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KINASE INHIBITORS USEFUL FOR THE TREATMENT OF MYLEOPROLIFIC DISEASES AND OTHER PROLIFERATIVE DISEASES

Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, leukemias, papillary thyroid carcinoma, non small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, mastocyctosis, mast cell leukemia, a disease caused by c-Abl kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, or a disease caused by c-Kit kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof.

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3-[5- or 3-Substituted-5- or 3-isoxazolyl]-1-allyl or alkyl-4-substituted-5-substituted or unsubstituted-2-imidazolidinones

Disclosed are compounds such as 3-[5-(1,1-dimethylethyl)-3-isoxazolyl]-1-methyl-4-hydroxy-2-imidazolidinone; their control of weeds such as johnsongrass; the process of making them; and intermediates for making them, the compounds being represented by a Formula I: STR1 wherein A is STR2 where R is an alkyl of up to six carbon atoms; an alkenyl of up to five carbon atoms; an alkynyl of up to five carbon atoms; a cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; a haloalkyl of up to six carbon atoms; –R4 –O–R5, or –R4 –S–R5, where R4 is an alkylene of up to six carbon atoms and R5 is an alkyl of up to six carbon atoms; STR3 where Z is nitro (NO2), chloro (Cl), bromo (Br), fluoro (F), or R5, and n is 0, 1, 2, or 3; R1 is an alkyl of up to three carbon atoms, or allyl; R2 is hydroxy (OH), chloro (Cl) or bromo (Br); and R3 is hydrogen (H), an alkyl of up to four carbon atoms, allyl, or hydroxy (OH).

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

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More research is needed about 3-(tert-Butyl)isoxazol-5-amine

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Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1, 1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E

The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAFV600E results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAFV600E inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAFV600E-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAFV600E versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAFV600E-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.

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BENZONITRILE DERIVATIVES AS KINASE INHIBITORS

Compounds of the formula I, in which R1, R2, X and Y have the meanings indicated in Claim 1, are inhibitors of TBK1 and IKKepsilon and can be employed, inter alia, for the treatment of cancer and inflammatory diseases.

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AZETIDINE 2 -CARBOXAMIDE DERIVATIVES WHICH MODULATE THE CB2 RECEPTOR

Compounds of the formula (I), (II) and (III) which modulate the CB2 receptor are disclosed. Compounds according to the invention bind to and are agonists of the CB2 receptor, and are useful for treating inflammation. Those compounds which are agonists are additionally useful for treating pain.

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An efficient synthesis of fused 3-formylpyridines and 5-formylpyrimidines

Cyclization of 2-dimethylaminomethylene-1,3-bis(dimethylimonio)propane diperchlorate with various amino heterocycles led to the formation of a series of fused heterocyclic systems containing a 3-formylpyridine or 5-formylpyrimidine unit. Georg Thieme Verlag Stuttgart.

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Discovery of a new class of p38 kinase inhibitors

The MAP kinase p38 has been implicated in cytokine signaling, and its inhibitors are potentially useful for the treatment of arthritis and osteoporosis. Novel small-molecule inhibitors of p38 kinase were derived from a combinatorial chemistry effort and exhibit activity in the nanomolar range. Very steep structure-activity relationships are observed within this class. (C) 2000 Elsevier Science Ltd.

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TRPV4 ANTAGONISTS

The present invention relates to spirocarbamate compounds of Formula (I) in which R1, (R2)Y, R3, R4, X and A have the meanings given in the specification. The invention further provides pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof and relates to their use of these compounds as TRPV4 antagonists in treating or preventing conditions associated with TRPV4 imbalance.

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Method for preparing 3-amino-5-(t-butyl)isoxazole

3-Amino-5-(t-butyl)isoxazole, in optimum yield, is prepared in a stepwise manner by reacting a lower alkyl pivalate and acetonitrile in the presence of a base to yield pivalyl acetonitrile, which in turn is allowed to react with hydroxylamine under controlled conditions of pH to yield the desired compound. The compound is a useful intermediate for the preparation of isoxazole derivatives having utility as herbicides.

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