WO2009026346A1 - Thiazolidine compounds, and methods of making and using same - Google Patents

Abstract

Provided herein are thiazolidine compounds, and methods of making and using the same. Such compounds may be used in inflammatory or immune-mediated disorders. The disclosure provides for treating respiratory or ocular disorders, treating arthritis, or may be used to treat cancer.

Description

THIAZOLIDINE COMPOUNDS, AND METHODS OF MAKING AND USING SAME

RELATED APPLICATIONS

[0001] This application claims priority to U.S.S.N. 60/956,831, filed August 20, 2007; U.S.S.N. 60/977,147, filed October 3, 2007; U.S.S.N. 61/022,217, filed January 18, 2008; U.S.S.N. 61/051,424, filed May 8, 2008; and U.S.S.N. 61/020,786, filed January 14, 2008, each of which is incorporated by reference in their entirety.

BACKGROUND

[0002] The phosphatidylinositol-3-kinase (PI3K) pathway plays an important role in cellular signaling. In addition to the key role that PI3Ks play in cell proliferation and survival, they have been implicated in disease states involving vasculostasis, vascularization, membrane trafficking, glucose transport, neurite outgrowth, membrane ruffling, superoxide production, actin reorganization, and chemotaxis. Further, the PI3K pathway is stimulated as a physiological consequence of many growth factors and regulators.

[0003] PI3Ks are lipid kinases, consist of eight identified members, and are divided into three sub-families based on their sub- structures and substrate specificities. Class I PI3Ks are further divided into two sub-classes, Class IA and Class IB. Class IA consists of pi 10a, pi lOβ, and pi 105 as catalytic sub-units and these are activated in tyrosine kinase receptor signaling. Class IB contains only the pi 10γ sub-unit, which is mostly activated by seven trans-membrane G-protein coupled receptors (GPCRs) via its regulatory sub-unit plOl and G-protein βγ sub- units. Class II PI3Ks have the α, β, and γisoforms. Class III PI3Ks include the phophatidylinositol specific 3-kinases. Overall the PI3K pathways play important roles in various disease states on account of their pivotal role in cell signaling.

[0004] The role of PI3K in cancers has received much attention. PI3K signaling is important to many aspects of cell growth and survival. Because the PI3K pathway is stimulated as a physiological consequence of many growth factors and regulators, it is quite frequently targeted by genomic aberrations including mutation, amplification and rearrangement, The activation of the PI3K pathway results in a disturbance of control of cell growth and survival, which contributes to a competitive growth advantage, metastatic competence and, often resistance to therapy. This makes the PI3Ks an attractive target for the development of novel anticancer agents.

[0005] Further, PI3Ks play a role in vasculostasis. Compromised vasculostasis has serious pathologic consequences. Examples where excessive vascular permeability leads to particularly deleterious effects include pulmonary edema, cerebral edema, and cardiac edema. In general, however, edema in any tissue or organ leads to some loss of normal function, and therefore to the risk of morbidity or even mortality. Similarly, excessive endothelial proliferation may damage tissues, such as the retina in proliferative retinopathies, or fuel unwanted tissue growth, such as with tumor growth. Many pathologic and disease situations are marked by multiple dysregulations in vasculostasis.

[0006] Angio genesis, for example, encompasses both enhanced vascular proliferation and permeability, as newly-formed blood vessels do not generally exhibit the same level of vascular barrier function as well-established or mature vessels. Examples of such hyper-permeable vasculature can be found in cancers, vasculo proliferative diseases, retinal diseases, and rheumatoid arthritis. The connection between angiogenesis and hyperpermeability may partly result from the dual action of factors such as vascular endothelial growth factor (VEGF), which induces both endothelial proliferation and vascular permeability.

[0007] The PI3K family may also play an important role in inflammatory responses, and in respiratory diseases. Therefore, in addition to direct roles in regulating vasculostasis, the PI3K family can also influence situations in which vasculostasis is compromised, including ischemia and ischemia-reperfusion injury, through their control of leukocyte functioning. Maintaining or restoring vasculostasis should be beneficial to overall patient outcome where such indications as, for example, inflammation, allergic diseases, cancer, cerebral stroke, myocardial infarction, pulmonary and cardiac insufficiency, renal failure, and retinopathies, are present.

SUMMARY

[0008] This disclosure is generally directed to compounds that include a thiazolidine moiety and/or a quinazoline moiety. In part, this disclosure also directed to compounds that are phosphoinositide 3-kinase (PI3K) enzyme or pathway inhibitors or modulators. [0009] For example, compounds are provided that inhibit a PI3K, with an IC₅₀ of about 100 nM or less, about 50 nM or less, from about 1 nM to about 50 nM, or about 10 nM or less. For example, the compound may inhibit or more of PBKoc, PDKγ, or PI3Kδ.

[0010] In an embodiment, a method of treating an respiratory or ocular disorder is provided, wherein the method comprise administering to a patient in need thereof an effective amount of a compound disclosed herein.

[0011] In another embodiment, a method of treating cancer is provided comprising administrating to a patient in need thereof an effective amount of a compound of any of the disclosed compounds. [0012] A method is provided herein for inhibiting tumor cell growth, tumor cell proliferation, or tumorigenesis comprising administering to a patient in need thereof an effective amount of a compound of any of the disclosed compounds..

[0013] Further, methods are provided for treating pain, diabetes, inflammation, platelet aggregation, ischemic heart disease, sclerosis, restenosis, disorders, HIV, bone resorption, cancer, non-small cell lung cancer, or brain cancer, comprising administering to a patient in need thereof an effective amount of any of the disclosed compounds.

BRIEF DESCRIPTION OF THE DRAWING

[0014] Figure IA depicts a PI-3K/mT0R inhibitor blocks tumor growth at oral doses that block PI-3K signaling; Figure IB depicts the results of a signaling study/biomarker.

DETAILED DESCRIPTION

[0015] The present disclosure is directed in part towards novel compounds and compositions that inhibit PI3K and methods of making and using the same. Such compounds may inhibit one or more of the phosphoinositide-3-kinas family, including PI3Kα, PI3Kδ, and/or PDKγ. [0016] Before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. [0017] The term "therapeutic agent" is art-recognized and refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject. Examples of therapeutic agents, also referred to as "drugs", are described in well-known literature references such as the Merck Index, the Physicians Desk Reference, and The Pharmacological Basis of Therapeutics, and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. [0018] The term "therapeutic effect" is art-recognized and refers to a local or systemic effect in animals, particularly mammals, and more particularly humans caused by a pharmacologically active substance. The term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and/or conditions in an animal or human. The phrase "therapeutically-effective amount" means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. The therapeutically effective amount of such substance will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. For example, certain compositions of the present invention may be administered in a sufficient amount to produce a at a reasonable benefit/risk ratio applicable to such treatment.

[0019] The term "modulation" is art-recognized and refers to up regulation (i.e., activation or stimulation), down regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart.

[0020] A "patient," "subject" or "host" to be treated by the subject method may mean either a human or non-human animal.

[0021] The term "treating" is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disease. [0022] The term "prodrug" is art-recognized and is intended to encompass compounds which, under physiological conditions, are converted into the agents of the present invention. A common method for making a prodrug is to select moieties which are hydrolyzed under physiological conditions to provide the desired compound. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal or the target organ or cell.

[0023] The term "alkyl" is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C₁-C_3O for straight chain, C₃-C₃₀ for branched chain), and alternatively, about 20 or fewer, e.g. from 1 to 6 carbons. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure. The term "alkyl" is also defined to include halosubstituted alkyls.

[0024] Moreover, the term "alkyl" (or "lower alkyl") includes "substituted alkyls", which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain may themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls may be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted alkyls, -CN, and the like.

[0025] The term "aralkyl" is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group). [0026] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0027] Unless the number of carbons is otherwise specified, "lower alkyl" refers to an alkyl group, as defined above, but having from one to about ten carbons, alternatively from one to about six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.

[0028] The term "heteroatom" is art-recognized and refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

[0029] The term "aryl" is art-recognized and refers to 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "heteroaryl" or "heteroaromatics." The aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

[0030] The terms ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho- dimethylbenzene are synonymous.

[0031] The terms "heterocyclyl" or "heterocyclic group" are art-recognized and refer to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.

[0032] The terms "polycyclyl" or "polycyclic group" are art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.

[0033] The term "carbocycle" is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

[0034] The term "nitro" is art-recognized and refers to -NO2; the term "halogen" is art- recognized and refers to -F, -Cl, -Br or -I; the term "sulfhydryl" is art-recognized and refers to - SH; the term "hydroxyl" means -OH; and the term "sulfonyl" is art-recognized and refers to - SO2^". [0035] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

R50 R50 I

/ I + N N R53

^R51 R52 wherein R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, - (CH2)m-R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In certain embodiments, only one of R50 or R51 may be a carbonyl, e.g., R50, R51 and the nitrogen together do not form an imide. In other embodiments, R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m- R61. Thus, the term "alkylamine" includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.

[0036] The term "amido" is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:

wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable.

[0037] The term "acylamino" is art-recognized and refers to a moiety that may be represented by the general formula:

O

N ^u R54

R50

wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or - (CH₂)_m-R61, where m and R61 are as defined above.

[0038] The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In certain embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m-R61, wherein m and R61 are defined above. Representative alkylthio groups include methylthio, ethyl thio, and the like. [0039] The term "carbonyl" is art recognized and includes such moieties as may be represented by the general formulas:

wherein X50 is a bond or represents an oxygen or a sulfur, and R55 and R56 represents a hydrogen, an alkyl, an alkenyl, -(CH₂)_m-R61or a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or -(CH₂)_m-R61, where m and R61 are defined above. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an "ester". Where X50 is an oxygen, and R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid". Where X50 is an oxygen, and R56 is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. Where X50 is a sulfur and R55 or R56 is not hydrogen, the formula represents a "thiolester." Where X50 is a sulfur and R55 is hydrogen, the formula represents a "thiolcarboxylic acid." Where X50 is a sulfur and R56 is hydrogen, the formula represents a "thiolformate." On the other hand, where X50 is a bond, and R55 is not hydrogen, the above formula represents a "ketone" group. Where X50 is a bond, and R55 is hydrogen, the above formula represents an "aldehyde" group.

[0040] The definition of each expression, e.g. alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0041] Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. [0042] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0043] It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.

[0044] The term "substituted" is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0045] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67^th Ed., 1986-87, inside cover. Also for purposes of this invention, the term "hydrocarbon" is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds that may be substituted or unsubstituted. [0046] The term "pharmaceutically-acceptable salts" is art-recognized and refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, including, for example, those contained in compositions of the present invention.

[0047] The term "pharmaceutically acceptable carrier" is art-recognized and refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0048] The terms "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" are art-recognized and refer to the administration of a subject composition, therapeutic or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0049] The terms "parenteral administration" and "administered parenterally" are art- recognized and refer to modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articulare, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. Compounds

[0050] Provided herein, in part, is a compound according to formula Ia or Ib:

wherein:

Z is S or O;

X is S, O or NR₁₂;

R₂ is H or alkyl;

R₃ and R₄ are each independently selected for each occurrence from the group consisting of H, halo, alkyl, alkynyl, alkenyl, hydroxyalkyl, alkoxy, carboxyl, cyano, N- arylamido, aryl, and heterocycle, or R₂ and R₃, or R₃ and R₄, form, together with the carbon atoms to which they are attached, a 5 or 6 membered carbocycle or heterocycle ring, wherein any of said alkyl, alkynyl, alkenyl, carbocycle, aryl, or heterocycle can be optionally substituted with one, two or three groups selected from the group consisting of: halo, cyano, hydroxyl, sulphamoyl, N-alkylsulphamoyl, alkoxy, ureido, alkyl, aryl, heterocycle each optionally substituted with one, two or three substituents selected from halo, cyano, hydroxyl, alkyl, or -alkyl-heterocycle optionally substituted by one, two, or three substituents selected from halo, cyano, hydroxyl, or alkyl; and

R₁₂ is selected from the group consisting of alkyl, aryl, heterocycle, or cycloalkyl, wherein R₁₂ may be optionally substituted by one, two, or three substituents selected from the group consisting of halo, hydroxyl, nitro, formyl, formamido, alkyoxy, alkyl, carboxyl, cyano, amino, amido, carbamoyl, sulphamoyl, or ureido; and the pharmaceutically acceptable salts and N- oxides thereof. [0051] For example, R₃ and R₄ may be each independently selected from H, -CH₃, or dimethylisoxazole. In a different embodiment, R₃ and R₄, taken together with the ring carbons on which they are attached, may form a bicyclic ring, for example, a bicyclic ring chosen from: benzofuran, benzothiophene, 2,3-dihydro-thieno[3,4b][l,4]dioxane, or 4,5,6,7- tetrahydrothieno[3,4-c]pyridine; wherein the bicyclic ring may be optionally substituted by one or two substituents selected from the group consisting of: halo, hydroxyl, cyano, and alkyl.

[0052] X may be O. In other embodiments, Z is S.

[0053] Also provided herein are compounds represented by formula II:

, wherein

X is O or NR₁₂;

Re is selected from the group consisting of:

Z is, independently for each occurrence, S or O;

W is, independently for each occurrence, CR_b, NH, N-alkyl, O, or S; R₁ is H or alkyl;

R₇ is H or alkyl;

R₈ and R₉ are each independently selected from H, Cl, F, alkyl, alkyne, alkenyl, carboxyl, hydroxyalkyl, hydroxyl, cyano, formyl, formamido, amido, amine,

sulphamoyl, ureido, R₁₁, -R₁₃R₁₁, or ; m is an integer from 0 to 8;

R_1O is independently selected for each occurrence from the group consisting of H, Cl, F, hydroxyl, cyano, alkoxy, or alkyl;

R₁₁ is selected from group consisting of heterocycle or aryl, wherein R₁₁ is optionally substituted at one to four substituents each independently selected from halo, hydroxyl, alkyl, alkoxy, cyano, sulphamoyl, N-alkylsulphamoyl, and alkyl-heterocycle optionally substituted by one or two substituents chosed from halo, alkyl, hydroxyl and cyano; R₁₂ is selected from aryl or alkyl;

R₁₃ is chosen from alkylene, alkenylene, and alkynylene; and pharmaceutically acceptable salts, prodrugs, N-oxides, and hydrates thereof. [0054] X may be O in certain embodiments.

[0055] In some embodiments, R₁₀ at each occurrence may be H. In other embodiments, R₇ may be H, methyl, or ethyl; or Rg may be H, methyl or ethyl. [0056] W may be, for example, NH for one, two, or more occurrences.

[0057] In some embodiments, m is 1 to 3, or 1 to 5, for example, m may be 1, 2, 3, 4, or 5. Alternativley, R₁₁ may be substituted at one or two positions by methyl. In some embodiments, R₁₁ is chosen from: pyrrolindyl, phenyl, or isoxazole. [0058] R₁₂, in some embodiments, may an aryl, for example, a phenyl or a substituted phenyl moiety.

[0059] Rg may be chosen, for example, from: H, Cl, F, methyl, phenyl, CO₂H, or 3,5- dimethyl-isoxazol-4-yl. [0060] Contemplated compounds include those selected from: 5-(4-Thiophen-2-yl- quinazolin-6-ylmethylene)-thiazolidine-2,4-dione; 5-(4-Benzo[b]thiophen-3-yl-quinazolin-6- ylmethylene)-thiazolidine-2,4-dione; 5-(4-Thiophen-3-yl-quinazolin-6-ylmethylene)- thiazolidine-2,4-dione; 5-[4-(3-Methyl-thiophen-2-yl)-quinazolin-6-ylmethylene]-thiazolidine- 2,4-dione; 5-[4-(4-Methyl-thiophen-3-yl)-quinazolin-6-ylmethylene]-thiazolidine-2,4-dione; 5- {4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-quinazolin-6-ylmethylene}-thiazolidine-2,4- dione; (Z)-5-((4-(Thiophen-3-yl)quinazolin-6-yl)methylene)thiazolidine-2,4-dione; (Z)-5-((4- (Thiophen-3-yl)quinazolin-6-yl)methylene)thiazolidine-2,4-dione; (Z)-5-((4-(4,5,6,7- Tetrahydrothieno[3,2-c]pyridin-2-yl)quinazolin-6-yl)methylene)-thiazolidine-2,4-dione;and pharmaceutically acceptable salts thereof. Dosages

[0061] The dosage of any compositions of the present invention will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition. Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for the compositions of the present invention may be readily determined by techniques known to those of skill in the art or as taught herein.

[0062] In certain embodiments, the dosage of the subject compounds will generally be in the range of about 0.01 ng to about 10 g per kg body weight, specifically in the range of about 1 ng to about 0.1 g per kg, and more specifically in the range of about 100 ng to about 10 mg per kg. [0063] An effective dose or amount, and any possible affects on the timing of administration of the formulation, may need to be identified for any particular composition of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals (preferably at least 5 animals per group), or in human trials if appropriate. The effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment.

[0064] The precise time of administration and amount of any particular subject composition that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a subject composition, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage and type of medication), route of administration, and the like. The guidelines presented herein may be used to optimize the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage and/or timing.

[0065] While the subject is being treated, the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period. Treatment, including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring. The patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters.

Adjustments to the amount(s) of subject composition administered and possibly to the time of administration may be made based on these reevaluations.

[0066] Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained.

[0067] The use of the subject compositions may reduce the required dosage for any individual agent contained in the compositions because the onset and duration of effect of the different agents may be complimentary.

[0068] Toxicity and therapeutic efficacy of subject compositions may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 and the ED50.

[0069] The data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans. The dosage of any subject composition lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For compositions of the present invention, the therapeutically effective dose may be estimated initially from cell culture assays.

Formulations

[0070] The compositions of the present invention may be administered by various means, depending on their intended use, as is well known in the art. For example, if compositions of the present invention are to be administered orally, they may be formulated as tablets, capsules, granules, powders or syrups. Alternatively, formulations of the present invention may be administered parenterally as injections (intravenous, intramuscular or subcutaneous), drop infusion preparations, suppositories or administration intranasally (for example, to deliver a dosage to the brain via the nose or to deliver a dosage to the nose directly) or by inhalation (e.g. to treat a condition of the respiratory tract or to pretreat or vaccinate via the respiratory tract). AFor application by the ophthalmic mucous membrane route, compositions of the present invention may be formulated as eyedrops or eye ointments. These formulations may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.

[0071] In formulations of the subject invention, wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the formulated agents.

[0072] Subject compositions may be suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration.

[0073] Methods of preparing these formulations include the step of bringing into association compositions of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association agents with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. [0074] Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a subject composition thereof as an active ingredient. Compositions of the present invention may also be administered as a bolus, electuary, or paste.

[0075] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0076] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0077] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0078] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. [0079] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent. Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0080] Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0081] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. [0082] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0083] Compositions and compounds of the present invention may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.

[0084] Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (T weens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0085] Dosages for administration by nasal delivery, e.g. delivered to or via the nasal cavity, can be applied as drops, ointments, gels, mists/sprays (aqueous or nonaqueous), aerosols

(liquids, suspensions or dry powders), powders, or combinations thereof. Such delivery can be achieved by commercially available devices such as droppers, nasal sprayers, metered dose aerosols, or other mechanisms known in the art. Pharmaceutical formulations for inhalation and/or delivery to the nose, may contain from 1% to 20% by weight of a penetrator enhancer (for example, surfactants, e.g. sugar esters, sugar ethers, carbohydrate esters) which may allow enhanced nose permeability of the active agent.

[0086] Dosages for administration by inhalation or by delivered to or via the lung, can be applied as mists/sprays (aqueous or nonaqueous), aerosols (liquids, suspensions or dry powders),liquids or suspensions (aqueous or nonaqueous), powders, or combinations thereof. Such delivery can be achieved by commercially available devices such as 1) nebulizers, 2) metered dose inhalers, 3) dry powder inhalers, 4) soft mist inhalers, or by instillation or insufflation, or other mechanisms and/or devices known in the art.

[0087] Pharmaceutical compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. [0088] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

Methods

[0089] Treatment or amelioration of disease states and pathological conditions that implicate PI3K pathways are contemplated herein, and such treatment comprises administering one or more of the disclosed compounds, such as those recited in Formulas I, II or III, or a composition as described herein comprising a disclosed compound. Methods of treating a patient suffering from diseases such as myocardial infarction, stroke, congestive heart failure, ischemia or reperfusion injury, vascular leakage syndrome (VLS),cancer, arthritis, (for example rheumatoid arthritis), or other arthropathy, eye diseases including uveitis, retinopathy or vitreoretinal disease, macular degeneration, autoimmune diseases, vascular leakage syndrome, inflammatory diseases, edema, transplant rejection, burn, respiratory diseases such as acute respiratory distress syndrome (ARDS), asthma, and chronic obstructive pulmonary disorder (COPD), and transplant rejection are contemplated, and may comprise administering a disclosed compound, such as those recited in Formulas I, II, or III or a composition comprising a disclosed compound. [0090] Also contemplated is the treatment of e.g. the edema formation that may be the unwanted consequence of other therapeutic interventions, such as immunotherapy, cancer chemotherapy and radiation therapy. Compounds and compositions disclosed herein, e.g. that inhibit vascular permeability may be used in a co-therapy to reduce the deleterious side-effects of such therapies. Furthermore, edema formation may cause uneven delivery of therapeutic agents to diseased tissues, therefore vasculostatic agents that inhibit vascular permeability could be used in a co-therapy approach to enhance delivery and efficacy of such therapies.

[0091] Acute and/or prophylactic treatment of the interruption of blood flow by pathologic conditions such as thrombus formation, or medical intervention such as cardioplegia, organ transplantation, and angioplasty, or physical trauma, using disclosed compounds is also contemplated.

[0092] The examples which follow are intended in no way to limit the scope of this invention but are provided to illustrate how to prepare and use compounds of the present invention. Many other embodiments of this invention will be apparent to one skilled in the art.

EXEMPLIFICATION

General Methods

[0093] All synthetic experiments were performed under anhydrous conditions (i.e. dry solvents) in an atmosphere of argon, except where stated, using oven-dried apparatus and employing standard techniques in handling air-sensitive materials. Aqueous solutions of sodium bicarbonate (NaHCO₃) and sodium chloride (brine) were saturated. Analytical thin layer chromatography (TLC) was carried out on Merck Kieselgel 60 F₂₅₄ plates with visualization by ultraviolet and/or anisaldehyde, potassium permanganate or phosphomolybdic acid dips. Reverse-phase HPLC chromatography was carried out on Gilson 215 liquid handler equipped with Waters SymmetryShield™ RP18 7μm (40 x 100mm) Prep-Pak cartridge. Mobile phase consisted of standard acetonitrile (ACN) and DI Water, each with 0.1% TFA added. Purification was carried out at a flow rate of 4OmL/ min. NMR spectra: ¹H Nuclear magnetic resonance spectra were recorded at 500 MHz. Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, dd = doublet of doublets, m = multiplet, br s = broad singlet), coupling constant (J/Hz) and integration. Coupling constants were taken directly from the spectra and are uncorrected. Low resolution mass spectra: Electrospray (ES+) ionization was used. The protonated parent ion (M+H) or fragment of highest mass is quoted. Analytical gradient consisted of 10% ACN in water ramping up to 100% ACN over 5 min unless otherwise stated.

Example 1: Preparation of 6-Bromo-4-thiophen-2-ylquinazoline 11

[0094] A solution of 6-bromo-4-chloroquinazoline (1 g, 4.1 mmol), 2-thienylboronic acid (0.52 g, 4.1 mmol), tetrakis(triphenylphosphine)palladium (0) (0.24 g, 0.21 mmol), potassium carbonate (0.86 g, 6.2 mmol) in dimethyl formamide (20 mL) under argon was heated at 150⁰C for 30 minutes in a microwave oven. The reaction mixture was filtered, concentrated and purified on a flash chromatography (SiO₂, 10% ethyl acetate in hexanes to 100% ethyl acetate over 15 minutes) to afford the title compound (0.51 g, 43%) as a pale yellow solid.

[0095] ¹H NMR (500 MHz, DMSOd₆): δ 9.26 (s, IH), 8.64 (d, J = 2.1 Hz, IH), 8.17 (dd, J = 8.9, 6.9 Hz, IH), 8.08 (d, J = 3.7 Hz, IH), 7.99-8.02 (m, 2H), 7.37 (t, J = 4.0 Hz, IH) MS (ES+): m/z 291 (M+H)⁺

Example 2: Preparation of 6-Ethenyl-4-thiophen-2-ylquinazoline (12)

12

[0096] A solution of 11 (0.5 g, 1.72 mmol), tributyl(vinyl)tin (0.65 g, 2.06 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.20 g, 0.17 mmol), in dioxane (17 mL) under argon was heated at 150⁰C for 20 min in a microwave oven. The reaction mixture was filtered through a silica plug, eluted with ethyl acetate. The filterate was concentrated and purified on a flash chromatography (SiO₂, 10% ethyl acetate in hexanes to 100% ethyl acetate over 15 minutes) to afford the title compound (0.38 g, 94%) as a pale yellow solid.

[0097] ¹H NMR (500 MHz, DMSOd₆): δ 9.18 (s, IH), 8.47 (d, J = 1.7 Hz, IH), 8.31 (dd, J = 8.8, 1.9 Hz, IH), 8.15 (d, J = 2.8 Hz, IH), 7.99-8.03 (m, 2H), 7.37 (t, J = 3.9 Hz, IH), 7.09 (dd, J = 17.7, 6.7 Hz, IH), 6.14 (d, J= 17.7, IH), 5.50 (d, J = 11 Hz)

MS (ES+): m/z 239 (M+H)⁺

Example 3: Preparation of 4-Thiophen-2-ylquinazoline-6-carbaldehyde (13)

[0098] A solution of 12 (0.35 g, 1.47 mmol), osmium tetroxide (7.6 mg, 0.03 mmol), 2,6- lutidine (0.32 g, 2.94 mmol), and sodium periodate (1.26 g, 5.88 mmol)in dioxane (9 mL) and water (3 mL) was stirred at room temperature for 90 minutes. Water (20 mL) was added to the reaction mixture and extracted with dichloromethane (2 X 50 mL). The organic layers were combined, dried (Na₂SO₄), filtered, concentrated and purified on a flash chromatography (SiO₂, 10% ethyl acetate in hexanes to 100% ethyl acetate over 15 minutes) to afford the title compound (0.27 g, 77%) as a pale yellow solid.

[0099] ¹H NMR (500 MHz, DMSO-d₆): δ 10.30 (s, IH), 9.34 (s, IH), 9.18 (d, J = 1.6 Hz, IH), 8.38 (dd, J = 8.7, 1.8 Hz, IH), 8.27 (dd, J= 3.9, 0.9 Hz, IH), 8.17 (d, J = 8.7, IH), 8.08 (dd, J = 4.9, 1.0 Hz, IH), 7.44 (dd, J= 5.0, 3.9 Hz, IH) MS (ES+): m/z 241 (M+H)⁺

Example 4: Preparation of (5Z)-5-[(4-Thiophen-2-ylquinazolin-6-yl)methylidene]-l,3- thiazolidine-2,4-dione

[0100] A solution of 13 (0.26 g, 1.1 mmol), 2,4-thiazolidinedione (0.15 g, 1.3 mmol), and cesium carbonate (0.72 g, 2.2 mmol) in ethanol (11 mL) was heated at 140 ⁰C for 15 min in a microwave oven. The reaction mixture was filtered. The filterate was concentrated and purified by high performance liquid chromatography (C- 18 column, water- acetonitrile) to afford the title compound (8 mg, 2%) as pale yellow solid.

[0101] ¹H NMR (500 MHz, DMSOd₆): δ 12.80 (br s, IH), 9.27 (s, IH), 8.75 (s, IH), 8.21- 8.23 (m, 2H), 8.17 (s, IH), 8.11 (s, IH), 8.06 (d, J = 4.3 Hz, IH), 7.42-7.44 (m, IH)

MS (ES+): m/z 340 (M+H)⁺

Example 5: Preparation of 4-Oxo-3,4-dihydro-quinazoline-6-carbonitrile (32)

32

[0102] To a stirred DMF (1.2 L) was added 6-bromo-3H-quinazolin-4-one (60 g, 0.27 mol), Zn(CN)₂ (22.8 g, 0.194 mol) and Pd(PPh₃ )₄ (18 g, 0.016 mol) under argon. The mixture was heated to -100 ⁰C and stirred for 2 h. Upon completion, the mixture was cooled to 30-35 ⁰C and water (2.4 L) was added drop-wise. The mixture was stirred for 30 min and the precipitate was collected by filtration. The solid was washed with CH₃CN (300 mL) and EtOAc (300 mL) to afford the title compound (42 g, 90%) as a green solid.

Example 6: Preparation of 4-Oxo-3,4-dihydro-quinazoline-6-carbaldehyde (33)

33

[0103] To a solution of 32 (42 g, 0.25 mol) in mixed solvent (120 mL) of AcOH and pyridine (1:1) was added Raney Ni (20 g) and NaH₂PO₂-H₂O (80 g, 0.75 mol). The mixture was heated to 70 °C-80 ⁰C for 10 h. Upon completion, the mixture was cooled to 30-35 ⁰C and filtered to remove the catalyst. The filtrate was added DCM (100 mL) and water (100 mL). After layers separation, the organic layer was then washed with brine, dried with Na₂SO₄ and concentrated under reduced pressure. The residue was added EtOAc (300 mL) and stirred for 30 min. The precipitate was collected by filtration to afford the title compound (25 g, 58.5%) as a yellow solid.

Example 7: Preparation of 4-Chloro-quinazoline-6-carbaldehyde (34)

34

[0104] To a solution of 33 (9 g, 0.052 mol) in toluene (630 mL) was added NEt₃ (18 g, 0.18 mol). Then POC13 (27 g, 0.174 mol) was added dropwise at 25-30 ⁰C to the mixture. The reaction was heated to reflux for 2 h. Upon completion, the mixture was cooled to 30-35 ⁰C and then poured into ice-water. The mixture was extracted with EtOAc (300 mLx2) and the organic layer was washed with saturated aq. NaHCO₃ solution and brine, dried with Na₂SO₄ and concentrated under reduced pressure. The residue was purified with column chromatography (Silica gel, DCM) to afford compound the title compound (1.9 g , 19%) as a yellow solid.

Example 8: Preparation of 4-(3-Methyl-thiophen-2-yl)-quinazoline-6-carbaldehyde (35)

35

[0105] To a solution of 34 (0.10 g, 0.50 mmol), 3-methylthiophene-2-boronic acid (0.10 g, 0.70 mmol), and Pd(PPh₃)₄ (50 mg, 0.044 mmol) in DMF (4 mL) was added Na₂CO₃ (2.0 M, 0.5 mL). The reaction mixture was heated for 20 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture was filtered, washed with DCM and the filtrate concentrated.

The crude product was purified by silica gel chromatography (hexanes to 50% EtOAc/hexanes) to afford the title compound as a yellow solid (74 mg, 56%).

[0106] MS (ES+): m/z 255 (M+H) +

Example 9: Preparation of 5-[4-(3-Methyl-thiophen-2-yl)-quinazolin-6-ylmethylene]- thiazolidine-2,4-dione

[0107] A suspension of 35 (74 mg, 0.29 mmol), thiazolidine-2,4-dione (50 mg, 0.43 mmol), Cs₂CO₃ (0.14 g, 0.43 mmol) in ethanol (4 mL) was heated at 140 ⁰C for 20 min in a Biotage microwave reactor. Upon cooling to room temperature, the mixture was concentrated. The crude product was purified by silica gel chromatography (DCM to 15% MeOH/DCM) to afford the title compound as a yellow solid (10 mg, 10%).

[0108] ¹H NMR (500 MHz, DMSO-J₆): δ 2.23 (s, 3H), 7.93 (d, J = 5.0 Hz, IH), 8.03 (s, IH), 8.19 (d, J = 8.8 Hz, IH), 8.21 (d, J = 1.8 Hz, IH), 8.25 (dd, J = 8.8, 2.0 Hz, IH), 9.38 (s, IH), 12.76 (br s, IH)

[0109] MS (ES+): m/z 354 (M+H)⁺

Example 10: Preparation of 4-(4-Methyl-thiophen-3-yl)-quinazoline-6-carbaldehyde (36)

36

[0110] To a solution of 34 (0.10 g, 0.50 mmol), 4-methylthiophene-3-boronic acid (0.10 g, 0.70 mmol), and Pd(PPh₃)₄ (50 mg, 0.044 mmol) in DMF (4 mL) was added Na₂CO₃ (2.0 M, 0.5 mL). The reaction mixture was heated for 20 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture was filtered, washed with DCM and the filtrate concentrated. The crude product was purified by silica gel chromatography (hexanes to 50% EtOAc/hexanes) to afford the title compound as a yellow solid (0.12 g, 91%).

[0111] MS (ES+): m/z 255 (M+H)⁺

Example 11: Preparation of 5-[4-(4-Methyl-thiophen-3-yl)-quinazolin-6-ylmethylene]- thiazolidine-2,4-dione

[0112] A suspension of 36 (0.12 g, 0.47 mmol), thiazolidine-2,4-dione (90 mg, 0.77 mmol), Cs₂CO₃ (0.25 g, 0.77 mmol) in ethanol (7 mL) was heated at 140 ⁰C for 20 min in a Biotage microwave reactor. Upon cooling to room temperature, the mixture was concentrated. The crude product was purified by silica gel chromatography (DCM to 20% MeOH/DCM) to afford the title compound as a brown solid (20 mg, 12%).

[0113] ¹H NMR (500 MHz, DMSO-J₆): δ 2.23 (s, 3H), 7.50 (dd, J = 3.2, 1.0 Hz, IH), 7.99 (s, IH), 8.03 (d, J = 3.1 Hz, IH), 8.17 (d, J = 8.7 Hz, IH), 8.20 (d, J = 1.7 Hz, IH), 8.24 (dd, J = 8.8, 2.0 Hz, IH), 9.39 (s, IH), 12.75 (br s, IH) [0114] MS (ES+): m/z 354 (M+H)⁺

Example 12: Preparation of 3,5-Dimethyl-4-thiophen-2-yl-isoxazole (37)

37 [0115] A mixture of thiophene-2-carbaldehyde (5.0 g, 45 mmol), nitoethane (7.0 mL, 98 mmol) and cesium carbonate (30 g, 92 mmol) in ethanol (45 mL) was heated at 110 ⁰C for 2 h. After cooling to room temperature, the resulting mixture was concentrated, taken up in water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous NCI₂SO₄ and filtered. The filtrate was concentrated and the crude product purified by silica gel chromatography (hexanes to 10% EtOAc/hexanes) to afford the title compound as a pale brown solid (3.6 g, 45%).

[0116] ¹H NMR (500 MHz, _DMso-dβ): δ 2.30 (s, 3H), 2.49 (s, 3H), 7.19 (dd, J = 5.0, 3.5 Hz, IH), 7.22 (dd, J = 3.5, 1.0 Hz, IH), 7.65 (dd, J= 5.1, 1.2 Hz, IH)

Example 13: Preparation of 5-(3,5-dimethylisoxazol-4-yl)thiophen-2-yl-2-boronic acid (38)

38

[0117] To a solution of 37 (3.5 g, 19.6 mmol) in THF (30 niL) cooled at -78 ⁰C under argon atmosphere was added ra-BuLi (2.5 M in hexanes; 10 rnL, 25 mmol). The mixture was stirred at the same temperature for 15 min and tri-isopropylborate added (8.5 mL, 37 mmol). The resulting mixture was stirred at at -78 ⁰C for 15 min and then stirred at RT for 2 h. The reaction was quenched with IM HCl (3 mL) and concentrated. The residue was taken up in water (40 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the crude product purified by silica gel chromatography (hexanes to 50% EtOAc/hexanes) to afford the title compound as a grey solid (2.1 g, 37%).

[0118] ¹H NMR (500 MHz, DMSO-J₆): δ 2.32 (s, 3H), 2.51 (s, 3H), 7.24 (d, J = 3.5 Hz, IH), 7.70 (d, J = 3.5 Hz, IH), 8.29 (s, 2H)

Example 14: Preparation of 4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-quinazoline-6- carbaldehyde (39)

[0119] To a solution of 34 (0.10 g, 0.52 mmol), 38 (0.16 g, 0.72 mmol), and Pd(PPh₃ )₄ (50 mg, 0.044 mmol) in DMF (4 mL) was added Na₂CO₃ (2.0 M, 0.5 mL). The reaction mixture was heated for 3 h at 105 ⁰C. The resulting mixture was filtered, washed with DCM and the filtrate concentrated. The residue was triturated in MeOH and the resulting solid filtered to afford the title compound as a brown solid (75 mg, 43%). [0120] ¹H NMR (500 MHz, DMSO- J₆): δ 2.44 (s, 3H), 2.63 (s, 3H), 7.53 (d, J = 4.1 Hz, IH), 8.18 (d, J = 8.6 Hz, IH), 8.36 (d, J = 4.2 Hz, IH), 8.39 (dd, J = 8.7, 1.7 Hz, IH), 9.22 (d, J = 1.5 Hz, IH), 9.34 (s, IH), 10.32 (s, IH)

[0121] MS (ES+): m/z 336 (M+H)⁺

Example 15: Preparation of 5-{4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-quinazolin-6- ylmethylene } -thiazolidine-2,4-dione

[0122] A solution of 39 (75 mg, 0.22 mmol), thiazolidine-2,4-dione (75 mg, 0.64 mmol), Boc-β-Ala-OH (115 mg, 0.61 mmol) in acetic acid (5 mL) was heated at 120 ⁰C for 4 h. Upon cooling to room temperature, water (7 mL) was added. The resulting solid was filtered and washed firstly with water (15 mL) and then with EtOH (15 mL) to afford the title compound as a reddish brown solid (65 mg, 67%).

[0123] ¹H NMR (500 MHz, DMSO-J₆): δ 2.43 (s, 3H), 2.63 (s, 3H), 7.51 (d, J = 4.0 Hz, IH), 8.11-8.16 (m, 2H), 8.19 (dd, / = 8.8, 1.9 Hz, IH), 8.29 (d, / = 4.0 Hz, IH), 8.76 (d, / = 1.6 Hz, IH), 9.25 (s, IH), 12.76 (br s, IH)

[0124] MS (ES+): m/z 435 (M+H)⁺

Example 16: Preparation of 4-(Thiophen-3-yl)quinazoline-6-carbaldehyde (51)

51 [0125] To a solution of 34 (193 mg, 1.0 mmol) in dimethoxyethane (DME, 10 mL) was added a solution of thiophen-3-yl-3-boronic acid (141 mg, 1.1 mmol) in EtOH (5 mL), 1.0 M Na₂CO₃ (2 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃ )₄, 116 mg, 0.1 mmol). The reaction mixture was heated at 110 ⁰C for 30 min under μ-wave. The hot solution was filtered and the solid was washed with EtOAc. The filtrate was washed with brine (100 rnL). The aqueous was extracted with EtOAc (3 x 20 rnL). Combined organic layer was dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was directly used for next step without further purification.

Example 17: Preparation of (Z)-5-((4-(Thiophen-3-yl)quinazolin-6-yl)methylene)thiazolidine- 2,4-dione

[0126] To a solution of 51 (210 mg, 0.82 mmol) in EtOH (15 rnL) was added thiazolidine- 2,4-dione (TZD, 234 mg, 2 mmol) and Cs₂CO₃ (0.65 g, 2 mmol). The reaction mixture was heated at 150 ⁰C for 30 min under μ-wave. The solvent was removed in vacuo. The crude product was purified by flash column (SiO₂/CH₂Cl₂:MeOH:NH₃.H₂O = 100:10:1). The title compound (25 mg, 7%) was obtained as a white solid.

[0127] ¹H NMR (500 MHz, DMSO-J₆): δ 7.50 (s, IH), 7.39 (d, J = 4.9 Hz, IH), 7.86-7.88 (m, IH), 8.07 (d, J = 8.8 Hz, IH), 8.18 (dd, J = 8.8, 1.8 Hz, IH), 8.36 (m, IH), 8.48 (s, IH), 9.26 (s, IH)

[0128] MS (ES+): m/z 340 (M+H)⁺

Example 18: Preparation of fer?-Butyl-2-(6-formylquinazolin-4-yl)-6,7-dihydrothieno[J,2- c]pyridine-5(4H)-carboxylate (54)

54 [0129] To a solution of 34 (193 mg, 1.0 mmol) in dimethoxyethane (DME, 10 niL) was added a solution of 52 (340 mg, 1.2 mmol) in EtOH (5 mL), 1.0 M Na₂CO₃ (4 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃ )₄, 116 mg, 0.1 mmol). The reaction mixture was heated at 110 ⁰C for 30 min under D -wave. The hot solution was filtered and the solid was washed with EtOAc. The filtrate was washed with brine (100 mL). The aqueous was extracted with EtOAc (3 x 20 mL). Combined organic layer was dried (Na₂SO₄). The solvent was removed in vacuo. The crude product was directly used for next step without further purification.

Example 19: Preparation of (Z)-5-((4-(4,5,6,7-Tetrahydrothieno[3,2-c]pyridin-2-yl)quinazolin- 6-yl)methylene)-thiazolidine-2,4-dione

[0130] To a solution of 54 (1 mmol) in EtOH (15 mL) was added thiazolidine-2,4-dione (TZD, 234 mg, 2 mmol) and Cs₂CO₃ (0.65 g, 2 mmol). The reaction mixture was heated at 150 ⁰C for 30 min under μ-wave. The solvent was removed in vacuo. The 50% TFA in CH₂Cl₂ was added and the mixture was stirred for 2 h at room temperature. The solvent was removed in vacuo. The crude product was purified by flash column (SiO₂/CH₂Cl₂:MeOH:NH₃.H₂O = 100:10:1). The title compound (48 mg, 12%) was obtained as a yellow solid.

[0131] ¹H NMR (500 MHz, DMSO-J₆): δ 3.18 (t, J = 5.8 Hz, 2H), 3.52 (t, J = 5.8 Hz, 2H), 4.34 (s, 2H), 7.82 (s, IH), 8.08 (s, IH), 8.10 (d, J = 8.8 Hz, IH), 8.21 (dd, J = 8.8, 1.9 Hz, IH), 8.66 (d, J = 1.9 Hz, IH), 9.21 (s, IH)

[0132] MS (ES+): m/z 395 (M+H)⁺

Example 20: Enzyme Assays

[0133] IC₅₀ values for compounds against the isoforms of PI3-Kinase (PI3K-γ, PI3K-α) were generated using either luminescence or fluorescence polarization based assays. A four order of magnitude serial dilution of the compounds was introduced into a buffered solution containing appropriate amounts of either PI3-kinase isoform, ATP (3 μM for luminescence or 25 μM for fluorescence polarization) and PIP3 (50 μM for luminescence and 10 μM for fluorescence polarization); the reaction was then allowed to proceed for an appropriate time. These reactions were then terminated by the addition of either the KinaseGlo reagent (Promega) for luminescence or the probe/detector solution for fluorescence polarization (Echelon Biosciences) and then allowed to proceed for an additional 10 min to maximize the luminescence or fluorescence polarization. Values were then measured and IC₅₀ values were derived from experimental data using the non-linear curve fitting capabilities of Prism (Version 4; GraphPad Software), the results, expressed as IC₅₀, are presented in Table 1.

[0134] Table 1 PI3K enzymatic and cellular data

Table 1. PI3K enzyme and cell data

Example 21: Pharmacokinetic testing

[0135] Pharmacokinetics parameters are determined rats and mice following a single intravenous (IV) and oral (PO) doses. Intravenous and oral dose formulations are prepared fresh. For the PO formulation, the compounds are dissolved in an aqueous solutions containing appropriate excipients or suspended in 0.5% MC and 0.05% TweenδO. For the IV formulation, the compounds are solubilized in an aqueous vehicle containing suitable excipients. The IV formulation is aseptically filtered through 0.22um filters.

[0136] Rats: Six jugular vein cannulated male Sprague-Dawley rats (~300g) are divided into three groups with three rats in IV dose group and three rats in the PO dose group. Animals are allowed food and water ad libitum.

[0137] Blood samples (approximately 500 μL per time point) are serially collected via jugular vein cannula and transferred into tubes containing sodium heparin anticoagulant at 0.083, 0.25, 0.5, 1, 3, 5, 7, and 24 hours post-dose for IV dose; and at 0.5, 1, 3, 5, 7, and 24 hours post dose for PO doses. Blood is maintained in an ice and water mixture prior to centrifugation to obtain plasma. Plasma samples are transferred to a -2O⁰C freezer and stored until analysis.

[0138] Matrix calibration standards and QC samples are prepared by spiking the compound into blank rat plasma (Valley Biomedical Inc., Lot # L51663). The final concentrations of a selected compound are 0, 1, 5, 10, 50, 100, 500, 1000, 2500 and 5000 ng/niL for calibration standards, and 2.50, 25.0, 250 and 2500 for QC samples.

[0139] Plasma samples are processed using a standard protocol. The samples are analyzed using a LC/MS/MS Waters Quattro LC by standard determined conditions. Chromatogram signals are integrated and calibrated using MassLynx 3.0. Pharmacokinetic parameters are estimated using WinNonlin (version 4.1) from mean plasma concentration-time profiles. The values for the maximum plasma concentration (C_max) and the time to maximum concentration (T_max) are determined from measure plasma concentrations. The area under the curves, AUC _(last) and AUC _(inf) are calculated from plasma concentration-time profiles using the linear trapezoidal rule. The oral bioavailability (F) is calculated using the following equation; F=(AUC(o-_inf),Po x Div)/(AUC(o-_inf),iv x D_PO)*100%

[0140] The PK evaluation in mice utilizes the same procedures described above except the number of mice is three per time point per dosed group and the blood samples are collected by cardiac puncture. Table 2 provides results of mouse PK data:

Example 22: Cell data for selected compounds against various cancer cell lines:

Table 3a

Table 3b

Example 23: Mouse Xenograft

[0141] A xenograft model in mice was used to evaluate multiple myeloma tumors was conducted. Tumor (RPMI-8266 cells) growth was blocked in a dose dependent manner by orally administering the compound identified as #4 in Table 1 above. Figure IA depicts tumor size as a function of dosage. Figure IB depicts the results of a parallel study of the phosphorylation of Akt, a biomarker for PI3K signaling, and shows that this was blocked in a dose-dependent manner in a MDA-MB468 (breast tumor) xenograft using the same oral doses of the same compound active in the myeloma model as shown in Figure IA. Example 24: In vitro characterization of GSH-dependent adducts

[0142] Compounds are evaluated in vitro for potential to form GSH-dependent adducts. Tested compounds were negative. Compound #1 was evaluated following preincubation with HLM for 30 minutes against CYP3A4:

Example 25: hERG inhibition

Example 26: AMES analysis.

[0143] Compounds are tested for AMES in the presence or absence of S9, at test concentrations of mutagenesis of 5, 10, 50, and 100 μM and at test concentrations for cytotoxicity of 0.63, 1.3, 2.5, 5, 10, 25, 50 and 100 μM.

References [0144] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Equivalents [0145] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. [0146] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

Claims

Claims 1. The compound represented by formula Ia or Ib:

wherein:

Z is S or O;

X is S, O or NR₁₂; R₂ is H or alkyl;

R₃ and R₄ are each independently selected for each occurence from the group consisting of H, halo, alkyl, alkynyl, alkenyl, hydroxyalkyl, alkoxy, carboxyl, cyano, N-arylamido, aryl, and heterocycle, or R₂ and R₃, or R₃ and R₄, form, together with the carbon atoms to which they are attached, a 5 or 6 membered carbocycle or heterocycle ring, wherein any of said alkyl, alkynyl, alkenyl, carbocycle, aryl, or heterocycle can be optionally substituted with one, two or three groups selected from the group consisting of: halo, cyano, hydroxyl, sulphamoyl, N-alkylsulphamoyl, alkoxy, ureido, alkyl, aryl, heterocycle each optionally substituted with one, two or three substituents selected from halo, cyano, hydroxyl, alkyl, or -alkyl-heterocycle optionally substituted by one, two, or three substituents selected from halo, cyano, hydroxyl, or alkyl; and R₁₂ is selected from the group consisting of alkyl, aryl, heterocycle, or cycloalkyl, wherein R₁₂ may be optionally substituted by one, two, or three substituents selected from the group consisting of halo, hydroxyl, nitro, formyl, formamido, alkyoxy, alkyl, carboxyl, cyano, amino, amido, carbamoyl, sulphamoyl, or ureido; and the pharmaceutically acceptable salts and N-oxides thereof.

2. The compound of claim 1, wherein R₃ and R₄ are each independently selected from H, - CH₃, or dimethylisoxazole.

3. The compound of claim 1, wherein R₃ and R₄, taken together with the ring carbons on which they are attached, form a bicyclic ring chosen from: benzofuran, benzothiophene, 2,3-dihydro- thieno[3,4b][l,4]dioxane, or 4,5,6,7-tetrahydrothieno[3,4-c]pyridine; wherein the bicyclic ring is optionally substituted by one or two substituents selected from the group consisting of: halo, hydroxyl, cyano, and alkyl.

4. The compound of claim 1, wherein X is O.

5. The compound of claim 1, wherein Z is O.

6. The compound of claim 1, wherein Z is S.

7. A compound represented by formula II:

, wherein

X is O or NR₁₂;

Re is selected from the group consisting of:

, and

Z is, independently for each occurrence, S or O;

W is, independently for each occurrence, CR_b, NH, N-alkyl, O, or S;

R₁ is H or alkyl;

R₇ is H or alkyl;

Rg and Rg are each independently selected from H, Cl, F, alkyl, alkyne, alkenyl, carboxyl, hydroxyalkyl, hydroxyl, cyano, formyl, formamido, amido, amine,

sulphamoyl, ureido, R₁₁, -R₁₃R₁₁, or ; m is an integer from 0 to 8;

R₁₀ is independently selected for each occurrence from the group consisting of H, Cl, F, hydroxyl, cyano, alkoxy, or alkyl;

R₁₁ is selected from group consisting of heterocycle or aryl, wherein R₁₁ is optionally substituted at one to four substituents each independently selected from halo, hydroxyl, alkyl, alkoxy, cyano, sulphamoyl, N-alkylsulphamoyl, and alkyl-heterocycle optionally substituted by one or two substituents chosed from halo, alkyl, hydroxyl and cyano;

R₁₂ is selected from aryl or alkyl; R₁₃ is chosen from alkylene, alkenylene, and alkynylene; and pharmaceutically acceptable salts, prodrugs, N-oxides, and hydrates thereof.

8. The compound of claim 7, wherein X is O.

9. The compound of claim 7, wherein R₁₀ at each occurrence is H.

10. The compound of claim 7, wherein R₇ is H.

11. The compound of claim 7, wherein R₇ is methyl.

12. The compound of claim 7, wherein R₈ is methyl.

13. The compound of claim 7, wherein W for one occurrence is NH.

14. A compound selected from: 5-(4-Thiophen-2-yl-quinazolin-6-ylmethylene)-thiazolidine- 2,4-dione; 5-(4-Benzo[b]thiophen-3-yl-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione; 5-(4- Thiophen-3-yl-quinazolin-6-ylmethylene)-thiazolidine-2,4-dione; 5-[4-(3-Methyl-thiophen-2- yl)-quinazolin-6-ylmethylene]-thiazolidine-2,4-dione; 5-[4-(4-Methyl-thiophen-3-yl)- quinazolin-6-ylmethylene]-thiazolidine-2,4-dione; 5-{4-[5-(3,5-Dimethyl-isoxazol-4-yl)- thiophen-2-yl]-quinazolin-6-ylmethylene}-thiazolidine-2,4-dione; (Z)-5-((4-(Thiophen-3- yl)quinazolin-6-yl)methylene)thiazolidine-2,4-dione; (Z)-5-((4-(Thiophen-3-yl)quinazolin-6- yl)methylene)thiazolidine-2,4-dione; (Z)-5-((4-(4,5,6,7-Tetrahydrothieno[3,2-c]pyridin-2- yl)quinazolin-6-yl)methylene)-thiazolidine-2,4-dione;and pharmaceutically acceptable salts thereof.

15. A composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier.

16. The composition of claim 15, wherein the composition is formulated for one of: oral administration, intraveneous administration, injectable administration, topical application, as a suppository, inhalation administration, or systemic administration.

17. The composition of claim 17 wherein the composition is formulated for use in the eye.

18. The composition of claim 17, wherein the composition is formulated as an eye drop.

19. The composition of claim 16, wherein the composition is suitable for use in the respiratory system.

20. The composition of claim 19, where composition is formulated for inhalation.

21. The compound of claim 1, wherein the compound inhibits PI3K with an IC₅₀ of about 200 nM or less, about 50 nM or less, from about 1 nM to about 50 nM, or about 10 nM or less.

22. The compound of claim 21, wherein the compound inhibits one or more of PI3Kα, PI3Kδ or PI3Kγ.

23. A method of treating asthma, COPD, or ocular disorder, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1-14.

24. A method of inhibiting tumor cell growth, tumor cell proliferation, or tumorigenesis comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1-14.

25. A method of treating pain, diabetes, inflammation, platelet aggregation, ischemic heart disease, sclerosis, restenosis, disorders, HIV, bone resorption, non-small cell lung cancer, or brain cancer, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1-14.

26. A method of treating rheumatoid arthritis, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1-14.