogen; where B, L or =r optionally suibstituted by halogen, up to perhalo, or W.~ wherein eacht W is independently selected from 0IRZ, NR7R7. C0R7. COW.' CONR'R 7 Nk 7 C(o)R 7 cyano, and itro where al is subsuited, L is substituted or L 0 is additionpaly substituted, the substituentta awe selected from the group consisting of halogen, up to per-bale, and Wn, where a is 0-3; wherein each W is independently selected from The group consisting of -CN, -co2R7, -C(Q)NR 7 R 7 -C(Q)4R7. -NO 2 oRZ, -SR 7 -NR7C(0)0R 7 NRC(O)R 7 -Q-Ar; and carbon based moieties of up to 24 carbon ams selected, from The group consisting of Ct-Clo alkyl CI-Cip Aioxy, Cj-ao cycloalicyl having 0-3 hetero atoms selected from N, S and 0, C 2 -i 0 alkenyi, Ci- 10 alkenoyl, C&. 1 4 arY), C3-1 heiryl having 1-3 heteroatomns selected from 0, N and S. C 7 2 4 aralcyl, Cr-C24 4*Lcrl optionally containing heteroatomn selected ftom N, S and 0 and optionally substituted by one or more substituents independently selected from te group consisting of -CN, -C0 2 -C(0)R 7 -C(O)NR 7 R 7 -0R7. -SR 7 -NPR 7 -N0 2 NR 7 C(0)R 7 -IW1~C(0)O1Q and halogen up to per-halo; with each k 7 indepedenTly selected from H or a carbon based moiety of up to 24 carbon atozas, optionally containing heieroatoms selected fromn N. S and 0 and optionally substituWe by halogen, wherein Q is 7 -CH(O1I)-. -(CI1~j)mO-,- (Ckt2)mS- -{CH 2 )mN(R 7 -O(CH 2 CUX'-, -S-{C 2 )0m anti -N(R 7 2 where m= 1-3, and V' is halogen; and Ar is a 5- or 6-member aromatic structure containing 0-2 members selected from the group consisting of nitrogen, oxygen and sulfur, which is optionally substituted by halogen, up To per-halo, and optionally substituted by ZI, wherein n I is 132 o To 3 and each Z is independently selected from thre group consisting of -CN, CO2e, -C(O)R 7 -C(O)N&R 7 -NO2, -OR 7 SIC -NRR7e, -WRC(0)0R 7 NRC(O)R 7 and IL carbon based moiety of up to 24 carbon atoms, optionally containing hertroatoxns selected fr N. S and 0 aud optionally substituted by one or more substituents selected from the group consisting of -CN. -C0 5 R 7 -C0R 7 C(0)NR 77 -SR 7 -NOz, -NR 7 R 7 -NR 7 C(O)R 7 and -NR 7 C(O)0R 7 with R7 as defined above.

29. A method as inclaim 28 wheein B is a substituted or unsubstituted group selected from The group consisting of phenyl, naplithyl, isoindolyl, ifdlydo dal4, b4OYP ITWU2ol bezimidazolyl, benzoxartolyl, pyridinyl, pyrimidiny), pyrrolyl, quimlinyJ, isoquinalinyl, tetrazolyl, t1iadiazoWYI thiazolyl and iTienyl; I- of formula I is 4 substituted or unsubstituted group selected from the group consisting of pheuyleane, naphthylene, thienylene, fujylene, pyridine-ene. quinalitw- ec isoquinoline-ene and indole-ene. M is selected from the group consisting of CH2O-, -CHf2S-, -SCflz., -CXVz-, and -CH(Okl)-. L' is a substitted or irosubtiftuted, group selected from the group consisting of phenyl, naphthyl, funy), isoindolyl, oxadiazolyl, oxazolyl, isooxazolyl, indoly), indazolyl. beazothazolyl, benziznidazolyl, benzaxazolyl. pyrazolyl. pyridinyl, pyriutdinyl, pytnolyl, quinolinyl, isoquinolinyl, terrazolyl, thiadiazolyl, rtiazolyl and thienyl- A method as in Claim 28 wherein at least one of 8, L or L' is a substituted group with 1-3 substituents selected from the group consisting of chioro, bromo, fluoro. methyl, triftuoromethyl. eibyl, n-propyl, n-butyl, i-propyl. t-buiyl, cyclopropyl, cyclobutyl, mathoxy, athoxy, propoxy and buTyoxy, pentoxy, mneihyl 133 sulionyl, trilluoromethyl sulfonyl, Cl, Br, F. cyano, nitio, hydroxy, amino, methylaniino, dimerhyiamino, ethylarnino and diethylamino.

31. A metod asin CW.2 8 whereinl B of formula I and L' are each, independently, a substituted or unsubstituted group selected from the group consisting of phenyl, Ipyiidinyl. pyrimiditayl, pyrazolyl, quinolinyl, andi isoquinalinyl, and L of formula I is a substituted o" unsubstitc4i gwup selected from fth group coinisling of phenylene and pyridiue-ette.

032. A method as inclaiin .28wherciuB La~nd L' follow one of the following of combinations., B3= pheny], L= phenyl and L' is phepyl. pyridiuyl, quinolinyl or isoquiuolinyl, phenyl, L- pyridinyl anti L' is phenyl. pyridinyl, quinolinyl or isoquinolinyl. pyridinyl, phenyl and L' is phanyl, pyridiny), quinolinyl or isoquinalinyl, 8- pyticlinyl, pyridinyl and L' is phenyl, pyridiyl, quinolinyl or isoquinolinyl, 8--isqciinolinyl. Lf= phenyl and L'is phenyl. pyridinyl, quinolinyl or isoquinolinyl, B- isoquinolinyl. L- pynidinyl and L' is phenyl, pyrdiyl, quinolinyl or isoquinolinyl, B= quinolinyl, phenyl and L' is phtnyl, pyridinyl, quinolinyl or isoquinolinyL, or B= quinolinyl, L- pyridinyl and L' is phenyl pyridicyl. quinolinyl or isoquinolinyl,

33. A method as in clahr 28. wherein L' is pheqyL pyridyl or pyrirnidinyl.

34. ~A method as i claim Ilwherein L'is pyridy!. A method as in Claim 28 wherein L' is Pynclyl anti is substituted by C(O)RA, wherein R, 4 isNR'

36. A method of claim 3 1 wherein at least one of B. L. or L' is subsifl4ted with 1-3 s bsruerns selected from the group consisting of C,. 1 t 0 alcyl, ttp to per halo substituted CINO aflkyl, -CN. -OH, halogep, C1. 1 o alkoxcy, up in per halo subsituted C1. jo alkoxy and C 3 0 heterocyclic moieties having at least a five cyclic members andi I to 2 heteroMrMS selected from the group of consist of nitrogen, ox~ygen and sulfuzr. 134

37. A method of claim 31 wherein at least oue of B, L or is substituted with 1-3 substiuemns selected from the group consisting of C 1 -Cb -alkyl up to per halo substituted C 1 -C 6 aiky), CN. On, halogen, CI-C6 ilkoxy and up to per halo, substituted CI-C6 alkoxy.

38. A method of claim-0i wherein M in the formulis for B is -Clii-, -O-CH 2 -or -Cf

39. A method of claim I wheein at phannceutically acceptable Salt Of 4 comapoud of formula1 I is administered which is selected from rhe group consisting of a) basic salts of organic acids and inorganic adids selected from the group consisting of hydroch~loric acid, hydrobromic acid, sulfuric acid, phosphoric acid, merhanesulfonica acid. trifluor osulfouic acid, benzenesaifonic acid, p-toluctie suffonic acid (tosylate salt). 1-ziapthaliene sulfoniic acid, 2-naptbaleue sulfonic acid, =ctic adid, trifluoroacetic acid, inalic acid, tartaric ai. citric acid, lactic acid, oxalic acid, succinic acid, furnaric acid, uialeic acid, benztoic acid, salicylic acid, plionylaceric: acid, and maodelic acid; and b) acid salts of organic and inorgaic bases containing cations selected from the group consisting of alkaline cations, alkaliua ea cations, the ammonium cation, aliphatic substituted ammonium cations a" aromatic substituted amraonium cations. A method of treating a disease mediated by p38 within a host, said method comprising administaring to said host 4 compotind of Formula 1. A-D-B (1 or a pharmaCcUtically acceptable Sat Or isolated stereoisomer thereof, wherein fD is 135 A is of the formulA: where L. is substituted or unsubstituted phenylene or pyridyleae bound directly to L' is pyridyl. substitated by at least one selected from the group consisting of -SOzRA, and-C(0)R, .and is optionally further substituted, and M is a bridging group selected from the group Consisting Of -CH- 2 -OCH 2 -CHzO-. -NHC(O)-L-C(0)NR-, CHZS-, -SCl2- -CX" 2 anld -CHWOH)-, wherein r~ is halogen, and B is substituted phenyl or unsubsTiruted phrayl, Fv is hydrogen. or a carbon based moity of up to 24 carbon atoms selected from the group consisting of Ca-Clo alkcyl, C 1 -Clo alkoxy, C 3 .jo cycloalkyl having 0-3 hetero atoms selected from N. S and 0. C 2 10 Alkenyl, CH 1 0 akeUoyl, C&. 14 axyl CI-2 heraryl having 1-3 beteroatomfs; selcted from, 0, N and S, C 7 24 aralicyl. C 7 -C24 alkaryl. optIonally containing beteroatoms selected from N, S and 0 and optionally halosubstiruted, ap to per halo; F, is hydrogen or a carbon based moiety of up to 30 carbon atom selected from die group consisting of CI-Clo alkyl, C 1 -C 30 alkoxy, C3..10 cycloallcyl having 0-3 hetero atoms selected from N. S aud 0, C 2 10 alkenyl. C 11 o alicenoyl, C6 51 4 aryl, C3-1 hetasyl 'having 1-3 beteroatoms selected from 0, N and S. C 7 .7A aralkyl. Cr-C2 4 alkaryl, optionally containing heterotonis selected from N, S an4 0 and optionaly substituted by halogen and hydroxy; is RorNRR 4 ,where and Rb are a) independently hydrogen, a carbon based moiety of up to 30 carbon atoms optionally containing heteroaroms selected from N. S and 0 and optionally substituted by halogen and hydroxy; or b) and 4~i together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and 0, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selecte from N, S and 0 subsituted by halogen, 136 hydroxy or carbon based sabstituents of up to 24 carbon atoms selected fom the group consisting of Cr-CIO alkyl. CI-CIO alkcoxy, C 3 1 CYCloa1WYl havins 0-3 heero atoms selected from N, S and 0, C 2 10 alkmnyl, C.wo alkeaoyL arYl, C3.1 2 h~erayl baving 1-3 hemeoatoms selected from 0. N and S, C7-24 aralkyl, CTC2Z 4 alkaryl, which optionally contain heteroatomas selected from N. S and 0 and are optionally substituted by batlogen; or C) one of or Rb is a C 1 -Cs divalcnt allylene group or a substituted CI-Cs divalent alkylene group bound to the moiety L. To form a cyclic structure with at least 5 members, wherein the substuents of the substituted CI-C$ divalent alkylene group 4re, selected from the group consistitig of halogen, hydroxy. and carbon based substituents of up 10 24 carbon atoms selected firm the group consisting of CI-CIa alkyl, Cr-CID alkoxy, C 3 cycloalkyl having 0-3 h=rTo atoms selected from N, S and 0, C 2 -10 alkenyl, CI-1 4lkenoyl, C&14 aryl C 3 -12 betazy hAVing 1-3 beteroatoms selected from 0, N and S. C 7 24 aralkyl, C 7 -C 2 4 aluwyl. which optiomally contain beteroatomns selected from N. S and 0 and are optionally surbstituted by balogcn; where S is substituted, L is substituted or Ll is additionally sirbstiluted. the substituents are selected from the groap, consisting of balogen, up to per-halo, and Wu, where n. is 0-3; wherein each W is independently selected ft the group consisting of -CN, -CO2R7Z. -C(O)NR7R?, -NO2, -01C. -SR7, -NRR7. -NR 7 C(0)YR 7 NR 7 C(0)R 7 and cabon based moieties of up to, 24 cazbon atoms, optionally containing heteroatoms selectd from N, S and 0 and optionally substituted by halogen with each R7 independently selected from H or a carbon based moiety of up to 24 carbon atoms, selected from the group consisting of C 3 -C 10 alkyl. Cl-CjO alkoxy, C 310 cyclOalkYl Waing 0-3 hetero atoms selected from N. S and 0. C 2 1 0 alkenYl, C 1 0 alkenoyl, C 6 1 4 tYL, C31 heraryI having 1-3 heteroatoms selected from 0. N anld S. C 7 24 araflyl, C 7 -C 24 alCarYl, optionally containing heteroatoms selected from N, S and 0 and optionally substituted by halogen, 137

41. A mthod as in claima %4 0 Wherein the dSrb~ireMiS Of the subsritUted structme of L. and B and optional aubstitutents On L' are selected frorn the grotsp consisting of methyl, triflouromethyL, ethyl, n-propyl. n-buryl. n-pernyl i-propyL, t- butyL, methoxy, etlioxy, propoxy, Cl, 13r, F. cyano. airo, hyroxY, amInO, meThylamino, dimethylatnino, ethYlamino, and diethYINMiiio.

42. A method as in ClaiM 4 0 wherein the substituents of the substituted srructurs of 13 and L' and Optional substitureats on L' are independently selected from the group consisting of muethyl, triilourornethyl, ten-buryL methoxy, CI, and dhinetbylarnino.

43. A netod as inclaim40. wherein L' is substituted by C(O)P,.

44. A method of claim 4 3 wheivin is MRaR.- DATED this 13 1hday of February, 2004 BAYER CORPORATION By Their Patent Attorneys DAVIES COLLISON CAVE 138