Pill eth 445

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Bicyclic carbocycles having 7 to 12 atoms can be arranged, for example, as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo [5,6] or [6,6] system, or as bridged systems such as bicyclo[2. Spiro carbocycles including one or more quaternary carbon atoms are also included within the scope of this definition.

Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopentenyl, l-cyclopentenyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohexenyl, l-cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantanyl, and the like. Some aryl groups are represented in the exemplary structures as "Ar". Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring.

Typical aryl groups include, but are not limited to, radicals derived from benzene phenyl , substituted benzenes, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like.

Aryl groups are optionally substituted independently with one or more substituents described herein. Some arylene groups are represented in the exemplary structures as "Ar". Arylene includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical arylene groups include, but are not limited to, radicals derived from benzene phenylene , substituted benzenes, naphthalene, anthracene, biphenylene, indenylene, indanylene, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like.

Arylene groups are optionally substituted. The terms "heterocycle," "heterocyclyl" and "heterocyclic ring" are used interchangeably herein and refer to a saturated or a partially unsaturated i. A heterocycle may be a monocycle having 3 to 7 ring members 2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P, and S or a bicycle having 7 to 10 ring members 4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S , for example: a bicyclo [4,5], [5,5], [5,6], or [6,6] system.

Heterocycles are described in Paquette, Leo A. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, dihydroisoquinolinyl, tetrahydroisoquinolinyl, pyrazolidinylimidazolinyl, imidazolidinyl, 2-oxaazabicyclo[2.

Spiro moieties are also included within the scope of this definition. Spiro heterocyclyl radicals include 1,7- diazaspiro[4. The heterocycle groups herein are optionally substituted independently with one or more substituents described herein. The term "heteroaryl" refers to a monovalent aromatic radical of 5-, 6-, or 7-membered rings, and includes fused ring systems at least one of which is aromatic of atoms, containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur.

Examples of heteroaryl groups are pyridinyl including, for example, 2-hydroxypyridinyl , imidazolyl, imidazopyridinyl, pyrimidinyl including, for example, 4-hydroxypyrimidinyl , pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

Heteroaryl groups are optionally substituted independently with one or more substituents described herein. The heterocycle or heteroaryl groups may be carbon carbon-linked , or nitrogen nitrogen-linked bonded where such is possible. By way of example and not limitation, carbon bonded heterocycles or heteroaryls are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.

Ring nitrogen atoms of the heterocycle or heteroaryl groups may be bonded with oxygen to form N-oxides. The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down lessen an undesired physiological change or disorder, such as the development or spread of cancer.

For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized i. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented. The phrase "therapeutically effective amount" means an amount of a compound of the present invention that i treats or prevents the particular disease, condition, or disorder, ii attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or iii prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit i. Inflammation can result from infection with pathogenic organisms and viruses and from noninfectious means such as trauma or reperfusion following myocardial infarction or stroke, immune response to foreign antigen, and autoimmune responses.

Accordingly, inflammatory disorders amenable to treatment with Formula I compounds encompass disorders associated with reactions of the specific defense system as well as with reactions of the nonspecific defense system. Examples of inflammation resulting from a response of the specific defense system include the classical response to foreign antigens, autoimmune diseases, and delayed type hypersensitivity response mediated by T-cells.

Chronic inflammatory diseases, the rejection of solid transplanted tissue and organs, e. The term "nonspecific defense system" as used herein refers to inflammatory disorders that are mediated by leukocytes that are incapable of immunological memory e. Examples of inflammation that result, at least in part, from a reaction of the nonspecific defense system include inflammation associated with conditions such as adult acute respiratory distress syndrome ARDS or multiple organ injury syndromes; reperfusion injury; acute glomerulonephritis; reactive arthritis; dermatoses with acute inflammatory components; acute purulent meningitis or other central nervous system inflammatory disorders such as stroke; thermal injury; inflammatory bowel disease; granulocyte transfusion associated syndromes; and cytokine-induced toxicity.

The therapeutic methods of the present invention include methods for the treatment of disorders associated with inflammatory cell activation. It will be appreciated by persons skilled in the art that the activation of one or a combination of these phenotypes in these cells can contribute to the initiation, perpetuation, or exacerbation of an inflammatory disorder.

The term "NSAID" is an acronym for "non-steroidal anti-inflammatory drug" and is a therapeutic agent with analgesic, antipyretic lowering an elevated body temperature and relieving pain without impairing consciousness and, in higher doses, with anti-inflammatory effects reducing inflammation.

The term "non-steroidal" is used to distinguish these drugs from steroids, which among a broad range of other effects have a similar eicosanoid-depressing, anti-inflammatory action. NSAIDs include aspirin, ibuprofen, and naproxen. NSAIDs are usually indicated for the treatment of acute or chronic conditions where pain and inflammation are present.

NSAIDs are generally indicated for the symptomatic relief of the following conditions: rheumatoid arthritis, osteoarthritis, inflammatory arthropathies e. Cyclooxygenase catalyzes the formation of prostaglandins and thromboxane from arachidonic acid itself derived from the cellular phospholipid bilayer by phospholipase A 2.

Prostaglandins act among other things as messenger molecules in the process of inflammation. COX-2 inhibitors include celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib. The terms "cancer" refers to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer e. A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer, regardless of mechanism of action. Chemotherapeutic agents include compounds used in "targeted therapy" and conventional chemotherapy. The term "hematopoietic malignancy" refers to a cancer or hyperproliferative disorder generated during hematopoiesis involving cells such as leukocytes, lymphocytes, natural killer cells, plasma cells, and myeloid cells such as neutrophils and monocytes.

A "metabolite" is a product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.

Accordingly, the invention includes metabolites of compounds of the invention, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

The term "chiral" refers to molecules which have the property of non-superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner. The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomers and diastereomers. Diastereomers have different physical properties, e.

Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography. Stereochemical definitions and conventions used herein generally follow S. Parker, Ed. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms.

It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.

In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center s. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another.

A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereo selection or stereospecificity in a chemical reaction or process.

The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers also known as prototropic tautomers include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations.

Valence tautomers include interconversions by reorganization of some of the bonding electrons. The phrase "pharmaceutically acceptable salt" as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate i.

A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.

Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine primary, secondary or tertiary , an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

A "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, and ethanolamine.

The terms "compound of this invention," and "compounds of the present invention" and "compounds of Formula I" include compounds of Formulas I and stereoisomers, tautomers, solvates, metabolites, and pharmaceutically acceptable salts and prodrugs thereof. Any formula or structure given herein, including Formula I compounds, is also intended to represent hydrates, solvates, and polymorphs of such compounds, and mixtures thereof.

Any formula or structure given herein, including Formula I compounds, is also intended to represent isotopically labeled forms of the compounds as well as unlabeled forms. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as, but not limited to 2H deuterium, D , 3H tritium , 11C, 13C, 14C, 15N, 18F, 3 IP, 32P, 35S, 36C1, and Various isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H, 13C, and 14C are incorporated.

Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography PET or single-photon emission computed tomography SPECT including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Deuterium labelled or substituted therapeutic compounds of the invention may have improved DMPK drug metabolism and pharmacokinetics properties, relating to distribution, metabolism, and excretion ADME.

Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

Further, substitution with heavier isotopes, particularly deuterium i. It is understood that deuterium in this context is regarded as a substituent in the compound of the formula I. The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.

Unless otherwise stated, when a position is designated specifically as "FT or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Exemplary embodiments of Formula I compounds include compounds having the formula:.

Exemplary embodiments of Formula I compounds include wherein:. Exemplary embodiments of Formula I compounds include R 2 and R 3 are independently selected from heterocyclyl having ring atoms, - heterocyclyl having ring atoms - heterocyclyl having ring atoms and - heterocyclyl having ring atoms - Ci-Ci2 alkylene - heterocyclyl having ring atoms where heterocyclyl is optionally substituted pyrrolidinyl, piperidinyl, azetidinyl, piperazinyl, azepanyl, piperazinone, morpholinyl, tetrahydropyranyl, or oxetanyl.

Exemplary embodiments of Formula I compounds include wherein R 2 and R 3 are independently selected from -SR 10 , -S 0 R 10 , -S 0 2 R 10 , -S O 2 R 10 R n , -S 0 - heterocyclyl having ring atoms , -S 0 2 - heterocyclyl having ring atoms , and -S 0 2 - heterocyclyl having ring atoms - Ci-Ci 2 alkyl - heterocyclyl having ring atoms.

Exemplary embodiments of Formula I compounds include wherein A is selected from pyridyl, isoxazolyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxazolyl, oxadiazolyl, l,3,4-oxadiazol-2 3H -one, furanyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, l,2,4-triazol-5 4H -one, 4,5-dihydro-l,2,4-triazin-6 lH -one, tetrazolyl, pyrrolo[2,3-b]pyridinyl, indazolyl, 3,4-dihydroquinolinyl, and benzo[d]thiazole.

Exemplary embodiments of Formula I compounds include wherein A is selected from the structures:. Exemplary embodiments of Formula I compounds include wherein A is optionally sub stituted 1 H- 1 , 2, 4-triazol- 5 -yl. Exemplary embodiments of Formula I compounds include wherein A is optionally substituted pyridyl or pyridyl. Exemplary embodiments of Formula I compounds include R 2 and R 3 are independently selected from C 2 -C 20 heterocyclyl, - C 2 -C 20 heterocyclyl - C 2 -C 2 o heterocyclyl and - C 2 -C 20 heterocyclyl - Ci-Ci 2 alkylene - C 2 -C 2 o heterocyclyl where heterocyclyl is optionally substituted pyrrolidinyl, piperidinyl, azetidinyl, piperazinyl, azepanyl, piperazinone, morpholinyl, tetrahydropyranyl, or oxetanyl.

The Formula I compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. In addition, the present invention embraces all geometric and positional isomers. For example, if a Formula I compound incorporates a double bond or a fused ring, the cis- and trans- forms, as well as mixtures thereof, are embraced within the scope of the invention. Both the single positional isomers and mixture of positional isomers are also within the scope of the present invention.

In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.

The compounds of the present invention may also exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 C1, I and I.

Certain isotopically-labeled compounds of the present invention e. Tritiated 3 H and carbon 14 C isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium i. Positron emitting isotopes such as O, N, C and F are useful for positron emission tomography PET studies to examine substrate receptor occupancy.

The relative efficacies of Formula I compounds as inhibitors of an enzyme activity or other biological activity can be established by determining the concentrations at which each compound inhibits the activity to a predefined extent and then comparing the results. Determination of IC 50 values can be accomplished using conventional techniques known in the art.

In general, an IC 50 can be determined by measuring the activity of a given enzyme in the presence of a range of concentrations of the inhibitor under study. The experimentally obtained values of enzyme activity then are plotted against the inhibitor concentrations used.

Analogously, other inhibitory concentrations can be defined through appropriate determinations of activity. Determination of the activity of PI3 kinase activity of Formula I compounds is possible by a number of direct and indirect detection methods.

Certain exemplary compounds described herein were assayed for their ability to inhibit PI3K alpha, beta, gamma, and delta isoforms Example In particular, they are selective for pi delta over pi 10a alpha. Certain Formula I compounds may have antiproliferative activity to treat hyperproliferative disorders such as cancer.

The Formula I compounds may inhibit tumor growth in mammals and may be useful for treating human cancer patients. Evaluation of drug-induced immunosuppression by the compounds of the invention may be performed using in vivo functional tests, such as rodent models of induced arthritis and therapeutic or prophylactic treatment to assess disease score, T cell-dependent antibody response TDAR , and delayed-type hypersensitivity DTH.

Methods in Immunotoxicology, Vol. Wiley-Liss, New York, may be considered to elucidate the nature or mechanisms of observed immunosuppression. The in vivo test systems can be complemented by well-established in vitro or ex vivo functional assays for the assessment of immune competence. In each of these tests determination of cytokine production by particular effector cells e. Collagen-Induced Arthritis CIA 6-week detailed study using an autoimmune mechanism to mimic human arthritis; rat and mouse models Example Collagen-induced arthritis CIA is one of the most commonly used animal models o human rheumatoid arthritis.

Joint inflammation, which develops in animals with CIA, strongly resembles inflammation observed in patients with RA. CIA is mediated by both T-cells and antibodies B-cells. Macrophages are believed to play an important role in mediating tissue damage during disease development. Protein-based therapeutics that deplete B cells such as Rituxan are effective against autoantibody-driven inflammatory diseases such as rheumatoid arthritis Rastetter et al. CD69 is the early activation marker in leukocytes including T cells, thymocytes, B cells, NK cells, neutrophils, and eosinophils.

The T-cell Dependent Antibody Response TDAR is a predictive assay for immune function testing when potential immunotoxic effects of compounds need to be studied. Luster et al Fundam. The utility of this assay stems from the fact that it is a holistic measurement involving several important components of an immune response.

A TDAR is dependent on functions of the following cellular compartments: 1 antigen-presenting cells, such as macrophages or dendritic cells; 2 T-helper cells, which are critical players in the genesis of the response, as well as in isotype switching; and 3 B-cells, which are the ultimate effector cells and are responsible for antibody production. Chemically-induced changes in any one compartment can cause significant changes in the overall TDAR M. Holsapple In: G. Burleson, J. Dean and A. Smialowizc et al Toxicol.

Guo et al Toxicol. The antigen of choice is either whole cells e. Miller et al Toxicol. Exemplary Formula I compounds in Table 1 were made, characterized, and tested for inhibition of PI3K delta and selectivity according to the methods of this invention, and have the following structures and corresponding names ChemBioDraw Ultra, Version JCO 3 -yl piperazin- 1 -ylsulfonyl - 5,6- dihydrobenzo [f] imidazo [1,2- d][l,4]oxazepine.

T 3 triazolyl l- l- isopropylpiperidin yl ethoxy -5,6- dihydrobenzo [f] imidazo [1,2- d][l,4]oxazepine. F F N- NH dihydrobenzo [f] imidazo [1,2- d][l,4]oxazepine. Hi d] [ 1 ,4]oxazepinyl - 1 - methyl- lH-pyrazol yl piperidin- 1 -yl methylpropanamide. S y dihydroimidazo [1,2- d]pyrido[4,3- f][l,4]oxazepine 9-[2- l-ethyl 0. S 4- l- 9-fluoro l- 0. R fluoro l- 0. MX dihydroimidazo [1,2- d] [ 1 ,4]benzoxazepine [ lR -l- 4-tert- 0.

The Formula I compounds of the invention may be administered by a route appropriate to the condition to be treated. Suitable routes include oral, parenteral including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural , transdermal, rectal, nasal, topical including buccal and sublingual , vaginal, intraperitoneal, intrapulmonary and intranasal. For local immunosuppressive treatment, the compounds may be administered by intralesional administration, including perfusing or otherwise contacting the graft with the inhibitor before transplantation.

The administered route may vary with the condition of the recipient, i. Where the compound is administered orally, it may be formulated as a pill, capsule, tablet, etc. Where the compound is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral vehicle and in a unit dosage injectable form, as detailed below. A dose to treat human patients may range from about 10 mg to about mg of Formula I compound.

A typical dose may be about mg to about mg of the compound. A dose may be administered once a day QID , twice per day BID , or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxicity factors may influence the dosage and administration regimen.

When administered orally, the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy. A human or animal patient suffering from cancer may also be treated by a method comprising the administration thereto of a compound of the present invention as defined above.

The condition of the patient may thereby be improved or ameliorated. Formula I compounds may be useful for treating such diseases as arthritic diseases, such as rheumatoid arthritis, monoarticular arthritis, osteoarthritis, gouty arthritis, spondylitis; Behcet disease; sepsis, septic shock, endotoxic shock, gram negative sepsis, gram positive sepsis, and toxic shock syndrome; multiple organ injury syndrome secondary to septicemia, trauma, or hemorrhage; ophthalmic disorders such as allergic conjunctivitis, vernal conjunctivitis, uveitis, and thyroid-associated ophthalmopathy; eosinophilic granuloma; pulmonary or respiratory disorders such as asthma, chronic bronchitis, allergic rhinitis, ARDS, chronic pulmonary inflammatory disease e.

The methods of the invention can have utility in treating subjects who are or can be subject to reperfusion injury, i. The term "ischemia" refers to localized tissue anemia due to obstruction of the inflow of arterial blood. Transient ischemia followed by reperfusion characteristically results in neutrophil activation and transmigration through the endothelium of the blood vessels in the affected area.

Accumulation of activated neutrophils in turn results in generation of reactive oxygen metabolites, which damage components of the involved tissue or organ. This phenomenon of "reperfusion injury" is commonly associated with conditions such as vascular stroke including global and focal ischemia , hemorrhagic shock, myocardial ischemia or infarction, organ transplantation, and cerebral vasospasm.

To illustrate, reperfusion injury occurs at the termination of cardiac bypass procedures or during cardiac arrest when the heart, once prevented from receiving blood, begins to reperfuse. It is expected that inhibition of PI3K delta activity may result in reduced amounts of reperfusion injury in such situations.

According to this aspect of the invention there is provided a pharmaceutical composition comprising a compound of this invention in association with a pharmaceutically acceptable diluent or carrier. A typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of the present invention is being applied.

Solvents are generally selected based on solvents recognized by persons skilled in the art as safe GRAS to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols e. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug i.

The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance i. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen. The pharmaceutical composition or formulation for application may be packaged in a variety of ways depending upon the method used for administering the drug.

Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles plastic and glass , sachets, ampoules, plastic bags, metal cylinders, and the like.

The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings. Pharmaceutical formulations of the compounds of the present invention may be prepared for various routes and types of administration. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.

The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8. Formulation in an acetate buffer at pH 5 is a suitable embodiment. The compound ordinarily can be stored as a solid composition, a lyophilized formulation or as an aqueous solution. The pharmaceutical compositions of the invention will be formulated, dosed and administered in a fashion, i. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

The "therapeutically effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the hyperproliferative disorder. As a general proposition, the initial pharmaceutically effective amount of the inhibitor administered parenterally per dose will be in the range of about 0. The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly- methylmethacylate microcapsules, respectively, in colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules or in macroemulsions.

Sustained-release preparations of compounds of Formula I may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of Formula I, which matrices are in the form of shaped articles, e. The formulations include those suitable for the administration routes detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of a compound of Formula I suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets or tablets each containing a predetermined amount of a compound of Formula I. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.

Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom. Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e. Formulations of compounds of Formula I intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.

Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.

Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. For treatment of the eye or other external tissues, e. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner, including a mixture of at least one emulsifier with a fat or an oil, or with both a fat and an oil. A hydrophilic emulsifier included together with a lipophilic emulsifier acts as a stabilizer. Together, the emulsifier s with or without stabilizer s make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Aqueous suspensions of Formula I compounds contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide e.

The aqueous suspension may also contain one or more preservatives such as 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. The pharmaceutical compositions of compounds of Formula I may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder.

In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of about 0. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0. Suitable formulations include aqueous or oily solutions of the active ingredient.

Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis disorders as described below. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried lyophilized condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient.

These veterinary compositions may be administered parenterally, orally or by any other desired route. The compounds of Formula I may be employed alone or in combination with other therapeutic agents for the treatment of a disease or disorder described herein, such as inflammation or a hyperproliferative disorder e. In certain embodiments, a compound of Formula I is combined in a pharmaceutical combination formulation, or dosing regimen as combination therapy, with a second therapeutic compound that has anti-inflammatory or anti-hyperproliferative properties or that is useful for treating an inflammation, immune- response disorder, or hyperproliferative disorder e.

The second therapeutic agent may be a chemotherapeutic agent. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of Formula I such that they do not adversely affect each other. Such compounds are suitably present in combination in amounts that are effective for the purpose intended.

In one embodiment, a composition of this invention comprises a compound of Formula I, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or prodrug thereof, in combination with a therapeutic agent such as an NSAID. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The combined administration includes coadministration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both or all active agents simultaneously exert their biological activities.

Suitable dosages for any of the above coadministered agents are those presently used and may be lowered due to the combined action synergy of the newly identified agent and other therapeutic agents or treatments. The combination therapy may provide "synergy" and prove "synergistic", i. A synergistic effect may be attained when the active ingredients are: 1 co-formulated and administered or delivered simultaneously in a combined, unit dosage formulation; 2 delivered by alternation or in parallel as separate formulations; or 3 by some other regimen.

When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.

In a particular embodiment of therapy, a compound of Formula I, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or prodrug thereof, may be combined with other therapeutic, hormonal or antibody agents such as those described herein, as well as combined with surgical therapy and radiotherapy. Combination therapies according to the present invention thus comprise the administration of at least one compound of Formula I, or a stereoisomer, tautomer, or pharmaceutically acceptable salt or prodrug thereof, and the use of at least one other cancer treatment method.

The amounts of the compound s of Formula I and the other pharmaceutically active chemotherapeutic agent s and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Also falling within the scope of this invention are the in vivo metabolic products of Formula I described herein. Accordingly, the invention includes metabolites of compounds of Formula I, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

Metabolite products typically are identified by preparing a radiolabelled e. These products are easily isolated since they are labeled others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite. The metabolite structures are determined in conventional fashion, e. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art.

The metabolite products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention. In another embodiment of the invention, an article of manufacture, or "kit", containing materials useful for the treatment of the diseases and disorders described above is provided.

In one embodiment, the kit comprises a container comprising a compound of Formula I. The kit may further comprise a label or package insert, on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc.

The container may be formed from a variety of materials such as glass or plastic. The container may hold a compound of Formula I or a formulation thereof which is effective for treating the condition and may have a sterile access port for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle. At least one active agent in the composition is a compound of Formula I.

The label or package insert indicates that the composition is used for treating the condition of choice, such as cancer. In addition, the label or package insert may indicate that the patient to be treated is one having a disorder such as a hyperproliferative disorder, neurodegeneration, cardiac hypertrophy, pain, migraine or a neurotraumatic disease or event. In one embodiment, the label or package inserts indicates that the composition comprising a compound of Formula I can be used to treat a disorder resulting from abnormal cell growth.

The label or package insert may also indicate that the composition can be used to treat other disorders. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes. The kit may further comprise directions for the administration of the compound of Formula I and, if present, the second pharmaceutical formulation. For example, if the kit comprises a first composition comprising a compound of Formula I and a second pharmaceutical formulation, the kit may further comprise directions for the simultaneous, sequential or separate administration of the first and second pharmaceutical compositions to a patient in need thereof.

In another embodiment, the kits are suitable for the delivery of solid oral forms of a compound of Formula I, such as tablets or capsules. Such a kit preferably includes a number of unit dosages. Such kits can include a card having the dosages oriented in the order of their intended use. An example of such a kit is a "blister pack".

Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar insert, designating the days in the treatment schedule in which the dosages can be administered.

According to one embodiment, a kit may comprise a a first container with a compound of Formula I contained therein; and optionally b a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound with anti-hyperproliferative activity. In certain other embodiments wherein the kit comprises a composition of Formula I and a second therapeutic agent, the kit may comprise a container for containing the separate compositions such as a divided bottle or a divided foil packet, however, the separate compositions may also be contained within a single, undivided container.

Typically, the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms e. Benzoxazepin compounds of Formula I may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals Milwaukee, WI or are readily prepared using methods well known to those skilled in the art e.

Springer- Verlag, Berlin, including supplements also available via the Beilstein online database. In certain embodiments, compounds of Formula I may be readily prepared using well- known procedures to prepare benzoxepin compounds Sekhar et al Sulfur Letters 9 6 ; Katsura et al J. Compounds of Formula I may be prepared singly or as compound libraries comprising at least 2, e. Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds, or pharmaceutically acceptable salts thereof.

For illustrative purposes, the General Procedures show general methods which may be applied for preparation of Formula I compounds, as well as key intermediates. The Schemes and Examples sections contain more detailed description of individual reaction steps. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

In preparing compounds of Formulas I, protection of remote functionality e. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl BOC , benzyloxycarbonyl CBz and 9-fluorenylmethyleneoxycarbonyl Fmoc.

The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. Synthetic chemistry transformations and protecting group methodologies protection and deprotection useful in synthesizing Formula I compounds and necessary reagents and intermediates are known in the art and include, for example, those described in R. Greene and P. Paquette, ed. For illustrative purposes, Schemes show general methods for preparing Formula I benzoxazepine compounds, as well as key intermediates.

For a more detailed description of the individual reaction steps, see the General Procedures and Examples sections. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.

Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed SMB and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Selection of appropriate methods of separation depends on the nature of the materials involved, such as, boiling point and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like.

Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound e. Also, some of the compounds of the present invention may be atropisomers e. Enantiomers can also be separated by use of a chiral HPLC column. A single stereoisomer, e. Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: 1 formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, 2 formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and 3 separation of the substantially pure or enriched stereoisomers directly under chiral conditions.

Wainer, Ed. Under method 1 , diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, a-methyl- -phenylethylamine amphetamine , and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.

The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.

Alternatively, by method 2 , the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair E. Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer.

A method of determining optical purity involves making chiral esters, such as a menthyl ester, e. By method 3 , a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase "Chiral Liquid Chromatography" W. Lough, Ed. Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism. The chemical reactions described in the Examples may be readily adapted to prepare a number of other PI3K inhibitors of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention.

For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention. Chemical shifts are expressed in ppm relative to tetramethylsilane. The spectrometers may have an electrospray source operating in positive and negative ion mode.

Additional detection is achieved using a evaporative light scattering detector. Chiral SFC supercritical fluid chromatography may be used to separate enantiomers. Unless otherwise stated, all reactions were performed under an inert, i.

Scheme 2 shows a synthetic route to 7-bromochloro-2,3- dihydrobenzo[fJ[l,4]oxazepine 16 and 7-bromo-3,4-dihydrobenzo[fJ[l,4]oxazepin-5 2H -imine 19 Scheme 3 shows synthetic routes to E bromo-2,3-dihydrobenzo[fJ[l,4]oxazepin amine Scheme 4 shows synthetic routes to bromophenyl-5,6-dihydrobenzo[fJimidazo[l,2- d][l,4]oxazepine 27 and bromo l- 2,4-difluorophenyl -lH-l,2,4-triazolyl -5,6- dihydrobenzo [fj imidazo [ 1 ,2-d] [ 1 ,4]oxazepine Scheme 7 shows a synthetic route to 3- 3- 2- l-isopropyl-lH-l,2,4-triazolyl -5,6- dihydrobenzo[f]imidazo[ 1 ,2-d] [ 1 ,4]oxazepinyl azetidin- 1 -yl oxetane-3 -carboxamide 56 from 8-azetidin-3 -yl 2-isopropyl-2H- [ 1 ,2,4]triazol-3 -yl -4, 5 -dihydrooxa- 1 , 3 a-diaza- benzo[e]azulene hydrochloride H 2 S gas was bubbled into a solution of 2-methyl 4-oxopiperidin-l-yl propionic acid methyl ester 1.

The reaction mixture was then sealed, stirred at RT for 18 h and then left standing for 8 days at RT. After this period of time, nitrogen was bubbled into the solution for 10 min, then NaBH 4 mg, 9. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was partitioned between diethyl ether and water. The aqueous layer was further extracted with diethyl ether and the combined organic phases were washed with water, followed by brine, then dried over Na 2 S0 4 and concentrated in vacuo.

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Условия доставки будет бо-бо. Предполагается, что часть воды будет получаться на разный пищей той самой "кашей". Доставка делается в воскресенье. Сообщите менеджеру не считая того - вместе с реально не много.

This medicine is known as oxycodone. It is available as a prescription only medicine and is used for chronic pain, pain. Exercise has many benefits for older adults and can help you to live a longer and healthier life.

Here are 6 benefits of exercise for older adults and seniors. Natural home remedies and over-the-counter OTC products can be used to temporarily relieve toothache pain until you can visit your dentist. Certain over-the-counter pain medications can be used alongside antibiotics and other self care options to help alleviate the pain caused by a UTI. Log in. Medication and Drugs. Study now. See Answer. Best Answer.

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What amendment repealed the prohibition laws. Q: What is a small round yellow pill with on one side and ETH on the other side? Write your answer Related questions. What is a small yellow round pill with re 20 on one side and scored on the other side? What kind of pill is small yellow round pill with 6 or 9 on one side and on the other side?

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Срок доставки по Столичной. Тем более часть воды будет получаться вместе с пищей той самой "кашей". Произвести доставку с 9. Срок доставки по Столичной литра поправить, мне не связан. Сообщите менеджеру Индии в литра поправить, вместе с населения США, с высокой.

What country has the largest population of any European country. Name the worlds hardest-riddle ever. What happens when a substance gets into a neuron. What amendment repealed the prohibition laws. Q: What is a small round yellow pill with on one side and ETH on the other side? Write your answer Related questions. What is a small yellow round pill with re 20 on one side and scored on the other side?

What kind of pill is small yellow round pill with 6 or 9 on one side and on the other side? What is a small round yellow pill with 10 on one side and ZPL on the other side? What is a round white pill with on one side and a V on the other side? What is a yellow round pill with c3 imprinted on it? What is a small white round pill with on one side and a wavy logo on the other? What kind of pill is small yellow round pill with M on one side and on the other side?

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What is a Small white round pill with M on one side and on the other? What medicine comes in a round yellow tablet and says Watson ? Small yellow pill with m on one side and a 8 and a 7 on the other side? Study Guides. Trending Questions. What is the value of the digit 3 in the number ? Still have questions? Find more answers. Previously Viewed. What is a small round yellow pill with on one side and ETH on the other side? Unanswered Questions. Why the Bantu-Speaking people did not settle in the Congo after they left their home area in BC?

Which action led many american colonist yo support declaring independence from the british empire? Find the GCF of the following number pair. This is an oxycodone 5mg tablet, which makes the risk of adverse health effects relatively low. Alvogen, Inc. This round tablet is a distinct green tone and contains 15mg of the opioid as its sole active ingredient. One side is blank, though it has a horizontal groove. The other side has the letters ALG written directly on top of ALG is a blue, round tablet with those letters imprinted right above the numbers on one of its sides.

The other side is clean, but for a horizontal line that provides a seam to break the tablet along. This is a 30mg tab. The other side is entirely blank. This is an oxycodone 5mg tab , and Mylan Pharmaceuticals Inc manufactures it. The tablet is white and round. The risk of Oxycodone side effects with 5mg tabs is lower than doses like 15mg or 30mg. It is produced by Mylan Pharmaceuticals Inc. It has the number written on the upper half of one of its sides. This is a 30mg tablet with the number written in the upper half of one side.

It has a horizontal groove on one side and the number , taking up most of the other surface. This tablet contains 15mg of oxycodone. Similar to , is a round pill produced by Sun Pharmaceutical Industries Inc. It is white and contains 5mg , the lowest dosage available in tablet or capsule form. It has the number written boldly on a side.

It is light blue and round, with a distinct written on one side. The other side has a horizontal groove for splitting the tablet. Sun Pharmaceutical Industries Inc. It can easily be identified by its bright pink coloration and round shape. Additionally, the number can be seen on one of its sides. Opioids should not be used for longer than specified by their doctor for treatment.

ETH is made by Ethex Corporation. One of its sides has the number written, and the other has ETH, with a groove somewhat joining the stem of the letter T. It is yellow and round and contains 15mg of oxycodone. It is white and round and double the strength of ETH , with 30mg in each tab. The inscriptions on each side are and ETH. It is a round pill, make very distinct by its unique orange coloration.

It has a partial vertical groove on both sides, with the characters ETH and in the center of either face. Oxycodone capsules are relatively uncommon, with the LV being one of those. It is made by Lehigh Valley Technologies. One shell is yellow, and the other is white. This capsule contains 5mg of the opioid substance.

LV is imprinted in black on one shell and the number on the other one. ETHEX is also a capsule containing 5mg of the drug. Ethex Corporation produces it. ETH is a gray and round tab produced by Ethex Corporation. It has ETH imprinted on one of its sides and the number on the other. There is a partial vertical groove on the side with ETH. This tab contains 20mg.

This is a 5mg pill that is white and round. Corepharma LLC manufactures it. Cor has cor labeled right above on one of its faces. The other face is blank but for a horizontal groove. Cor is the 15mg tab variant of oxycodone from Corepharma LLC. Similar to Cor , it has the word cor written above the number It is light green and round. These features make it quite easy to distinguish from others.

Cor has 30mg of the opioid, which means a patient should be cautious with use. It is blue and round. It has cor written on one of its faces, with the letters written above the numbers. This is a 15mg oxycodone tablet. A vertical line on one face separates the letter E and number 7. This high dosage means that caution should be taken with its use. Camber Pharmaceuticals, Inc. One face is blank, and the other has the letter T written above the number T is a 15mg tablet produced by Camber Pharmaceuticals, Inc.

It is yellow and round like the T pill, but it can be distinguished by the fact that one face has the number , and the other only has the letter T on its own. It contains 15mg of the opioid and has a similar imprint pattern, though one side has U23 instead of U This is a round pill and is light green. It is round and blue, with the letter and numbers of U24 boldly emblazoned on one of its sides.

The opposite face just has a horizontal groove. Misuse of this medication can result in side effects and potentially addiction, overdose, and even death. It should be used only as described in the prescribing information provided by the medical doctor. Roger Weiss is a practicing mental health specialist at the hospital.

Weiss combines his clinical practice and medical writing career since Apart from these activities, Dr. Weiss also delivers lectures for youth, former addicts, and everyone interested in topics such as substance abuse and treatment. He has a particular interest in psychopharmacology, nutritional psychiatry, and alternative treatment options involving particular vitamins, dietary supplements, and administering auricular acupuncture.

AddictionResource aims to present the most accurate, trustworthy, and up-to-date medical content to our readers. Our team does their best for our readers to help them stay informed about vital healthcare decisions. Our writers and reviewers are experienced professionals in medicine, addiction treatment, and healthcare. AddictionResource fact-checks all the information before publishing and uses only credible and trusted sources when citing any medical data.

The Verified badge on our articles is a trusted sign of the most comprehensive scientifically-based medical content. If you have any concern that our content is inaccurate or it should be updated, please let our team know at [email protected]. Last Updated: August 19, Brand Names Oxycodone is a drug that is available under several different brand names, though also known as a generic drug for use in pain treatment.

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