US20030105091A1 - Omega-carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors - Google Patents

Omega-carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors Download PDF

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US20030105091A1
US20030105091A1 US10/086,417 US8641702A US2003105091A1 US 20030105091 A1 US20030105091 A1 US 20030105091A1 US 8641702 A US8641702 A US 8641702A US 2003105091 A1 US2003105091 A1 US 2003105091A1
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substituted
phenyl
heteroatoms selected
group
halogen
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Bernd Riedl
Jacques Dumas
Uday Khire
Timothy Lowinger
Scott William
Roger Smith
Jill Wood
Mary-Katherine Monahan
Reina Naero
Joel Renick
Robert Sibley
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Bayer Healthcare LLC
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Priority to US10/086,417 priority Critical patent/US20030105091A1/en
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Priority to US11/845,597 priority patent/US7897623B2/en
Priority to US12/249,386 priority patent/US20090118268A1/en
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Definitions

  • 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.
  • 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, TNF ⁇ or stress (p38, JNK).
  • the MAP kinases are responsible for the activation of a wide variety of transcription factors and proteins involved in transcriptional control of cytokine production.
  • a pair of novel protein kinases involved in the regulation of cytokine synthesis was recently described by a group from SmithKline Beecham (Lee et al. Nature 1994, 372, 739).
  • CSAIDSs cytokine suppressive anti-inflammatory drugs
  • CSAIDs function by interfering with m-RNA translational events during cytokine biosynthesis. Inhibition of p38 has been shown to inhibit both cytokine production (eg., TNF ⁇ , IL-1, IL-6, IL-8) and proteolytic enzyme production (eg., MMP-1, MMP-3) in vitro and/or in vivo.
  • cytokine production eg., TNF ⁇ , IL-1, IL-6, IL-8
  • proteolytic enzyme production eg., MMP-1, MMP-3
  • TNF ⁇ production and/or signaling have linked TNF ⁇ production and/or signaling to a number of diseases including rheumatoid arthritis (Maini. J. Royal Coll. Physicians London 1996, 30, 344).
  • excessive levels of TNF ⁇ 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.
  • TNF ⁇ 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.
  • HIV human immunodeficiency virus
  • 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 human immunodeficiency virus
  • MMP matrix-destroying metalloprotease
  • TMPs tissue inhibitors of metalloproteinases
  • Inhibitors of p38 are active in animal models of TNF ⁇ production, including a muirne lipopolysaccharide (LPS) model of TNF ⁇ 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.
  • LPS muirne lipopolysaccharide
  • This invention provides compounds, generally described as aryl ureas, including both aryl and heteroaryl analogues, which inhibit p38 mediated events and thus inhibit the production of cytokines (such as TNF ⁇ , IL-1 and IL-8) and proteolytic enzymes (such as MMP-1 and MMP-3).
  • cytokines such as TNF ⁇ , IL-1 and IL-8
  • 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 TNF ⁇ , 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.
  • proteases include, but are not limited to collagenase (MMP-1) and stromelysin (MMP-3).
  • 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
  • NIDDM non
  • HIV human immunodeficiency virus
  • 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, e.g., disease states mediated by one or more cytokines or proteolytic enzymes produced and/or activated by a p38 mediated process.
  • 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.
  • D is —NH—C(O)—NH—
  • A is a substituted moiety of up to 40 carbon atoms of the formula: -L-(M-L 1 ) q , where L is a 5 or 6 membered cyclic structure 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 1 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,
  • L 1 is substituted by at least one substituent selected from the group consisting of —SO 2 R x , —C(O)R x and —C(NR y ) R z ,
  • R y is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally halosubstituted, up to per halo,
  • R z is hydrogen or a carbon based moiety of up to 30 carbon atoms optionally containing heteroatoms selected from N, S and O 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 O and are optionally substituted by halogen;
  • R x is R z or NR a R b where R a and R b are
  • R f is hydrogen or a carbon based moiety of up to 24 carbon atoms optionally containing heteroatoms selected from N, S and O and optionally substituted by halogen, hydroxy and carbon based substituents of up to 24 carbon atoms, which optionaly contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or
  • R a and R b together form a 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O, or a substituted 5-7 member heterocyclic structure of 1-3 heteroatoms selected from N, S and O substituted by halogen, hydroxy or carbon based substituents of up to 24 carbon atoms, which optionally contain heteroatoms selected from N, S and O and are optionally substituted by halogen; or
  • R a or R b is —C(O)—, a C 1 -C 5 divalent alkylene group or a substituted C 1 -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 C 1 -C 5 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 O and are optionally substituted by halogen;
  • 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;
  • each W is independently selected from the group consisting of —CN, —CO 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 , —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 O 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 7 C(O)OR 7 and halogen up to per-halo; with each R
  • 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 Z n1 , wherein n1 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 O 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 7 , —OR 7 , —SR
  • 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, e.g., 1-4 carbon atoms in one or more of the rings can be replaced by oxygen, nitrogen or sulfur atoms.
  • Each ring typically has 3-7 atoms.
  • B can be 2- or 3-furyl, 2- or 3-thienyl, 2- or 4-triazinyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazoyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thi
  • B can be 4-methyl-phenyl, 5-methyl-2-thienyl, 4-methyl-2-thienyl, 1-methyl-3-pyrryl, 1-methyl-3-pyrazolyl, 5-methyl-2-thiazolyl or 5-methyl-1,2,4-thiadiazol-2-yl.
  • Suitable alkyl groups and alkyl portions of groups, e.g., alkoxy, etc. throughout include methyl, ethyl, propyl, butyl, etc., including all straight-chain and branched isomers such as isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
  • Suitable aryl groups which do not contain heteroatoms include, for example, phenyl and 1- and 2-naphthyl.
  • cycloalkyl refers to cyclic structures with or without alkyl substituents such that, for example, “C 4 cycloakyl” includes methyl substituted cyclopropyl groups as well as cyclobutyl groups.
  • cycloalkyl as used herein also includes saturated heterocyclic groups.
  • Suitable halogen groups include F, Cl, Br, and/or I, from one to per-substitution (i.e. all H atoms on a group replaced by a halogen atom) being possible where an alkyl group is substituted by halogen, mixed substitution of halogen atom types also being possible on a given moiety.
  • the invention also relates to compounds per se, of formula I.
  • Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benzenesulphonic acid, p-toluenesulfonic acid, 1-naphthalenesulfonic 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.
  • basic salts of inorganic and organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, trifluoromethanesulfonic acid, benz
  • pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li + Na + or K + ), alkaline earth cations (e.g., Mg +2 , Ca +2 or Ba +2 ), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation or peralkylation of triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabiclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,8-diazabicyclo[5.4.0]undec-7-ene (D
  • 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.
  • 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)).
  • 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.
  • 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)).
  • 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.
  • Nitroaryls are commonly formed by electrophilic aromatic nitration using HNO 3 , or an alternative NO 2 + source. Nitroaryls may be further elaborated prior to reduction. Thus, nitroaryls substituted with
  • potential leaving groups may undergo substitution reactions on treatment with nucleophiles, such as thiolate (exemplified in Scheme II) or phenoxide. Nitroaryls may also undergo Ullman-type coupling reactions (Scheme II).
  • Nitroaryls may also undergo transition metal mediated cross coupling reactions.
  • nitroaryl electrophiles such as nitroaryl bromides, iodides or triflates
  • 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 (5).
  • aryl nucleophiles such as arylboronic acids (Suzuki reactions, exemplified below), aryltins (Stille reactions) or arylzincs (Negishi reaction) to afford the biaryl (5).
  • Either nitroaryls or anilines may be converted into the corresponding arenesulfonyl chloride (7) on treatment with chlorosulfonic acid.
  • Reaction of the sulfonyl chloride with a fluoride source, such as KF then affords sulfonyl fluoride (8).
  • Reaction of sulfonyl fluoride 8 with trimethylsilyl trifluoromethane in the presence of a fluoride source, such as tris(dimethylamino)sulfonium difluorotrimethylsiliconate (TASF) leads to the corresponding trifluoromethylsulfone (9).
  • TASF tris(dimethylamino)sulfonium difluorotrimethylsiliconate
  • sulfonyl chloride 7 may be reduced to the arenethiol (10), for example with zinc amalgum.
  • Reaction of thiol 10 with CHClF 2 in the presence of base gives the difluoromethyl mercaptam (11), 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. Khim. 1970, 6, 568).
  • non-symmetrical urea formation may involve reaction of an aryl isocyanate (14) with an aryl amine (13).
  • the heteroaryl isocyanate may be synthesized from a heteroaryl amine by treatment with phosgene or a phosgene equivalent, such as trichloromethyl chloroformate (diphosgene), bis(trichloromethyl) carbonate (triphosgene), or N,N′-carbonyldiimidazole (CDI).
  • the isocyanate may also be derived from a heterocyclic carboxylic acid derivative, such as an ester, an acid halide or an anhydride by a Curtius-type rearrangement.
  • 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.
  • DPPA diphenylphosphoryl azide
  • ureas may be further manipulated using methods familiar to those skilled in the art.
  • the invention also includes pharmaceutical compositions including a compound of Formula I, and a physiologically acceptable carrier.
  • the compounds may be administered orally, topically, parenterally, by inhalation or spray, vaginally, rectally or sublingually in dosage unit formulations.
  • administration by injection includes intravenous, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques.
  • Dermal administration may include topical application or transdermal administration.
  • One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired other active ingredients.
  • compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions.
  • Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • 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.
  • 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.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • 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.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
  • 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.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • 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.
  • a dispersing or wetting agent exemplified by those already mentioned above.
  • Additional excipients for example, sweetening, flavoring and coloring agents, may also be present.
  • the compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • 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. WO94/04157 Mar. 3, 1994).
  • a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bacteriocides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms.
  • 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 include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated C 8 -C 18 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated C 8 -C 18 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, di
  • 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 18 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 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.
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the compounds may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
  • suitable non-irritating excipient include cocoa butter and polyethylene glycols.
  • the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily 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.
  • the optimal course of treatment i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt 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 FIG. I are producible from known compounds (or from starting materials which, in turn, are producible from known compounds), e.g., through the general preparative methods shown above.
  • the activity of a given compound to inhibit raf kinase can be routinely assayed, e.g., according to procedures disclosed below.
  • the following examples are for illustrative purposes only and are not intended, nor should they be construed to limit the invention in any way.
  • N-cyclohexyl-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 2-methoxy-5-(trifluoromethyl)aniline, 4-tert-butyl-2-nitroaniline, 3-amino-2-naphthol, ethyl 4-isocyanatobenzoate, N-acetyl-4-chloro-2-methoxy-5-(trifluoromethyl)aniline and 4-chloro-3-(trifluoromethyl)phenyl isocyanate were purchased and used without further purification.
  • TLC Thin-layer chromatography
  • Visualization of plates was effected by one or more of the following techniques: (a) ultraviolet illumination, (b) exposure to iodine vapor, (c) immersion of the plate in a 10% solution of phosphomolybdic acid in ethanol followed by heating, (d) immersion of the plate in a cerium sulfate solution followed by heating, and/or (e) immersion of the plate in an acidic ethanol solution of 2,4-dinitrophenylhydrazine followed by heating.
  • Column chromatography flash chromatography
  • Electron impact ionization was performed with electron energy of 70 eV and a trap current of 300 ⁇ A.
  • Liquid-cesium secondary ion mass spectra FAB-MS
  • FAB-MS Liquid-cesium secondary ion mass spectra
  • CI-MS Chemical ionization mass spectra
  • 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.
  • GC-MS Gas chromatography-ion selective mass spectra
  • Step 1a Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide via the Menisci Reaction
  • the resulting opaque brown solution was diluted with H 2 O (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3 ⁇ 500 mL). The organic phases were washed separately with a saturated NaCl solution (3 ⁇ 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 oil crystallized at 0° C.
  • Step 1b Synthesis of 4-chloropyridine2-carbonyl Chloride HCl Salt via Picolinic Acid
  • Step 3a Synthesis of 4-chloro-N-methyl-2-pyridinecarboxamide from methyl 4-chloropyridine-2-carboxylate
  • Step 2 Synthesis of 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chlorophenyl (222-trifluoro)acetamide
  • One of the anilines to be coupled was dissolved in dichloroethane (0.10 M). This solution was added to a 8 mL vial (0.5 mL) containing dichloroethane (1 mL). To this was added a 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.
  • N-(4-chloro-3-((trifluoromethyl)phenyl)-N′-(4-(N-(3-(N-(3-pyridyl)carbamoyl)phenyl)carbamoyl)phenyl) urea (0.024 g, 59%): TLC (70% EtOAc/30% hexane) R f 0.12.
  • N-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-((4-(3-(5-methoxycarbonylpyridyl) oxyphenyl) urea was synthesized from 4-chloro-3-(trifluoromethyl)phenyl isocyanate and 4-(3-(5-methoxycarbonylpyridyl) oxyaniline (Method A14, Step 2) in a manner analogous to Method C1a.
  • Entry 1 4-(3-N-Methylcarbamoylphenoxy)aniline was prepared according to Method A13. According to Method C3, 3-tert-butylaniline was reacted with bis(trichloromethyl)carbonate followed by 4-(3-N-Methylcarbamoylphenoxy)aniline to afford the urea.
  • Entry 2 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene.
  • 4-(4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline.
  • Step C3 3-tert-butylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea.
  • Entry 7 4-(1-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. According to Method 2d, 5-tert-butyl-2-methoxyaniline was reacted with CDI followed by 4-(1-oxoisoindolin-5-yloxy)aniline to afford the urea.
  • Entry 8 4-(3-N-Methylcarbamoylphenoxy)aniline was synthesized according to Method A13. According to Method C2a, 2-methoxy-5-(trifluoromethyl)aniline was reacted with CDI followed by 4-(3-N-methylcarbamoylphenoxy)aniline to afford the urea.
  • Entry 9 4-Hydroxyacetophenone was reacted with 2-chloro-5-nitropyridine to give 4-(4-acetylphenoxy)-5-nitropyridine according to Method A3, Step 2. According to Method A8, Step 4, 4-(4-acetylphenoxy)-5-nitropyridine was reduced to 4-(4-acetylphenoxy)-5-aminopyridine.
  • 2-Methoxy-5-(trifluoromethyl)aniline was converted to 2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1. The isocyanate was reacted with 4-(4-acetylphenoxy)-5-aminopyridine according to Method C1a to afford the urea.
  • Entry 10 4-Fluoro-1-nitrobenzene and p-hydroxyacetophenone were reacted according to Method A13, Step 1 to afford the 4-(4-acetylphenoxy)-1-nitrobenzene.
  • 4-(4-4-Acetylphenoxy)-1-nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline.
  • Method C3 5-(trifluoromethyl)-2-methoxybutylaniline was reacted with bis(trichloromethyl) carbonate followed by 4-(4-acetylphenoxy)aniline to afford the urea.
  • Entry 11 4-Chloro-N-methyl-2-pyridinecarboxamide, 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 DMP to give 3-(-2-(N-methylcarbamoyl)4-pyridyloxy)aniline.
  • Method C4 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
  • Entry 12 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide.
  • 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 3-(2-carbamoyl-4-pyridyloxy)aniline.
  • Method C2a 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
  • Entry 14 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide.
  • 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline.
  • Method C4 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
  • Entry 16 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized according to Method A5. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. The isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-methylaniline according to Method C1c to afford the urea.
  • Entry 17 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline according to Method C1a to afford the urea.
  • Entry 18 According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.
  • Entry 19 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.
  • 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-chloroaniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.
  • Entry 21 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-1-aniline. According to Method C1a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-methylsulfonylphenoxy)-1-aniline to afford the urea.
  • Entry 22 4-(3-carbamoylphenoxy)-1-nitrobenzene was reduced to 4-(3-carbamoylphenoxy)aniline according to Method A15, Step 4. According to Method C1a, 5-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-carbamoylphenoxy)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 5 -(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.
  • 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione according to Method C1a 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-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.
  • Entry 25 4-(1-Oxoisoindolin-5-yloxy)aniline was synthesized according to Method A12. 5-(Trifluoromethyl)-2-methoxyaniline was treated with CDI, followed by 4-(1-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 nitrobenzene was reduced according to Method A13, Step 4 to afford 4-(4-acetylphenoxy)aniline, which was converted to the 4-(4-(1-(N-methoxy)iminoethyl)phenoxyaniline HCl salt according to Method A16.
  • 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.
  • Entry 27 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to Method C1a to afford the urea.
  • Entry 29 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline.
  • 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.
  • 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline according to Method C1a 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-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1.
  • Entry 31 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a to afford the urea.
  • N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide according to Method D4, Step 2.
  • Entry 32 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a to afford the urea.
  • N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to afford the amide.
  • Entry 33 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B 1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a to afford the urea.
  • N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with N,N-dimethylethylenediamine according to Method D4, Step 2 to afford the amide.
  • Entry 34 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl) urea, which was coupled with 3-aminopyridine according to Method D1c.
  • Entry 35 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl) urea, which was coupled with N-(4-fluorophenyl)piperazine according to Method D1c.
  • Entry 36 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl) urea, which was coupled with 4-fluoroaniline according to Method D1c.
  • Entry 38 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl) urea, which was coupled with 5-amino-2-methoxypyridine according to Method D1c.
  • Entry 39 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl) urea, which was coupled with 4-morpholinoaniline according to Method D1c.
  • Entry 40 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N′-(3-carboxyphenyl) urea, which was coupled with N-(2-pyridyl)piperazine according to Method D1c.
  • Entry 41 4-(3-(N-Methylcarbamoyl)phenoxy)aniline was synthesized according to Method A13. According to Method C3, 4-chloro-3-(trifluoromethyl)aniline was converted to the isocyanate, then reacted with 4-(3-(N-Methylcarbamoyl)phenoxy)aniline to afford the urea.
  • Entry 42 4-(2-N-Methylcarbamyl-4-pridyloxy)aniline was synthesized according to Method A2. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-N-methylcarbamyl-4-pyridyloxy)aniline according to Method C1a to afford the urea.
  • Entry 43 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide.
  • 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to form 4-(2-carbamoyl-4-pyridyloxy)aniline.
  • Method C1a 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
  • Entry 44 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide.
  • 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A2, Step 4 to form 3-(2-carbamoyl-4-pyridyloxy)aniline.
  • Method C1a 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
  • Entry 45 4-Chloro-N-methyl-2-pyridinecarboxamide, 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-methylcarbamoyl)-4-pyridyloxy)aniline.
  • Method C1a 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
  • Entry 46 5-(4Aminophenoxy)isoindoline-1,3-dione was synthesized according to Method A3. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.
  • Entry 47 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-methylaniline was synthesized according to Method A5. According to Method C1c, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)isoindoline-1,3-dione to afford the urea.
  • Entry 48 4-(3-N-Methylsulfamoyl)phenyloxy)aniline was synthesized according to Method A15. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.
  • Entry 49 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the urea.
  • Entry 50 According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline to afford the urea.
  • Entry 51 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)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-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-3-chloroaniline to afford the urea.
  • Entry 53 4-(4-Methylthiophenoxy)-1-nitrobenzene was oxidized according to Method A19, Step 1 to give 4-(4-methylsulfonylphenoxy)-1-nitrobenzene. The nitrobenzene was reduced according to Method A19, Step 2 to give 4-(4-methylsulfonylphenoxy)-1-aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-methylsulfonylphenoxy)-1-aniline to afford the urea.
  • Entry 54 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method A15, Step 2 to afford 4-(4-(N-methylsulfamoyl)phenoxy)benzene. 4-(4-(N-Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3.
  • Entry 55 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene.
  • the methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene.
  • the nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline.
  • the aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to Method C1a to afford the urea.
  • Entry 56 5-Hydroxy-2-methylpyridine was coupled with 1-fluoro-4-nitrobenzene according to Method A18, Step 1 to give 4-(5-(2-Methyl)pyridyloxy)-1-nitrobenzene.
  • the methylpyridine was oxidized according to the carboxylic acid, then esterified according to Method A18, Step 2 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)-1-nitrobenzene.
  • the nitrobenzene was reduced according the Method A18, Step 3 to give 4-(5-(2-methoxycarbonyl)pyridyloxy)aniline.
  • the aniline was reacted with 4-chloro-3-(trifluoromethyl)phenyl isocyanate according to Method C1a 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-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-5-pyridyloxy)phenyl) urea.
  • Entry 59 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-amninophenol according to Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
  • Entry 60 4-Hydroxyacetophenone was reacted with 4-fluoronitrobenzene according to Method A13, 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)iminoethyl) phenoxyaniline HCl salt according to Method A16.
  • Method C1a 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-acetylphenoxy)aniline to afford the urea.
  • Entry 61 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 4-(2-aminoethyl)morpholine according to Method A13, Step 3 to give 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-morpholinylethyl)carbamoyl)phenoxy)aniline.
  • Entry 62 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 1-(2-aminoethyl)piperidine according to Method A13, Step 3 to give 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(2-piperidylethyl)carbamoyl)phenoxy)aniline.
  • Entry 63 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with tetrahydrofurfurylamine according to Method A13, Step 3 to give 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene. According to Method A13 Step 4, 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-(tetrahydrofurylmethyl)carbamoyl)phenoxy)aniline.
  • Entry 64 4-(3-Carboxyphenoxy)-1-nitrobenzene was synthesized according to Method A13, Step 2. 4-(3-Carboxyphenoxy)-1-nitrobenzene was coupled with 2-aminomethyl-1-ethylpyrrolidine according to Method A13, Step 3 to give 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene.
  • Step 4 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline.
  • Method C1a 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(N-((1-methylpyrrolidinyl)methyl)carbamoyl)phenoxy)aniline to afford the urea.
  • Entry 65 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to afford the urea.
  • Entry 66 4-Chloropyridine-2-carbonyl chloride was reacted with isopropylamine according to Method A2, Step 3b. The resulting 4-chloro-N-isopropyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-isopropylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
  • N-(4-Chloro-3-(trifluoromethyl)phenyl-N′-(4-carboxyphenyl) urea was coupled with 3-methylcarbamoylaniline according to Method D1b to give N-(4-chloro-3-(trifluoromethyl)phenyl-N′-(4-(3-methylcarbamoylphenyl)carbamoylphenyl) urea.
  • Entry 68 5-(4-Aminophenoxy)-2-methylisoindoline-1,3-dione was synthesized according to Method A9. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 5-(4-aminophenoxy)-2-methylisoindoline-1,3-dione to afford the urea.
  • Entry 69 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline to afford the urea.
  • Entry 70 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-(2-morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea.
  • Entry 71 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a to afford the urea.
  • N-(4-Chloro-3-(trifluoromethyl)phenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl) oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with 4-(2-aminoethyl)morpholine to afford the amide.
  • Entry 72 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a to afford the urea. N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, Step 1, and the corresponding acid was coupled with methylamine according to Method D4, Step 2 to afford the amide.
  • Entry 73 4-(3-(5-Methoxycarbonyl)pyridyloxy)aniline was synthesized according to Method A14. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1a to afford the urea.
  • N-(5-(Trifluoromethyl)-2-methoxyphenyl)-N′-(4-(3-(5-methoxycarbonylpyridyl)oxy)phenyl) urea was saponified according to Method D4, 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-carbonyl chloride HCl salt was reacted with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide.
  • 4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.
  • Entry 75 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-(5-methoxycarbonyl)pyridyloxy)aniline according to Method C1f to afford the urea, which was coupled with 3-aminopyridine according to Method D1c.
  • Entry 76 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to afford the urea, which was coupled with N-(4-acetylphenyl)piperazine according to Method D1c.
  • Entry 77 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to afford the urea, which was coupled with 4-fluoroaniline according to Method D1c.
  • Entry 78 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to afford the urea, which was coupled with 4-(dimethylamino)aniline according to Method D1c.
  • Entry 79 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to afford the urea, which was coupled with N-phenylethylenediamine according to Method D1c.
  • Entry 80 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to afford the urea, which was coupled with 2-methoxyethylamine according to Method D1c.
  • Entry 81 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to afford the urea, which was coupled with 5-amino-2-methoxypyridine according to Method D1c.
  • Entry 82 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to afford the urea, which was coupled with 4-morpholinoaniline according to Method D1c.
  • Entry 83 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 4-Chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-carboxyphenoxy)aniline according to Method C1f to afford the urea, which was coupled with N-(2-pyridyl)piperazine according to Method D1c.
  • Entry 84 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with 2-hydroxyethylamine according to Method A2, Step 3b to form 4-chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide.
  • 4-Chloro-N-(2-triisopropylsilyloxy)ethylpyridine-2-carboxamide was reacted with triisopropylsilyl chloride, followed by 4-aminophenol according to Method A17 to form 4-(4-(2-(N-(2-triisopropylsilyloxy)ethylcarbamoyl)pyridyloxyaniline.
  • Entry 85 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Bromo-3-(trifluoromethyl)aniline was converted to 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
  • Entry 86 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethylphenyl isocyanate was reacted with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline to afford the urea.
  • Entry 87 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-chloroaniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.
  • Entry 88 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.
  • Entry 89 4-Chloro-N-methyl-2-pyridinecarboxamide, 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-methylcarbamoyl)-4-pyridyloxy)aniline.
  • 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.
  • Method C1a 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
  • Entry 90 According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.
  • Entry 91 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.
  • Entry 92 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 4-aminothiophenol according to Method A2, Step 4 to give 4-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.
  • Entry 93 4-Chloro-N-methylpyridinecarboxamide was synthesized as described in Method A2, Step 3b. The chloropyridine was reacted with 3-aminothiophenol according to Method A2, Step 4 to give 3-(4-(2-(N-methylcarbamoyl)phenylthio)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1.
  • Entry 94 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline was synthesized according to Method A10. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-(2-Morpholin-4-ylethyl)carbamoyl)pyridyloxy)aniline to afford the urea.
  • Entry 95 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1.
  • Entry 96 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)-2-chloroaniline was synthesized according to Method A6. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1.
  • Entry 97 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-chloroaniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1.
  • Entry 98 4-Chloro-N-methyl-2-pyridinecarboxamide, 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-methylcarbamoyl)-4-pyridyloxy)aniline.
  • 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7.
  • 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1.
  • Entry 99 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1.
  • Entry 100 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was synthesized according to Method A7. 4-Chloro-2-methoxy-5-(trifluoromethyl)aniline was converted into 4-chloro-2-methoxy-5-(trifluoromethyl)phenyl isocyanate according to Method B1.
  • Entry 101 4-Chloro-N-methyl-2-pyridinecarboxamide, 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-methylcarbamoyl)-4-pyridyloxy)aniline.
  • 2-Amino-3-methoxynaphthalene was synthesized as described Method A1.
  • 2-amino-3-methoxynaphthalene was reacted with bis(trichloromethyl) carbonate followed by 3-(-2-(N-methylcarbamoyl)-4-pyridyloxy)aniline to form the urea.
  • Entry 102 4-(2-(N-Methylcarbamoyl)-4-pyridyloxy)aniline was synthesized according to Method A2. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was synthesized according to Method A4. 5-tert-Butyl-2-(2,5-dimethylpyrrolyl)aniline was reacted with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline according to Method C2d to afford the urea.
  • Entry 103 4-Chloro-N-methyl-2-pyridinecarboxamide was synthesized according to Method A2, Step 3b. 4-Chloro-N-methyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline. According to Method C2b, reaction of 3-amino-2-methoxyquinoline with CDI followed by 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline afforded bis(4-(2-(N-methylcarbamoyl)-4-pyridlyoxy)phenyl)urea.

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Cited By (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6872726B2 (en) 2002-08-08 2005-03-29 Boehringer Ingelheim Pharmaceuticals Inc. Fluorinated di-aryl urea compounds
WO2006060318A2 (en) 2004-11-30 2006-06-08 Amgen Inc. Quinolines and quinazoline analogs and their use as medicaments for treating cancer
US20060216288A1 (en) * 2005-03-22 2006-09-28 Amgen Inc Combinations for the treatment of cancer
US20070054909A1 (en) * 1999-06-30 2007-03-08 Daiichi Pharmaceutical Co., Ltd. VLA-4 inhibitor compounds
US20070104731A1 (en) * 1994-07-01 2007-05-10 Dermot Kelleher Helicobacter proteins and vaccines
US20070110765A1 (en) * 1996-01-04 2007-05-17 William Bryne Helicobacter pylori bacterioferritin
WO2007089445A2 (en) 2006-01-27 2007-08-09 Amgen Inc. Ang2 and vegf inhibitor combinations
US20070243204A1 (en) * 1992-03-02 2007-10-18 Antonello Covacci Helicobacter pylori proteins useful for vaccines and diagnostics
US20080051416A1 (en) * 2004-10-05 2008-02-28 Smithkline Beecham Corporation Novel Compounds
WO2008079291A2 (en) 2006-12-20 2008-07-03 Amgen Inc. Substituted heterocycles and methods of use
WO2008086014A2 (en) 2007-01-09 2008-07-17 Amgen Inc. Bis-aryl amide derivatives useful for the treatment of cancer
WO2008103277A2 (en) 2007-02-16 2008-08-28 Amgen Inc. Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors
US20080242707A1 (en) * 2005-03-07 2008-10-02 Bayer Healthcare Ag Pharmaceutical Composition for the Treatment of Cancer
US20090098157A1 (en) * 2001-08-31 2009-04-16 Novartis Vaccines And Diagnostics S.R.I. Helicobacter Pylori Vaccination
US20100016449A1 (en) * 2006-12-21 2010-01-21 Boehringer Ingelheim International Gmbh Formulations with Improved Bioavailability
US20100081812A1 (en) * 2005-12-21 2010-04-01 Roger Smith Substituted pyrimidine derivatives useful in the treatment of cancer and other disorders
US20110003859A1 (en) * 2008-02-29 2011-01-06 Array Biopharma Inc. N- (6-aminopyridin-3-yl) -3- (sulfonamido) benzamide derivatives as b-raf inhibitors for the treatment of cancer
US20110003809A1 (en) * 2008-02-29 2011-01-06 Array Biopharma Inc. Imidazo [4,5-b] pyridine derivatives used as raf inhibitors
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US20110092479A1 (en) * 2008-02-29 2011-04-21 Array Biopharma Inc. Pyrazole [3, 4-b] pyridine raf inhibitors
US20110110889A1 (en) * 2008-02-29 2011-05-12 Array Bio Pharma Inc. Raf inhibitor compounds and methods of use thereof
EP2341067A1 (en) 2003-07-18 2011-07-06 Amgen, Inc Specific binding agents to hepatocyte growth factor
US8076488B2 (en) 2003-02-28 2011-12-13 Bayer Healthcare Llc Bicyclic urea derivatives useful in the treatment of cancer and other disorders
WO2011161217A2 (en) 2010-06-23 2011-12-29 Palacký University in Olomouc Targeting of vegfr2
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8242147B2 (en) 2002-02-11 2012-08-14 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
WO2012129344A1 (en) 2011-03-23 2012-09-27 Amgen Inc. Fused tricyclic dual inhibitors of cdk 4/6 and flt3
EP2578583A1 (en) 2006-07-14 2013-04-10 Amgen Inc. Fused heterocyclic derivatives and methods of use
EP2589610A1 (en) 2007-08-21 2013-05-08 Amgen, Inc Human c-fms antigen binding proteins
WO2013132044A1 (en) 2012-03-08 2013-09-12 F. Hoffmann-La Roche Ag Combination therapy of antibodies against human csf-1r and uses thereof
US20130324551A1 (en) * 2011-02-24 2013-12-05 Nerviano Medical Sciences S.R.L. Thiazolylphenyl-benzenesulfonamido derivatives as kinase inhibitors
WO2014036022A1 (en) 2012-08-29 2014-03-06 Amgen Inc. Quinazolinone compounds and derivatives thereof
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
WO2016112111A1 (en) 2015-01-08 2016-07-14 The Board Of Trustees Of The Leland Stanford Junior University Factors and cells that provide for induction of bone, bone marrow, and cartilage
EP3170824A1 (en) 2008-01-15 2017-05-24 Amgen, Inc 6-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)-1,6-naphthyridin-5(6h)-one derivatives as c-met inhibitors
US9745288B2 (en) 2011-08-16 2017-08-29 Indiana University Research And Technology Corporation Compounds and methods for treating cancer by inhibiting the urokinase receptor
WO2018119183A2 (en) 2016-12-22 2018-06-28 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2018217651A1 (en) 2017-05-22 2018-11-29 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2019051291A1 (en) 2017-09-08 2019-03-14 Amgen Inc. Inhibitors of kras g12c and methods of using the same
WO2019213526A1 (en) 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2019213516A1 (en) 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2019217691A1 (en) 2018-05-10 2019-11-14 Amgen Inc. Kras g12c inhibitors for the treatment of cancer
WO2019232419A1 (en) 2018-06-01 2019-12-05 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2019241157A1 (en) 2018-06-11 2019-12-19 Amgen Inc. Kras g12c inhibitors for treating cancer
WO2020050890A2 (en) 2018-06-12 2020-03-12 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2020102730A1 (en) 2018-11-16 2020-05-22 Amgen Inc. Improved synthesis of key intermediate of kras g12c inhibitor compound
WO2020106647A2 (en) 2018-11-19 2020-05-28 Amgen Inc. Combination therapy including a krasg12c inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
WO2020106640A1 (en) 2018-11-19 2020-05-28 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2020132651A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Kif18a inhibitors
WO2020132649A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
WO2020132653A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
WO2020132648A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Kif18a inhibitors
WO2021026101A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
WO2021026100A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Pyridine derivatives as kif18a inhibitors
WO2021026099A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
WO2021026098A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
WO2021081212A1 (en) 2019-10-24 2021-04-29 Amgen Inc. Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer
WO2021097212A1 (en) 2019-11-14 2021-05-20 Amgen Inc. Improved synthesis of kras g12c inhibitor compound
WO2021097207A1 (en) 2019-11-14 2021-05-20 Amgen Inc. Improved synthesis of kras g12c inhibitor compound
WO2021108683A1 (en) 2019-11-27 2021-06-03 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
US11236091B2 (en) 2019-05-21 2022-02-01 Amgen Inc. Solid state forms
US11426404B2 (en) 2019-05-14 2022-08-30 Amgen Inc. Dosing of KRAS inhibitor for treatment of cancers
WO2022235866A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
WO2024081916A1 (en) 2022-10-14 2024-04-18 Black Diamond Therapeutics, Inc. Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives
US12459896B2 (en) 2022-03-07 2025-11-04 Amgen Inc. Process for preparing 4-methyl-2-propan-2-yl-pyridine-3-carbonitrile

Families Citing this family (144)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7517880B2 (en) 1997-12-22 2009-04-14 Bayer Pharmaceuticals Corporation Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas
US7329670B1 (en) 1997-12-22 2008-02-12 Bayer Pharmaceuticals Corporation Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas
US6858617B2 (en) 1998-05-26 2005-02-22 Smithkline Beecham Corporation Substituted imidazole compounds
WO2000025791A1 (en) 1998-11-04 2000-05-11 Smithkline Beecham Corporation Pyridin-4-yl or pyrimidin-4-yl substituted pyrazines
US20020065296A1 (en) * 1999-01-13 2002-05-30 Bayer Corporation Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors
WO2000042012A1 (en) * 1999-01-13 2000-07-20 Bayer Corporation φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
EP1690853B1 (en) * 1999-01-13 2010-03-10 Bayer HealthCare LLC Use of omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7351834B1 (en) 1999-01-13 2008-04-01 Bayer Pharmaceuticals Corporation ω-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
AU1781601A (en) 1999-11-23 2001-06-04 Smithkline Beecham Corporation 3,4-dihydro-(1h)quinazolin-2-one compounds as csbp/p38 kinase inhibitors
EP1233951B1 (en) 1999-11-23 2005-06-01 SmithKline Beecham Corporation 3,4-dihydro-(1h)quinazolin-2-one compounds as csbp/p38 kinase inhibitors
US6608052B2 (en) 2000-02-16 2003-08-19 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US7235551B2 (en) 2000-03-02 2007-06-26 Smithkline Beecham Corporation 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases
US7235576B1 (en) * 2001-01-12 2007-06-26 Bayer Pharmaceuticals Corporation Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
EE200300437A (et) 2001-03-09 2004-02-16 Pfizer Products Inc. Triasolopüridiinid kui põletikuvastased ained
CA2440211A1 (en) 2001-03-09 2002-09-19 Pfizer Products Inc. Benzimidazole anti-inflammatory compounds
ES2247271T3 (es) 2001-04-04 2006-03-01 Pfizer Products Inc. Nuevos benzotriazoles como compuestos antiinflamatorios.
MXPA03009000A (es) 2001-04-13 2004-02-12 Boehringer Ingelheim Pharma Compuestos benzo-fusionados 1,4-disustituidos.
CA2443950C (en) * 2001-04-20 2011-10-18 Bayer Corporation Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas
US7371763B2 (en) 2001-04-20 2008-05-13 Bayer Pharmaceuticals Corporation Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas
EP1709965A3 (en) 2001-07-11 2006-12-27 Boehringer Ingelheim Pharmaceuticals, Inc. Methods of treating cytokine mediate diseases
JP2005503400A (ja) * 2001-09-13 2005-02-03 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド サイトカイン媒介病の治療方法
GB0124941D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124938D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124928D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124931D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
US20080108672A1 (en) * 2002-01-11 2008-05-08 Bernd Riedl Omega-Carboxyaryl Substituted Diphenyl Ureas As Raf Kinase Inhibitors
MXPA04007830A (es) * 2002-02-11 2005-07-01 Bayer Pharmaceuticals Corp Arilureas como inhibidores de cinasa.
US10653684B2 (en) 2002-02-11 2020-05-19 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
ATE386030T1 (de) 2002-02-25 2008-03-15 Boehringer Ingelheim Pharma 1,4-disubstituierte benzokondensierte cycloalkyl- harnstoffverbindungen zur behandlung von zytokinvermittelten erkrankungen
TW200406374A (en) 2002-05-29 2004-05-01 Novartis Ag Diaryl urea derivatives useful for the treatment of protein kinase dependent diseases
DE60310730T2 (de) 2002-07-09 2007-05-16 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmazeutische zusammensetzungen aus anticholinergica und p38 kinase hemmern zur behandlung von erkrankungen der atemwege
EP1539121A4 (en) 2002-08-29 2008-08-13 Scios Inc METHOD OF REQUESTING OSTEOGENESIS
US7005523B2 (en) 2002-08-30 2006-02-28 Pfizer Inc. Cycloalkyl-[4-(trifluorophenyl)-oxazol-5yl]-triazolo-pyridines
US7012143B2 (en) 2002-08-30 2006-03-14 Dombroski Mark A Cycloalkyl-[4-(difluorophenyl)-oxazol-5-yl]-triazolo-pyridines
US7037923B2 (en) 2002-08-30 2006-05-02 Pfizer, Inc. Alkyl-[4-(trifluorophenyl)-oxazol-5-yl]-triazolo-pyridines
US6949652B2 (en) 2002-08-30 2005-09-27 Pfizer, Inc. Crystalline forms of 3-isopropyl-6-[4-(2,5-difluoro-phenyl)-oxazol-5-yl]-[1,2,4]triazolo-[4,3-A]pyridine
PA8579601A1 (es) 2002-08-30 2004-05-07 Pfizer Prod Inc Compuestos antiinflamatorios de di y trifloruro-triazolo-piridinas
US7115644B2 (en) * 2002-09-13 2006-10-03 Boehringer Ingelheim Pharmaceuticals Inc. Heterocyclic compounds
US7144911B2 (en) 2002-12-31 2006-12-05 Deciphera Pharmaceuticals Llc Anti-inflammatory medicaments
US7279576B2 (en) 2002-12-31 2007-10-09 Deciphera Pharmaceuticals, Llc Anti-cancer medicaments
US7202257B2 (en) 2003-12-24 2007-04-10 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
CA2511970C (en) 2003-01-14 2012-06-26 Cytokinetics, Inc. Urea derivatives useful in the treatment of heart failure
CA2515190A1 (en) 2003-02-14 2004-08-26 Pfizer Products Inc. Triazolo-pyridines as anti-inflammatory compounds
DE202004021759U1 (de) * 2003-02-21 2010-10-07 ResMed Ltd., Bella Vista Nasale Anordnung
EP1603879A2 (en) * 2003-02-28 2005-12-14 Bayer Pharmaceuticals Corporation Substituted pyridine derivatives useful in the treatment of cancer and other disorders
EP1608639A2 (en) 2003-02-28 2005-12-28 Bayer Pharmaceuticals Corporation Novel bicyclic urea derivatives useful in the treatment of cancer and other disorders
GB0308186D0 (en) * 2003-04-09 2003-05-14 Smithkline Beecham Corp Novel compounds
EA010485B1 (ru) * 2003-07-23 2008-10-30 Байер Фамэсьютиклс Копэрейшн Производное n,n'-дифенилмочевины, фармацевтическая композиция (варианты) и способ лечения и предупреждения заболеваний и состояний с его использованием (варианты)
US7244441B2 (en) 2003-09-25 2007-07-17 Scios, Inc. Stents and intra-luminal prostheses containing map kinase inhibitors
US20070161677A1 (en) * 2004-01-30 2007-07-12 Merck Patent Gmbh Bisarylurea derivatives
TW200530236A (en) 2004-02-23 2005-09-16 Chugai Pharmaceutical Co Ltd Heteroaryl phenylurea
CN101010315A (zh) 2004-04-30 2007-08-01 拜耳制药公司 用于治疗癌症的取代的吡唑基脲衍生物
JP5080970B2 (ja) 2004-06-17 2012-11-21 サイトキネティクス・インコーポレーテッド 心疾患を治療するための置換尿素誘導体
US20060035893A1 (en) 2004-08-07 2006-02-16 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders
MY191349A (en) 2004-08-27 2022-06-17 Bayer Pharmaceuticals Corp New pharmaceutical compositions for the treatment of hyper-proliferative disorders
AU2011244932B9 (en) * 2004-08-27 2014-06-12 Bayer Pharmaceuticals Corporation New pharmaceutical compositions comprising 4-(4-(3-(4-chloro-3-trifluoromethyl-phenyl)-ureido)-3-fluoro-phenoxy)-pyridine-2-carboxylic acid for the treatment of hyper-proliferative disorders
KR101381454B1 (ko) 2004-09-29 2014-04-04 바이엘 인텔렉쳐 프로퍼티 게엠베하 열역학적으로 안정한 형태의 ｂａｙ 43-9006 토실레이트
EP1824843A2 (en) 2004-12-07 2007-08-29 Locus Pharmaceuticals, Inc. Inhibitors of protein kinases
JP2008523071A (ja) 2004-12-07 2008-07-03 ルーカス ファーマシューティカルズ， インコーポレイテッド Ｍａｐキナーゼの尿素インヒビター
PE20060777A1 (es) 2004-12-24 2006-10-06 Boehringer Ingelheim Int Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas
EP1676574A3 (en) 2004-12-30 2006-07-26 Johnson &amp; Johnson Vision Care, Inc. Methods for promoting survival of transplanted tissues and cells
US7538223B2 (en) 2005-08-04 2009-05-26 Cytokinetics, Inc. Compounds, compositions and methods
JP4195074B2 (ja) 2005-09-14 2008-12-10 第一三共株式会社 置換シクロアルケン誘導体
EP1953148B1 (en) 2005-10-28 2012-02-29 Takeda Pharmaceutical Company Limited Heterocyclic amide compound and use thereof
CA2627875A1 (en) 2005-10-31 2007-05-10 Bayer Pharmaceuticals Corporation Combinations comprising sorafenib and interferon for the treatment of cancer
CA2633411A1 (en) * 2005-12-15 2007-06-21 Bayer Healthcare Ag Diaryl ureas for treating inflammatory skin, eye and/or ear diseases
TW200808321A (en) 2005-12-15 2008-02-16 Cytokinetics Inc Certain chemical entities, compositions and methods
US7825120B2 (en) 2005-12-15 2010-11-02 Cytokinetics, Inc. Certain substituted ((piperazin-1-ylmethyl)benzyl)ureas
EP1959962A2 (en) 2005-12-16 2008-08-27 Cytokinetics, Inc. Certain chemical entities, compositions, and methods
EP1962852B1 (en) 2005-12-19 2017-01-25 Cytokinetics, Inc. Compounds, compositions and methods
US20080045589A1 (en) 2006-05-26 2008-02-21 Susan Kelley Drug Combinations with Substituted Diaryl Ureas for the Treatment of Cancer
JP2009543810A (ja) 2006-07-13 2009-12-10 ザイモジェネティクス， インコーポレイテッド インターロイキン２１およびチロシンキナーゼ阻害剤の併用治療の方法
AR062927A1 (es) * 2006-10-11 2008-12-17 Bayer Healthcare Ag 4- [4-( [ [ 4- cloro-3-( trifluorometil) fenil) carbamoil] amino] -3- fluorofenoxi) -n- metilpiridin-2- carboxamida monohidratada
US20100113533A1 (en) * 2006-11-14 2010-05-06 Bayer Schering Pharma Aktiengesellschaft Polymorph II of 4-[4-(Amino)-3- Fluorophenoxy]-N-Methylpyridine-2-Carboxamide
JP2010514692A (ja) 2006-12-20 2010-05-06 バイエル ヘルスケア リミティド ライアビリティ カンパニー 癌の治療に有用なヒドロキシメチルフェニルピラゾリル尿素化合物
JP5885012B2 (ja) 2007-01-19 2016-03-15 バイエル・ヘルスケア・エルエルシーＢａｙｅｒ ＨｅａｌｔｈＣａｒｅＬＬＣ Ｋｉｔ阻害剤に対して獲得した抵抗性を有する癌の処置
EP1992344A1 (en) 2007-05-18 2008-11-19 Institut Curie P38 alpha as a therapeutic target in pathologies linked to FGFR3 mutation
CL2008001626A1 (es) 2007-06-05 2009-06-05 Takeda Pharmaceuticals Co Compuestos derivados de heterociclos fusionados, agente farmaceutico que los comprende y su uso en la profilaxis y tratamiento del cancer.
JP2010533729A (ja) 2007-07-17 2010-10-28 プレキシコン，インコーポレーテッド キナーゼ調節のための化合物と方法、及びそのための適応
EP2181987B9 (en) 2007-08-23 2014-09-03 Takeda Pharmaceutical Company Limited 2-Carbonylaminobenzothiazoles and their use for the prophylaxis and treatment of cancer
US8344135B2 (en) 2007-08-29 2013-01-01 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
EP2195286A2 (en) 2007-09-10 2010-06-16 Cipla Limited Process for the preparation of a raf kinase inhibitor and intermediates for use in the process
WO2009054004A2 (en) * 2007-10-22 2009-04-30 Natco Pharma Limited Process for the preparation of sorafenib
WO2009092070A1 (en) 2008-01-17 2009-07-23 Sicor Inc. Polymorph form iii of sorafenib tosylate, sorafenib tosylate methanol solvate and sorafenib tosylate ethanol solvate, and processes for preparation thereof
DE102008031035A1 (de) 2008-06-30 2009-12-31 Dömling, Alexander, Priv.-Doz. Dr. Nexavar zur Anwendung in der Organtransplantation
WO2010033655A1 (en) * 2008-09-19 2010-03-25 Complegen, Inc. Compounds and methods for pkc theta inhibition
US8697874B2 (en) 2008-12-01 2014-04-15 Takeda Pharmaceutical Company Limited Heterocyclic compound and use thereof
JO3101B1 (ar) 2008-12-02 2017-09-20 Takeda Pharmaceuticals Co مشتقات بنزوثيازول كعوامل مضادة للسرطان
WO2010108503A1 (en) 2009-03-24 2010-09-30 Life & Brain Gmbh Promotion of neuronal integration in neural stem cell grafts
FR2945210B1 (fr) 2009-05-07 2011-07-01 Sanofi Aventis Combinaison antitumorale comprenant l'ave8062 et le sorafenib
JP2013516442A (ja) 2010-01-07 2013-05-13 アクロン・モレキュールズ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 肥満症に用いる小分子
US10166142B2 (en) 2010-01-29 2019-01-01 Forsight Vision4, Inc. Small molecule delivery with implantable therapeutic device
AR081060A1 (es) 2010-04-15 2012-06-06 Bayer Schering Pharma Ag Procedimiento para preparar 4-{4-[({[4-cloro-3-(trifluorometil)fenil]amino}carbonil)amino]-3-fluorofenoxi}-n-metilpiridin-2-carboxamida
CA2796744A1 (en) 2010-04-17 2011-10-20 Bayer Healthcare Llc Synthetic metabolites of fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
KR20130091331A (ko) 2010-07-16 2013-08-16 교와 핫꼬 기린 가부시키가이샤 함질소 방향족 복소환 유도체
CA2805874A1 (en) 2010-07-19 2012-01-26 Bayer Healthcare Llc Drug combinations with fluoro-substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions
EP2611437B1 (en) 2010-09-02 2017-03-29 Kyoto University Pharmaceutical composition for prevention and treatment of amyotrophic lateral sclerosis
JP5778161B2 (ja) 2010-09-24 2015-09-16 第一三共株式会社 置換シクロアルケン誘導体の結晶
EP2621483A1 (en) 2010-09-27 2013-08-07 Exelixis, Inc. Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases
BRPI1004176A2 (pt) * 2010-10-25 2015-08-11 Univ Rio De Janeiro Compostos aril e/ou hetero aril uréias funcionalizados; processo de síntese desses composto; composição farmacêutica contendo tais compostos e usos
WO2012068549A2 (en) 2010-11-19 2012-05-24 Forsight Vision4, Inc. Therapeutic agent formulations for implanted devices
WO2012071425A1 (en) 2010-11-22 2012-05-31 Teva Pharmaceutical Industries Ltd. Solid state forms of sorafenib besylate, and processes for preparations thereof
AU2012230809B2 (en) 2011-03-23 2017-06-29 The Regents Of The University Of California Methods and compositions for improving antiangiogenic therapy with anti-integrins
CN103402519B (zh) 2011-04-18 2015-11-25 卫材R&D管理有限公司 肿瘤治疗剂
CN102786469B (zh) * 2011-05-18 2016-09-14 中国医学科学院药物研究所 邻吡啶酰肼衍生物及其制法和药物组合物与用途
EP2799537B1 (en) 2011-12-28 2021-09-22 Kyoto Prefectural Public University Corporation Normalization of culture of corneal endothelial cells
US8461179B1 (en) 2012-06-07 2013-06-11 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
CN103570613B (zh) * 2012-07-18 2016-06-15 苏州泽璟生物制药有限公司 氘代ω-二苯基脲或其盐的多晶型物
US20150210722A1 (en) 2012-08-29 2015-07-30 Respivert Limited Kinase inhibitors
EP2890701B1 (en) 2012-08-29 2017-03-29 Respivert Limited Kinase inhibitors
US20150225373A1 (en) 2012-08-29 2015-08-13 Respivert Limited Kinase inhibitors
CN105209031A (zh) * 2012-12-27 2015-12-30 德雷克塞尔大学 针对hbv感染的新型抗病毒剂
CA2905496A1 (en) 2013-03-14 2014-09-25 Forsight Vision4, Inc. Systems for sustained intraocular delivery of low solubility compounds from a port delivery system implant
KR102283876B1 (ko) 2013-04-02 2021-07-29 옥슬러 액퀴지션즈 리미티드 키나제 저해제로서 유용한 우레아 유도체
CN105764501A (zh) 2013-07-26 2016-07-13 现代化制药公司 改善比生群治疗效益的组合物
PT3039424T (pt) 2013-08-28 2020-09-03 Crown Bioscience Inc Taicang Assinaturas de expressão genética que permitem prever a resposta de um sujeito a um inibidor multiquinase e métodos de utilização do mesmo
WO2015072580A1 (ja) 2013-11-14 2015-05-21 学校法人同志社 細胞増殖促進または細胞障害抑制による角膜内皮治療薬
EP3083604A1 (en) 2013-12-20 2016-10-26 Respivert Limited Urea derivatives useful as kinase inhibitors
BR112017002466A2 (pt) 2014-08-08 2017-12-05 Forsight Vision4 Inc formulações estáveis e solúveis de inibidores da tirosina cinase do receptor, e métodos para a sua preparação
MA40774A (fr) 2014-10-01 2017-08-08 Respivert Ltd Dérivés de diaryle-urée en tant qu'inhibiteurs de kinase p38
WO2017151409A1 (en) 2016-02-29 2017-09-08 University Of Florida Research Foundation, Incorporated Chemotherapeutic methods
PL3423061T3 (pl) 2016-03-02 2024-12-16 Medivir Aktiebolag Leczenie skojarzone sorafenibem lub regorafenibem i amidofosforanowym prolekiem troksacytabiny
JP6904970B2 (ja) 2016-03-07 2021-07-21 エナンタ ファーマシューティカルズ インコーポレイテッド Ｂ型肝炎抗ウイルス剤
CA3015978A1 (en) 2016-04-06 2017-10-12 Topivert Pharma Limited Kinase inhibitors
US10952978B2 (en) 2017-08-28 2021-03-23 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
IL276398B2 (en) 2018-01-31 2026-03-01 Deciphera Pharmaceuticals Llc Combination therapy for mastocytosis
KR102708177B1 (ko) 2018-01-31 2024-09-23 데시페라 파마슈티칼스, 엘엘씨. 위장관 기질 종양의 치료를 위한 병용 요법
EP3749654B1 (en) 2018-02-06 2025-04-23 The Board of Trustees of the University of Illinois Substituted benzothiophene analogs as selective estrogen receptor degraders
US11179322B2 (en) 2018-07-10 2021-11-23 Novocure Gmbh Methods and compositions for treating tumors with TTFields and sorafenib
UY38383A (es) 2018-09-21 2020-04-30 Enanta Pharm Inc Heterociclos funcionalizados como agentes antivirales
CN113677346A (zh) 2018-11-01 2021-11-19 希洛斯医药品股份有限公司 周期蛋白依赖性激酶7(cdk7)的抑制剂
US11198693B2 (en) 2018-11-21 2021-12-14 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
EP3938363A1 (en) 2019-03-11 2022-01-19 Teva Pharmaceuticals International GmbH Solid state forms of ripretinib
AU2020271855B2 (en) * 2019-04-12 2025-11-27 National Health Research Institutes Heterocyclic compounds as kinase inhibitors for therapeutic uses
US11738019B2 (en) 2019-07-11 2023-08-29 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
EP4725489A2 (en) 2019-08-02 2026-04-15 OneHealthCompany, Inc. Treatment of canine cancers
PT4013412T (pt) 2019-08-12 2026-03-18 Deciphera Pharmaceuticals Llc Ripretinib para o tratamento de tumores estromais gastrointestinais
LT4013412T (lt) 2019-08-12 2026-03-25 Deciphera Pharmaceuticals, Llc Ripretinibas, skirtas virškinamojo trakto stromos navikų gydymui
US11236108B2 (en) 2019-09-17 2022-02-01 Enanta Pharmaceuticals, Inc. Functionalized heterocycles as antiviral agents
CN115243681B (zh) 2019-12-30 2024-08-16 德西费拉制药有限责任公司 1-(4-溴-5-(1-乙基-7-(甲氨基)-2-侧氧基-1,2-二氢-1,6-萘啶-3-基)-2-氟苯基)-3-苯基脲的组合物
HRP20231699T1 (hr) 2019-12-30 2024-05-10 Deciphera Pharmaceuticals, Llc Formulacije inhibitora amorfne kinaze i postupci njihove primjene
WO2021188414A1 (en) 2020-03-16 2021-09-23 Enanta Pharmaceuticals, Inc. Functionalized heterocyclic compounds as antiviral agents
IT202000022636A1 (it) 2020-09-25 2022-03-25 Ente Ospedaliero Specializzato In Gastroenterologia Istituto Nazionale Di Ricovero E Cura A Caratter “terapia di combinazione di sorafenib e/o regorafenib con la proteina ricombinante umana proteoglicano-4 per il trattamento dell'epatocarcinoma”
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors

Citations (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US502504A (en) * 1893-08-01 Hermann thoms
US3284433A (en) * 1963-07-17 1966-11-08 Merck & Co Inc 4-phenoxy-carbanilides
US4111683A (en) * 1975-06-27 1978-09-05 Chevron Research Company N-alkyl or alkoxy-N'-substituted hydrocarbyl urea
US4279639A (en) * 1978-11-02 1981-07-21 Toshihiko Okamoto N-(2-Substituted-4-pyridyl)ureas and thioureas as well as plant growth regulators containing same, and method for using compounds as plant growth regulators
US4546191A (en) * 1979-03-19 1985-10-08 Ishihara Sangyo Kaisha Ltd. Trifluoromethyl-2-pyridinone or pyridinthione compounds and process for the preparation of the same
US4973675A (en) * 1989-04-13 1990-11-27 University Of Tennessee Research Center Hybrid nitrosoureidoanthracyclines having antitumor activity
US5447957A (en) * 1994-06-02 1995-09-05 Smithkline Beecham Corp. Anti-inflammatory compounds
US5559137A (en) * 1994-05-16 1996-09-24 Smithkline Beecham Corp. Compounds
US5596001A (en) * 1993-10-25 1997-01-21 Pfizer Inc. 4-aryl-3-(heteroarylureido)quinoline derivatves
US5710094A (en) * 1994-10-27 1998-01-20 Nippon Paper Industries Co. Ltd. Reversible multi-color thermal recording medium
US5773459A (en) * 1995-06-07 1998-06-30 Sugen, Inc. Urea- and thiourea-type compounds
US5780483A (en) * 1995-02-17 1998-07-14 Smithkline Beecham Corporation IL-8 receptor antagonists
US5886044A (en) * 1995-02-17 1999-03-23 Smithkline Beecham Corporation IL-8 receptor antagonists
US5891895A (en) * 1996-04-15 1999-04-06 Takeda Chemical Industries, Ltd. Hydroxypyridine derivatives their production and use
US5908865A (en) * 1996-05-13 1999-06-01 Senju Pharmaceutical Co., Ltd. Chlorhexidine gluconate-containing, stabilized aqueous pharmaceutical preparations
US5929250A (en) * 1997-01-23 1999-07-27 Smithkline Beecham Corporation IL-8 receptor antagonists
US5965573A (en) * 1996-10-23 1999-10-12 Zymogenetics, Inc. Compositions and methods for treating bone deficit conditions
US6004965A (en) * 1994-12-20 1999-12-21 Hoffmann-La Roche Inc. Sulfonamides
US6005008A (en) * 1996-02-16 1999-12-21 Smithkline Beecham Corporation IL-8 receptor antagonists
US6020345A (en) * 1996-11-21 2000-02-01 Pierre Fabre Medicament Pyridin-2-yl-methylamine derivatives, method of preparing and application as medicine
US6022884A (en) * 1997-11-07 2000-02-08 Amgen Inc. Substituted pyridine compounds and methods of use
US6040339A (en) * 1995-09-18 2000-03-21 Sankyo Company, Limited Urea derivatives having ACAT inhibitory activity, their preparation and their therapeutic and prophylactic use
US6093742A (en) * 1997-06-27 2000-07-25 Vertex Pharmaceuticals, Inc. Inhibitors of p38
US6133319A (en) * 1996-06-27 2000-10-17 Smithkline Beecham Corporation IL-8 receptor antagonists
US6143764A (en) * 1995-11-07 2000-11-07 Kirin Beer Kabushiki Kaisha Quinoline and quinazoline derivatives inhibiting platelet-derived growth factor receptor autophosphorylation and pharmaceutical compositions containing the same
US6147116A (en) * 1997-04-10 2000-11-14 Pharmacia & Upjohn Company Polyaromatic antiviral compositions
US6150415A (en) * 1996-08-13 2000-11-21 The Regents Of The University Of California Epoxide hydrolase complexes and methods therewith
US6174901B1 (en) * 1998-12-18 2001-01-16 Amgen Inc. Substituted pyridine and pyridazine compounds and methods of use
US6178399B1 (en) * 1989-03-13 2001-01-23 Kabushiki Kaisha Toshiba Time series signal recognition with signal variation proof learning
US6187799B1 (en) * 1997-05-23 2001-02-13 Onyx Pharmaceuticals Inhibition of raf kinase activity using aryl ureas
US6211373B1 (en) * 1996-03-20 2001-04-03 Smithkline Beecham Corporation Phenyl urea antagonists of the IL-8 receptor
US6218539B1 (en) * 1996-06-27 2001-04-17 Smithkline Beecham Corporation IL-8 receptor antagonists
US6242601B1 (en) * 1999-01-18 2001-06-05 Hoffman-La Roche Inc. Heterocyclic sulfamides
US6262113B1 (en) * 1996-03-20 2001-07-17 Smithkline Beecham Corporation IL-8 receptor antagonists
US6271261B1 (en) * 1996-06-27 2001-08-07 Smithkline Beecham Corporation IL-8 receptor antagonists
US6310068B1 (en) * 1995-04-05 2001-10-30 Merck Patent Gesellschaft Mit Beschrankter Haftung Benzonitriles and benzofluorides
US6339045B1 (en) * 1995-12-28 2002-01-15 Kureha Kagaku Kogyo Kabushiki Kaisha N-(unsubstituted or substituted)-4-substituted-6-(unsubstituted or substituted)phenoxy-2-pyridinecarboxamides or thiocarboxamides, processes for producing the same, and herbicides
US6344476B1 (en) * 1997-05-23 2002-02-05 Bayer Corporation Inhibition of p38 kinase activity by aryl ureas
US6380218B1 (en) * 1997-04-04 2002-04-30 Pfizer Inc Nicotinamide derivatives
US6391917B1 (en) * 1998-01-21 2002-05-21 Zymogenetics, Inc. Dialkyl ureas as calcitonin mimetics

Family Cites Families (451)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1792156A (en) * 1928-01-17 1931-02-10 Gen Aniline Works Inc 5-halogen-2-amino-1-alkyloxy and 1-aralkyloxy-benzenes and intermediate products thereof and process of preparing them
US2093265A (en) 1931-03-31 1937-09-14 Ici Ltd Process for the manufacture of diaryl ureas
US2046375A (en) 1931-06-04 1936-07-07 Ici Ltd p-halogen-omicron-alkoxy-aniline derivatives and process of preparing the same
US2288422A (en) 1938-11-11 1942-06-30 Gen Aniline & Film Corp Mixed ureas
US2973386A (en) * 1943-01-05 1961-02-28 Harry A Weldon Purification of sym dichloro-bis (2, 4, 6-trichlorophenyl)urea
DE920245C (de) 1950-04-29 1954-11-18 Variapat Ag Verfahren zur Herstellung von aromatischen, farblosen, wasserloeslichen Trifluormethyl- und Sulfosaeuregruppen enthaltenden unsymmetrischen Harnstoffen bzw. Thioharnstoffen
US2683082A (en) 1950-12-09 1954-07-06 Ethyl Corp Nu-aryl-nu'-(p-hydroxyphenyl) ureas as antioxidants for petroleum hydrocarbon fuels
US2722544A (en) 1950-12-26 1955-11-01 Variapat Ag Trifluoromethyl halogenated diphenylcarbamide sulfonic acids and their preparation
US2781330A (en) * 1953-02-09 1957-02-12 Monsanto Chemicals Rubber containing urea compound as an anti-exposure cracking agent
NL90162C (https=) 1953-03-06
US2745874A (en) 1953-06-18 1956-05-15 Geigy Ag J R Insecticidal derivatives of diphenyl urea
NL193403A (https=) * 1953-12-22 1924-02-17
GB771333A (en) 1953-12-22 1957-03-27 Geigy Ag J R Improvements relating to halogen substituted diphenyl urea and thiourea compounds and their use
GB828231A (en) 1955-10-20 1960-02-17 Geigy Ag J R Improvements relating to insecticidal compounds and their use
US2877268A (en) * 1956-12-24 1959-03-10 Monsanto Chemicals Substituted ureas
US2960488A (en) 1958-04-25 1960-11-15 Eastman Kodak Co Poly-alpha-olefins containing substituted ureas
NL254871A (https=) * 1959-08-14
NL277511A (https=) 1961-04-21
CH479557A (de) 1961-09-11 1969-10-15 Wander Ag Dr A Verfahren zur Herstellung neuer mehrbasischer Verbindungen
US3200035A (en) 1962-06-01 1965-08-10 Ciba Ltd Treatment of synthetic products, especially synthetic fibers
FR1457172A (fr) 1964-12-12 1966-10-28 Ferrania Spa Procédé pour la production d'images photographiques en couleurs et matériel photographique correspondant
FR90420E (https=) 1965-06-09 1968-02-21
US3424762A (en) * 1966-03-07 1969-01-28 Robins Co Inc A H Certain 3-ureidopyrrolidines
US3424761A (en) * 1966-03-07 1969-01-28 Robins Co Inc A H 3-ureidopyrrolidines
US3424760A (en) * 1966-03-07 1969-01-28 Robins Co Inc A H 3-ureidopyrrolidines
US3743498A (en) 1967-10-31 1973-07-03 Du Pont Method of selectively controlling undesirable vegetation
US3547940A (en) 1967-10-31 1970-12-15 Du Pont Substituted ureido isoxazoles
SE370866B (https=) 1968-03-21 1974-11-04 Ciba Geigy Ag
DE1768244A1 (de) * 1968-04-19 1971-10-14 Bayer Ag N-(2,2,4,4-Tetrafluor-1,3-benz-dioxanyl)-harnstoffe und Verfahren zu ihrer Herstellung
US3646059A (en) * 1969-05-05 1972-02-29 Du Pont Plant growth regulatory ureidopyrazoles
US3754887A (en) 1969-05-05 1973-08-28 Du Pont Ureidopyrazoles defoliants
US3668222A (en) 1969-05-14 1972-06-06 Sandoz Ltd 11-desacetoxy-wortmannin
BE754782A (fr) 1969-08-14 1971-02-12 May & Baker Ltd Derives du thiophene a action herbicide
US3823161A (en) 1970-05-07 1974-07-09 Exxon Research Engineering Co Aminothiophene derivatives
US3860645A (en) * 1973-05-23 1975-01-14 Givaudan Corp Bacteriostatic substituted carbanilides
US4212981A (en) 1973-07-27 1980-07-15 Shionogi & Co., Ltd. Process for preparing 3-isoxazolylurea derivatives
US4116671A (en) 1973-07-27 1978-09-26 Shionogi & Co., Ltd. 3-Isoxazolylcarbamate derivatives
JPS5031039A (https=) 1973-07-27 1975-03-27
US4062861A (en) 1973-07-27 1977-12-13 Shionogi & Co., Ltd. 3-Isoxazolylurea derivatives
CH575208A5 (https=) 1973-07-30 1976-05-14 Ciba Geigy Ag
US4001256A (en) * 1973-12-26 1977-01-04 The Upjohn Company Pyridylalkyl phenyl ureas and their n-oxides
US3931201A (en) 1974-01-22 1976-01-06 The Dow Chemical Company Substituted pyridinyloxy(thio)phenyl -acetamides, -ureas and urea derivatives
US4009847A (en) * 1974-04-17 1977-03-01 E. I. Du Pont De Nemours And Company 1-Tertiary-alkyl-3-(substituted thienyl)ureas and 1-tertiary-alkyl-3-(substituted thietyl)ureas as antihypertensive agents
US3990879A (en) 1974-12-26 1976-11-09 Eli Lilly And Company Method of controlling aquatic weeds
DE2637947C2 (de) 1976-08-24 1985-09-19 Bayer Ag, 5090 Leverkusen Tetrafluor-1,3-benzodioxanyl-benzoylharnstoffe, Verfahren zu ihrer Herstellung und ihre Verwendung als Insektizide
JPS5840946B2 (ja) 1976-10-29 1983-09-08 石原産業株式会社 Ｎ−ベンゾイル−ｎ′−ピリジルオキシフエニルウレア系化合物、それらの製造方法及びそれらを含有する殺虫剤
US4173637A (en) 1976-10-29 1979-11-06 Ishihara Sangyo Kaisha Ltd. N-Benzoyl-N'-pyridyloxy phenyl urea and insecticidal compositions thereof
US4071524A (en) * 1976-11-08 1978-01-31 Riker Laboratories, Inc. Derivatives of urea
US4183854A (en) * 1976-11-10 1980-01-15 John Wyeth & Brother Limited Thiazole compound
US4042372A (en) 1976-11-19 1977-08-16 Eli Lilly And Company Substituted thiadiazolotriazinediones and method of preparation
DE2817449A1 (de) 1978-04-21 1979-10-31 Bayer Ag Mittel zur regulierung des pflanzenwachstums
GB1590870A (en) 1978-05-31 1981-06-10 Shionogi & Co N-(5-t-butyl-3-isoxazolyl) alkanamide derivatives having herbicidal activity
DE2848330A1 (de) 1978-11-03 1980-05-14 Schering Ag Verfahren zur herstellung von 1,2, 3-thiadiazol-5-yl-harnstoffen
FI800559A7 (fi) 1979-03-14 1981-01-01 F Hoffmann La Roche & Co Virtsa-ainejohdannaiset.
DE2928485A1 (de) 1979-07-14 1981-01-29 Bayer Ag Verwendung von harnstoffderivaten als arzneimittel bei der behandlung von fettstoffwechselstoerungen
US4468380A (en) 1979-12-26 1984-08-28 Eli Lilly And Company Anticoccidial combinations comprising polyether antibiotics and carbanilides
CH649078A5 (de) 1980-01-25 1985-04-30 Reanal Finomvegyszergyar Verfahren zur herstellung von n-mono- oder disubstituierten n-aryl-harnstoff-derivaten.
DE3174885D1 (en) 1981-02-03 1986-07-31 Ici Plc Process for the extraction of metal values and novel metal extractants
US4526997A (en) 1981-05-06 1985-07-02 Doherty George O P O Anticoccidial combinations comprising polyether antibiotics and carbanilides
US4511571A (en) * 1981-10-20 1985-04-16 Ciba Geigy Corporation N-(2-Pyridyloxyphenyl)-N'-benzoyl ureas, pesticidal compositions containing same and pesticidal methods of use
US4623662A (en) 1985-05-23 1986-11-18 American Cyanamid Company Antiatherosclerotic ureas and thioureas
US4473579A (en) 1982-01-26 1984-09-25 American Cyanamid Company Antiatherosclerotic tetrasubstituted ureas and thioureas
DE3211851A1 (de) * 1982-03-31 1983-10-06 Basf Ag Dihydrothiophen-carbonester, verfahren zu ihrer herstellung und ihre verwendung zur bekaempfung unerwuenschten pflanzenwuchses
JPS58203957A (ja) * 1982-05-25 1983-11-28 Ube Ind Ltd 尿素誘導体の製法
IL69621A0 (en) 1982-09-02 1983-12-30 Duphar Int Res Pharmaceutical compositions having antitumor activity,comprising certain phenylurea derivatives
CA1254212A (en) * 1982-11-12 1989-05-16 Shiro Hirai Amine derivatives, salts thereof, process for preparing the same and an anti-ulcer agent containing the same
DE3305866A1 (de) 1983-02-19 1984-08-23 Basf Ag, 6700 Ludwigshafen Thiophen-carbonester, verfahren zu ihrer herstellung und ihre verwendung zur bekaempfung unerwuenschten pflanzenwuchses
US4499097A (en) * 1983-03-10 1985-02-12 American Cyanamid Company 2-(Pyridyl)imidazolyl ketones
GB8325496D0 (en) 1983-09-23 1983-10-26 Hider R C Pharmaceutical compositions
US4540566A (en) 1984-04-02 1985-09-10 Forest Laboratories, Inc. Prolonged release drug dosage forms based on modified low viscosity grade hydroxypropylmethylcellulose
JPS6120039A (ja) 1984-07-06 1986-01-28 Konishiroku Photo Ind Co Ltd ハロゲン化銀カラ−写真感光材料
US4727077A (en) 1985-02-20 1988-02-23 Ishihara Sangyo Kaisha Ltd. Benzoyl urea compounds, process for their production, and antitumorous compositions containing them
DE3529247A1 (de) 1985-05-17 1986-11-20 Bayer Ag, 5090 Leverkusen Verwendung von thienylharnstoffen und -isoharnstoffen als leistungsfoerdernde mittel bei tieren, neue thienylharnstoffe und -isoharnstoffe und ihre herstellung
DE3540377A1 (de) 1985-11-14 1987-05-21 Bayer Ag Thienooxazinone, verfahren zu ihrer herstellung und ihre verwendung als leistungsfoerderer
DE3541631A1 (de) * 1985-11-26 1987-05-27 Bayer Ag Selektiv-fungizide verwendung von thienylharnstoff-derivaten
AU594098B2 (en) 1985-12-11 1990-03-01 Ishihara Sangyo Kaisha Ltd. N-benzoyl urea compounds, antitumorous compositions containing them, and process for their preparation
EP0230400A3 (de) 1986-01-21 1990-02-14 Ciba-Geigy Ag N-3-(5-Trifluormethyl-pyridyl-2-oxy)-phenyl-N'-benzoylharnstoffe zur Bekämpfung von Helminthen an Nutztieren
JPS62185013A (ja) 1986-02-08 1987-08-13 Green Cross Corp:The 易吸収性医薬組成物
DE3612830A1 (de) 1986-04-16 1987-10-22 Basf Ag Thiadiazolylharnstoff enthaltendes mittel zur entblaetterung von pflanzen
EP0255297B1 (en) * 1986-07-31 1993-04-21 Beecham Group Plc Azabicyclic compounds, process for their preparation, and their pharmaceutical use
NZ221964A (en) * 1986-10-03 1990-03-27 Ishihara Sangyo Kaisha Benzoylurea compounds and insecticidal compositions
EP0264904A3 (en) 1986-10-23 1988-08-17 Ishihara Sangyo Kaisha, Ltd. Pharmaceutical compositions containing benzoyl urea derivatives
DE3636190A1 (de) * 1986-10-24 1988-04-28 Bayer Ag Verfahren zur herstellung von n,n-diaryl-harnstoffen
DD253997A1 (de) 1986-11-26 1988-02-10 Karl Marx Uni Buero Fuer Neuer Verfahren zur herstellung von substituierten 2-arylureidophenolen
JPH06100808B2 (ja) 1987-05-28 1994-12-12 富士写真フイルム株式会社 ハロゲン化銀カラ−写真感光材料の処理方法
ATE121742T1 (de) 1987-10-16 1995-05-15 Ciba Geigy Ag Schädlingsbekämpfungsmittel.
DE3810382A1 (de) 1988-03-26 1989-10-12 Bayer Ag 5-amino-1-phenylpyrazole, verfahren sowie 5-halogen-1-phenylpyrazole als zwischenprodukte zu deren herstellung und ihre verwendung als herbizide
JPH0223337A (ja) 1988-07-12 1990-01-25 Konica Corp 新規なカプラーを含有するハロゲン化銀写真感光材料
WO1990002112A1 (en) 1988-08-23 1990-03-08 The Nutrasweet Company Substituted aryl ureas as high potency sweeteners
JPH0278699A (ja) 1988-09-12 1990-03-19 Green Cross Corp:The ベンゾイルウレア系化合物・アルブミン複合体
FR2639636B1 (fr) 1988-11-30 1994-03-04 Novapharme Nouveaux composes heterocycliques a activite anticonvulsivante, procede de preparation et compositions therapeutiques les contenant
FR2662692B1 (fr) 1990-05-30 1995-04-28 Novapharme Derives heterocycliques doues d'activite anticonvulsivante, procede de preparation et composition pharmaceutique.
JPH02196719A (ja) 1989-01-24 1990-08-03 Green Cross Corp:The 粉末状医薬組成物
JPH02237922A (ja) 1989-01-24 1990-09-20 Green Cross Corp:The 抗ウィルス剤
EP0379915A1 (de) 1989-01-26 1990-08-01 Bayer Ag Substituierte Phenoxybenzonitril-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung als Herbizide und Pflanzenwuchsregulatoren
JPH0395153A (ja) 1989-06-15 1991-04-19 Mitsubishi Kasei Corp ジフェニル尿素誘導体
US5665543A (en) 1989-07-18 1997-09-09 Oncogene Science, Inc. Method of discovering chemicals capable of functioning as gene expression modulators
IL95860A0 (en) 1989-10-13 1991-07-18 Ciba Geigy Ag Thienylthioureas,-isothioureas and-carbodiimides
EP0425443A1 (de) 1989-10-27 1991-05-02 Ciba-Geigy Ag Injizierbares parasitizides Mittel
US5177110A (en) * 1989-10-27 1993-01-05 Ciba-Geigy Corporation Injectable parasiticidal composition
CN1034934C (zh) * 1990-06-19 1997-05-21 明治制果株式会社 血管紧张素ii拮抗性吡啶衍生物的制备方法
GB9017892D0 (en) 1990-08-15 1990-09-26 May & Baker Ltd New compositions of matter
PT98990A (pt) 1990-09-19 1992-08-31 American Home Prod Processo para a preparacao de esteres de acidos carboxilicos de rapamicina
ATE157355T1 (de) 1991-01-21 1997-09-15 Shionogi & Co 3-benzyliden-1-carbamoyl-2-pyrrolidon-analoga
JP2671693B2 (ja) 1991-03-04 1997-10-29 松下電器産業株式会社 バイオセンサおよびその製造法
US5120842A (en) 1991-04-01 1992-06-09 American Home Products Corporation Silyl ethers of rapamycin
US5185438A (en) * 1991-04-02 1993-02-09 The Trustees Of Princeton University Nucleic acids encoding hencatoporetic stem cell receptor flk-2
US5270458A (en) 1991-04-02 1993-12-14 The Trustees Of Princeton University Nucleic acids encoding fragments of hematopoietic stem cell receptor flk-2
US5100883A (en) * 1991-04-08 1992-03-31 American Home Products Corporation Fluorinated esters of rapamycin
US5118678A (en) 1991-04-17 1992-06-02 American Home Products Corporation Carbamates of rapamycin
FI921595A7 (fi) 1991-04-17 1992-10-18 American Home Prod Rapamysiinikarbamaatteja
US5721237A (en) * 1991-05-10 1998-02-24 Rhone-Poulenc Rorer Pharmaceuticals Inc. Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties
US5118677A (en) 1991-05-20 1992-06-02 American Home Products Corporation Amide esters of rapamycin
US5162360A (en) 1991-06-24 1992-11-10 Warner-Lambert Company 2-heteroatom containing urea and thiourea ACAT inhibitors
US5185358A (en) * 1991-06-24 1993-02-09 Warner-Lambert Co. 3-heteroatom containing urea and thiourea ACAT inhibitors
WO1993004170A1 (en) 1991-08-23 1993-03-04 The United States Of America Represented By The Secretary, Department Of Health And Human Services Raf protein kinase therapeutics
US5151413A (en) 1991-11-06 1992-09-29 American Home Products Corporation Rapamycin acetals as immunosuppressant and antifungal agents
FR2683818B1 (fr) 1991-11-14 1993-12-31 Adir Cie Nouveaux derives de 3-sulfonylamino-2-(1h)-quinoleinone, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
EP0630373A1 (en) * 1992-03-12 1994-12-28 Smithkline Beecham Plc Indole derivatives as 5ht1c antagonists
WO1993024458A1 (en) 1992-05-28 1993-12-09 Pfizer Inc. New n-aryl and n-heteroarylurea derivatives as inhibitors of acyl coenzyme a:cholesterol acyl transferase (acat)
ZA935112B (en) 1992-07-17 1994-02-08 Smithkline Beecham Corp Rapamycin derivatives
US5312820A (en) 1992-07-17 1994-05-17 Merck & Co., Inc. Substituted carbamoyl and oxycarbonyl derivatives of biphenylmethylamines
ZA935111B (en) 1992-07-17 1994-02-04 Smithkline Beecham Corp Rapamycin derivatives
WO1994004541A2 (en) 1992-08-12 1994-03-03 The Upjohn Company Protein kinase inhibitors and related compounds combined with taxol
US5256790A (en) 1992-08-13 1993-10-26 American Home Products Corporation 27-hydroxyrapamycin and derivatives thereof
DE4227989A1 (de) 1992-08-21 1994-06-09 Schering Ag Mittel zur transdermalen Applikation enthaltend 3-Keto-desogestrel
JP2717481B2 (ja) 1992-08-25 1998-02-18 富士写真フイルム株式会社 ハロゲン化銀カラー写真感光材料
US5258389A (en) 1992-11-09 1993-11-02 Merck & Co., Inc. O-aryl, O-alkyl, O-alkenyl and O-alkynylrapamycin derivatives
US6177401B1 (en) * 1992-11-13 2001-01-23 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften Use of organic compounds for the inhibition of Flk-1 mediated vasculogenesis and angiogenesis
WO1994014801A1 (en) 1992-12-29 1994-07-07 Smithkline Beecham Plc Heterocyclic urea derivatives as 5ht2c and 5ht2b antagonists
US5512473A (en) 1993-01-29 1996-04-30 Brent; Roger Max-interacting proteins and related molecules and methods
GB9302275D0 (en) 1993-02-05 1993-03-24 Smithkline Beecham Plc Novel compounds
TW272942B (https=) 1993-02-10 1996-03-21 Takeda Pharm Industry Co Ltd
DK41193D0 (da) 1993-04-07 1993-04-07 Neurosearch As Ionkanalaabnere
WO1994023755A1 (en) 1993-04-09 1994-10-27 Board Of Regents Of The University Of Nebraska Novel methods and compositions for the treatment of ras-activated cancer with heterotypic anti-raf antisense oligonucleotides
GB9308802D0 (en) 1993-04-28 1993-06-09 Smithkline Beecham Plc Treatment
DE4322806A1 (de) 1993-07-08 1995-01-12 Janich Gmbh & Co Vorrichtung zur Abdichtung zwischen zwei Anlagenteilen
IL110296A (en) 1993-07-16 1999-12-31 Smithkline Beecham Corp Imidazole compounds process for their preparation and pharmaceutical compositions containing them
US6514745B1 (en) * 1993-07-19 2003-02-04 The Regents Of The University Of California Oncoprotein protein kinase
US5378725A (en) * 1993-07-19 1995-01-03 The Arizona Board Of Regents Inhibition of phosphatidylinositol 3-kinase with wortmannin and analogs thereof
NZ264063A (en) * 1993-08-13 1995-11-27 Nihon Nohyaku Co Ltd N-(2-phenylpyrid-3-yl)- and n-(4-phenylpyrimidin-5-yl)-n'-phenylurea derivatives and pharmaceutical compositions
US5441947A (en) 1993-08-25 1995-08-15 Eli Lilly And Company Methods of inhibiting vascular restenosis
US5468773A (en) 1993-08-25 1995-11-21 Eli Lilly And Company Methods for inhibiting bone loss and cartilage degradation using wortmannin and its analogs
US5783664A (en) 1993-09-17 1998-07-21 Smithkline Beecham Corporation Cytokine suppressive anit-inflammatory drug binding proteins
US6361773B1 (en) * 1993-09-17 2002-03-26 Smithkline Beecham Corporation Antibodies produced against cytokine suppressive anti-inflammatory drug binding proteins
PT724588E (pt) 1993-09-17 2000-05-31 Smithkline Beecham Corp Proteina de ligacao a farmacos
US5869043A (en) * 1993-09-17 1999-02-09 Smithkline Beecham Corporation Drug binding protein
US5547966A (en) 1993-10-07 1996-08-20 Bristol-Myers Squibb Company Aryl urea and related compounds
CA2133815A1 (en) * 1993-10-12 1995-04-13 Jeffrey Alan Dodge Inhibition of phosphatidylinositol 3-kinase with viridin, demethoxyviridin, viridiol, demethoxyviridiol, virone, wortmannolone, and analogs thereof
JPH09505055A (ja) 1993-11-08 1997-05-20 スミスクライン・ビーチャム・コーポレイション サイトカイン媒介疾患治療用オキサゾール
JPH07141053A (ja) 1993-11-17 1995-06-02 Nec Niigata Ltd クロック発生回路
WO1995014023A1 (en) 1993-11-19 1995-05-26 Abbott Laboratories Semisynthetic analogs of rapamycin (macrolides) being immunomodulators
US5912253A (en) 1993-12-17 1999-06-15 Novartis Ag Rapamycin derivatives
US5700823A (en) 1994-01-07 1997-12-23 Sugen, Inc. Treatment of platelet derived growth factor related disorders such as cancers
CH686211A5 (de) 1994-01-27 1996-02-15 Ciba Geigy Ag Motten- und Koferschutzmittel.
US6524832B1 (en) 1994-02-04 2003-02-25 Arch Development Corporation DNA damaging agents in combination with tyrosine kinase inhibitors
US6811779B2 (en) 1994-02-10 2004-11-02 Imclone Systems Incorporated Methods for reducing tumor growth with VEGF receptor antibody combined with radiation and chemotherapy
DE4412334A1 (de) 1994-04-11 1995-10-19 Hoechst Ag Substituierte N-Heteroaroylguanidine, Verfahren zu ihrer Herstellung, ihre Verwendung als Medikament oder Diagnostikum sowie sie enthaltendes Medikament
US5656612A (en) 1994-05-31 1997-08-12 Isis Pharmaceuticals, Inc. Antisense oligonucleotide modulation of raf gene expression
US5744362A (en) 1994-05-31 1998-04-28 Isis Pharmaceuticals, Inc. Antisense oligonucleotide modulation of raf gene expression
US5470882A (en) 1994-06-02 1995-11-28 Smithkline Beecham Corp. Anti-inflammatory compounds
WO1995033458A1 (en) * 1994-06-02 1995-12-14 Smithkline Beecham Corporation Anti-inflammatory compounds
US5786362A (en) 1994-06-16 1998-07-28 University Of Miami Method of treating Hormone independent cancer
EP0690344A1 (en) 1994-06-29 1996-01-03 Konica Corporation Silver halide color photographic light-sensitive material
US5480906A (en) * 1994-07-01 1996-01-02 Eli Lilly And Company Stereochemical Wortmannin derivatives
FR2722319B1 (fr) 1994-07-08 1996-08-14 Thomson Csf Dispositif de visualisation couleurs
US5597719A (en) * 1994-07-14 1997-01-28 Onyx Pharmaceuticals, Inc. Interaction of RAF-1 and 14-3-3 proteins
EP0784612A1 (en) 1994-10-04 1997-07-23 Fujisawa Pharmaceutical Co., Ltd. Urea derivatives and their use as acat-inhibitors
ATE220661T1 (de) 1994-10-19 2002-08-15 Novartis Erfind Verwalt Gmbh Antivirale ether von aspartat-protease-substrat- isosteren
JP3591938B2 (ja) 1994-10-27 2004-11-24 キヤノン株式会社 インクジェット用記録媒体及びこれを用いた画像形成方法
DE69520951T2 (de) 1994-10-28 2001-11-22 Novozymes A/S, Bagsvaerd Verfahren zur chemischen ausrüstung von unlöslichen polymerfasern
US5814646A (en) 1995-03-02 1998-09-29 Eli Lilly And Company Inhibitors of amyloid beta-protein production
US5624937A (en) * 1995-03-02 1997-04-29 Eli Lilly And Company Chemical compounds as inhibitors of amyloid beta protein production
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
IL118544A (en) 1995-06-07 2001-08-08 Smithkline Beecham Corp History of imidazole, the process for their preparation and the pharmaceutical preparations containing them
US5710173A (en) 1995-06-07 1998-01-20 Sugen, Inc. Thienyl compounds for inhibition of cell proliferative disorders
EP0833828B1 (en) 1995-06-09 2002-11-20 Novartis AG Rapamycin derivatives
GB9514265D0 (en) 1995-07-13 1995-09-13 Wellcome Found Hetrocyclic compounds
US5849761A (en) 1995-09-12 1998-12-15 Regents Of The University Of California Peripherally active anti-hyperalgesic opiates
US6075040A (en) 1996-09-05 2000-06-13 Eli Lilly And Company Selective β3 adrenergic agonists
SE510846C2 (sv) 1995-11-06 1999-06-28 Moelnlycke Health Care Ab Innerförpackning för i en yttre förpackning sterilförpackade bukdukar
US5807876A (en) 1996-04-23 1998-09-15 Vertex Pharmaceuticals Incorporated Inhibitors of IMPDH enzyme
US6011029A (en) 1996-02-26 2000-01-04 Bristol-Myers Squibb Company Inhibitors of farnesyl protein transferase
US6103692A (en) 1996-03-12 2000-08-15 The General Hospital Corporation Inhibiting protein interactions
CA2252465C (en) 1996-04-23 2007-07-03 Vertex Pharmaceuticals Incorporated Urea derivatives as inhibitors of impdh enzyme
US6232299B1 (en) 1996-05-01 2001-05-15 Eli Lilly And Company Use of protein kinase C inhibitors to enhance the clinical efficacy of oncolytic agents and radiation therapy
US6417393B1 (en) 1996-05-24 2002-07-09 Neurosearch A/S Phenyl derivatives containing an acidic group, their preparation and their use as chloride channel blockers
US5910417A (en) 1996-05-31 1999-06-08 National Jewish Center For Immunology And Respiratory Medicine Regulation of cytokine production in a hematopoietic cell
WO1997049399A1 (en) 1996-06-27 1997-12-31 Smithkline Beecham Corporation Il-8 receptor antagonists
NZ329847A (en) 1996-06-29 1999-01-28 Samjin Pharm Co Ltd Piperazine derivatives and process for the preparation thereof
US6019793A (en) 1996-10-21 2000-02-01 Synthes Surgical prosthetic device
WO1998017267A1 (en) 1996-10-23 1998-04-30 Zymogenetics, Inc. Compositions and methods for treating bone deficit conditions
CA2271693C (en) * 1996-11-15 2009-01-20 The Picower Institute For Medical Research Guanylhydrazones useful for treating diseases associated with t cell activation
GB9623833D0 (en) 1996-11-16 1997-01-08 Zeneca Ltd Chemical compound
WO1998022432A1 (en) 1996-11-18 1998-05-28 Yamanouchi Pharmaceutical Co., Ltd. Novel acylamino-substituted acylanilide derivatives or pharmaceutical composition comprising the same
BR9807083A (pt) 1997-01-23 2000-04-18 Smithkline Beckman Corp Antagonistas ao receptor de il-8
CA2280048A1 (en) 1997-02-12 1998-08-13 Katherine L. Widdowson Il-8 receptor antagonists
US20020111495A1 (en) 1997-04-04 2002-08-15 Pfizer Inc. Nicotinamide acids, amides, and their mimetics active as inhibitors of PDE4 isozymes
WO1998049150A1 (en) 1997-04-25 1998-11-05 Takeda Chemical Industries, Ltd. Triazine derivatives, their production and agrochemical composition
US6210710B1 (en) 1997-04-28 2001-04-03 Hercules Incorporated Sustained release polymer blend for pharmaceutical applications
AR012634A1 (es) * 1997-05-02 2000-11-08 Sugen Inc Compuesto basado en quinazolina, composicion famaceutica que lo comprende, metodo para sintetizarlo, su uso, metodos de modulacion de la funcion deserina/treonina proteinaquinasa con dicho compuesto y metodo in vitro para identificar compuestos que modulan dicha funcion
US6316479B1 (en) 1997-05-19 2001-11-13 Sugen, Inc. Isoxazole-4-carboxamide compounds active against protein tryosine kinase related disorders
AU7726898A (en) 1997-05-22 1998-12-11 G.D. Searle & Co. Pyrazole derivatives as p38 kinase inhibitors
US6514977B1 (en) 1997-05-22 2003-02-04 G.D. Searle & Company Substituted pyrazoles as p38 kinase inhibitors
EP0983260A2 (en) 1997-05-22 2000-03-08 G.D. Searle & Co. 3(5)-HETEROARYL SUBSTITUTED PYRAZOLES AS p38 KINASE INHIBITORS
WO1998052558A1 (en) * 1997-05-23 1998-11-26 Bayer Corporation INHIBITION OF p38 KINASE ACTIVITY BY ARYL UREAS
ATE399007T1 (de) * 1997-05-23 2008-07-15 Bayer Pharmaceuticals Corp Raf kinase hemmer
US6150395A (en) 1997-05-30 2000-11-21 The Regents Of The University Of California Indole-3-carbinol (I3C) derivatives and methods
US5985592A (en) * 1997-06-05 1999-11-16 Dalhousie University Uses for pentoxifylline or functional derivatives/metabolites thereof
US6294350B1 (en) 1997-06-05 2001-09-25 Dalhousie University Methods for treating fibroproliferative diseases
CA2294057A1 (en) 1997-06-13 1998-12-17 Smithkline Beecham Corporation Novel pyrazole and pyrazoline substituted compounds
AU749337B2 (en) 1997-06-27 2002-06-27 Kureha Kagaku Kogyo Kabushiki Kaisha 6-phenoxypicolinic acid, alkylidenehydrazide derivatives, process for producing the same, and herbicide
US6525065B1 (en) * 1997-06-30 2003-02-25 Targacept, Inc. Pharmaceutical compositions and methods for effecting dopamine release
AUPP003197A0 (en) 1997-09-03 1997-11-20 Fujisawa Pharmaceutical Co., Ltd. New heterocyclic compounds
UA71555C2 (en) * 1997-10-06 2004-12-15 Zentaris Gmbh Methods for modulating function of serine/threonine protein kinases by 5-azaquinoline derivatives
WO1999020617A1 (en) 1997-10-21 1999-04-29 Active Biotech Ab Antiinflammatory thiadiazolyl ureas which act as lfa-1 and mac-1 inhibitors
BR9813331A (pt) 1997-10-31 2000-08-22 Aventis Pharma Ltd Composto, uso do mesmo, composição farmacêutica, processo para o tratamento de um paciente humano ou animal não humano que sofra ou esteja sujeito a condições que possam ser melhoradas pela administração de um inibidor da adesão celular mediada pela a4b1, e, resina
WO1999023091A1 (en) 1997-11-03 1999-05-14 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as anti-inflammatory agents
NZ503491A (en) 1997-11-10 2002-08-28 Bristol Myers Squibb Co 2-substituted amino-1,3-benzothiazole derivatives useful as protein tyrosine kinase inhibitors
US6018065A (en) 1997-11-10 2000-01-25 Advanced Technology Materials, Inc. Method of fabricating iridium-based materials and structures on substrates, iridium source reagents therefor
GB9723789D0 (en) 1997-11-12 1998-01-07 Zeneca Ltd Chemical compounds
WO1999026657A1 (en) 1997-11-25 1999-06-03 Musc Foundation For Research Development Inhibitors of nitric oxide synthase
AU1407899A (en) 1997-12-01 1999-06-16 E.I. Du Pont De Nemours And Company Fungicidal cyclic amides
US6635421B1 (en) 1997-12-09 2003-10-21 Children's Medical Center Corporation Neuropilins and use thereof in methods for diagnosis and prognosis of cancer
SK282727B6 (sk) 1997-12-19 2002-11-06 Slovakofarma, A. S. 1,3-Disubstituované močoviny - inhibítory ACAT a spôsob ich prípravy
MXPA00006233A (es) * 1997-12-22 2002-09-18 Bayer Ag Inhibicion de la actividad de la cinasa p38 utilizando ureas heterociclicas sustituidas.
US20080300281A1 (en) 1997-12-22 2008-12-04 Jacques Dumas Inhibition of p38 Kinase Activity Using Aryl and Heteroaryl Substituted Heterocyclic Ureas
SK286213B6 (sk) 1997-12-22 2008-05-06 Bayer Corporation Substituované heterocyklické močoviny, farmaceutický prípravok ich obsahujúci a ich použitie
US7329670B1 (en) * 1997-12-22 2008-02-12 Bayer Pharmaceuticals Corporation Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas
JP3887769B2 (ja) * 1997-12-22 2007-02-28 バイエル コーポレイション 対称および非対称ジフェニル尿素を用いるｐ３８キナーゼの阻害
US7517880B2 (en) 1997-12-22 2009-04-14 Bayer Pharmaceuticals Corporation Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas
ID26328A (id) 1997-12-22 2000-12-14 Bayer Ag Penghambat raf kinase menggunakan urea heterosiklik tersubstitusi aril dan heteroaril
DE69836563T2 (de) 1997-12-22 2007-05-16 Bayer Pharmaceuticals Corp., West Haven INHIBIERUNG DER p38 KINASE-AKTIVITÄT DURCH DIE VERWENDUNG VON ARYL- UND HETEROARYL-SUBSTITUIERTEN HARNSTOFFEN
US20070244120A1 (en) 2000-08-18 2007-10-18 Jacques Dumas Inhibition of raf kinase using substituted heterocyclic ureas
BR9814375A (pt) * 1997-12-22 2002-05-21 Bayer Ag Inibição de raf cinase usando difenil uréias substituìdas simétricas e assimétricas
AU1712899A (en) 1997-12-23 1999-07-12 Bristol-Myers Squibb Company 7-deoxy-6-nitrogen substituted paclitaxels
WO1999033458A1 (en) 1997-12-25 1999-07-08 Daiichi Pharmaceutical Co., Ltd. Medicinal composition for percutaneous administration
GB9800575D0 (en) 1998-01-12 1998-03-11 Glaxo Group Ltd Heterocyclic compounds
FR2774824B1 (fr) 1998-02-09 2000-04-28 Moving Magnet Tech Actionneur lineaire ameliore
CA2321480A1 (en) * 1998-02-18 1999-08-26 Laurence Anthony Seabra Treating cancer
MY132496A (en) 1998-05-11 2007-10-31 Vertex Pharma Inhibitors of p38
US6413773B1 (en) * 1998-06-01 2002-07-02 The Regents Of The University Of California Phosphatidylinositol 3-kinase inhibitors as stimulators of endocrine differentiation
UA60365C2 (uk) 1998-06-04 2003-10-15 Пфайзер Продактс Інк. Похідні ізотіазолу, спосіб їх одержання, фармацевтична композиція та спосіб лікування гіперпроліферативного захворювання у ссавця
US6667340B1 (en) 1998-06-26 2003-12-23 Arizona Board Of Regents On Behalf Of The University Of Arizona Inhibitors of phosphatidyl myo-inositol cycle
US6352977B1 (en) * 1998-07-13 2002-03-05 Aventis Pharma Limited Substituted β-alanines
US6184226B1 (en) 1998-08-28 2001-02-06 Scios Inc. Quinazoline derivatives as inhibitors of P-38 α
WO2000017175A1 (en) 1998-09-18 2000-03-30 Vertex Pharmaceuticals Incorporated INHIBITORS OF p38
US6383734B1 (en) 1998-09-30 2002-05-07 Advanced Research And Technology Institute, Inc. Method to determine inhibition of PAK3 activation of Raf-1
US6130053A (en) 1999-08-03 2000-10-10 Cell Pathways, Inc. Method for selecting compounds for inhibition of neoplastic lesions
GB9823873D0 (en) 1998-10-30 1998-12-30 Pharmacia & Upjohn Spa 2-ureido-thiazole derivatives,process for their preparation,and their use as antitumour agents
TR200102278T2 (tr) 1998-11-06 2001-12-21 Basf Aktiengesellschaft Vasküler hiperpermeabilite oluşumunun önlenmesi.
CA2352486A1 (en) 1998-11-25 2000-06-02 Genetica, Inc. Methods and reagents for increasing proliferative capacity and preventing replicative senescence
US6114517A (en) 1998-12-10 2000-09-05 Isis Pharmaceuticals Inc. Methods of modulating tumor necrosis factor α-induced expression of cell adhesion molecules
US6337338B1 (en) 1998-12-15 2002-01-08 Telik, Inc. Heteroaryl-aryl ureas as IGF-1 receptor antagonists
UY25842A1 (es) 1998-12-16 2001-04-30 Smithkline Beecham Corp Antagonistas de receptores de il-8
EP1140087A4 (en) 1998-12-18 2002-04-03 Du Pont Pharm Co N-UREIDOALKYL-PIPERIDINES FOR USE AS MODULATORS OF THE ACTIVITY OF CHIMIOKIN RECEPTORS
US6331541B1 (en) * 1998-12-18 2001-12-18 Soo S. Ko N-ureidoalkyl-piperidines as modulators of chemokine receptor activity
US6147107A (en) 1998-12-20 2000-11-14 Virginia Commonwealth University Specific inhibition of the P42/44 mitogen activated protein (map) kinase cascade sensitizes tumor cells
US20080269265A1 (en) 1998-12-22 2008-10-30 Scott Miller Inhibition Of Raf Kinase Using Symmetrical And Unsymmetrical Substituted Diphenyl Ureas
GB9828511D0 (en) 1998-12-24 1999-02-17 Zeneca Ltd Chemical compounds
AU765492B2 (en) * 1998-12-25 2003-09-18 Teikoku Hormone Mfg. Co., Ltd. Aminopyrazole derivatives
WO2000042012A1 (en) 1999-01-13 2000-07-20 Bayer Corporation φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
US7351834B1 (en) 1999-01-13 2008-04-01 Bayer Pharmaceuticals Corporation ω-Carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7928239B2 (en) 1999-01-13 2011-04-19 Bayer Healthcare Llc Inhibition of RAF kinase using quinolyl, isoquinolyl or pyridyl ureas
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
ATE538794T1 (de) 1999-01-13 2012-01-15 Bayer Healthcare Llc Gamma carboxyarylsubstituierte diphenylharnstoffverbindungen als p38 kinasehemmer
US20020065296A1 (en) 1999-01-13 2002-05-30 Bayer Corporation Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors
UA73492C2 (en) 1999-01-19 2005-08-15 Aromatic heterocyclic compounds as antiinflammatory agents
IL144461A0 (en) 1999-01-22 2002-05-23 Kirin Brewery Quinoline and quinazoline derivatives and pharmaceutical compositions containing them
AU2804400A (en) 1999-02-12 2000-08-29 Smithkline Beecham Plc Phenyl urea and phenyl thiourea derivatives as orexin receptor antagonists
MXPA01008440A (es) 1999-02-22 2002-04-24 Boehringer Ingelheim Pharma Derivados heterociclicos policiclos como agentes anti-inflamatorios..
WO2000055152A1 (en) 1999-03-12 2000-09-21 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as anti-inflammatory agents
NZ528846A (en) 1999-03-12 2005-05-27 Boehringer Ingelheim Pharma Compounds useful as anti-inflammatory agents
CA2367017C (en) 1999-03-19 2009-05-26 Vertex Pharmaceuticals Incorporated Inhibitors of impdh enzyme
CA2368631A1 (en) 1999-03-26 2000-10-05 Euro-Celtique S.A. Aryl substituted pyrazoles, imidazoles, oxazoles, thiazoles and pyrroles, and the use thereof
US6140124A (en) 1999-04-06 2000-10-31 Isis Pharmaceuticals Inc. Antisense modulation of P38 mitogen activated protein kinase expression
US6316462B1 (en) 1999-04-09 2001-11-13 Schering Corporation Methods of inducing cancer cell death and tumor regression
ATE263162T1 (de) 1999-05-05 2004-04-15 Aventis Pharma Ltd Harnstoffderivate und ihr gebrauch als zell adhesion modulatoren
HK1047236A1 (zh) 1999-05-14 2003-02-14 Imclone Llc 用表皮生长因子受体拮抗剂治疗难治的人肿瘤
HN2000000051A (es) 1999-05-19 2001-02-02 Pfizer Prod Inc Derivados heterociclicos utiles como agentes anticancerosos
TWI234557B (en) 1999-05-26 2005-06-21 Telik Inc Novel naphthalene ureas as glucose uptake enhancers
DE19927835A1 (de) 1999-06-18 2000-12-21 Clariant Gmbh Verwendung von verbesserten Cyanpigmenten in elektrophotographischen Tonern und Entwicklern, Pulverlacken und Ink-Jet-Tinten
ATE312823T1 (de) 1999-07-09 2005-12-15 Boehringer Ingelheim Pharma Verfahren zur herstellung heteroarylsubstituierter ureaverbindungen
US6958333B1 (en) 1999-07-26 2005-10-25 Banyu Pharmaceutical Co., Ltd. Biarylurea derivatives
ATE321751T1 (de) 1999-07-28 2006-04-15 Kirin Brewery Harnstoffderivate als ccr-3 rezeptor-inhibitoren
US6387900B1 (en) 1999-08-12 2002-05-14 Pharmacia & Upjohn S.P.A. 3(5)-ureido-pyrazole derivatives process for their preparation and their use as antitumor agents
US6372933B1 (en) 1999-08-26 2002-04-16 Smithkline Beecham Corporation Process for preparing certain phenyl urea compounds
AU1201801A (en) 1999-10-15 2001-08-07 Van Kampen Group, Inc., The Treatment of dermal tumors, warts, and viral infections using heat-killed p. acnes
US6420378B1 (en) 1999-10-15 2002-07-16 Supergen, Inc. Inhibition of abnormal cell proliferation with camptothecin and combinations including the same
US6794393B1 (en) 1999-10-19 2004-09-21 Merck & Co., Inc. Tyrosine kinase inhibitors
WO2001036403A1 (en) 1999-11-16 2001-05-25 Boehringer Ingelheim Pharmaceuticals, Inc. Urea derivatives as anti-inflammatory agents
CA2396579A1 (en) 1999-12-29 2001-07-05 Wyeth Tricyclic protein kinase inhibitors
US6525046B1 (en) * 2000-01-18 2003-02-25 Boehringer Ingelheim Pharmaceuticals, Inc. Aromatic heterocyclic compounds as antiinflammatory agents
US7740841B1 (en) 2000-01-28 2010-06-22 Sunnybrook Health Science Center Therapeutic method for reducing angiogenesis
JP2003521543A (ja) 2000-02-07 2003-07-15 アボット ゲーエムベーハー ウント カンパニー カーゲー ２−ベンゾチアゾリル尿素誘導体およびそのプロテインキナーゼ阻害剤としての使用
US6608052B2 (en) 2000-02-16 2003-08-19 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
US6658473B1 (en) 2000-02-25 2003-12-02 Sun Microsystems, Inc. Method and apparatus for distributing load in a computer environment
PT1259248E (pt) 2000-03-02 2005-04-29 Ludwig Inst Cancer Res Metodos para tratar, rastrear e detectar cancros que expressam o factor de crescimento vascular endotelial d
GB0005357D0 (en) 2000-03-06 2000-04-26 Smithkline Beecham Plc Compounds
AU2001235804A1 (en) 2000-03-06 2001-09-17 Astrazeneca Ab Therapy
US6667300B2 (en) 2000-04-25 2003-12-23 Icos Corporation Inhibitors of human phosphatidylinositol 3-kinase delta
US6403588B1 (en) 2000-04-27 2002-06-11 Yamanouchi Pharmaceutical Co., Ltd. Imidazopyridine derivatives
WO2002007008A1 (en) 2000-04-28 2002-01-24 Ubink Cornelis Hubertus Johann Network procurement system
US6390102B1 (en) 2000-07-14 2002-05-21 General Electric Company Silicone compositions for personal care products and method for making
EP1311277A4 (en) 2000-07-18 2004-08-25 Joslin Diabetes Center Inc METHODS OF FIBROSIS MODULATION
US6565880B2 (en) 2000-07-24 2003-05-20 Boehringer Ingelheim Pharmaceuticals, Inc. Oral dosage formulations of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea
PY0117895A (es) 2000-07-31 2003-11-03 Pfizer Prod Inc Derivados de imidazol
EP1355933A2 (en) 2000-08-04 2003-10-29 Loma Linda University Medical Center Iron regulating protein-2 (irp-2) as a diagnostic for neurodegenerative diseases
JP4993838B2 (ja) 2000-08-11 2012-08-08 バーテックス ファーマシューティカルズ インコーポレイテッド Ｐ３８のインヒビターとしてのピリジン誘導体
US20020173507A1 (en) 2000-08-15 2002-11-21 Vincent Santora Urea compounds and methods of uses
ATE321770T1 (de) 2000-08-17 2006-04-15 Kitasato Inst Pseudoerythromycin-derivate
IL154016A0 (en) 2000-08-31 2003-07-31 Pfizer Prod Inc Pyrazole derivatives and their use as protein kinase inhibitors
AU2001291172A1 (en) 2000-09-20 2002-04-02 The President And Fellows Of Harvard College Methods for the diagnosis of neoplastic disorders using angiogenin
AUPR034000A0 (en) 2000-09-25 2000-10-19 Fujisawa Pharmaceutical Co., Ltd. Aminoalcohol derivatives
DE60137273D1 (de) 2000-10-20 2009-02-12 Eisai R&D Man Co Ltd Verfahren zur Herstellung von 4-Phenoxy chinolin Derivaten
JP3768800B2 (ja) 2000-10-31 2006-04-19 キヤノン株式会社 画像形成装置
JP2004513935A (ja) 2000-11-17 2004-05-13 ノボ　ノルディスク　アクティーゼルスカブ グルカゴンアンタゴニスト／逆アゴニスト
JP2004513783A (ja) 2000-11-27 2004-05-13 ブリル，エリック，エー． 対象物を仕分けるためのシステム、方法及びプログラム
CZ20031315A3 (cs) 2000-11-28 2004-04-14 Pfizer Products Inc. Soli isothiazolkarboxamidu a jejich použití jako prostředků proti hyperproliferaci
AU2002232439A1 (en) 2000-11-29 2002-06-11 Glaxo Group Limited Benzimidazole derivatives useful as tie-2 and/or vegfr-2 inhibitors
DE60133781T2 (de) * 2000-12-08 2009-06-25 Kyowa Hakko Kogyo Co., Ltd. Orale zubereitungen mit juckreizlindernder oder antipruritischer wirkung
CN1492874A (zh) 2000-12-21 2004-04-28 大环内酯
KR100362390B1 (ko) 2000-12-29 2002-11-23 삼성전자 주식회사 화상형성장치의 현상기-토너 카트리지 조립체
US7235576B1 (en) 2001-01-12 2007-06-26 Bayer Pharmaceuticals Corporation Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
JP2004532187A (ja) 2001-01-25 2004-10-21 ギルフォード ファーマシュウティカルズ インコーポレイテッド 三置換カルボサイクリックサイクロフィリン結合化合物とその用途
FR2820136A1 (fr) 2001-01-26 2002-08-02 Aventis Pharma Sa Nouveaux derives de l'uree, leur procede de preparation, leur application a titre de medicaments, compositions pharmaceutiques et nouvelle utilisation
WO2002059081A2 (en) 2001-01-26 2002-08-01 Kirin Beer Kabushiki Kaisha Urea derivatives as inhibitors of ccr-3 receptor
US6670364B2 (en) 2001-01-31 2003-12-30 Telik, Inc. Antagonists of MCP-1 function and methods of use thereof
PL409579A1 (pl) 2001-02-19 2015-03-02 Novartis Ag Leczenie raka
UA76977C2 (en) 2001-03-02 2006-10-16 Icos Corp Aryl- and heteroaryl substituted chk1 inhibitors and their use as radiosensitizers and chemosensitizers
US6525091B2 (en) * 2001-03-07 2003-02-25 Telik, Inc. Substituted diarylureas as stimulators for Fas-mediated apoptosis
AU2002306618B2 (en) 2001-03-07 2006-11-09 Telik, Inc. Substituted diarylureas as stimulators for Fas-mediated apoptosis
MXPA03008659A (es) 2001-03-23 2005-04-08 Bayer Ag Inhibidores de rho-cinasa.
IL157946A0 (en) 2001-04-02 2004-03-28 Genentech Inc Combination therapy
MXPA03009000A (es) 2001-04-13 2004-02-12 Boehringer Ingelheim Pharma Compuestos benzo-fusionados 1,4-disustituidos.
MXPA03009361A (es) 2001-04-13 2004-01-29 Boehringer Ingelheim Pharma Compuestos de urea utilies como agentes anti-inflamatorios.
US20030207914A1 (en) 2001-04-20 2003-11-06 Bayer Corporation Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas
CA2443950C (en) 2001-04-20 2011-10-18 Bayer Corporation Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas
US7371763B2 (en) 2001-04-20 2008-05-13 Bayer Pharmaceuticals Corporation Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas
WO2002088090A2 (en) 2001-04-27 2002-11-07 Vertex Pharmaceuticals Incorporated Pyrazole derived kinase inhibitors
WO2002092576A1 (en) 2001-05-16 2002-11-21 Boehringer Ingelheim Pharmaceuticals, Inc. Diarylurea derivatives useful as anti-inflammatory agents
WO2003004523A1 (en) 2001-07-02 2003-01-16 Bayer Aktiengesellschaft Regulation of human citron rho/rac-interacting kinase
JP2004536845A (ja) 2001-07-11 2004-12-09 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド サイトカイン媒介疾患の治療方法
JP4982685B2 (ja) 2001-12-03 2012-07-25 バイエル、ファーマシューテイカルズ、コーポレイション ヒトがんを処置するための他の細胞毒剤又は細胞増殖抑制剤と組合わせたアリール尿素化合物
CA2466762A1 (en) 2001-12-04 2003-06-12 Onyx Pharmaceuticals, Inc. Raf-mek-erk pathway inhibitors to treat cancer
NZ532780A (en) 2001-12-21 2006-10-27 Wellcome Trust Isolated naturally occurring mutant human B-Raf polypeptides and nucleic acids encoding them
WO2003060111A2 (en) 2001-12-24 2003-07-24 Catalyst Biomedica Limited Cancer-specific mutants of b-raf genes and uses thereof
US20040096855A1 (en) 2001-12-24 2004-05-20 Michael Stratton Genes
US20030207872A1 (en) 2002-01-11 2003-11-06 Bayer Corporation Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US20080108672A1 (en) 2002-01-11 2008-05-08 Bernd Riedl Omega-Carboxyaryl Substituted Diphenyl Ureas As Raf Kinase Inhibitors
AU2003207961A1 (en) 2002-01-16 2003-07-30 Ramot At Tel Aviv University Ltd. Compositions and their use for enhancing and inhibiting fertilization
US6998391B2 (en) 2002-02-07 2006-02-14 Supergen.Inc. Method for treating diseases associated with abnormal kinase activity
MXPA04007830A (es) 2002-02-11 2005-07-01 Bayer Pharmaceuticals Corp Arilureas como inhibidores de cinasa.
US20040023961A1 (en) * 2002-02-11 2004-02-05 Bayer Corporation Aryl ureas with raf kinase and angiogenisis inhibiting activity
WO2003068229A1 (en) 2002-02-11 2003-08-21 Bayer Pharmaceuticals Corporation Pyridine, quinoline, and isoquinoline n-oxides as kinase inhibitors
MXPA04007832A (es) 2002-02-11 2005-09-08 Bayer Pharmaceuticals Corp Aril-ureas con actividad inhibitoria de angiogenesis.
NZ535985A (en) 2002-03-29 2007-04-27 Chiron Corp Substituted benzazoles and use thereof as RAF kinase inhibitors
US8299108B2 (en) 2002-03-29 2012-10-30 Novartis Ag Substituted benzazoles and methods of their use as inhibitors of raf kinase
DE10221524A1 (de) 2002-05-14 2003-12-04 Kmb Produktions Ag Felben Verfahren und Vorrichtung zum Herstellen von Verzehrgütern
US20040018528A1 (en) 2002-05-17 2004-01-29 Sugen, Inc. Novel biomarkers of tyrosine kinase inhibitor exposure and activity in mammals
TW200406374A (en) 2002-05-29 2004-05-01 Novartis Ag Diaryl urea derivatives useful for the treatment of protein kinase dependent diseases
US20060063782A1 (en) 2002-07-03 2006-03-23 Murray Christopher W 3-Hetero arylmethoxy ! pyridines and their analogues as p38 map kinase inhibitors
DE60322544D1 (de) 2002-08-27 2008-09-11 Merck Patent Gmbh Glycinamid-derivate als raf-kinase-hemmer
MXPA05002493A (es) 2002-09-05 2005-05-27 Neurosearch As Derivados de diarilurea y su uso como bloqueadores del canal del cloro.
JP4690889B2 (ja) 2002-10-24 2011-06-01 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング メチレン尿素誘導体
ES2421516T3 (es) 2002-11-06 2013-09-03 Dana Farber Cancer Inst Inc Composiciones para tratar el cáncer usando el inhibidor de proteasomas PS-341
PL376169A1 (en) 2002-11-15 2005-12-27 Novartis Ag Drug delivery system
ES2397380T3 (es) 2002-12-06 2013-03-06 Takeda Gmbh Procedimiento para preparar compuestos activos ópticamente puros
SE0203654D0 (sv) 2002-12-09 2002-12-09 Astrazeneca Ab New compounds
US20030232400A1 (en) 2002-12-20 2003-12-18 Susan Radka Methods of screening subjects for expression of soluble receptors of vascular endothelial growth factor (VEGF) for use in managing treatment and determining prognostic outcome
US7202257B2 (en) 2003-12-24 2007-04-10 Deciphera Pharmaceuticals, Llc Anti-inflammatory medicaments
EP1603879A2 (en) 2003-02-28 2005-12-14 Bayer Pharmaceuticals Corporation Substituted pyridine derivatives useful in the treatment of cancer and other disorders
DE602004030222D1 (de) 2003-02-28 2011-01-05 Bayer Healthcare Llc 2-oxo-1,3,5-perhydrotriazapinderivate, die sich zur behandlung von hyperproliferativen, angiogenen und entzündlichen erkrankungen eignen
US7557129B2 (en) 2003-02-28 2009-07-07 Bayer Healthcare Llc Cyanopyridine derivatives useful in the treatment of cancer and other disorders
EP1608639A2 (en) 2003-02-28 2005-12-28 Bayer Pharmaceuticals Corporation Novel bicyclic urea derivatives useful in the treatment of cancer and other disorders
US7531553B2 (en) 2003-03-21 2009-05-12 Amgen Inc. Heterocyclic compounds and methods of use
CA2520009A1 (en) 2003-03-24 2004-10-07 Merck Patent Gesellschaft Mit Beschrankter Haftung Oxamide derivatives useful as raf-kinase inhibitors
WO2004084889A1 (en) 2003-03-28 2004-10-07 Pfizer Inc. Use of protein kinase c inhibitor for suppressing sustained slow postsynaptic excitation (sspe) of enteric neurons
US6896863B2 (en) 2003-04-01 2005-05-24 E. I. Du Pont De Nemours And Company Sodium cyanide process
WO2004113274A2 (en) 2003-05-20 2004-12-29 Bayer Pharmaceuticals Corporation Diaryl ureas with kinase inhibiting activity
EP1636210A1 (en) 2003-06-05 2006-03-22 Warner-Lambert Company LLC Cycloalkyl and heterocycloalkyl substituted benzothiophenes as therapeutic agents
US20040259926A1 (en) 2003-06-05 2004-12-23 Bruendl Michelle M. 3-Aryloxy and 3-heteroaryloxy substituted benzo[b]thiophenes as therapeutic agents
WO2005002673A1 (en) 2003-07-03 2005-01-13 Astex Therapeutics Limited Raf kinase inhibitors
CA2531485C (en) 2003-07-07 2013-03-26 Merck Patent Gmbh Malonamide derivatives
AU2004255340B2 (en) 2003-07-08 2008-05-01 Novartis Ag Use of rapamycin and rapamycin derivatives for the treatment of bone loss
EP1648900A4 (en) 2003-07-11 2010-02-10 Ariad Pharma Inc PHOSPHORUS MACROCYCLES
WO2005004863A1 (en) 2003-07-11 2005-01-20 Merck Patent Gmbh Benzimidazole carboxamides as raf kinase inhibitors
CA2531859C (en) 2003-07-11 2013-08-06 Merck Patent Gesellschaft Mit Beschraenkter Haftung Benzimidazole derivatives as raf kinase inhibitors
WO2005009367A2 (en) 2003-07-17 2005-02-03 Ambit Biosciences Corporation Treatment of diseases with kinase inhibitors
EA010485B1 (ru) * 2003-07-23 2008-10-30 Байер Фамэсьютиклс Копэрейшн Производное n,n'-дифенилмочевины, фармацевтическая композиция (варианты) и способ лечения и предупреждения заболеваний и состояний с его использованием (варианты)
AR045134A1 (es) 2003-07-29 2005-10-19 Smithkline Beecham Plc Compuesto de 1h - imidazo [4,5-c] piridin-ilo, composicion farmaceutica que lo comprende, proceso para prepararla, su uso para preparar dicha composicion farmaceutica, combinacion farmaceutica, uso de la combinacion farmaceutica para la preparacion de un medicamento, procedimientos para preparar dic
DE10334663A1 (de) 2003-07-30 2005-03-10 Merck Patent Gmbh Harnstoffderivate
AU2004264948A1 (en) * 2003-08-15 2005-02-24 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Multifactorial assay for cancer detection
BRPI0414698A (pt) 2003-09-23 2006-11-28 Novartis Ag combinação de um inibidor receptor de vegf com um agente quimioterapêutico
DE10344223A1 (de) 2003-09-24 2005-04-21 Merck Patent Gmbh 1,3-Benzoxazolylderivate als Kinase-Inhibitoren
WO2005040100A1 (en) * 2003-10-15 2005-05-06 Bayer Healthcare Ag Tetrahydro-naphthalene and urea derivatives
CN1882345A (zh) 2003-10-16 2006-12-20 希龙公司 作为raf激酶抑制剂以治疗癌症的2,6－二取代的喹唑啉、喹喔啉、喹啉和异喹啉
PT1682126E (pt) 2003-10-16 2009-10-02 Novartis Vaccines & Diagnostic Benzazois substituídos e sua utilização como inibidores da quinase raf
DE10349587A1 (de) 2003-10-24 2005-05-25 Merck Patent Gmbh Benzimidazolylderivate
US20050192314A1 (en) 2003-11-13 2005-09-01 Ambit Biosciences Corporation Urea derivatives as C-kit modulators
DE10352979A1 (de) 2003-11-13 2005-06-09 Merck Patent Gmbh Pyridopyrimidinone
DE10354060A1 (de) 2003-11-19 2005-06-02 Merck Patent Gmbh Pyrrolderivate
CN1946417A (zh) 2003-12-05 2007-04-11 阿德内克休斯治疗公司 2型血管内皮生长因子受体的抑制剂
CN1889958A (zh) 2003-12-09 2007-01-03 美国政府健康及人类服务部 抑制免疫应答或治疗增生性疾病的方法
WO2005058832A1 (en) 2003-12-10 2005-06-30 Merck Patent Gmbh Diacylhydrazine derivatives
US20070134670A1 (en) 2003-12-12 2007-06-14 Bayer Pharmaceuticals Corporation Methods for prediction and prognosis of cancer, and monitoring cancer therapy
US20070161677A1 (en) 2004-01-30 2007-07-12 Merck Patent Gmbh Bisarylurea derivatives
BRPI0508970A (pt) 2004-03-19 2007-08-21 Penn State Res Found método combinatórios e composições para o tratamento de melanoma
CN101010315A (zh) 2004-04-30 2007-08-01 拜耳制药公司 用于治疗癌症的取代的吡唑基脲衍生物
MY191349A (en) * 2004-08-27 2022-06-17 Bayer Pharmaceuticals Corp New pharmaceutical compositions for the treatment of hyper-proliferative disorders
WO2006026501A1 (en) 2004-08-27 2006-03-09 Bayer Pharmaceuticals Corporation New pharmaceutical compositions for the treatment of cancer
AU2005281704A1 (en) 2004-09-06 2006-03-16 Nycomed Gmbh Novel pyrazolopyrimidines
KR101381454B1 (ko) 2004-09-29 2014-04-04 바이엘 인텔렉쳐 프로퍼티 게엠베하 열역학적으로 안정한 형태의 ｂａｙ 43-9006 토실레이트
AU2005289099B2 (en) 2004-09-29 2012-07-19 Bayer Healthcare Llc Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide
WO2006076592A1 (en) 2005-01-14 2006-07-20 Cgi Pharmaceuticals, Inc. 1,3 substituted diaryl ureas as modulators of kinase activity
SG160364A1 (en) 2005-03-07 2010-04-29 Bayer Schering Pharma Ag Pharmaceutical composition comprising an omega-carboxyaryl substituted diphenyl urea for the treatment of cancer
DE102005015253A1 (de) 2005-04-04 2006-10-05 Merck Patent Gmbh Pyrazolderivate
CA2609387A1 (en) 2005-05-27 2006-11-30 Bayer Healthcare Ag Combination therapy comprising diaryl ureas for treating diseases
KR20080018908A (ko) 2005-05-27 2008-02-28 바이엘 헬스케어 아게 암 치료용 디아릴 우레아 화합물 및 ｐｉ３, ａｋｔ 키나제또는 ｍｔｏｒ 억제제 (라파마이신)를 포함하는 병용요법
EP1937837A2 (en) 2005-07-29 2008-07-02 Siemens Healthcare Diagnostics Inc. Methods and kits for the prediction of therapeutic success, recurrence free and overall survival in cancer therapies
US20070037224A1 (en) * 2005-08-11 2007-02-15 Hamer Peter J Quantitative assays for PDGFR-beta in body fluids
CN101287706A (zh) 2005-09-21 2008-10-15 尼科梅德有限责任公司 作为组蛋白脱乙酰基酶抑制剂的磺酰基吡咯盐酸盐
BRPI0617167B8 (pt) 2005-09-21 2021-05-25 Nycomed Gmbh sulfonilpirróis como inibidores de hdac's, seu uso, composição farmacêutica e combinação
BRPI0617488A2 (pt) 2005-10-21 2011-07-26 Bayer Healthcare Llc mÉtodo para a monitoraÇço do estado de uma doenÇa associada a uma via de vegf-165 ativada por ultra-expressço ou por mutaÇço de proteÍna vegf-165 em um paciente, mÉtodo de seleÇço de terapia para um paciente humano com uma doenÇa e mÉtodo de dignàstico para detectar uma doenÇa associada a uma via de vegf-165 ativada por ultra-expressço ou por mutaÇço de proteÍna vegf-165 em um paciente
CA2627873A1 (en) 2005-10-31 2007-05-10 Scott Wilhelm Treatment of cancer with sorafenib
US8329408B2 (en) 2005-10-31 2012-12-11 Bayer Healthcare Llc Methods for prognosis and monitoring cancer therapy
CA2627875A1 (en) * 2005-10-31 2007-05-10 Bayer Pharmaceuticals Corporation Combinations comprising sorafenib and interferon for the treatment of cancer
CN101351709A (zh) 2005-11-02 2009-01-21 拜尔健康护理有限责任公司 癌症的预测和预后以及监控癌症治疗的方法
CA2628091A1 (en) 2005-11-02 2007-05-18 Bayer Healthcare Llc Methods for prediction and prognosis of cancer, and monitoring cancer therapy
CA2628849A1 (en) * 2005-11-10 2007-05-18 Bayer Healthcare Ag Diaryl urea for treating pulmonary hypertension
WO2007054215A1 (en) 2005-11-10 2007-05-18 Bayer Healthcare Ag Diaryl ureas for treating pulmonary hypertension
KR20080073745A (ko) 2005-11-14 2008-08-11 바이엘 헬스케어 엘엘씨 암의 예측 및 예후 방법, 및 암 치료 요법을 모니터하는방법
WO2007059155A1 (en) 2005-11-14 2007-05-24 Bayer Pharmaceuticals Corporation Treatment of cancers having resistance to chemotherapeutic agents
WO2007059154A2 (en) 2005-11-14 2007-05-24 Bayer Healthcare Llc Treatment of cancers with acquired resistance to kit inhibitors
JP2009518298A (ja) 2005-12-01 2009-05-07 バイエル ヘルスケア リミティド ライアビリティ カンパニー 癌治療に有用な尿素化合物
US20090227637A1 (en) 2005-12-15 2009-09-10 Olaf Weber Diaryl ureas for treating virus infections
WO2007087575A2 (en) 2006-01-24 2007-08-02 University Of Chicago Compositions and methods for treating pulmonary hypertension
MX2008010799A (es) 2006-02-22 2008-11-06 4Sc Ag Indolopiridinas como moduladores de quinesina eg5.
EP3862354A1 (en) 2006-02-22 2021-08-11 4Sc Ag Indolopyridines as eg5 kinesin modulators
US7908091B2 (en) 2006-03-17 2011-03-15 Prometheus Laboratories Inc. Methods of predicting and monitoring tyrosine kinase inhibitor therapy
WO2007123722A2 (en) 2006-03-31 2007-11-01 Bayer Healthcare Llc Methods for prediction and prognosis of cancer, and monitoring cancer therapy
US20080045589A1 (en) * 2006-05-26 2008-02-21 Susan Kelley Drug Combinations with Substituted Diaryl Ureas for the Treatment of Cancer
AU2007316558A1 (en) 2006-11-09 2008-05-15 Abbott Gmbh & Co. Kg Pharmaceutical dosage form for oral administration of tyrosine kinase inhibitor
DK2111401T3 (da) 2006-12-20 2011-05-30 Bayer Healthcare Llc 4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)-amino]-3-fluorphenoxy}-N-methylpyridin-2-carboxamid samt prodrug og salte heraf til behandling af cancer
JP2010514692A (ja) 2006-12-20 2010-05-06 バイエル ヘルスケア リミティド ライアビリティ カンパニー 癌の治療に有用なヒドロキシメチルフェニルピラゾリル尿素化合物
JP5885012B2 (ja) 2007-01-19 2016-03-15 バイエル・ヘルスケア・エルエルシーＢａｙｅｒ ＨｅａｌｔｈＣａｒｅＬＬＣ Ｋｉｔ阻害剤に対して獲得した抵抗性を有する癌の処置
EP2195286A2 (en) 2007-09-10 2010-06-16 Cipla Limited Process for the preparation of a raf kinase inhibitor and intermediates for use in the process
WO2009054004A2 (en) 2007-10-22 2009-04-30 Natco Pharma Limited Process for the preparation of sorafenib
WO2010054009A1 (en) 2008-11-07 2010-05-14 Novabay Pharmaceuticals, Inc. Antimicrobial oxazolidinone, hydantoin and imidazolidinone compositions
GB0823587D0 (en) 2008-12-29 2009-01-28 South West Refrigeration Dairy heat reclamation system
JP5821626B2 (ja) 2011-12-27 2015-11-24 富士ゼロックス株式会社 画像形成装置及びプログラム

Patent Citations (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US502504A (en) * 1893-08-01 Hermann thoms
US3284433A (en) * 1963-07-17 1966-11-08 Merck & Co Inc 4-phenoxy-carbanilides
US4111683A (en) * 1975-06-27 1978-09-05 Chevron Research Company N-alkyl or alkoxy-N'-substituted hydrocarbyl urea
US4279639A (en) * 1978-11-02 1981-07-21 Toshihiko Okamoto N-(2-Substituted-4-pyridyl)ureas and thioureas as well as plant growth regulators containing same, and method for using compounds as plant growth regulators
US4546191A (en) * 1979-03-19 1985-10-08 Ishihara Sangyo Kaisha Ltd. Trifluoromethyl-2-pyridinone or pyridinthione compounds and process for the preparation of the same
US6178399B1 (en) * 1989-03-13 2001-01-23 Kabushiki Kaisha Toshiba Time series signal recognition with signal variation proof learning
US4973675A (en) * 1989-04-13 1990-11-27 University Of Tennessee Research Center Hybrid nitrosoureidoanthracyclines having antitumor activity
US5596001A (en) * 1993-10-25 1997-01-21 Pfizer Inc. 4-aryl-3-(heteroarylureido)quinoline derivatves
US5559137A (en) * 1994-05-16 1996-09-24 Smithkline Beecham Corp. Compounds
US5447957A (en) * 1994-06-02 1995-09-05 Smithkline Beecham Corp. Anti-inflammatory compounds
US5710094A (en) * 1994-10-27 1998-01-20 Nippon Paper Industries Co. Ltd. Reversible multi-color thermal recording medium
US6004965A (en) * 1994-12-20 1999-12-21 Hoffmann-La Roche Inc. Sulfonamides
US5780483A (en) * 1995-02-17 1998-07-14 Smithkline Beecham Corporation IL-8 receptor antagonists
US5886044A (en) * 1995-02-17 1999-03-23 Smithkline Beecham Corporation IL-8 receptor antagonists
US6180675B1 (en) * 1995-02-17 2001-01-30 Smithkline Beecham Corporation IL-8 receptor antagonists
US6310068B1 (en) * 1995-04-05 2001-10-30 Merck Patent Gesellschaft Mit Beschrankter Haftung Benzonitriles and benzofluorides
US5773459A (en) * 1995-06-07 1998-06-30 Sugen, Inc. Urea- and thiourea-type compounds
US6040339A (en) * 1995-09-18 2000-03-21 Sankyo Company, Limited Urea derivatives having ACAT inhibitory activity, their preparation and their therapeutic and prophylactic use
US6143764A (en) * 1995-11-07 2000-11-07 Kirin Beer Kabushiki Kaisha Quinoline and quinazoline derivatives inhibiting platelet-derived growth factor receptor autophosphorylation and pharmaceutical compositions containing the same
US6339045B1 (en) * 1995-12-28 2002-01-15 Kureha Kagaku Kogyo Kabushiki Kaisha N-(unsubstituted or substituted)-4-substituted-6-(unsubstituted or substituted)phenoxy-2-pyridinecarboxamides or thiocarboxamides, processes for producing the same, and herbicides
US6005008A (en) * 1996-02-16 1999-12-21 Smithkline Beecham Corporation IL-8 receptor antagonists
US6262113B1 (en) * 1996-03-20 2001-07-17 Smithkline Beecham Corporation IL-8 receptor antagonists
US6211373B1 (en) * 1996-03-20 2001-04-03 Smithkline Beecham Corporation Phenyl urea antagonists of the IL-8 receptor
US5891895A (en) * 1996-04-15 1999-04-06 Takeda Chemical Industries, Ltd. Hydroxypyridine derivatives their production and use
US5908865A (en) * 1996-05-13 1999-06-01 Senju Pharmaceutical Co., Ltd. Chlorhexidine gluconate-containing, stabilized aqueous pharmaceutical preparations
US6271261B1 (en) * 1996-06-27 2001-08-07 Smithkline Beecham Corporation IL-8 receptor antagonists
US6133319A (en) * 1996-06-27 2000-10-17 Smithkline Beecham Corporation IL-8 receptor antagonists
US6218539B1 (en) * 1996-06-27 2001-04-17 Smithkline Beecham Corporation IL-8 receptor antagonists
US6150415A (en) * 1996-08-13 2000-11-21 The Regents Of The University Of California Epoxide hydrolase complexes and methods therewith
US5965573A (en) * 1996-10-23 1999-10-12 Zymogenetics, Inc. Compositions and methods for treating bone deficit conditions
US6020345A (en) * 1996-11-21 2000-02-01 Pierre Fabre Medicament Pyridin-2-yl-methylamine derivatives, method of preparing and application as medicine
US5929250A (en) * 1997-01-23 1999-07-27 Smithkline Beecham Corporation IL-8 receptor antagonists
US6043374A (en) * 1997-01-23 2000-03-28 Smithkline Beecham Corporation Benzisothiazolidine Compounds
US6015908A (en) * 1997-01-23 2000-01-18 Smithkline Beecham Corporation IL-8 receptor antagonists
US6380218B1 (en) * 1997-04-04 2002-04-30 Pfizer Inc Nicotinamide derivatives
US6147116A (en) * 1997-04-10 2000-11-14 Pharmacia & Upjohn Company Polyaromatic antiviral compositions
US6187799B1 (en) * 1997-05-23 2001-02-13 Onyx Pharmaceuticals Inhibition of raf kinase activity using aryl ureas
US6344476B1 (en) * 1997-05-23 2002-02-05 Bayer Corporation Inhibition of p38 kinase activity by aryl ureas
US6093742A (en) * 1997-06-27 2000-07-25 Vertex Pharmaceuticals, Inc. Inhibitors of p38
US6022884A (en) * 1997-11-07 2000-02-08 Amgen Inc. Substituted pyridine compounds and methods of use
US6333341B1 (en) * 1997-11-07 2001-12-25 Amgen Inc. Substituted pyridine compounds and methods of use
US6391917B1 (en) * 1998-01-21 2002-05-21 Zymogenetics, Inc. Dialkyl ureas as calcitonin mimetics
US6174901B1 (en) * 1998-12-18 2001-01-16 Amgen Inc. Substituted pyridine and pyridazine compounds and methods of use
US6242601B1 (en) * 1999-01-18 2001-06-05 Hoffman-La Roche Inc. Heterocyclic sulfamides

Cited By (125)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070243204A1 (en) * 1992-03-02 2007-10-18 Antonello Covacci Helicobacter pylori proteins useful for vaccines and diagnostics
US20070104731A1 (en) * 1994-07-01 2007-05-10 Dermot Kelleher Helicobacter proteins and vaccines
US7901907B2 (en) 1996-01-04 2011-03-08 The Provost Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth Near Dublin Process for production of Helicobacter pylori bacterioferritin
US20070110765A1 (en) * 1996-01-04 2007-05-17 William Bryne Helicobacter pylori bacterioferritin
US7897623B2 (en) 1999-01-13 2011-03-01 Bayer Healthcare Llc ω-carboxyl aryl substituted diphenyl ureas as p38 kinase inhibitors
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US8841330B2 (en) 1999-01-13 2014-09-23 Bayer Healthcare Llc Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US20070054909A1 (en) * 1999-06-30 2007-03-08 Daiichi Pharmaceutical Co., Ltd. VLA-4 inhibitor compounds
US20090098157A1 (en) * 2001-08-31 2009-04-16 Novartis Vaccines And Diagnostics S.R.I. Helicobacter Pylori Vaccination
US8618141B2 (en) 2002-02-11 2013-12-31 Bayer Healthcare Llc Aryl ureas with angiogenesis inhibiting activity
US8242147B2 (en) 2002-02-11 2012-08-14 Bayer Healthcare Llc Aryl ureas with angiogenisis inhibiting activity
US6872726B2 (en) 2002-08-08 2005-03-29 Boehringer Ingelheim Pharmaceuticals Inc. Fluorinated di-aryl urea compounds
US8076488B2 (en) 2003-02-28 2011-12-13 Bayer Healthcare Llc Bicyclic urea derivatives useful in the treatment of cancer and other disorders
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
EP2341067A1 (en) 2003-07-18 2011-07-06 Amgen, Inc Specific binding agents to hepatocyte growth factor
US20080051416A1 (en) * 2004-10-05 2008-02-28 Smithkline Beecham Corporation Novel Compounds
WO2006060318A2 (en) 2004-11-30 2006-06-08 Amgen Inc. Quinolines and quinazoline analogs and their use as medicaments for treating cancer
US20080242707A1 (en) * 2005-03-07 2008-10-02 Bayer Healthcare Ag Pharmaceutical Composition for the Treatment of Cancer
US9737488B2 (en) 2005-03-07 2017-08-22 Bayer Healthcare Llc Pharmaceutical composition for the treatment of cancer
US20060216288A1 (en) * 2005-03-22 2006-09-28 Amgen Inc Combinations for the treatment of cancer
US8580798B2 (en) 2005-12-21 2013-11-12 Bayer Intellectual Property Gmbh Substituted pyrimidine derivatives useful in the treatment of cancer and other disorders
US20100081812A1 (en) * 2005-12-21 2010-04-01 Roger Smith Substituted pyrimidine derivatives useful in the treatment of cancer and other disorders
US20090304694A1 (en) * 2006-01-27 2009-12-10 Amgen Inc. Ang2 and Vegf Inhibitor Combinations
WO2007089445A2 (en) 2006-01-27 2007-08-09 Amgen Inc. Ang2 and vegf inhibitor combinations
EP3093289A1 (en) 2006-07-14 2016-11-16 Amgen, Inc [1,2,4]triazolo[4,3-a]pyridine derivatives useful as inhibitors of the hepatocyte growth factor receptor
EP2578583A1 (en) 2006-07-14 2013-04-10 Amgen Inc. Fused heterocyclic derivatives and methods of use
WO2008079291A2 (en) 2006-12-20 2008-07-03 Amgen Inc. Substituted heterocycles and methods of use
US20100016449A1 (en) * 2006-12-21 2010-01-21 Boehringer Ingelheim International Gmbh Formulations with Improved Bioavailability
WO2008086014A2 (en) 2007-01-09 2008-07-17 Amgen Inc. Bis-aryl amide derivatives useful for the treatment of cancer
WO2008103277A2 (en) 2007-02-16 2008-08-28 Amgen Inc. Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors
EP3330292A1 (en) 2007-08-21 2018-06-06 Amgen, Inc Human c-fms antigen binding proteins
EP2589610A1 (en) 2007-08-21 2013-05-08 Amgen, Inc Human c-fms antigen binding proteins
EP2592093A1 (en) 2007-08-21 2013-05-15 Amgen, Inc Human c-fms antigen binding proteins
EP3170824A1 (en) 2008-01-15 2017-05-24 Amgen, Inc 6-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)-1,6-naphthyridin-5(6h)-one derivatives as c-met inhibitors
US8394795B2 (en) 2008-02-29 2013-03-12 Array Biopharma Inc. Pyrazole [3, 4-B] pyridine Raf inhibitors
US20110003859A1 (en) * 2008-02-29 2011-01-06 Array Biopharma Inc. N- (6-aminopyridin-3-yl) -3- (sulfonamido) benzamide derivatives as b-raf inhibitors for the treatment of cancer
US20110110889A1 (en) * 2008-02-29 2011-05-12 Array Bio Pharma Inc. Raf inhibitor compounds and methods of use thereof
US20110092479A1 (en) * 2008-02-29 2011-04-21 Array Biopharma Inc. Pyrazole [3, 4-b] pyridine raf inhibitors
US8338452B2 (en) 2008-02-29 2012-12-25 Array Biopharma Inc. Raf inhibitor compounds and methods of use thereof
US20110003809A1 (en) * 2008-02-29 2011-01-06 Array Biopharma Inc. Imidazo [4,5-b] pyridine derivatives used as raf inhibitors
WO2011161217A2 (en) 2010-06-23 2011-12-29 Palacký University in Olomouc Targeting of vegfr2
US20130324551A1 (en) * 2011-02-24 2013-12-05 Nerviano Medical Sciences S.R.L. Thiazolylphenyl-benzenesulfonamido derivatives as kinase inhibitors
US9199979B2 (en) * 2011-02-24 2015-12-01 Nerviano Medical Sciences S.R.L. Thiazolylphenyl-benzenesulfonamido derivatives as kinase inhibitors
WO2012129344A1 (en) 2011-03-23 2012-09-27 Amgen Inc. Fused tricyclic dual inhibitors of cdk 4/6 and flt3
EP2937349A1 (en) 2011-03-23 2015-10-28 Amgen Inc. Fused tricyclic dual inhibitors of cdk 4/6 and flt3
US9745288B2 (en) 2011-08-16 2017-08-29 Indiana University Research And Technology Corporation Compounds and methods for treating cancer by inhibiting the urokinase receptor
WO2013132044A1 (en) 2012-03-08 2013-09-12 F. Hoffmann-La Roche Ag Combination therapy of antibodies against human csf-1r and uses thereof
WO2014036022A1 (en) 2012-08-29 2014-03-06 Amgen Inc. Quinazolinone compounds and derivatives thereof
WO2016112111A1 (en) 2015-01-08 2016-07-14 The Board Of Trustees Of The Leland Stanford Junior University Factors and cells that provide for induction of bone, bone marrow, and cartilage
US10532042B2 (en) 2016-12-22 2020-01-14 Amgen Inc. KRAS G12C inhibitors and methods of using the same
EP4001269A1 (en) 2016-12-22 2022-05-25 Amgen Inc. Benzoisothiazole, isothiazolo[3,4-b]pyridine, quinazoline, phthalazine, pyrido[2,3-d]pyridazine and pyrido[2,3-d]pyrimidine derivatives as kras g12c inhibitors for treating lung, pancreatic or colorectal cancer
US11285135B2 (en) 2016-12-22 2022-03-29 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2018119183A2 (en) 2016-12-22 2018-06-28 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2018217651A1 (en) 2017-05-22 2018-11-29 Amgen Inc. Kras g12c inhibitors and methods of using the same
EP3974429A1 (en) 2017-05-22 2022-03-30 Amgen Inc. Precursors of kras g12c inhibitors
US11905281B2 (en) 2017-05-22 2024-02-20 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US10519146B2 (en) 2017-05-22 2019-12-31 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US11993597B2 (en) 2017-09-08 2024-05-28 Amgen Inc. Inhibitors of KRAS G12C and methods of using the same
US11306087B2 (en) 2017-09-08 2022-04-19 Amgen Inc. Inhibitors of KRAS G12C and methods of using the same
EP4403175A2 (en) 2017-09-08 2024-07-24 Amgen Inc. Inhibitors of kras g12c and methods of using the same
US10640504B2 (en) 2017-09-08 2020-05-05 Amgen Inc. Inhibitors of KRAS G12C and methods of using the same
EP4141005A1 (en) 2017-09-08 2023-03-01 Amgen Inc. Inhibitors of kras g12c and methods of using the same
WO2019051291A1 (en) 2017-09-08 2019-03-14 Amgen Inc. Inhibitors of kras g12c and methods of using the same
US11766436B2 (en) 2018-05-04 2023-09-26 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US11045484B2 (en) 2018-05-04 2021-06-29 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US12440491B2 (en) 2018-05-04 2025-10-14 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2019213526A1 (en) 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2019213516A1 (en) 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
US11090304B2 (en) 2018-05-04 2021-08-17 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2019217691A1 (en) 2018-05-10 2019-11-14 Amgen Inc. Kras g12c inhibitors for the treatment of cancer
US10988485B2 (en) 2018-05-10 2021-04-27 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2019232419A1 (en) 2018-06-01 2019-12-05 Amgen Inc. Kras g12c inhibitors and methods of using the same
US11096939B2 (en) 2018-06-01 2021-08-24 Amgen Inc. KRAS G12C inhibitors and methods of using the same
EP4268898A2 (en) 2018-06-11 2023-11-01 Amgen Inc. Kras g12c inhibitors for treating cancer
US12583854B2 (en) 2018-06-11 2026-03-24 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2019241157A1 (en) 2018-06-11 2019-12-19 Amgen Inc. Kras g12c inhibitors for treating cancer
US12083121B2 (en) 2018-06-12 2024-09-10 Amgen Inc. Substituted piperazines as KRAS G12C inhibitors
WO2020050890A2 (en) 2018-06-12 2020-03-12 Amgen Inc. Kras g12c inhibitors and methods of using the same
US11285156B2 (en) 2018-06-12 2022-03-29 Amgen Inc. Substituted piperazines as KRAS G12C inhibitors
US11299491B2 (en) 2018-11-16 2022-04-12 Amgen Inc. Synthesis of key intermediate of KRAS G12C inhibitor compound
US12391689B2 (en) 2018-11-16 2025-08-19 Amgen Inc. Synthesis of key intermediate of KRAS G12C inhibitor compound
WO2020102730A1 (en) 2018-11-16 2020-05-22 Amgen Inc. Improved synthesis of key intermediate of kras g12c inhibitor compound
US12391691B2 (en) 2018-11-16 2025-08-19 Amgen Inc. Synthesis of key intermediate of KRAS G12C inhibitor compound
EP4234546A2 (en) 2018-11-16 2023-08-30 Amgen Inc. Improved synthesis of key intermediate of kras g12c inhibitor compound
US11918584B2 (en) 2018-11-19 2024-03-05 Amgen Inc. Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
US12280056B2 (en) 2018-11-19 2025-04-22 Amgen Inc. Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
WO2020106640A1 (en) 2018-11-19 2020-05-28 Amgen Inc. Kras g12c inhibitors and methods of using the same
US11053226B2 (en) 2018-11-19 2021-07-06 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2020106647A2 (en) 2018-11-19 2020-05-28 Amgen Inc. Combination therapy including a krasg12c inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
EP4685160A2 (en) 2018-11-19 2026-01-28 Amgen Inc. Combination therapy including a krasg12c inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
US12582657B2 (en) 2018-11-19 2026-03-24 Amgen Inc. Combination therapy including a KRAS G12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
US11439645B2 (en) 2018-11-19 2022-09-13 Amgen Inc. Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
US11236069B2 (en) 2018-12-20 2022-02-01 Amgen Inc. KIF18A inhibitors
US12441736B2 (en) 2018-12-20 2025-10-14 Amgen Inc. KIF18A inhibitors
US12441705B2 (en) 2018-12-20 2025-10-14 Amgen Inc. KIF18A inhibitors
WO2020132651A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Kif18a inhibitors
WO2020132649A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
US12459932B2 (en) 2018-12-20 2025-11-04 Amgen Inc. KIF18A inhibitors
US12509442B2 (en) 2018-12-20 2025-12-30 Amgen Inc. KIF18A inhibitors
WO2020132648A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Kif18a inhibitors
WO2020132653A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
US12054476B2 (en) 2018-12-20 2024-08-06 Amgen Inc. KIF18A inhibitors
US11426404B2 (en) 2019-05-14 2022-08-30 Amgen Inc. Dosing of KRAS inhibitor for treatment of cancers
US12421234B1 (en) 2019-05-21 2025-09-23 Amgen Inc. Solid state forms
US11827635B2 (en) 2019-05-21 2023-11-28 Amgen Inc. Solid state forms
US12398133B2 (en) 2019-05-21 2025-08-26 Amgen Inc. Solid state forms
US12415806B1 (en) 2019-05-21 2025-09-16 Amgen Inc. Solid state forms
US11236091B2 (en) 2019-05-21 2022-02-01 Amgen Inc. Solid state forms
WO2021026099A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
WO2021026101A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
US12540129B2 (en) 2019-08-02 2026-02-03 Amgen Inc. KIF18A inhibitors
US12435058B2 (en) 2019-08-02 2025-10-07 Amgen Inc. KIF18A inhibitors
WO2021026100A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Pyridine derivatives as kif18a inhibitors
WO2021026098A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
WO2021081212A1 (en) 2019-10-24 2021-04-29 Amgen Inc. Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer
EP4684786A2 (en) 2019-10-24 2026-01-28 Amgen Inc. Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer
US12466825B2 (en) 2019-11-14 2025-11-11 Amgen Inc. Synthesis of KRAS G12C inhibitor compound
US12473281B2 (en) 2019-11-14 2025-11-18 Amgen Inc. Synthesis of KRAS G12C inhibitor compound
WO2021097212A1 (en) 2019-11-14 2021-05-20 Amgen Inc. Improved synthesis of kras g12c inhibitor compound
EP4700030A2 (en) 2019-11-14 2026-02-25 Amgen, Inc. Improved synthesis of kras g12c inhibitor compound
WO2021097207A1 (en) 2019-11-14 2021-05-20 Amgen Inc. Improved synthesis of kras g12c inhibitor compound
WO2021108683A1 (en) 2019-11-27 2021-06-03 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
WO2022235866A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
US12459896B2 (en) 2022-03-07 2025-11-04 Amgen Inc. Process for preparing 4-methyl-2-propan-2-yl-pyridine-3-carbonitrile
WO2024081916A1 (en) 2022-10-14 2024-04-18 Black Diamond Therapeutics, Inc. Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives

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CA2359244C (en) 2013-10-08
ATE538794T1 (de) 2012-01-15
WO2000041698A1 (en) 2000-07-20
CA2359244A1 (en) 2000-07-20
EP1158985A1 (en) 2001-12-05
HK1042251B (en) 2012-07-20
EP1158985B1 (en) 2011-12-28
ES2384160T3 (es) 2012-07-02
AU2725000A (en) 2000-08-01
US20080027061A1 (en) 2008-01-31
EP2298311A1 (en) 2011-03-23
IL144144A0 (en) 2002-05-23
ATE556713T1 (de) 2012-05-15
EP1158985A4 (en) 2008-03-12
US20090118268A1 (en) 2009-05-07
HK1155944A1 (en) 2012-06-01
US7897623B2 (en) 2011-03-01

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