WO2009026345A1 - Thiazolidinone compounds, and methods of making and using same - Google Patents

Abstract

Provided herein are thiazolidinone 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, such as prostate or breast cancer, or multiple myeloma.

Description

THIAZOLIDINONE 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 its 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 thiazolidinone 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 200 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 one or more of PI3Kα, PI3Kβ, PI3Kγ, 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.

DETAILED DESCRIPTION

[0014] 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-kinase family, including PI3Kα, PI3Kβ, PI3Kδ, and/or PI3Kγ.

[0015] 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.

[0016] 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.

[0017] 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. [0018] 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.

[0019] A "patient," "subject" or "host" to be treated by the subject method may mean either a human or non-human animal. [0020] The term "treating" is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disease. [0021] 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.

[0022] 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-C₃O 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.

[0023] 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. [0024] The term "aralkyl" is art-recognized and refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group). [0025] 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.

[0026] 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.

[0027] 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.

[0028] 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" or aromatic, 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 heterocyclyl s.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] The term "carbocycle" is art-recognized and refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

[0033] 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^". [0034] 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.

[0035] 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.

[0036] 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.

[0037] 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. [0038] 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.

[0039] 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.

[0040] 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. [0041] 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.

[0042] 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.

[0043] 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.

[0044] 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. [0045] 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.

[0046] 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.

[0047] 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.

[0048] 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

[0049] Provided herein, in part, is a compound according to formula I:

wherein

A₁ is a nine or ten membered bicyclic heterocycle, for example a nine or ten membered bicyclic aromatic heterocycle, containing one to three heteroatoms chosen from nitrogen, oxygen or sulfur optionally substituted by one to four substituents each independently selected from halo, hydroxyl, or alkyl;

A₂ is an heterocycle group, for example an aromatic heterocyclic group, which may contain an heteroatom chosen from sulfur or oxygen;

X is O, S or NR₁₂;

R₁ is selected from the group consisting of H, amide, ester, carbamate or alkyl;

wherein A₂ is optionally substituted by one to four substituents each independently selected from the group consisting of halo, hydroxyl, mercapto, nitro, formyl, formamido, carboxy, cyano, amino, amide, carbamoyl, sulphamoyl, ureido, alkyl, alkenyl, alkynyl, alkoxy, alkanoyl, alkoxycarbonyl, thiocarbonyl, N-alkylureido, N-alkylamino, N-alkylsulphamoyl, N- alkylcarbamoyl, N-arylamide, N-alkylamide, aryl, heterocycle, or cycloalkyl, wherein said alkyl, alkenyl, alkynyl or alkoxy may be optionally substituted by one or more groups selected from R_a, and wherein said aryl, heterocycle or cycloalkyl may each be optionally substituted by one, two or three substituents selected from hydroxyl, halo, amino, cyano, carboxy, nitro, amido, amino, carbamoyl, sulphamoyl, alkoxy, or alkyl, or another heterocycle, aryl, or alkylheterocycle . [0050] R_a is independently selected from halo, hydroxyl, nitro, formyl, formamido, alkyl, alkoxy, carboxyl, cyano, amino, amido, carbamoyl, sulphamoyl, ureido, aryl, heterocycle, or cycloalkyl.

[0051] R₁₂ is selected from the group consisting of alkyl, alkenyl, alkynl, aryl, heterocycle, or cycloalkyl. In some embodiments, the moieties of 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, ureido, aryl, heterocycle, or cycloalkyl. For example, R₁₂ may be CF₃.

[0052] The pharmaceutically acceptable salts, prodrugs, N-oxides, and hydrates of the disclosed compounds, including formula I, are contemplated herein.

[0053] A₁ may be, in some embodiments, a nine or ten membered aromatic bicyclic heterocycle containing one to three heteroatoms chosen, for each occurrence, from nitrogen or oxygen. In other embodiments, A₁ is selected from the group consisting of: indolyl, naphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzofuryl, benzthienyl, cinnolinyl, and pteridinyl. For example, A₁ can be selected from quinolinyl or quinazolinyl.

[0054] A₂ may be selected from thiopene, furan, pyran, chromene, isothiazole, isoxazole, benzothiophene, 2,3-dihydrothieno[3,4-b][l,4]dioxine, 4,5,6,7-tetrahydrothieno[3,4-c]pyridine, or benzofuran. In an embodiments, A₂ may be substituted on a ring carbon with 1 or 2 substituents each independently chosen from: halo, carboxyl, cyano, amino, amide, formyl, formamido, alkoxy, carbamoyl, sulphamoyl, ureido, an optionally substituted alkyl (for example CF₃), an optionally substituted aryl, or an optionally substituted heterocycle group.

[0055] For example, A₂ can be substituted on a ring carbon with 1 or 2 substituents each independently chosen from halo, methyl, phenyl, or isoxazole, wherein said phenyl and isoxazole are optionally substituted on a ring carbon by 1 or 2 substituents chosen from halo, alkyl, aryl or heterocycle.

[0056] In some embodiments, a disclosed compound is represented by formula Ia or Ib:

wherein X and R₁ are as defined above;

Y is CR_b or N;

Z is S or O;

R₂, R₃, R₄ are each independently selected from the group consisting of H, halo, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxy, cyano, carboxyl, 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 carbocycle or heterocycle ring, wherein any of said alkyl, alkenyl, alkynyl, carbocycle, aryl, or heterocycle can be optionally substituted with halo, hydroxyl, cyano, alkoxy, ureido, sulphamoyl, N-alkylsulphamoyl, alkyl, aryl, heterocycle or alkylheterocycle. For example, R₃ may be phenyl or N-phenylacetamide wherein the phenyl is optionally substituted with hydroxyl, alkyl, N-alkylsulphamoyl, alkoxy, or an alkylmorpholino.

[0057] R_b is selected from H, halo, hydroxyl, or alkyl.

[0058] In some embodiments, Z is S or O. In other embodiments R₂ is H. In an embodiment, R₃ and R₄ are each independently selected from H, -CH₂OH, -CH₂CH₂OH, CH₃, phenyl, F, Cl, CO₂H,-C(O)NH-phenyl, -C(O)NCH₂CH₂-pyrrolidine, or dimethylisoxazole, wherein the phenyl is optionally substituted by, for example, one or two substituents selected from the group consisting of halo, cyano, hydroxyl, alkyl, alkoxy, N-alkylsulphamoyl, and sulphamoyl.

[0059] In another embodiment, R₃ and R₄, taken together with the ring carbons on which they are attached, form a bicyclic ring such as benzofuran, benzothiophene, 2,3-dihydro- thieno[3,4b][l,4]dioxin or 4,5,6,7-tetrahydrothieno[3,2-c]pyridine. Such bicyclic rings may be substituted by, for example, one or two substituents selected from the group consisting of halo, hydroxyl, cyano, and alkyl. [0060] X may be, for example NR₁₂, wherein R₁₂ is phenyl optionally substituted by one or two halogen moities; or X may be, for example, O.

[0061] Also provided herein is a compound represented by formula II:

wherein

Re is selected from the group consisting of:

X is O, S or NR₁₂;

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

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

R_b is selected from H, halo, hydroxyl, or alkyl;

R₁ is H or alkyl; R₇ is H or alkyl;

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

alkylsulphamoyl, ureido, R₁₁, -R₁₃R₁₁, or ;

m is an integer from 0 to 8;

R_1O is independently selected for each occurrence from H, Cl, F, hydroxyl, cynao, or alkyl;

R₁₁ is selected from group consisting of heterocycle, aryl, or cycloalkyl; wherein R₁₁ is optionally substituted at one to four substituents each independently selected from halo, hydroxyl, carboxyl, sulphamoyl, N-alkylsulphamoyl, -alkyl-heterocycle, -alkyl-carbocycle or alkyl;

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, ureido, aryl, heterocycle, or cycloalkyl;

R₁₃ is alkylene, alkenylene, or alkynyl; or

pharmaceutically acceptable salts, prodrugs, N-oxides, and hydrates thereof. [0062] In some embodiments, formula II may be represented by:

[0063] In some embodiments, m is 1 to 3, or 1 to 5, for example, m may be 1, 2, 3, 4, or 5. [0064] In some embodiments, R_1O at each occurrence is H.

[0065] R₁₁ may be substituted at one or two positions by methyl. In some embodiments, R₁₁ is chosen from: pyrrolindyl, phenyl, isoxazole, or thiazolidinedione. [0066] In some embodiments, R₇ is H or methyl.

[0067] In some embodiments, Rg may be H, methyl, or ethyl. .

[0068] Rg may be chosen, for example, from: H, Cl, phenyl, co_2H, or 3,5-dimethyl-isoxazol- 4-yl.

Dosages [0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 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

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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. [0086] 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.

[0087] 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.

[0088] 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.

[0089] 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. [0090] 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. [0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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

[0097] 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 or II, 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 or II, or a composition comprising a disclosed compound. [0098] 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. [0099] Disclosed herein are methods of treating tumor cell growth, tumor cell proliferation, or tumorigenesis by administering to a patient a disclosed compound. For example, disclosed herein are methods of treating breast or prostate cancer. Other exemplary methods of treating cancers include treatment of myeloma. [0100] 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.

[0101] 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

[0102] 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 4-Chloro-6-vinylquinoline (1)

[0103] To a solution of 6-bromo-4-chloroquinoline (2.0 g, 8.3 mmol) and Pd(PPh₃)₄ (0.095 g, 0.83 mmol) in 1,4-dioxane (7.5 mL) was added tributyl(vinyl)tin (2.4 mL, 8.3 mmol). The reaction mixture was heated for 20 min at 150 C in a Biotage microwave reactor. The resulting mixture was concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 70:30 gradient) to afford the title compound as a white solid (1.3 g, 84 %).

[0104] ¹H NMR (500 MHz, DMSOd₆): δ 5.49 (d, J = 11.0 Hz, IH), 6.10 (d, J = 17.7 Hz, IH), 7.05 (dd, J = 17.7, 11.0 Hz, IH), 7.76 (d, J= 4.8 Hz, IH), 8.06 (d, J= 6.5 Hz, IH), 8.12 (d, J = 6.5 Hz, IH), 8.13 (s, IH), 8.80 (d, J = 4.6 Hz, IH)

MS (ES+): m/z 190 (M+H)⁺

Example 2: Preparation of 4-Chloroquinoline-6-carbaldehyde (2)

2

[0105] To a solution of 1 (1.0 g, 5.3 mmol) in 1,4-dioxane (2.8 mL) was sequentially added H₂O (1 mL), OsO₄ (2.5% solution in tert-butanol, 1.3 mL, 0.11 mmol), 2,6-lutidine (1.3 mL, 10.6 mmol), and and NaIO₄ (4.5 g, 21.1 mmol). The reaction mixture was stirred for 2 h at room temperature, quenched by adding H₂O (20 mL), and extracted two times with CH₂Cl₂ (2 x 20 mL). The combined organic layers were dried over MgSO₄, concentrated, and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 50:50 gradient) to afford the title compound as a white solid (0.55 g, 55 %).

[0106] ¹H NMR (500 MHz, DMSO-d₆): δ 7.93 (d, J= 1.0 Hz, IH), 8.24 (s, IH), 8.84 (dd, J = 1.3, 1.1 Hz, IH), 9.00 (d, J= 4.6 Hz, IH), 10.28 (s, IH) MS (ES+): m/z 192 (M+H)⁺ Example 3: Preparation of 4-(4-Methylthiophen-2-yl)quinoline-6-carbaldehyde (3)

[0107] To a solution of 2 (0.25 g, 1.27 mmol), 4-methylthiophene-2-boronic acid (0.18 g, 1.27 mmol), and Pd(PPh₃)₄ (0.15 g, 0.13 mmol) in DMF (4 mL) was added Na₂CO₃ (2.0 M, 1.1 mL). The reaction mixture was heated for 15 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture was filtered through a pad of silica gel, concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 50:50 gradient) to afford the title compound as a yellow solid (0.29 g, 90 %). [0108] ¹H NMR (500 MHz, DMSOd₆): δ 2.35 (s, 3H), 7.50 (s, IH), 7.50 (s, IH), 7.67 (d, J = 4.8 Hz, IH), 8.19 (dd, J = 8.9, 1.3 Hz, IH), 8.22 (d, J = 8.8 Hz, IH), 8.91 (d, J= 1.6 Hz, IH), 9.03 (d, J = 5.0 Hz, IH), 10.20 (s, IH)

MS (ES+): m/z 254 (M+H)⁺

Example 4: Preparation of (Z)-5-((4-(4-Methylthiophen-2-yl)quinolin-6- yl)methylene)thiazolidine-2,4-dione:

[0109] A microwave vial was charged with 3 (0.13 g, 0.51 mmol), thiazolidine-2,4-dione (0.10 g, 0.77 mmol), and Cs₂CO₃ (0.33 g, 1.03 mmol) in ethanol (3 mL). The reaction mixture was heated for 30 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture was separated by preparative HPLC. Fractions that contained the desired product were combined, neutralized with saturated Na₂CO₃, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, and concentrated to afford the title compound as a yellow solid (0.006 g, 3%).

[0110] ¹H NMR (500 MHz, DMSOd₆): δ 2.36 (s, 3H), 7.49 (s, IH), 7.51 (s, IH), 7.62 (d, J = 4.5 Hz, IH), 7.95 (s, IH), 8.03 (dd, J = 8.8, 1.9 Hz, IH), 8.18 (d, J = 8.8 Hz, IH), 8.48 (d, J = 1.8 Hz, IH), 8.95 (d, J= 4.5 Hz, IH), 12.60 (br s, IH)

MS (ES+): m/z 353 (M+H)⁺

Example 5: Preparation of 4-(3-Methylthiophen-2-yl)quinoline-6-carbaldehyde (4)

[0111] To a solution of 2 (0.13 g, 0.63 mmol), 3-methylthiophene-2-boronic acid (0.089 g, 0.63 mmol), and Pd(PPh₃)₄ (0.072 g, 0.063 mmol) in DMF (2 mL) was added Na₂CO₃ (2.0 M, 0.55 mL). The reaction mixture was heated for 15 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture was filtered through a pad of silica gel, concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 70:30 gradient) to afford the title compound as a yellow solid (0.098 g, 62 %).

[0112] ¹H NMR (500 MHz, DMSO-d₆): δ 7.21 (d, J= 5.1 Hz, IH), 7.64 (d, J= 4.4 Hz, IH), 7.80 (d, J = 5.1 Hz, IH), 8.20 (dd, J = 8.7, 1.7 Hz, IH), 8.26 (d, / = 8.8 Hz, IH), 8.39 (d, / = 1.6 Hz, IH), 9.10 (d, / = 4.5 Hz, IH), 10.15 (s, IH)

MS (ES+): m/z 254 (M+H)⁺ Example 6: Preparation of (Z)-5-((4-(3-Methylthiophen-2-yl)quinolin-6- yl)methylene)thiazolidine-2,4-dione:

[0113] A microwave vial was charged with 4 (0.10 g, 0.40 mmol), thiazolidine-2,4-dione (0.70 g, 0.59 mmol), and Cs₂CO₃ (0.26 g, 0.79 mmol) in ethanol (2 mL). The reaction mixture was heated for 30 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture was separated by preparative HPLC. Fractions that contained the desired product were combined, neutralized with saturated Na₂CO₃, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO₄, and concentrated to afford the title compound as a yellow solid (0.082 g, 59%).

[0114] ¹H NMR (500 MHz, DMSO-d₆): δ 2.07 (s, 3H), 7.21 (d, J = 5.1 Hz, IH), 7.58 (d, J = 4.3 Hz, IH), 7.80 (d, J = 5.1 Hz, IH), 7.92 (s, IH), 7.94 (d, J = 1.2 Hz, IH), 8.02 (dd, J = 8.8, 1.7 Hz, IH), 8.20 (d, J = 8.7 Hz, IH), 9.01 (d, J = 4.3 Hz, IH), 12.70 (br s, IH)

MS (ES+): m/z 353 (M+H)⁺

Example 7: Preparation of 4-(Benzo[b]thiophen-2-yl)quinoline-6-carbaldehyde (5)

[0115] To a solution of 2 (0.20 g, 1.04 mmol), benzo(£)thiophen-2-ylboronic acid (0.19 g, 1.04 mmol), and Pd(PPh₃)₄ (0.12 g, 0.10 mmol) in DMF (3 mL) was added Na₂CO₃ (2.0 M, 0.9 mL). The reaction mixture was heated for 15 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture was filtered through a pad of silica gel, concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 65:35 gradient) to afford the title compound as a yellow solid (0.24 g, 79 %).

[0116] ¹H NMR (500 MHz, DMSO-d₆): δ 7.50-7.52 (m, 2H), 7.82 (d, J = 4.5 Hz, IH), 7.99 (s, IH), 7.99-8.04 (m, IH), 8.13-8.15 (m, IH), 8.21 (dd, J= 8.6, 1.6 Hz, IH), 8.27 (d, J = 8.9 Hz, IH), 8.97 (d, J = 1.7 Hz, IH), 9.13 (d, J = 4.5 Hz, IH), 10.21 (s, IH)

MS (ES+): m/z 290 (M+H) Example 8: Preparation of (Z)-5-((4-(Benzo[b]thiophen-2-yl)quinolin-6- yl)methylene)thiazolidine-2,4-dione

[0117] A microwave vial was charged with 5 (0.12 g, 0.42 mmol), thiazolidine-2,4-dione (0.73 g, 0.62 mmol), and Cs₂CO₃ (0.27 g, 0.83 mmol) in ethanol (3 mL). The reaction mixture was heated for 30 min at 150 ⁰C in a Biotage microwave reactor. Precipitate from the resulting mixture was filtered and washed with ethanol (10 mL) followed by H₂O (10 mL) to afford the title compound as an orange solid (0.066 g, 41%).

[0118] IH NMR (500 MHz, DMSO-d₆): δ 7.47-7.53 (m, 3H), 7.69 (d, J = 4.4 Hz, IH), 7.96 (s, IH), 7.99 (dd, J = 8.8, 1.7 Hz, IH), 8.01 (d, J = 8.4 Hz, IH), 8.12 (d, J= 6.3 Hz, IH), 8.15 (d, J = 8.6 Hz, IH), 8.53 (s, IH), 8.94 (d, J = 4.4 Hz, IH)

MS (ES+): m/z 389 (M+H)⁺

Example 9: Preparation of 4-(Thiophen-2-yl)quinoline-6-carbaldehyde (6)

6

[0119] To a solution of 2 (0.30 g, 1.57 mmol), thiophene-2-boronic acid (0.21 g, 1.64 mmol), and Pd(PPh₃ )₄ (0.09 g, 0.078 mmol) in DMF (3 mL) was added Na₂CO₃ (2.0 M, 1.4 mL). The reaction mixture was heated for 15 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture was filtered through a pad of silica gel, concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 70:30 gradient) to afford the title compound as a yellow solid (0.31 g, 84 %).

[0120] MS (ES+): m/z 240 (M +H)⁺ Example 10: Preparation of (Z)-5-((4-(Thiophen-2-yl)quinolin-6-yl)methylene)thiazolidine- 2,4-dione:

[0121] To a solution of 6 (0.05 g, 0.21 mmol), thiazolidine-2,4-dione (0.27 g, 0.21 mmol), and in ethanol (1 rnL) was added 1-methylpiperazine (0.042 g, 0.42 mmol). The reaction mixture was heated for 30 min at 150 ⁰C in a Biotage microwave reactor. Precipitate from the resulting mixture was filtered and washed with ethanol (10 mL) to afford the title compound as a yellow solid (0.023 g, 33%).

[0122] ¹H NMR (500 MHz, DMSOd₆): δ 7.39 (dd, J = 5.0, 3.5 Hz, IH), 7.64-7.70 (m, 2H), 7.94 (d, J = 5.0 Hz, IH), 7.99 (s, IH), 8.03 (dd, J = 8.9, 1.9 Hz, IH), 8.20 (d, J= 8.8 Hz, IH), 8.46 (d, J = 1.9 Hz, IH), 8.97 (d, J = 4.5 Hz, IH), 12.70 (br s, IH)

MS (ES+): m/z 339 (M+H)⁺

Example 11: Preparation of 4-(5-(Hydroxymethyl)thiophen-2-yl)quinoline-6-carbaldehyde (7)

[0123] To a solution of 2 (1.0 g, 5.2 mmol), 5-hydroxymethylthiophene-2-boronic acid (0.82 g, 5.2 mmol), and Pd(PPh₃)₄ (0.60 g, 0.078 mmol) in DMF (16 mL) was added Na₂CO₃ (2.0 M, 4.6 mL). The reaction mixture was heated for 15 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture was filtered through a pad of silica gel, concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 0:100 gradient) to afford the title compound as a yellow solid (0.93 g, 66 %).

[0124] MS (ES+): m/z 270 (M +H)⁺ Example 12: Preparation of (Z)-5-((4-(5-(Hydroxymethyl)thiophen-2-yl)quinolin-6- yl)methylene)thiazolidine-2,4-dione

[0125] A microwave vial was charged with 7 (0.2 g, 0.74 mmol), thiazolidine-2,4-dione (0.15 g, 1.11 mmol), Cs₂CO₃ (0.48 g, 1.49 mmol) in ethanol (4.5 mL). The reaction mixture was heated for 30 min at 150 ⁰C in a Biotage microwave reactor. Upon cooling to room temperature, the reaction mixture added MeOH (50 mL). Precipitate from the resulting mixture was filtered to afford the title compound as a brown solid (0.079 g, 29%).

[0126] ¹H NMR (500 MHz, DMSO-d₆): δ 4.76 (d, J = 5.5 Hz, 2H), 5.70 (t, J = 5.7 Hz, IH), 7.21 (d, J = 3.8 Hz, IH), 7.51 (d, J = 3.6 Hz, IH), 7.61 (d, J = 4.5 Hz, IH), 7.97 (s, IH), 8.02 (dd, J = 8.8, 2.0 Hz, IH), 8.19 (d, J= 8.7 Hz, IH), 8.49 (d, J= 1.9 Hz, IH), 8.96 (d, J= 4.6 Hz, IH), 12.70 (br s, IH)

[0127] MS (ES+): m/z 369 (M+H)⁺

Example 13: Preparation of 4-(5-Phenyl-thiophen-2-yl)-quinoline-6-carbaldehyde (8)

[0128] To a solution of 2 (0.20 g, 1.0 mmol), 5-phenylthiophene-2-boronic acid (0.30 g, 1.5 mmol), and Pd(PPh₃ )₄ (0.12 g, 0.10 mmol) in DMF (6 mL) was added Na₂CO₃ (2.0 M, 1.5 mL) and the reaction mixture heated for 2 h at 130 ⁰C. The resulting mixture was filtered, washed with DCM and the filtrate concentrated. The crude product was purified by silica gel chromatography (hexanes to 40% EtOAc/hexanes) to afford the title compound as a yellow solid (0.1 I g, 33%).

[0129] MS (ES+) : m/z 316 (M +H)⁺

Example 14: Preparation of 5-[4-(5-Phenyl-thiophen-2-yl)-quinolin-6-ylmethylene]- thiazolidine-2,4-dione

A suspension of 8 (70 mg, 0.22 mmol), thiazolidine-2,4-dione (40 mg, 0.34 mmol), Cs₂CO₃ (0.10 g, 0.31 mmol) in ethanol (8 mL) was heated at 120 ⁰C for 4 h. Upon cooling to room temperature, the resulting solid was filtered, washed firstly with water (15 mL) then with EtOH (15 mL). The title compound was obtained as a yellow solid (81 mg, 88%).

[0130] ¹H NMR (500 MHz, DMSO-d₆): δ 7.38 (t, J = 7.0 Hz, IH), 7.45-7.51 (m, 3H), 7.65 (d, J = 4.6 Hz, IH), 7.68 (d, J = 3.8 Hz, IH), 7.79 (d, J = 3.7 Hz, IH), 7.80 (s, IH), 7.82 (s, IH), 7.97 (dd, J = 8.8, 1.9 Hz, IH), 8.11 (d, J= 8.8 Hz, IH), 8.54 (d, J= 1.8 Hz, IH), 8.90 (d, J = 4.5 Hz, IH) [0131] MS (ES+): m/z 415 (M+H)⁺

Example 15: Preparation of 4-(5-Chlorothiophen-2-yl)quinoline-6-carbaldehyde (9)

[0132] A solution of 2 (0.2 g, 1.04 mmol), 5-chlorothienyl-2-boronic acid (0.17 g, 1.04 mmol), tetrakis(triphenylphosphine)palladium (0) (0.060 g, 0.052 mmol), and potassium carbonate (0.22 g, 1.56 mmol) in dimethyl formamide (10 mL) under argon was heated at 150 ⁰C for 60 min in a microwave oven. The reaction mixture was filtered, and concentrated under reduced pressure. The concentrated reaction mixture was purified on a flash chromatography (SiO₂, 10% ethyl acetate in hexanes to 100% ethyl acetate over 15 minutes) to afford the title compound (0.10 g, 35%) as a pale yellow solid. [0133] ¹H NMR (500 MHz, DMSOd₆): δ 10.22 (s IH), 9.08 (d, J = 4.5 Hz, IH), 8.88 (d, J = 1.3 Hz, IH), 8.20-8.26 (m, 2H), 7.71 (d, J = 4.5 Hz, IH), 7.58 (d, J = 4.0 Hz, IH), 7.43 (d, J = 4.0 Hz, IH)

MS (ES+): m/z 21 A (M+H)⁺

Example 16: Preparation of (5Z)-5-{ [4-(5-Chlorothiophen-2-yl)quinolin-6-yl]methylidene}- l,3-thiazolidine-2,4-dione

[0134] A solution of 9 (0.07 g, 0.24 mmol), 2,4-thiazolidinedione (0.11 g, 0.96 mmol), and cesium carbonate (0.31 g, 0.96 mmol) in ethanol (4.8 mL) was heated at 150 ⁰C for 30 min in a microwave oven. The solid was filtered, washed with water, and ethanol to afford the title compound (0.05 g, 57%) as pale yellow solid.

[0135] ¹H NMR (500 MHz, DMSOd₆): δ 8.89 (d, J = AA Hz, IH), 8.39 (s, IH), 8.10 (d, J = 8.7 Hz, IH), 7.96 (d, J = 8.7 Hz, IH)

[0136] MS (ES+): m/z 373 (M+H)⁺

Example 17: Preparation of 5-{4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-quinolin-6- ylmethylene } -thiazolidine-2,4-dione

[0137] To a suspension of (5Z)-5-{ [4-(5-Chlorothiophen-2-yl)quinolin-6-yl]methylidene}- l,3-thiazolidine-2,4-dione (50 mg, 0.13 mmol), 3,5-dimethylisoxazole-4-boronic acid (30 mg, 0.21 mmol), and Pd(PPh₃)₄ (15 mg, 0.013 mmol) in DMF (4 mL) was added Na₂CO₃ (2.0 M, 0.5 mL). The mixtures was sealed in a microwave reaction tube and irradiated with microwave at 160 ⁰C for 25 min. After cooling to room temperature, the resulting mixture was filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO₃ solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and the residue triturated in EtOH. After filtration, the title compound was obtained as a red solid (5 mg, 9%).

[0138] ¹H NMR (500 MHz, DMSO-d₆): δ 2.42 (s, 3H), 2.61 (s, 3H), 7.49 (d, J = 3.8 Hz, IH), 7.70-7.73 (m, 2H), 7.98 (s, IH), 8.04 (dd, J = 8.7, 1.0 Hz, IH), 8.21 (d, J = 8.8 Hz, IH), 8.52 (d, J = 1.0 Hz, IH), 8.99 (d, J = 4.6 Hz, IH), 12.80 (br s, IH) MS (ES+): m/z 434 (M+H)⁺

Example 18 Preparation of 4-(2,3-Dihydro-thieno[3,4-b][l,4]dioxin-5-yl)-quinoline-6- carbaldehyde (10)

[0139] To a solution of 2 (0.20 g, 1.04 mmol), 5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)-2,3-dihydro-thieno[3,4-£][l,4]dioxine (0.35 g, 1.3 mmol), and Pd(PPh₃)₄ (0.10 g, 0.087 mmol) in DMF (5 mL) was added Na₂CO₃ (2.0 M, 1.5 mL). The reaction mixture was heated for 20 min at 170 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 40% EtOAc/hexanes) to afford the title compound as a yellow solid (0.30 g, 97 %). [0140] MS (ES+): m/z 298 (M+H)⁺

Example 19: 5-[4-(2,3-Dihydro-thieno[3,4-b][l,4]dioxin-5-yl)-quinolin-6-ylmethylene]- thiazolidine-2,4-dione:

[0141] A suspension of 10 (0.30 g, 1.0 mmol), thiazolidine-2,4-dione (0.18 g, 1.5 mmol), Cs₂CO₃ (0.50 g, 1.5 mmol) in ethanol (20 mL) was heated at 100 ⁰C for 3 h. Upon cooling to room temperature, the resulting solid was filtered, washed firstly with water (15 mL) then with EtOH (15 mL). The title compound was obtained as a yellow solid (0.15 g, 38%).

[0142] ¹H NMR (500 MHz, DMSO-d₆): δ 4.28 (d, J = 3.5 Hz, 2H), 4.33 (d, J = 3.4 Hz, 2H), 6.98 (s, IH), 7.46 (s, IH), 7.50 (d, J = 4.4 Hz, IH), 7.92 (dd, J = 8.8, 1.4 Hz, IH), 8.06 (d, J = 8.7 Hz, IH), 8.24 (s, IH), 8.87 (d, J = 4.5 Hz, IH)

[0143] MS (ES+): m/z 397 (M+H)⁺

Example 20: Preparation of 4-(l-Benzothiophen-3-yl)quinoline-6-carbaldehyde (14)

[0144] A solution of 2 (0.4 g, 2.08 mmol), benzothienyl-3-boronic acid (0.38 g, 2.08 mmol), tetrakis(triphenylphosphine)palladium (0) (0.12 g, 0.1 mmol), potassium carbonate (0.58 g, 4.2 mmol) in dimethyl formamide (20 mL) under argon was heated at 150 ⁰C for 60 min in a microwave oven. The reaction mixture was filtrered, and concentrated under reduced pressure. The reaction mixture was purified on a flash chromatography (SiO₂, 10% ethyl acetate in hexanes to 100% ethyl acetate over 15 minutes) to afford the title compound (0.37 g, 61%) as a pale yellow solid. [0145] ¹H NMR (500 MHz, DMSO-d₆): δ 10.05 (s, IH), 9.16 (d, J = 4.4 Hz, IH), 8.40 (d, / = 1.7 Hz, IH), 8.29 (d, J = 8.7 Hz, IH), 8.18-8.21 (m, 2H), 8.17 (s, IH), 7.74 (d, J = 4.4 Hz, IH), 7.48-7.51 (m, 2H), 7.38-7.41 (m, IH)

MS (ES+): m/z 290 (M+H)⁺

Example 21: Preparation of (5Z)-5-{ [4-(l-Benzothiophen-3-yl)quinolin-6-yl]methylidene}- 1 ,3-thiazolidine-2,4-dione:

[0146] A solution of 14 (0.29 g, 1 mmol), 2,4-thiazolidinedione (0.23 g, 2 mmol), cesium carbonate (0.65 g, 2 mmol) in ethanol (10 mL) was heated at 150 ⁰C for 30 min in a microwave oven. The solid was filtered, washed with water, and ethanol to afford the title compound (0.28 g, 72%) as pale yellow solid.

[0147] ¹H NMR (500 MHz, DMSOd₆): δ 8.99 (d, J= AA Hz, IH), 8.18 (d, J= 8.0 Hz, IH), 8.13 (dd, J = 8.2, 1.2 Hz, IH), 8.10 (s, IH), 7.95 (d, J = 2.0 Hz, IH), 7.93 (s, IH), 7.60 (d, J = AA Hz, IH), 7.36-7.49 (m, 3H), 7.32 (s, IH) MS (ES+): m/z 389 (M+H)⁺

Example 22: Preparation of 4-Furan-2-ylquinoline-6-carbaldehyde (15)

15

[0148] To a solution of 2 (115 mg, 0.6 mmol) in dimethoxyethane (DME, 10 mL) was added a solution of furan-2-yl-2-boronic acid (74 mg, 0.66 mmol) in EtOH (50 mL), 1.0 M

Na₂CO₃ (2 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃ )₄, 69 mg, 0.06 mmol). The reaction mixture was heated at 110 ⁰C for 20 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 and the crude material was used for next reaction without further purification.

Example 23: Preparation of (5Z)-5-[(4-Furan-2-ylquinolin-6-yl)methylidene]-l,3-thiazolidine- 2,4-dione:

[0149] To a solution of 15 (0.5 mmol) in EtOH (10 mL) was added thiazolidine-2,4-dione (TZD, 70 mg, 0.6 mmol) and Cs₂CO₃ (782 mg, 2.4 mmol). The reaction mixture was heated at 120 ⁰C for 20 min under μ-wave. The hot solution was filtered and the solid was washed with EtOAc. The filtrate was concentrated and residue was purified by HPLC. The HPLC fractions containing product were combined and neutralized with saturated NaHCO₃ (50 mL). The free base was extracted with EtOAc (2 x 50 mL). The combined organic layer was dried (Na₂SO₄). The solvent was removed in vacuo. The title compound (10 mg, 5%) was afforded as a yellow solid.

[0150] ¹H NMR (500 MHz, DMSO-d₆): δ 6.86-6.87 (m, IH), 7.46 (d, J = 3.4 Hz, IH), 7.84 (d, J = 4.7 Hz, IH), 8.00 (dd, J = 8.8, 2.0 Hz, IH), 8.03 (s, IH), 8.11 (d, J = 1.2 Hz, IH), 8.16 (d, J = 8.8 Hz, IH), 8.76 (d, J = 1.8 Hz, IH), 8.97 (d, J = 4.6 Hz, IH), 12.62 (br s, IH) MS

(ES+): m/z 323 (M+H)⁺ Example 24: Preparation of 4-Benzofuran-2-ylquinoline-6-carbaldehyde (16)

[0151] To a solution of 2 (115 mg, 0.6 mmol) in dimethoxyethane (DME, 10 niL) was added a solution of benzofuran-2-yl-2-boronic acid (107 mg, 0.66 mmol) in EtOH (50 mL), 1.0 M Na₂CO₃ (2 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃)₄, 69 mg, 0.06 mmol). The reaction mixture was heated at 110 ⁰C for 20 min under μ-wave. The hot solution was filtered and the solid was washed with EtOAc. The filtrate was washed with brine (100 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL). The organic layers were combined was dried (Na₂SO₄). The solvent was removed in vacuo and the crude material was used for the next reaction without further purification.

Example 25: Preparation of: (5Z)-5-{ [4-(l-benzofuran-2-yl)quinolin-6-yl]methylidene}-l,3- thiazolidine-2,4-dione

[0152] To a solution of 16 (369 mg, 1.35 mmol) in EtOH (15 mL) was added thiazolidine- 2,4-dione (TZD, 316 mg, 2.7 mmol) and Cs₂CO₃ (1.3 g, 4.0 mmol). The reaction mixture was heated at 120 ⁰C for 30 min under μ-wave. The solvent was removed in vacuo and the residue was suspended in H₂O-EtOAc. The solid was collected and washed with water and then

MeOH. The solid was dried in air and the title compound (327 mg, 65%) was afforded as a yellow solid.

[0153] ¹H NMR (500 MHz, DMSO-d₆): δ 7.39 (t, J = 7.4 Hz, IH), 7.49 (t, J = 7.1 Hz, IH), 7.55 (s, IH), 7.78 (d, J = 8.3 Hz, IH), 7.83 (s, IH), 7.84 (d, J = 8.3 Hz, IH), 7.97 (d, J = 4.5 Hz, IH), 8.00 (dd, J = 8.8, 2.0 Hz, IH), 8.13 (d, J = 8.8 Hz, IH), 8.84 (d, J = 1.7 Hz, IH), 8.98 (d, J = 4.5 Hz, IH), 12.62 (br s, IH)

MS (ES+): m/z 373 (M+H)⁺ Example 26: Preparation of: 5-(6-Formylquinolin-4-yl)thiophene-2-carboxylic acid (17)

[0154] To a solution of 2 (192 mg, 1.0 mmol) in dimethoxyethane (DME, 10 rnL) was added a solution of 2-carboxythiophene-5-boronic acid (172 mg, 1.0 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 20 min under μ-wave. The hot solution was filtered and the solid was washed with water. The filtrate was mixed with H₂O (50 mL) and EtOAc (50 mL). The organic layer was separated and the aqueous layer was neutralized with 1 M HCl. The solid was collected by filtration and washed with water. The title compound (70 mg, 25%) was obtained as a white solid.

Example 27: Preparation of: 5-{6-[(Z)-(2,4-Dioxo-l,3-thiazolidin-5-ylidine)methyl]quinolin- 4-yl}thiophene-2-carboxylic acid

[0155] To a solution of 17 (30 mg, 0.1 mmol) in EtOH (15 mL) was added thiazolidine-2,4- dione (TZD, 24 mg, 0.2 mmol) and Cs₂CO₃ (130 mg, 0.4 mmol). The reaction mixture was heated at 120 ⁰C for 30 min under μ-wave. The reaction mixture was concentrated and the residue was purified by HPLC. The HPLC fractions containing the product were combined and concentrated. The title compound (4 mg, 8%) was obtained as the TFA salt as a yellow solid.

[0156] ¹H NMR (500 MHz, DMSO-d₆): δ 7.67 (d, J = 3.8 Hz, IH), 7.72 (d, J = 4.5 Hz, IH), 7.92 (d, J = 3.8 Hz, IH), 8.01 (s, IH), 8.05 (dd, J = 8.8, 1.8 Hz, IH), 8.23 (d, J= 8.8 Hz, IH), 8.40 (d, J = 1.8 Hz, IH), 9.02 (d, J = 4.5 Hz, IH), 12.62 (br s, IH), 13.40 (br s, IH); MS (ES+): m/z 383 (M+H)⁺

Example 28: reparation of: 5-(6-Formylquinolin-4-yl)-N-(2-pyrrolidin-l-ylethyl)thiophene-2- carboxamide (18)

[0157] The compound 17 (120 mg, 0.42 mmol) was dissolved in SOCl₂ (15 mL) and heated under reflux for 2 h. The excess SOCl₂ was removed in vacuo. The residue was suspended in PhMe (20 mL) and added l-(2-aminoethyl)-pyrrolidine (57 mg, 0.5 mmol) and Et₃N (0.5 mL). The mixture was heated under reflux overnight. After cooling, the saturated NaHCO₃ (50 mL) was added and organic layer was separated. The aqueous was extracted with EtOAc (2 x 20 mL). Combined organic layer was dried (Na₂SO₄). Solvent was removed in vacuo. The crude material was used for next step without further purification.

Example 29: Preparation of: 5-{6-[(Z)-(2,4-Dioxo-l,3-thiazolidin-5-ylidine)methyl]quinolin-4- yl } -,/V-(2-pyrrolidin- 1 -ylethyl)thiophene-2-carboxamide:

[0158] To a solution of 18 (0.42 mmol) in EtOH (15 mL) was added thiazolidine-2,4-dione (TZD, 98 mg, 0.84 mmol) and Cs₂CO₃ (0.52 g, 1.6 mmol). The reaction mixture was heated at 120 ⁰C for 30 min under μ-wave. The reaction mixture was concentrated and residue was purified by HPLC. The HPLC fractions containing the product were combined and concentrated. The title compound (7 mg, 3%) TFA salt was obtained as a yellow solid. [0159] ¹H NMR (500 MHz, DMSO-d₆): δ 1.88-1.89 (m, 2H), 2.03 (br, 2H), 3.08-3.11 (m, 2H), 3.34-3.38 (m 2H), 3.62-3.66 (m, 4H), 7.70-7.71 (m, 2H), 7.98 (d, J = 3.9 Hz, IH), 8.01 (s, IH), 8.06 (dd, J = 8.8, 1.9 Hz, IH), 8.23 (d, J = 8.8 Hz, IH), 8.40 (d, J = 1.9 Hz, IH), 9.00 (s, IH), 9.02 (d, J = 4.5 Hz, IH), 9.65 (br s, IH), 12.80 (br s, IH)

MS (ES+): m/z 479 (M+H)⁺

Example 30: Preparation of 5-(6-Formyl-quinolin-4-yl)-thiophene-2-carboxylic acid amide (19)

19 [0160] Compound 17 (420 mg, 1.5 mmol) was dissolved in thionyl chloride (10 mL) and heated under reflux for 4 h. The excess thionyl chloride was removed in vacuo. The residue was suspended in NH₃-H₂O (20 mL) and heated under reflux overnight. The solid was collected by filtration and washed with water. The title compound (100 mg, 24%) was obtained as a yellow solid. Example 31: Preparation of: 5-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4-yl]- thiophene-2-carboxylic acid amide

[0161] To a solution of 19 (100 mg, 0.35 mmol) in EtOH (15 mL) was added thiazolidine- 2,4-dione (TZD, 62 mg, 0.53 mmol) and Cs₂CO₃ (0.46 g, 1.4 mmol). The reaction mixture was heated at 120 ⁰C for 30 min under μ-wave. The solvent was removed in vacuo and the residue was suspended in H₂O-EtOAc. The solid was collected and washed with water and then MeOH. The solid was dried in air and the title compound (80 mg, 60%) was afforded as a brown solid.

[0162] ¹H NMR (500 MHz, DMSOd₆): δ 7.55 (br s, IH), 7.61-7.63 (m, 2H), 7.96-7.98 (m, 2H), 8.10 (d, J = 8.7 Hz, IH), 8.20 (br s, IH), 8.39 (d, J = 1.8 Hz, IH), 8.90 (d, J = 4.5 Hz, IH)

[0163] MS (ES+): m/z 382 (M+H)⁺

Example 32: Preparation of: l-Bromo-3-(2,2-dimethoxy-ethylsulfanyl)-benzene (20)

20 [0164] To a stirred solution of compound 3-bromo-benzenethiol (15O g, 0.80 mol) and compound 2-bromo-l,l-dimethoxy-ethane (135 g) in DMF (1500 mL) was added K2CO3 (165 g, 1.20 mol). The mixture was stirred overnight at room temperature (30 ⁰C). The mixture was filtered and the solvent of the filtrate was removed under reduced pressure. The residue was re- dissolved in EtOAc (2000 mL), washed with NaOH (IM, 500 mL), brine, dried over Na₂SO₄ and concentrated to give a crude product, which was purified by column chromatography (silica, elute; PE to PE:EtOAc=5: 1) to afford the title compound (135 g, 70 %) as a light yellow oil.

Example 33: Preparation of: 6-Bromo-benzo[b]thiophene (21) and 4-Bromo-benzo[b]thiophene

(22)

22

[0165] Chlorobenzene (1000 mL) and PPA (280 g) were combined and heated to reflux (130 ⁰C). The solution of compound 20 (130 g, 0.48 mol) in chlorobenzene (300 mL) was added drop wise to the mixture over 1.5 h. The reaction mixture was refluxed for 3-4 h and then cooled. The solvent was decanted from the residue and toluene (400 mLx2 ) was added to the residue, stirred and decanted. The chlorobenzene/toluene extracts were combined and concentrated under vacuum, and the residue was then taken up with PE (800 mL) and water (400 mL). After layers separation the organic phase was washed with saturated NaHCO₃, brine, dried over Na₂SO₄ and concentrated to give a crude product, which was purified by column chromatography (silica gel, elute: PE) to afford a mixture of 21 and 22 (80 g, 70 %) as a colorless oil.

Example 34: Preparation of: Benzo[b]thiophene-6-carbonitrile (23) and Benzo[b]thiophene-4- carbonitrile (24)

[0166] Under Ar atmosphere, to the mixture of compound 21 and compound 22 (40 g, 0.19 mol) and Zn(CN)₂ (16 g, 0.132 mol) were added Pd(PPh3)₄ (10 g) and DMF (800 mL) and the mixture was stirred at 90 ⁰C -100 ⁰C for 3 h. The reaction solution was cooled to room temperature (30 ⁰C) and filtered. The filtrate was concentrated under reduced pressure and the residue was then taken up with EtOAc (1000 mL) and saturated aq. NaHCO₃ (500 mL), the insoluble solid was discarded via filtration. The filtrate layers were separated. The organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated to give a mixture product, which was purified by careful column chromatography (silica, elute; PE to EtO Ac:PE= 1:40) to afford compound 23 (14 g, 46.2 %) as an oil and compound 24 (7 g, 23%) as a solid.

Example 35: Preparation of 6-Cyano-benzothiophene-2-boronic acid (25)

25

[0167] Compound 23 (14 g, 0.088 mol) in dry THF (350 mL) was purged with nitrogen. The mixture was then cooled (-90 ⁰C) with liquid nitrogen bath and ra-BuLi (2.5 M in hexanes, 42 niL, 0.105 mol) was added dropwise with stirred. The mixture was stirred for a further 30 min, and B(OMe)₃ (18 g, 0.173 mol) was added at -90 ⁰C. After 30 min, aqueous HCl (2M, 200 mL) was added. The mixture was stirred for a further 30 min, allowed to warm to room temperature (30 ⁰C), poured into water (100 mL). The mixture was extracted with EtOAc (400 mLx3). The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated to give a crude product, which was crystallized with EtOAc/PE (1:2, 100 mL) to give the title compound (12 g, 72%) as a white solid.

Example 36: Preparation of: 4-Cyano-benzothiophene-2-boronic acid (26)

26

[0168] Compound 24 (12 g, 0.076 mol) in dry THF (300 mL) was purged with nitrogen. The mixture was then cooled (-90 ⁰C) with liquid nitrogen bath and ra-BuLi (2.5 M in hexanes, 35 mL, 0.083 mol) was added dropwise with stirred. The mixture was stirred for a further 30 min, and B(OMe)₃ (16 g, 0.154 mol) was added at -90 ⁰C. After 30 min, aqueous HCl (2M, 200 mL) was added and solid was precipitated out. The mixture was stirred for a further 30 min, allowed to warm to room temperature (30 ⁰C), poured into water (100 mL). The mixture was extracted with EtOAc (300 mLx3). The combined organic layers were washed with water, brine, dried over Na₂SO₄ and concentrated to give a crude product, which was crystallized with EtOAc/PE (1:2, 100 mL) to give the title compound (H g, 73%) as a white solid. Example 37: Preparation of Benzo[b]thiophene-7-carbonitrile (27)

27

[0169] Under Ar atmosphere, to a mixture of 7-bromo-benzo[b]thiophene (40 g, 0.19 mol) and Zn(CN)₂ (16 g, 0.132 mol) were added Pd(PPh3)₄ (10 g) and DMF (800 mL) and the mixture was stirred at 90 ⁰C -100 ⁰C for 3 h. The reaction solution was cooled to room temperature (30 ⁰C) and filtered. The filtrate was concentrated under reduced pressure. The residue was taken up with EtOAc (1000 mL) and saturated aq. NaHCO₃ (500 mL) and then filtered. The filtrate layers were separated. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated to give a crude product, which was purified by column chromatography (silica, elute; PE to EtOAc:PE=l:30) to afford the title compound (24 g, 80 %) as a white solid.

Example 38: Preparation of 7-Cyano-benzothiophene-2-boronic acid (28)

28

[0170] Compound 27 (20 g, 0.126 mol) in dry THF (500 mL) was purged with nitrogen. The mixture was then cooled (-90 ⁰C) with liquid nitrogen bath and ra-BuLi (2.5 M in hexanes, 60 mL, 0.15 mol) was added dropwise with stirred. The mixture was stirred for a further 30 min, and B(OMe)₃ (26 g, 0.25 mol) was added at -90 ⁰C. After 30 min, aqueous HCl (2M, 300 mL) was added and solid was precipitated out. The mixture was stirred for a further 30 min, allowed to warm to room temperature (30 ⁰C), poured into water (200 mL). The solid was filtered, washed with ice- water and dried to give the title compound (18 g, 72%) as a white solid.

Example 39: Preparation of 2-(6-Formyl-quinolin-4-yl)-benzo[b]thiophene-6-carbonitrile (29)

29 [0171] To a solution of 2 (0.30 g, 1.6 mmol), 25 (0.40 g, 2.0 mmol), and Pd(PPh₃)₄ (0.15 g, 0.13 mmol) in DMF (5 mL) was added Na₂CO₃ (2.0 M, 2.0 mL). The reaction mixture was heated for 20 min at 140 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 60% EtOAc/hexanes) to afford the title compound as a white solid (0.17 g, 35%).

[0172] MS (ES+) : m/z 315 (M+H)⁺

Example 40: Preparation of 2-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4-yl]- benzo[b]thiophene-6-carbonitrile

[0173] A suspension of 29 (0.17 g, 0.54 mmol), thiazolidine-2,4-dione (0.12 g, 1.0 mmol), Cs₂CO₃ (0.30 g, 0.92 mmol) in ethanol (10 mL) was heated at 100 ⁰C for 2 h. Upon cooling to room temperature, the resulting solid was filtered and washed with water (15 mL). The title compound was obtained as a brownish orange solid (80 mg, 36%).

[0174] ¹H NMR (500 MHz, DMSO-J₆): δ 7.48 (s, IH), 7.72 (d, J = 4.4 Hz, IH), 7.88 (dd, J = 8.2, 1.3 Hz, IH), 8.02 (dd, J = 8.8, 1.8 Hz, IH), 8.09 (s, IH), 8.16 (d, J = 8.8 Hz, IH), 8.19 (d, J = 8.3 Hz, IH), 8.46 (d, J = 1.6 Hz, IH), 8.78 (d, J = 0.7 Hz, IH), 8.98 (d, J = 4.4 Hz, IH)

[0175] MS (ES+): m/z 414 (M+H)⁺ Example 41: Preparation of 2-(6-Formyl-quinolin-4-yl)-benzo[b]thiophene-4-carbonitrile (30)

30

[0176] To a solution of 2 (0.30 g, 1.6 mmol), 26 (0.40 g, 2.0 mmol), and Pd(PPh₃)₄ (0.15 g, 0.13 mmol) in DMF (4 mL) was added Na₂CO₃ (2.0 M, 2.0 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 white solid (0.14 g, 28%).

[0177] MS (ES+) : m/z 315 (M+H)⁺

Example 42: Preparation of 2-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4-yl]- benzo [b] thiophene-4-carbonitrile

[0178] A suspension of 30 (0.14 g, 0.44 mmol), thiazolidine-2,4-dione (70 mg, 0.60 mmol),

Cs₂CO₃ (0.20 g, 0.60 mmol) in ethanol (10 mL) was heated at 100 ⁰C for 2 h. Upon cooling to room temperature, the resulting solid was filtered and washed with water (15 mL). The title compound was obtained as a reddish brown solid (75 mg, 41%).

[0179] ¹H NMR (500 MHz, DMSO-J₆): δ 7.48 (s, IH), 7.67 (t, J = 1.9 Hz, IH), 7.77 (d, J = 4.4 Hz, IH), 7.99 (s, IH), 8.02 (dd, J = 8.8, 1.8 Hz, IH), 8.07 (d, J= 8.0 Hz, IH), 8.16 (d, J = 8.8 Hz, IH), 8.47 (d, J = 1.8 Hz, IH), 8.55 (d, J = 8.2 Hz, IH), 8.98 (d, J = 4.4 Hz, IH)

[0180] MS (ES+): m/z 414 (M+H)⁺ Example 43: Preparation of 2-(6-Formyl-quinolin-4-yl)-benzo[b]thiophene-7-carbonitrile (31)

31

[0181] To a solution of 2 (0.30 g, 1.6 mmol), 28 (0.45 g, 2.2 mmol), and Pd(PPh₃)₄ (0.15 g, 0.13 mmol) in DMF (5 mL) was added Na₂CO₃ (2.0 M, 2.0 mL). The reaction mixture was heated for 30 min at 110 ⁰C in a Biotage microwave reactor. 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 white solid (0.10 g, 20%). [0182] MS (ES+) : m/z 315 (M+H)⁺

Example 44: Preparation of 2-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4-yl]- benzo[b]thiophene-7-carbonitrile

[0183] A solution of 31 (0.06 g, 0.19 mmol), thiazolidine-2,4-dione (90 mg, 0.77 mmol), Boc-β-Ala-OH (0.14 g, 0.74 mmol) in acetic acid (7 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 was obtained as a brick red solid (65 mg, 87%). [0184] ¹H NMR (500 MHz, DMSO-J₆): δ 7.73 (t, J = I. S Hz, IH), 7.82 (d, J = 4.2 Hz, IH), 8.02-8.07 (m, 2H), 8.09 (d, J = 1.3 Hz, IH), 8.14 (s, IH), 8.26 (d, J = 8.8 Hz, IH), 8.37 (d, J = 8.0 Hz, IH), 8.52 (s, IH), 9.07 (d, J = 4.4 Hz, IH), 12.68 (br s, IH)

[0185] MS (ES+): m/z 414 (M+H)⁺

Example 45: Preparation of (3-Bromophenyl)(2,2-dimethoxypropyl)sulfane (40)

40

[0186] A mixture of 3-bromobenzenethiol (630 μL, 5.33 mmol), l-bromo-2,2- dimethoxypropane (715 μL, 5.29 mmol), and K₂CO₃ (1.10 g, 7.96 mmol) in DMF (11 mL) was heated at 150 ⁰C for 2.5 hours. The crude reaction mixture was cooled, filtered, and concentrated. The residue was purified using flash chromatography (0-30% ethyl acetate in hexanes) to afford the title compound as a clear oil (1.66 g, 108% with some trapped solvent). The material was used as is for the next reaction. [0187] ¹H NMR (500 MHz, DMSO-J₆) δ 1.33 (s, 3H), 3.12 (s, 6H), 3.25 (s, 2H), 7.25 (dd, J = 8.4, 7.5 Hz, IH), 7.36 (dd, J = 7.9, 1.9 Hz, 2H), 7.54 (t, J= 1.8 Hz, IH)

Example 46: Preparation of 6-Bromo-3-methylbenzo[b]thiophene (41) and 4-bromo-3- methylbenzo[b]thiophene (42)

41 42

[0188] Polyphosphoric acid (3.92 g) was added to chlorobenzene (12 rnL). The biphasic mixture was heated to 130 ⁰C and a solution of 40 (1.66 g, 5.33 mmol) in chlorobenzene (2.5 mL) was added dropwise over 5 minutes. The reaction was heated at reflux for two hours, then cooled to room temperature. The organic solvent was decanted and the residue washed with toluene (2x5 mL) and in turn decanted. The combined organic layers were concentrated in vacuo. The residue was taken up in petroleum ether (10 mL) and washed with water (5 mL), sat. aq. NaHCO₃ (5 mL), dried (Na₂SO₄), and concentrated in vacuo. The crude material was purified using flash chromatography (petroleum ether) to afford a mixture of the title compound as a clear oil (1.006 g, 77%). The material was used as is for the next reaction.

[0189] 41 and 42: ¹H NMR (500 MHz, DMSO-J₆) δ 2.39 (d, J = 0.8 Hz, 4.2H), 2.66 (d, J = 0.7 Hz, 3.7H), 7.23 (t, J = 7.8 Hz, 1.1H), 7.42 (d, J= 0.9 Hz, 1.4H), 7.53-7.56 (m, 2.2H) 7.61 (d, J = 7.8 Hz, 1.0H), 7.70 (d, J= 8.5 Hz, 1.3H), 8.00 (d, J = 7.9 Hz, 1. OH), 8.25 (d, J= 1.8 Hz, 1.0H)

Example 47: Preparation of 3-Methylbenzo[b]thiophene-6-carbonitrile (43) and 3- methylbenzo [b] thiophene-4-carbonitrile (44)

43 44

[0190] To a solution of 41 and 42 ( 1.0Og, 4.40 mmol) in DMF (10 mL) was added zinc cyanide (364 mg, 3.10 mmol) and Pd(PPh₃ )₄ (253 mg, 0.2 mmol) with a further 12 mL of DMF. The reaction was heated at 95 ⁰C for 5 hours then cooled to room temperature. The DMF was removed in vacuo and the residue was partitioned between ethyl acetate (25 rnL) and sat. aq. NaHCO₃ (12 rnL). The insoluable solids were removed by filtration and the organic layer was separated, washed with brine (5 mL), dried (Na₂SO₄), and concentrated in vacuo. The crude material was purified using flash chromatography (1:40 ethyl acetate/petroleum ether) to afford each title compound separately: 43 as a clear oil that crystallized on standing (361 mg, 47%) and 44 as a white solid (264 mg, 35%).

[0191] 43: ¹H NMR (500 MHz, DMSO-J₆) δ 2.44 (d, J = 1.1 Hz, 3H), 7.76 (d, J = 1.2 Hz, IH), 7.78 (dd, J = 8.3, 1.5 Hz, IH), 7.95 (d, J= 8.2 Hz, IH), 8.61 (d, J= 1.2 Hz, IH)

[0192] 44: ¹H NMR (500 MHz, DMSO-J₆) δ 2.66 (d, J = 1.3 Hz, 3H), 7.51 (t, J = 7.8 Hz, IH), 7.75 (d, J = 1.0 Hz, IH), 7.92 (dd, J = 7.4, 0.9 Hz, IH), 8.36 (dd, J= 8.0, 0.9 Hz, IH)

Example 48: Preparation of 6-Cyano-3-methylbenzo[b]thiophen-2-ylboronic acid (45)

45

[0193] To an argon flushed, -78 ⁰C solution of 43 (358 mg, 2.07 mmol) in anhydrous THF (8.3 mL) was added dropwise 2.5 M nBuLi in hexanes (1.0 mL, 2.5 mmol). The resulting solution was stirred for 30 min. Trimethylborate (0.46 mL, 4.13 mmol) was added dropwise and the cold bath removed. The reaction was allowed to warm naturally to 0 ⁰C over 15 min at which point it was held there with an ice bath for another 15 min. 2M HCl (4.6 mL) was added and the ice bath was removed, and allowed to warm to room temperature over 30 minutes. The reaction mixture was poured into 2 mL water and 6 mL ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate (3x18 mL). The combined organic layers were washed with water (2 mL), brine (4 mL), dried (Na₂SO₄), and concentrated in vacuo. The crude residue was triturated in ethyl acetate (3 mL) and then fully precipitated with petroleum ether (6 mL) to afford the title compound as an off-white solid (206 mg, 46%). The material was used as is for the next reaction.

Example 49: Preparation of 2-(6-Formylquinolin-4-yl)-3-methylbenzo[b]thiophene-6- carbonitrile (46)

46

[0194] To a solution of 2 (150 mg, 0.78 mmol) and 45 (202 mg, 0.93 mmol) in anhydrous THF (5.2 niL) was added IM NaHCO₃ (4.3 niL, 4.3 mmol) and Pd(PPh₃)₂Cl₂ (26.4 mg, 0.04 mmol). The resulting solution was heated to 50 ⁰C for 1 hour. The reaction mixture was concentrated by half and water used to rinse down sides of flask. The mixture was cooled in an ice bath for 1 hour before filtering to obtain white and black solids. The crude material was purified using preparative HPLC to afford the title compound as a beige solid (160 mg, 62%).

[0195] MS (ES+): m/z 329 (M+H)⁺ Example 50: Preparation of (Z)-2-(6-((2,4-Dioxothiazolidin-5-ylidene)methyl)quinolin-4-yl)- 3-methylbenzo[b]thiophene-6-carbonitrile

[0196] A mixture of 46 (157 mg, 0.48 mmol), thiazolidine-2,4-dione, 90% (129 mg, 1.10 mmol), and Boc-β- AIa-OH (185 mg, 0.98 mmol) in acetic acid (4.8 mL) was heated at 120 ⁰C for 1 hour. The reaction was cooled and water (5mL) was added to precipitate the product. The crude solid was slurried in EtOH (1 mL) and filtered to afford the title compound as a beige solid (41 mg, 20%)

[0197] ¹H NMR (500 MHz, DMSO-J₆) δ 2.25 (s, 3H), 7.73 (d, J = 4.4 Hz, IH), 7.93 (dd, J = 8.4, 1.4 Hz, IH), 7.96 (s, IH), 7.99 (d, J = 1.8 Hz, IH), 8.03 (dd, J = 8.7, 2.1 Hz, IH), 8.13 (d, J = 8.4 Hz, IH), 8.26 (d, J = 8.8 Hz, IH), 8.74 (d, J= 1.1 Hz, IH), 9.10 (d, J= 4.4 Hz, IH), 12.68 (br s, IH)

[0198] MS (ES+): m/z 428 (M+H)⁺

Example 51: Preparation of 4-Cyano-3-methylbenzo[b]thiophen-2-ylboronic acid (47)

[0199] To an argon flushed, -78 ⁰C solution of 44 (279 mg, 1.61 mmol) in anhydrous THF (6.4 rnL) was added dropwise 2.5 M nBuLi in hexanes (0.77 rnL, 1.93 mmol). The resulting solution was stirred for 30 min. Trimethylborate (0.36 mL, 3.23 mmol) was added dropwise and the cold bath removed. The reaction was allowed to warm naturally to 0 ⁰C over 15 min at which point it was held there with an ice bath for another 15 min. 2M HCl (3.6 mL) was added and the ice bath was removed, and allowed to warm to room temperature over 30 minutes. The reaction mixture was poured into 2 mL water and 6 mL ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate (3x18 mL). The combined organic layers were washed with water (2 mL), brine (4 mL), dried (Na₂SO₄), and concentrated in vacuo. The crude residue was triturated in ethyl acetate (3 mL) and then fully precipitated with petroleum ether (6 mL) to afford the title compound as a mustard colored solid (168 mg, 48%). The material was used as is for the next reaction.

Example 52: Preparation of 2-(6-Formylquinolin-4-yl)-3-methylbenzo[b]thiophene-4- carbonitrile (48)

48

[0200] To a solution of 2 (125 mg, 0.65 mmol) and 47 (156 mg, 0.72 mmol) in anhydrous THF (4.4 mL) was added IM NaHCO₃ (3.6 mL, 3.6 mmol) and Pd(PPh₃)₂Cl₂ (22.6 mg, 0.03 mmol). The resulting solution was heated to 50 ⁰C for 1 hour. The reaction mixture was concentrated by half and water used to rinse down sides of flask. The mixture was cooled in an ice bath for 1 hour before filtering to obtain white and black solids. The crude material was purified using preparative HPLC to afford the title compound as a beige solid (104 mg, 49%). [0201] MS (ES+): m/z 329 (M+H)⁺

Example 53: Preparation of (Z)-2-(6-((2,4-Dioxothiazolidin-5-ylidene)methyl)quinolin-4-yl)- 3-methylbenzo[b]thiophene-4-carbonitrile

[0202] A mixture of 48 (100 mg, 0.30 mmol), thiazolidine-2,4-dione, 90% (70 mg, 0.54 mmol), and Boc-β- AIa-OH (118 mg, 0.62 mmol) in acetic acid (4 mL) was heated at 120 ⁰C for 2 hours. The reaction was cooled and water (4 mL) was added to precipitate the product. The crude solid was slurried in EtOH (1 mL) and filtered to afford the title compound as a beige solid (37 mg, 29%)

[0203] ¹H NMR (500 MHz, DMSO-J₆) δ 2.45 (d, J = 3.2 Hz, 3H), 7.66 (t, J= I. S Hz, IH), 7.73 (d, J = 4.4 Hz, IH), 8.01 (d, J = 2.8 Hz, 2H), 8.03 (dd, J = 8.8, 1.2 Hz, IH), 8.08 (dd, J = 7.5, 0.8 Hz, IH), 8.27 (d, J= 8.8 Hz, IH), 8.51 (dd, J= 8.0, 0.8 Hz, IH), 9.11 (d, J = 4.3 Hz, IH), 12.65 (br s, IH)

[0204] MS (ES+): m/z 428 (M+H)⁺

Example 54: Preparation of N-fer?-Butyl-3-[5-(6-formyl-quinolin-4-yl)-thiophen-2-yl]- benzenesulfonamide (49)

49

[0205] To a solution of 9 (73 mg, 0.27 mmol) in dimethoxyethane (DME, 10 niL) was added a solution of 3-(jV-te/t-butylsulfamoyl)-phenylboronic acid (78 mg, 0.3 mmol) in EtOH (5 mL), 1.0 M Na₂CO₃ (2 mL), and tetrakis(triphenylphosphine)palladium (0) (Pd(PPh₃)₄, 35 mg, 0.03 mmol). The reaction mixture was heated at 150 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 mL). The aqueous was extracted with EtOAc (3 x 20 mL). Combined organic layer was dried (Na₂SO₄). The solvent was removed in vacuo. The residue was purified by flash column (SiO₂/CH₂Cl₂). The title compound (90 mg, 74%) was obtained as a yellow solid. Example 55: Preparation of N-fer?-Butyl-3-{5-[6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)- quinolin-4-yl] -thiophen-2-yl } -benzenesulfonamide

[0206] To a solution of 49 (90 mg, 0.2 mmol) in EtOH (15 mL) was added thiazolidine-2,4- dione (TZD, 62 mg, 0.53 mmol) and Cs₂CO₃ (0.35 g, 1.1 mmol). The reaction mixture was heated at 140 ⁰C for 30 min under μ-wave. The solvent was removed in vacuo. The crude product was purified by HPLC. The HPLC fractions containing product were combined and concentrated. The title compound (9 mg, 8%) was obtained as an orange solid.

[0207] ¹H NMR (500 MHz, DMSO-J₆): δ 1.13 (s, 9H), 7.67-7.69 (m, 2H), 7.74-7.76 (m, 2H), 7.82 (d, J = 7.9 Hz, IH), 7.90 (d, J = 3.8 Hz, IH), 8.04-8.06 (m, 3H), 8.20 (br s, IH), 8.23 (d, J = 8.8 Hz, IH), 8.56 (s, IH), 9.02 (d, J = 4.5 Hz, IH), 12.42 (s, IH)

[0208] MS (ES+): m/z 550 (M+H)⁺

Example 56: Preparation of 4-(4-Methylthiophen-3-yl)quinoline-6-carbaldehyde (50)

50

[0209] To a solution of 2 (191 mg, 1.0 mmol) in dimethoxyethane (DME, 10 niL) was added a solution of 4-methylthiophen-3-yl-3-boronic acid (156 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 mL). The aqueous was extracted with EtOAc (3 x 20 mL). Combined organic layer was dried (Na₂SO₄). The solvent was removed in vacuo. The residue was added MeOH (10 mL) and sonicated. The solid was collected by centrifuge. The title compound (210 mg, 82%) was obtained as a yellow solid.

Example 57: Preparation of (Z)-5-((4-(4-Methylthiophen-3-yl)quinolin-6- yl)methylene)thiazolidine-2,4-dione

[0210] To a solution of 50 (210 mg, 0.82 mmol) in EtOH (15 mL) was added thiazolidine- 2,4-dione (TZD, 194 mg, 1.6 mmol) and Cs₂CO₃ (0.54 g, 1.6 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 HPLC. The HPLC fractions containing product were combined and concentrated. The title compound (17 mg, 6%) was obtained as a yellow solid. [0211] ¹H NMR (500 MHz, DMSO-J₆): δ 2.02 (s, 3H), 7.51-7.52 (m, IH), 7.52 (d, J = 4.4 Hz, IH), 7.72 (d, J = 3.2 Hz, IH), 7.83 (d, J = 1.9 Hz, IH), 7.93 (s, IH), 8.00 (d, J = 2.0 Hz, IH), 8.02 (d, J = 2.0 Hz, IH), 8.18 (d, J = 8.8 Hz, IH), 9.01 (d, J = 4.4 Hz, IH), 12.67 (br s, IH)

[0212] MS (ES+): m/z 353 (M+H)⁺ Example 58: Preparation of 5-(fert-Butoxycarbonyl)-4,5,6,7-tetrahydrothieno[J,2-c]pyridin-2- yl-2-boronic acid (52)

52 [0213] To a stirred solution of diisopropylamine (24.1 g, 0.24 mol) in THF (400 rnL) was added dropwise ra-BuLi (2.5 M, 96 rnL, 0.24 mol) at -60 ⁰C under Argon. The mixture was warmed to -30 ⁰C and stirred for 30 min. Upon completion, the mixture was re-cooled to -65 ⁰C, and then added dropwise a solution of tert-butyl 6,7-dihydrothieno[3,2-c]pyridine-5(4H)- carboxylate (48 g, 0.2 mol) in TΗF (200 mL). The resulting mixture was stirred at -65 ⁰C for 2 h, and then added dropwise trimethyl borate (33.4 g, 0.32 mol). After the addition completed, the mixture was allowed to warm to room temperature (10 ⁰C) and stirred overnight. Saturated NH₄Cl (300 mL) was added to the mixture, and the resulting mixture was stirred for 30 min. Two layers were separated. The aqueous layer was extracted with MTBE (500 mL x 2). The combined organic layer was washed with brine, dried over Na₂SO₄, and then concentrated. The obtained residue was purified by column chromatography (silica, eluting with PE: EtOAc =1:1) to give the title compound (26 g, 46%) as a white solid.

Example 59: Preparation of tert-Butyl 2-(6-formylquinolin-4-yl)-6,7-dihydrothieno[3,2- c]pyridine-5(4H)-carboxylate (53)

53

[0214] To a solution of 2 (193 mg, 1.0 mmol) in dimethoxyethane (DME, 10 mL) was added a solution of 53 (340 mg, 1.1 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 120 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 niL). 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 60: Preparation of (Z)-5-((4-(4,5,6,7-Tetrahydrothieno[3,2-c]pyridin-2-yl)quinolin-6- yl)methylene) thiazolidine-2,4-dione

[0215] To a solution of 53 (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.

[0216] ¹H NMR (500 MHz, DMSO-J₆): δ 3.18 (t, J = 5.8 Hz, 2H), 3.53 (t, J = 5.8 Hz, 2H), 4.33 (s, 2H), 7.52 (s, IH), 7.62 (d, J = 4.5 Hz, IH), 8.00 (s, IH), 8.03 (dd, J = 8.8, 1.9 Hz, IH), 8.22 (d, J = 8.8 Hz, IH), 8.47 (d, J = 1.9 Hz, IH), 8.88 (d, J = 4.5 Hz, IH), 9.29 (br s, IH), 12.36 (br s, IH)

[0217] MS (ES+): m/z 394 (M+H)⁺

Example 61: Preparation of 5-Cyano-4-methylthiophen-2-yl-2-boronic acid (55)

55

[0218] To a stirred solution of diisopropylamine (4.8 g, 0.64 mol) in dry THF (1500 rnL) being cooled below -65 ⁰C under N₂ was added dropwise ra-BuLi (234 rnL, 0.58 mol). The mixture was warmed to -30 ⁰C slowly, and stirred at this temperature for -30 min, and then re- cooled below -65 ⁰C. The 3-methy\thiophene-2-carbonitrile (60 g, 0.49 mol) was added dropwise, and the mixture was stirred at below -65 ⁰C for an additional 3 h. Then B(OMe)₃ was added. The mixture was stirred at 10 ⁰C overnight. Upon completion, the reaction mixture was poured into ice water. The resulting mixture was acidified to pH<2 with 1 N HCl. The aqueous layer was extracted with MTBE (1000 mL x X). The combined organic layers were washed with brine, dried over sodium sulfate, and then concentrated. The crude product was crystallized from dichloromethane to give the compound (28 g, 34.5%) as a light yellow solid.

Example 62: Preparation of 5-(6-Formylquinolin-4-yl)-3-methylthiophene-2-carbonitrile (56)

56 [0219] To a solution of 2 (191 mg, 1.0 mmol) in dimethoxyethane (DME, 10 mL) was added a solution of 55 (201 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 120 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 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 63: Preparation of 3-Methyl-5-(6-((Z)-(2,4-dioxothiazolidin-5- ylidene)methyl)quinolin-4-yl)thiophene-2-carbonitrile

[0220] To a solution of 56 (1 mmol) in EtOH (15 niL) 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 HPLC. The HPLC fractions containing product were combined and concentrated. The title compound (5 mg, 1%) was obtained as a yellow solid.

[0221] ¹H NMR (500 MHz, DMSO-J₆): δ 2.54 (s, 3H), 7.68 (s, IH), 7.72 (d, J = 4.5 Hz, IH), 8.04 (d, J = 1.9 Hz, IH), 8.05 (s, IH), 8.24 (d, J = 8.8 Hz, IH), 8.38 (d, J = 1.9 Hz, IH), 9.04 (d, J = 4.5 Hz, IH), 12.73 (s, IH) [0222] MS (ES+): m/z 378 (M+H)⁺

Example 64: Preparation of 4-(5-(3-Isopropylphenyl)thiophen-2-yl)quinoline-6-carbaldehyde (57)

57 [0223] To a solution of 9 (0.200 g, 0.73 mmol), 3-isopropylphenylboronic acid (0.120 g, 0.73 mmol), and Pd(PPh₃)₄ (0.084 g, 0.073 mmol) in DMF (3 mL) was added Na₂CO₃ (2.0 M, 0.6 mL). The reaction mixture was heated 1 h at 180 ⁰C in a Biotage microwave reactor. The resulting mixture was concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 70:30 gradient) to afford the title compound as a yellow solid (0.130 g, 50 %). [0224] ¹H NMR (500 MHz, DMSO-J₆): δ 1.27 (d, J= 6.9 Hz, 6H), 2.99 (quin, J= 6.9 Hz, IH), 7.32 (d, J = 1.9 Hz, IH), 7.43 (t, J = 5.8 Hz, IH), 7.67 (d, J = 6.2 Hz, IH), 7.68 (s, IH), 7.84 (d, J = 4.1 Hz, IH), 8.17 (d, J = 8.7 Hz, IH), 8.32 (d, J= 4.0 Hz, IH), 8.39 (dd, J= 8.7, 1.7 Hz, IH), 9.23 (d, J= 1.6 Hz, IH), 9.34 (s, IH), 10.32 (s, IH)

[0225] MS (ES+): m/z 359 (M +H)⁺

Example 65: Preparation of (Z)-5-((4-(5-(3-Isopropylphenyl)thiophen-2-yl)quinolin-6- yl)methylene)thiazolidine-2,4-dione

[0226] A microwave vial was charged with 57 (0.130 g, 0.37 mmol), thiazolidine-2,4-dione (0.071 g, 0.55 mmol), and Cs₂CO₃ (0.24 g, 0.73 mmol) in ethanol (2 mL). The reaction mixture was heated 30 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture concentrated and purified by silica gel chromatography (CH₂Cl₂:Me0H 100:0 to 90: 10 gradient) to afford the title compound in a 1:1 ratio of E and Z isomers as an orange solid (0.033 g, 20 %).

[0227] ¹H NMR (500 MHz, DMSO-J₆): δ 1.26 (d, J= 7.0 Hz, 6H), 1.27 (d, J= 7.0 Hz, 6H), 2.94 (quin, J = 6.8 Hz, IH), 2.99 (quin, J = 6.7 Hz, IH), 7.31 (d, J= 7.6 Hz, 2H), 7.31 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 7.66 (d, J = 7.0 Hz, 2H), 6.80 (d, J = 5.8 Hz, 2H), 7.71 (s, 2H), 7.75 (d, J = 4.0 Hz, IH), 7.85 (d, J = 4.0 Hz, IH), 8.03 (d, J = 8.8 Hz, 2H), 8.13 (d, J = 8.8 Hz, IH), 8.22 (dd, J = 8.9, 1.8 Hz, IH), 8.27 (d, J = 4.1 Hz, IH), 8.32 (d, J = 4.1 Hz, IH), 8.40 (dd, J = 8.9, 1.7 Hz, IH), 8.77 (s, IH), 12.65 (br s, 2H)

[0228] MS (ES+): m/z 458 (M +H)⁺

Example 66: Preparation of 4-(5-(3-Isopropoxyphenyl)thiophen-2-yl)quinoline-6-carbaldehyde (58)

58

[0229] To a solution of 9 (0.200 g, 0.73 mmol), 3-isopropoxyphenylboronic acid (0.132 g, 0.73 mmol), and Pd(PPh₃)₄ (0.084 g, 0.073 mmol) in DMF (3 mL) was added Na₂CO₃ (2.0 M, 0.6 mL). The reaction mixture was heated 1 h at 180 ⁰C in a Biotage microwave reactor. The resulting mixture was concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 70:30 gradient) to afford the title compound as a yellow solid (0.261 g, 96 %).

[0230] MS (ES+): m/z 359 (M +H) +

Example 67: Preparation of (Z)-5-((4-(5-(3-Isopropoxyphenyl)thiophen-2-yl)quinolin-6- yl)methylene)thiazolidine-2,4-dione

[0231] A microwave vial was charged with 58 (0.273 g, 0.73 mmol), thiazolidine-2,4-dione (0.143 g, 1.1 mmol), and Cs₂CO₃ (0.476 g, 1.46 mmol) in ethanol (4 mL). The reaction mixture was heated 30 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture concentrated and purified by silica gel chromatography (CH₂Cl₂:Me0H 100:0 to 90: 10 gradient) to afford the title compound as an orange solid (0.033 g, 20 %).

[0232] ¹H NMR (500 MHz, DMSO-J₆): δ 1.31 (d, J= 6.1 Hz, 6H), 4.76 (quin, J= 3.9 Hz, IH), 6.96-6.99 (m, IH), 7.32-7.43 (m, 3H), 7.84 (d, J= 4.0 Hz, IH), 8.15 (s, IH), 8.19 (dd, / = 8.8, 1.8 Hz, IH), 8.25 (d, /= 4.1 Hz), 8.77 (s, IH), 9.25 (s, 1H)\ [0233] MS (ES+): m/z 474 (M +H)⁺ Example 68: Preparation of 4-(5-(2,6-Dimethoxyphenyl)thiophen-2-yl)quinoline-6- carbaldehyde (59 )

59 [0234] To a solution of 9 (0.200 g, 0.73 mmol), 3-isopropoxyphenylboronic acid (0.132 g, 0.73 mmol), and Pd(PPh₃)₄ (0.084 g, 0.073 mmol) in DMF (3 mL) was added Na₂CO₃ (2.0 M, 0.6 mL). The reaction mixture was heated 1 h at 180 ⁰C in a Biotage microwave reactor. The resulting mixture was concentrated and purified by silica gel chromatography (hexanes/EtOAc 100:0 to 50:50 gradient) to afford the title compound as an orange solid (0.197 g, 72 %). [0235] ¹H NMR (500 MHz, DMSO-J₆): δ 3.29 (s, 6H), 5.75 (s, IH), 6.85 (d, J = 8.5 Hz,

2H), 7.39 (t, J = 8.5 Hz, IH), 7.72 (d, J = 4.0 Hz, IH), 8.16 (d, J = 8.7 Hz, IH), 8.22 (d, J = 5.6 Hz, IH), 8.38 (dd, J = 8.7, 1.6 Hz, IH), 9.23 (s, IH), 9.32 (s, IH), 10.31 (s, IH)

[0236] MS (ES+): m/z 311 (M +H)⁺

Example 69: Preparation of (Z)-5-((4-(5-(2,6-Dimethoxyphenyl)thiophen-2-yl)quinolin-6- yl)methylene)thiazolidine-2,4-dione

[0237] A microwave vial was charged with 59 (0.150 g, 0.40 mmol), thiazolidine-2,4-dione (0.070 g, 0.60 mmol), and Cs₂CO₃ (0.260 g, 0.80 mmol) in ethanol (4 mL). The reaction mixture was heated 30 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture concentrated and purified by HPLC to afford the title compound as a brown solid (0.024 g, 13 %). [0238] ¹H NMR (500 MHz, DMSO-J₆): δ 3.88 (s, 6H), 6.83-6.85 (m, 2H), 7.35-7.40 (m, IH), 7.64 (d, 2.2 Hz, IH), 7.65-7.67 (m, IH), 8.12-8.19 (m, 3H), 8.23 (d, J = 2.2 Hz, IH), 8.80 (s, IH), 9.24 (s, IH)

[0239] MS (ES+): m/z 47 '6 (M +H)⁺

Example 70: Preparation o/3-(te/t-Butyldimethylsilyloxy)aniline (60)

60

[0240] A solution of 3-aminophenol (3.0 g, 27.5 mmol), te/t-butyldimethylsilyl chloride (4.56 g, 30.2 mmol), and imidazole (2.34 g, 34.4 mmol) in DMF (9 mL) was stirred for 4 h at room temperature and EtOAc (15 mL) and H₂O (20 mL). The aqueous layer was extracted two times with EtOAc. The organic layers were combined and washed with H₂O, washed with brine, and dried over MgSO₄. The crude mixture was purified by silica gel chromatography (hexanes/EtOAc 100:0 to 60:40 gradient) to afford the title compound as an orange solid (4.62 g, 75 %). [0241] ¹H NMR (500 MHz, DMSO-J₆): δ 0.92 (s, 9H), 5.00 (s, 2H), 5.97 (d, 7.9 Hz, IH), 6.07 (t, J = 2.3 Hz, IH), 6.14 (dt, J = 9.5, 0.8 Hz, IH), 6.83 (t, J= 8.1 Hz, IH)

Example 71 : Preparation of 5-(6-Formylquinolin-4-yl)-N-(3-hydroxyphenyl)thiophene-2- carboxamide (61)

61

[0242] To a solution of 17 (0.50 g, 1.76 mmol) and 2-chloro-4,6-dimethoxy-l,3,5-triazine (0.47 g, 2.68 mmol) in CH₂Cl₂ (10 mL) was added JV-methylmorpholine (0.78 mL, 7.1 mmol). The reaction mixture was stirred for 2 h at room temperature and 60 (0.60 g, 2.68 mmol) was added. The reaction mixture was stirred additional 2 h at room temperature and concentrated. The crude mixture was purified by silica gel chromatography (hexanes/EtOAc 100:0 to 0:100 gradient) to afford the title compound as a white solid (0.352 g, 41 %).

[0243] ¹H NMR (500 MHz, DMSO-J₆): δ 0.23 (s, 6H), 0.97 (s, 9H), 3.96 (s, IH), 6.62 (d, J = 8.0 Hz, IH), 7.24 (t, J = 8.1 Hz, IH), 7.36 (d, J = 1.6 Hz, IH), 7.42 (d, J = 2.1 Hz, IH), 7.76 (d, J = 3.8 Hz, IH), 7.80 (d, J = 4.6 Hz, IH), 8.22-8.28 (m, 3H), 8.88 (d, J = 1.6 Hz, IH), 9.12 (d, J = 4.6 Hz, IH), 10.22 (s, IH), 10.36 (s, IH)

Example 72: Preparation of (Z)-5-(6-((2,4-Dioxothiazolidin-5-ylidene)methyl)quinolin-4-yl)- jV-(3-hydroxyphenyl)thiophene-2-carboxamide

[0244] A microwave vial was charged with 61 (0.150 g, 0.31 mmol), thiazolidine-2,4-dione

(0.054 g, 0.46 mmol), and Cs₂CO₃ (0.325 g, 0.92 mmol) in ethanol (3 mL). The reaction mixture was heated 30 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture concentrated and purified by silica gel chromatography (CH₂Cl₂:Me0H 100:0 to 50:50 gradient) to afford the title compound a brown solid (0.079 g).

[0245] ¹H NMR (500 MHz, DMSO-J₆): δ 6.54 (d, J = 1.5 Hz, IH), 7.13-7.32 (m, 3H), 7.34 (s, IH), 7.67 (d, J = 4.6 Hz, IH), 7.69 (d, J = 4.5 Hz, IH), 7.76 (s, IH), 8.02 (dd, J = 8.8, 1.8 Hz, IH), 8.18 (d, J = 8.8 Hz, IH), 8.26 (d, J = 3.9 Hz, IH), 8.43 (s, IH), 8.98 (d, J = 4.5 Hz, IH), 9.48 (br s, IH), 10.34 (s, IH) [0246] MS (ES+): m/z AlA (M +H)⁺

Example 73: Preparation of 4-(te/t-Butyldimethylsilyloxy)aniline (62)

62

[0247] A solution o/4-aminophenol (3.0 g, 27.5 mmol), tert-butyldimethylsilyl chloride (4.56 g, 30.2 mmol), and imidazole (2.34 g, 34.4 mmol) in DMF (9 mL) was stirred for 4 h at room temperature and EtOAc (15 mL) and H₂O (20 mL). The aqueous layer was extracted two times with EtOAc. The organic layers were combined and washed with H₂O, washed with brine, and dried over MgSO₄. The crude mixture was purified by silica gel chromatography (hexanes/EtOAc 100:0 to 60:40 gradient) to afford the title compound yellow oil (4.03 g, 66 %). [0248] ¹H NMR (500 MHz, DMSO-J₆): δ 0.10 (s, 6H), 0.91 (s, 9H), 4.60 (br s, 2H), 6.45 (d, J = 6.5 Hz, 2H), 6.52 (d, J = 6.5 Hz, 2H)

Example 74: Preparation of N-(4-(fert-Butyldimethylsilyloxy)phenyl)-5-(6-formylquinolin-4- yl)thiophene-2-carboxamide (63)

63

[0249] To a solution of 17 (0.30 g, 1.06 mmol) and 2-chloro-4,6-dimethoxy-l,3,5-triazine (0.22 g, 1.27 mmol) in CH₂Cl₂ (6 mL) was added JV-methylmorpholine (0.47 mL, 4.2 mmol). The reaction mixture was stirred for 1 h at room temperature and 62 (0.28 g, 1.27 mmol) was added. The reaction mixture was stirred additional 2 h at room temperature and concentrated. The crude mixture was purified by silica gel chromatography (hexanes/EtOAc 100:0 to 0: 100 gradient) to afford the title compound as a yellow solid (0.333 g, 64 %). [0250] ¹H NMR (500 MHz, DMSO-J₆): δ 0.20 (s, 6H), 0.96 (s, 9H), 6.86-6.91 (m, 2H), 7.33 (d, J = 6.7 Hz, 2H), 7.62 (d, J = 8.9 Hz, 2H), 8.17-8.21 (m, IH), 8.43 (dd, J = 8.9, 1.7 Hz, IH), 8.72 (d, J= 1.6 Hz, IH), 8.88 (s, IH), 9.01 (d, J = 4.5 Hz, IH), 10.31 (s, IH)

[0251] MS (ES+): m/z 489 (M +H)⁺

Example 75: Preparation of (Z)-5-(6-((2,4-Dioxothiazolidin-5-ylidene)methyl)quinolin-4-yl)- jV-(4-hydroxyphenyl)thiophene-2-carboxamide

[0252] A microwave vial was charged with 63 (0.185 g, 0.38 mmol), thiazolidine-2,4-dione

(0.074 g, 0.57 mmol), and Cs₂CO₃ (0.408 g, 1.14 mmol) in ethanol (4 mL). The reaction mixture was heated 30 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture concentrated and purified by silica gel chromatography (CH₂Cl₂:Me0H 100:0 to 50:50 gradient) to afford the title compound an orange solid (0.068 g).

[0253] ¹H NMR (500 MHz, DMSO-J₆): δ 6.77 (d, J = 8.5 Hz, 2H), 7.53 (d, J= S3 Hz, 2H), 7.67-7.71 (m, 3H), 8.00 (d, J= 8.6 Hz, IH), 8.15 (d, J= 8.8 Hz, IH), 8.20 (d, J= 3.3 Hz, IH), 8.43 (s, IH), 8.95 (d, J = 4.2 Hz, IH), 9.34 (br s, IH), 10.28 (s, IH)

[0254] MS (ES+): m/z 502 (M +H)⁺

Example 76: Preparation of 5-(6-Formylquinolin-4-yl)-/V-(4- (morp/zo/mome?/ry/)phenyl)thiophene-2-carboxamide (64)

64

[0255] To a solution of 17 (0.20 g, 0.71 mmol) and 2-chloro-4,6-dimethoxy-l,3,5-triazine (0.15 g, 0.85 mmol) in CH₂Cl₂ (4 mL) was added N-methylmorpholine (0.31 mL, 2.8 mmol). The reaction mixture was stirred for 1 h at room temperature and 4-(morpholin-4- ylmethyl) aniline (0.163 g, 0.85 mmol) was added. The reaction mixture was stirred additional 2 h at room temperature and concentrated. The crude mixture was purified by silica gel chromatography (CH₂Cl₂: MeOH 100:0 to 70:30 gradient) to afford the title compound as yellow oil (0.229 g, 11 %).

[0256] MS (ES+): m/z 458 (M +H)⁺

Example 77: Preparation of (Z)-5-(6-((2,4-Dioxothiazolidin-5-ylidene)methyl)quinolin-4-yl)- N-(4-(morpholinomethyl)phenyl)thiophene-2-carboxamide

[0257] A microwave vial was charged with 65 (0.200 g, 0.44 mmol), thiazolidine-2,4-dione (0.085 g, 0.66 mmol), and Cs₂CO₃ (0.46 g, 1.3 mmol) in ethanol (4 mL). The reaction mixture was heated 30 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture concentrated and purified by silica gel chromatography (CH₂Cl₂:Me0H 100:0 to 50:50 gradient) to afford the title compound a yellow solid (0.103 g, 42%). [0258] ¹H NMR (500 MHz, DMSO-J₆): δ 2.39 (br s, 4H), 3.58 (m, 4H), 3.85 (s, 2H), 5.40 (br s, IH), 7.32 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 4.5 Hz, IH), 7.71-7.75 (m, 3H), 8.02 (dd, J = 8.8, 1.9 Hz, IH), 8.17 (d, J = 8.7 Hz, IH), 8.26 (d, J = 3.9 Hz, IH), 8.43 (d, J = 1.8 Hz, IH), 8.98 (d, J= 4.5 Hz, IH), 10.47 (s, IH)

[0259] MS (ES+): m/z 557 (M +H)⁺

Example 78: Preparation of 5-(6-Formylquinolin-4-yl)-/V-(3- (moφholinomethyl)phenyl)thiophene-2-carboxamide (65)

65 [0260] To a solution of 17 (0.20 g, 0.71 mmol) and 2-chloro-4,6-dimethoxy-l,3,5-triazine (0.15 g, 0.85 mmol) in CH₂Cl₂ (4 mL) was added JV-methylmorpholine (0.31 mL, 2.8 mmol). The reaction mixture was stirred for 1 h at room temperature and 3-(morpholin-4- ylmethyl) aniline (0.163 g, 0.85 mmol) was added. The reaction mixture was stirred additional 2 h at room temperature and concentrated. The crude mixture was purified by silica gel chromatography (CH₂Cl₂:Me0H 100:0 to 75:25 gradient) to afford the title compound a yellow solid (0.280 g, 87 %).

[0261] MS (ES+): m/z 458 (M +H)⁺

Example 79: Preparation of (Z)-5-(6-((2,4-Dioxothiazolidin-5-ylidene)methyl)quinolin-4-yl)- N-(3-(morpholinomethyl)phenyl)thiophene-2-carboxamide

[0262] A microwave vial was charged with 65 (0.275 g, 0.58 mmol), thiazolidine-2,4-dione (0.113 g, 0.87 mmol), and Cs₂CO₃ (0.64 g, 1.8 mmol) in ethanol (3 mL). The reaction mixture was heated 30 min at 150 ⁰C in a Biotage microwave reactor. The resulting mixture concentrated and purified by silica gel chromatography (CH₂Cl₂IMeOH 100:0 to 50:50 gradient) to afford the title compound a yellow solid (0.180 g, 56%).

[0263] ¹H NMR (500 MHz, DMSO-J₆): δ 2.42 (br s, 4H), 3.52 (br s, 4H), 3.60 (s, 2H), 7.09 (d, J = 6.8 Hz, IH), 7.35 (t, J = 7.7 Hz, IH), 7.71-7.75 (m, 4H), 8.02 (d, J = 8.5 Hz, IH), 8.17 (d, J = 9.1 Hz, IH), 8.30 (s, IH), 8.43 (s, IH), 8.97 (s, IH), 10.53 (s, IH) [0264] MS (ES+): m/z 557 (M +H)⁺

Example 80: Preparation of 4-(5-Formylthiophen-2-yl)quinoline-6-carbaldehyde (66)

66

[0265] To a mixture of 5-formyl-2-thiopheneboronic acid (0.50 g, 3.2 mmol), 2 (0.61 g, 3.2 mmol), and PdP(PPh₃)₄ (0.37 g, 0.32 mmol) in DMF (15 mL) was added 2.0 M Na₂CO₃ (2.75 mL). The reaction mixture was heated at 160 ⁰C for 30 min in a Biotage microwave reactor. The resulting mixture was added sat Na₂CO₃ (5 mL) and washed extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over MgSO₄, and concentrated. The crude mixture was purified by silica gel chromatography (hexanes/EtOAc 100:0 to 0:100 gradient) to afford the title compound as a peach solid (0.145 g, 17 %). [0266] ¹H NMR (500 MHz, DMSO-J₆): δ 7.83 (d, J = 4.6 Hz, IH), 7.86 (d, J = 3.9 Hz, IH), 8.22-8.29 (m, 3H), 8.82 (d, J = 1.5 Hz, IH), 9.13 (d, J = 4.5 Hz, IH), 10.07 (s, IH), 10.21 (s, IH)

[0267] MS (ES+): m/z 268 (M +H)⁺

Example 81: Preparation of (Z)-5-((5-(6-((Z)-(2,4-Dioxothiazolidin-5-ylidene)methyl)quinolin- 4-yl)thiophen-2-yl)methylene)thiazolidine-2,4-dione

[0268] A microwave vial was charged with 66 (0.140 g, 0.52 mmol), thiazolidine-2,4-dione (0.204 g, 1.57 mmol), and Cs₂CO₃ (1.11 g, 3.14 mmol) in ethanol (4 mL). The reaction mixture was heated 30 min at 160 ⁰C in a Biotage microwave reactor. The resulting mixture concentrated and purified by silica gel chromatography (CH₂Cl₂:Me0H 100:0 to 0:100 gradient) to afford the title compound a brown solid (0.042 g, 17%).

[0269] ¹H NMR (500 MHz, DMSO-d₆): δ 7.69 (d, J = 4.5 Hz, IH), 7.74 (s, 3H), 7.88 (s, IH), 8.00 (dd, J = 8.8, 1.9 Hz, IH), 8.16 (d, J= 8.8 Hz, IH), 8.44 (d, J= 1.8 Hz, IH), 8.95 (d, J = 4.5 Hz, IH), 12.02-12.08 (br s, 2H)

Example 82: Preparation of 4-(5-(3-Methoxyphenyl)thiophen-2-yl)quinoline-6-carbaldehyde (67)

67 [0270] To a solution of 17 (0.25 g, 0.88 mmol) and 2-chloro-4,6-dimethoxy-l,3,5-triazine (0.186 g, 1.06 mmol) in CH₂Cl₂ (5 mL) was added JV-methylmorpholine (0.39 mL, 3.53 mmol). The reaction mixture was stirred for 1 h at room temperature and m-anisidine (0.13 g, 1.06 mmol) was added. The reaction mixture was stirred additional 3 h at room temperature and concentrated. The crude mixture was purified by silica gel chromatography (hexanes/EtOAc 100:0 to 0:100 gradient) to afford the title compound as a yellow solid (0.326 g, 95 %).

[0271] MS (ES+): m/z 389 (M +H)⁺

Example 83: Preparation of (Z)-5-((4-(5-(3-Methoxyphenyl)thiophen-2-yl)quinolin-6- yl)methylene)thiazolidine-2,4-dione

[0272] A microwave vial was charged with 67 (0.32 g, 0.82 mmol), thiazolidine-2,4-dione (0.161 g, 1.24 mmol), and Cs₂CO₃ (0.805 g, 2.47 mmol) in ethanol (6 mL). The reaction mixture was heated 30 min at 160 ⁰C in a Biotage microwave reactor. The resulting mixture concentrated and purified by preparative HPLC to afford the title compound a brown solid (0.202 g, 50%).

[0273] ¹H NMR (500 MHz, DMSO-J₆): δ 3.77 (s, 3H), 6.72 (dd, J = 8.5, 2.4 Hz, IH), 7.28 (t, J = 8.1 Hz, IH), 7.39 (d, J = 7.8 Hz, IH), 7.47 (s, IH), 7.72 (s, IH), 7.73 (s, IH), 8.00 (s, IH), 8.05 (dd, J = 8.8, 2.0 Hz, IH), 8.22 (d, J = 8.8 Hz, IH), 8.30 (d, J = 4.0 Hz, IH), 8.43 (d, J = 1.8 Hz, IH), 9.02 (d, J = 4.5 Hz, IH), 10.47 (s, IH)

[0274] MS (ES+): m/z 488 (M +H)⁺

[0275] Exam Paul Van Dyk f. Ashley Tomberlin

Example 84: Complicatedple 84103 Preparation of tert-Butyl-(3-ethynyl-phenoxy)-dimethyl- silane (68)

68

[0276] 3-Ethynyl-phenol (4.0 g, 33.9 mmol), tert-butyldimethylsilyl chloride (5.62 g, 37.3 mmol) and imidazole (2.88 g, 42.4 mmol) were combined and diluted with DMF (25 mL). This was stirred at room temperature for 14h. Reaction contents were then poured onto water and extracted with EtOAc (3 x 100 mL). Organic phase was evaporated to provide desired product as an amber oil (7.9g, 98%).

Example 85: Preparation of te/t-Butyl-dimethyl-(3-thiophen-2-ylethynyl-phenoxy)-silane (69)

69

[0277] A solution of 2-bromothiophene ( 1.5 g, 9.2 mmol) in TEA (6 mL) and DMF ( 1.2 mL) was treated with copper iodide (0.175 g, 0.92 mmol) and purged with argon for 3 min. 68 (3.2 g, 13.8 mmol) and PdCl₂(PPhS)₂ (0.323 g, 0.46 mmol) were then added and microwaved at 12O⁰C for 20 min. The reaction mixture was diluted with DCM (20 mL), filtered and evaporated. This was then purified by silica gel flash chromatography to afford the title compound as a clear oil (2.2 g, 79%).

Example 86: Preparation of te/t-Butyl-dimethyl-(3-thiophen-2-ylethynyl-phenoxy)-silane-2- boronic acid (70)

[0278] A solution of 69 (0.542 g, 1.73 mmol) and triisopropyl borate (0.595 niL, 2.59 mmol) in THF (12mL) was chilled to -1O⁰C and treated with LDA (1.5 molar solution in cyclohexane, 2.3 rnL, 3.45 mmol). The reaction was removed from cooling bath and allowed to come to room temperature and stir for 16 h. This was then poured onto IN HCl, stirred vigorously for 15 min and then extracted with EtOAc. Organic phase was dried and evaporated to afford the title compound as a brown oil (0.42 g, 68%).

Example 87: Preparation of 4-[5-(3-Hydroxy-phenylethynyl)-thiophen-2-yl]-quinoline-6- carbaldehyde (71)

71

[0279] A mixture of 2 (0.078 g, 0.406 mmol), 70 (0.160 g, 0.447 mmol), Pd(PPh₃)₄ (0.047 g, 0.041 mmol) and solid sodium carbonate (0.086 g, 0.813 mmol) were suspended in DMF (5 mL) in a sealed microwave tube and heated in oil bath at 160° C for 5h. The reaction mixture was cooled to room temperature and purified on silica gel column to afford the title compound (0.076 g, 53%).

Example 88: Preparation of 5-{4-[5-(3-Hydroxy-phenylethynyl)-thiophen-2-yl]-quinolin-6- ylmethylene } -thiazolidine-2,4-dione

[0280] A mixture of 71 (0.076 g, 0.214 mmol), thiazolidine dione (0.05 g, 0.428 mmol) and Boc-β-Ala-OH (0.081 g, 0.428 mmol) were suspended in acetic acid (2.2 mL) and heated to 120° C for 3h. Reaction was then cooled to room temperature and poured onto water and filtered (0.015 g, 15%).

[0281] ¹H NMR (500 MHz, DMSO-J₆): δ 6.86-6.88 (m, IH), 6.94-6.95 (m, IH), 7.01-7.03 (m, IH), 7.26 (t, J = 7.9 Hz, IH), 7.64-7.70 (m, 3H), 8.01-8.05 (m, 2H), 8.19-8.22 (m, IH), 8.45-8.48 (m, IH), 8.99-9.00 (m, IH), 9.78 (s, IH), 12.7 (br s, IH)

[0282] MS (ES+): m/z 455 (M+H)⁺ Example 89: Preparation of phenyl thiourea 72:

72 [0283] To a solution of isothiocyanato-benzene (1.0 g, 7.4 mmol) in ethanol (7.0 mL) was added ammonia (7 N in MeOH; 2.5 mL, 17.5 mmol). The reaction mixture was heated at 60 ⁰C for 2 h. The reaction mixture was concentrated and triturated in water. The resulting solid was filtered to afford the title compound as a white solid (1.08 g, 96%). ¹H NMR (500 MHz, DMSO-J₆): δ 7.11 (t, J = 7.4 Hz, IH), 7.32 (t, J = 7.9 Hz, 2H), 7.39 (d, J = 7.7 Hz, 2H) [0284] MS (ES+): m/z 153 (M+H)⁺

Example 90: Preparation of 2-Phenylimino-thiazolidin-4-one (73)

73

[0285] A microwave vial was charged with 72 (0.50 g, 3.3 mmol), chloro-acetic acid (0.32 g, 3.4 mmol), and sodium acetate (0.30 g, 3.7 mmol) in acetic acid (3 mL). The reaction mixture was heated for 20 min at 150 ⁰C in a Biotage microwave reactor. Water was added (20 mL) and the resulting solid filtered to afford the title compound (a 1/1 mixture of E/Z isomers) as a yellow solid (0.46 g, 73%).

[0286] ¹H NMR (500 MHz, DMSO-J₆, isomeric mixture): δ 3.96 (s, 2H), 4.01 (s, 2H), 6.99 (br d, J = 5.8 Hz, 2H), 7.15 (t, J = 7.2 Hz, 2H), 7.30-7.43 (m, 4H), 7.69 (d, J = 1.6 Hz, 2H), 11.16 (s, IH), 11.74 (s, IH)

[0287] MS (ES+): m/z 193 (M+H)⁺ Example 91: Preparation of 2-Phenylimino-5-(4-thiophen-2-yl-quinolin-6-ylmethylene)- thiazolidin-4-one

2-Phenylimino-5-(4-thiophen-2-yl-quinolin-6-ylmethylene)-thiazolidin-4-one [0288] A microwave vial was charged with 3 (55 mg, 0.23 mmol), 73 (50 mg, 0.26 mmol), and Cs₂CO₃ (0.15 g, 0.46 mmol) in ethanol (4 mL). The reaction mixture was heated for 30 min at 140 ⁰C in a Biotage microwave reactor. The resulting solid was filtered, washed with ethanol followed by water to afford the title compound (a 2/3 mixture of isomers) as a yellow solid (45 mg, 47%). [0289] ¹H NMR (500 MHz, DMSO-J₆, isomeric mixture): δ 6.87 (d, J = 7.3 Hz, 3H), 7.01 (dd, J = 5.0, 3.7 Hz, IH), 7.09 (t, J= 7.7 Hz, IH), 7.18 (t, J= 7.7 Hz, 2H), 7.19-7.35 (m, 5H), 7.38 (s, IH), 7.39-7.41 (m, IH), 7.47 (d, J= 3.2 Hz, IH), 7.54 (d, J= 4.5 Hz, IH), 7.59 (d, J = 4.5 Hz, IH), 7.67 (d, J = 3.2 Hz, IH), 7.71 (d, J = 4.6 Hz, IH), 7.88 (dd, J = 8.8, 1.8 Hz, IH), 7.93-8.06 (m, 2H), 8.11 (d, J = 8.7 Hz, IH), 8.33 (d, J = 1.5 Hz, IH), 8.44 (d, J = 1.2 Hz, IH), 8.83 (d, J = 4.5 Hz, IH), 8.88 (d, J = 4.5 Hz, IH)

[0290] MS (ES+): m/z 414 (M+H)⁺

Example 92: Preparation of (2-Chloro-5-fluoro-phenyl)-thiourea (74)

74 [0291] To a solution of l-chloro-4-fluoro-2-isothiocyanato-benzene (1.0 g, 5.3 mmol) in ethanol (10 mL) was added ammonia (7 N in MeOH; 3.0 mL, 21 mmol). The reaction mixture was heated at 70 ⁰C for 1 h. The reaction mixture was concentrated and triturated in water. The resulting solid was filtered to afford the title compound as a white solid (0.85 g, 78%). MS (ES+): m/z 205 (M+H)⁺

Example 93: Preparation of 2-(2-Chloro-5-fluoro-phenylimino)-thiazolidin-4-one (75)

75

[0292] A microwave vial was charged with 74 (0.85 g, 4.1 mmol), chloro-acetic acid (0.45 g, 4.7 mmol), and sodium acetate (0.40 g, 4.9 mmol) in acetic acid (6 mL). The reaction mixture was heated for 20 min at 150 ⁰C in a Biotage microwave reactor. Water was added (20 mL) to the reaction mixture and the resulting solid filtered to afford the title compound as a white solid (0.71 g, 70%).

[0293] ¹H NMR (500 MHz, DMSO-J₆): δ 4.05 (s, 2H), 6.94 (br d, J = 9.0 Hz, IH), 7.00 (t, J = 8.4 Hz, IH), 7.53 (dd, J = 8.8, 5.7 Hz, IH), 12.09 (s, IH)

Example 94: Preparation of 2-(2-Chloro-5-fluoro-phenylimino)-5-(4-thiophen-2-yl-quinolin-6- ylmethylene)-thiazolidin-4-one

2-(2-Chloro-5-fluoro-phenylimino)-5-(4-thiophen-2-yl-quinolin-6-ylmethylene)-thiazolidin-4- one

[0294] A microwave vial was charged with 3 (50 mg, 0.21 mmol), 75 (70 mg, 0.29 mmol), and Cs₂CO₃ (0.13 g, 0.40 mmol) in ethanol (4 mL). The reaction mixture was heated for 30 min at 140 ⁰C in a Biotage microwave reactor. The resulting solid was filtered, washed with ethanol followed by water to afford the title compound as an orange solid (55 mg, 57%). [0295] ¹H NMR (500 MHz, DMSO-J₆): δ 6.82 (t, J = 6.9 Hz, IH), 7.11-7.24 (m, 2H), 7.39 (dd, J = 8.7, 6.0 Hz, IH), 7.49 (s, IH), 7.54 (d, J = 3.8 Hz, IH), 7.56 (d, J = 4.5 Hz, IH), 7.76 (d, J= 4.9 Hz, IH), 7.92 (dd, J= 8.8, 1.9 Hz, IH), 8.10 (d, J = 8.7 Hz, IH), 8.38 (d, J = 1.7 Hz, IH), 8.88 (d, J = 4.5 Hz, IH) MS (ES+): m/z 466 (M+H)⁺ Example 95: Enzyme Assays

[0296] IC₅₀ values for compounds against the isoforms of PI3-Kinase (PI3K-γ, PI3K-β, 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.

Example 96: ELISA for C5a-induced phosphorylation of AKT in Raw 264.7 macrophages.

[0297] Raw 264.7 mouse macrophage cells (ATCC#TIB-71) were cultured in DMEM containing 10% heat inactivated serum and IX penicillin/streptomycin. 7.5xl0⁴ cells were seeded into a 96 well plate were allowed to adhere overnight. Cells were then washed one time with serum-free medium, and then incubated under serum-free conditions for 3-4 hours at 37°C/5%CO₂. Cells were pretreated with the indicated compound (10 μM - 0.0045 μM) for 1 h, followed by stimulation with 0.5 μg/ml C5a (Sigma) for 5 min. Cells were immediately placed on ice, and washed one time with cold PBS. Cells were lysed with 65 μL of 1% Triton- X-100 lysis buffer containing protease inhibitors (Cell Signaling Technology) and further incubated in this solubilization buffer for 20-30 min on ice with mild agitation. Lysates were then centrifuged at 5000 rpm at 4 ⁰C for 10-15 min. Thereafter, an ELISA specific for phosphorylated AKT (pAKT-Ser473) (Cell Signaling Technology) was performed. Absorbance was measured at 450-540 nm. Background was subtracted from each pAKT absorbance and EC₅₀ values were determined using the GraphPad Prism 4.0 software with OD_pAkt plotted in the y-axis and logarithmic values of concentration (μM) on the x-axis. The C5a data give a direct read of blocking signal downstream of PI3K-γ and PI3K-5. Results, expressed as IC₅₀, are presented in Table 1.

Example 97: VEGF- induced hRMVEC proliferation assay [0298] For cellular proliferation assays, early passage human retinal microvascular endothelial cells (hRMVECs) cells (Cell Systems, Kirkland, WA) were plated at a density of -1.5 x 10³ cells/well in a 96-well plate (Corning, Corning, NY), and allowed to adhere for ~6 hours or overnight. Medium was then changed into CSC-Maintenance Medium (Cell Systems, Kirkland, WA) and further incubated for at least 24 h - 48 h at 37°C/5% CO₂. As indicated by the manufacturer, this specialized medium contains 10% FBS but no growth factor, and renders proliferating cells into a quiescent state. The cells were then pre-treated with varying concentrations of the indicated compound (20 μM - 0.00914 μM or 10 μM - 0.00457 μM or DMSO (as a vehicle control) prepared in basal CSC-medium containing 10% FBS and 50 μg/ml heparin for -60 minutes at 37°C/5% CO₂. Human recombinant VEGF (Peprotech, Rocky Hill, NJ) was then added to a final concentration of 50 ng/ml. After 48-72 h of incubation, cellular proliferation was quantified using the Cell Proliferation Kit (Roche, Alameda, CA) as described by the manufacturer. Briefly, for one 96-well plate, 100 μL of electron-coupling reagent was added to 5 mL of XTT labeling solution. 50 μL of this solution was then added to each well, and the reaction was allowed to develop at 37°C/5% CO₂. The colored formazan product that is generated by metabolically active cells was measured spectrophotometrically using the SpectraMax spectrophotometer (Molecular Devices, Sunnyvale, CA) at 492 nm with correction at 690 nm. The effective concentration at which VEGF-induced cellular proliferation was inhibited by 50% (EC₅₀) was determined by using the GraphPad Prism 4.0 software (San Diego, CA). Data shown in Table 1 in nM. [0299] Table 1 PI3K enzymatic and cellular data Table 1 PI3K enzyme and cell data

Example 98: Pharmacokinetic testing

[0300] Pharmacokinetics parameters were determined in rats and mice following a single intravenous (IV) and oral (PO) doses. Intravenous and oral dose formulations were prepared fresh. For the PO formulation, the compounds were dissolved in an aqueous solutions containing appropriate excipients or suspended in 0.5% MC and 0.05% Tween80. For the IV formulation, the compounds were solubilized in an aqueous vehicle containing suitable excipients. The IV formulation was aseptically filtered through 0.22um filters.

[0301] Rats: Six jugular vein cannulated male Sprague-Dawley rats (~300g) with were divided into three groups with three rats in IV dose group and three rats in the PO dose group. Animals were allowed food and water ad libitum. The study was conducted at TargeGen. (San Diego, CA).

[0302] Blood samples (approximately 500 μL per time point) were 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 was 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.

[0303] Matrix calibration standards and QC samples were prepared by spiking the compound into blank rat plasma (Valley Biomedical Inc., Lot # L51663). The final concentrations of a selected compound were 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.

[0304] Plasma samples were processed using a standard protocol. The samples were analyzed using a LC/MS/MS Waters Quattro LC by standard determined conditions. Chromatogram signals were integrated and calibrated using MassLynx 3.0. Pharmacokinetic parameters were 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) were determined from measure plasma concentrations. The area under the curves, AUC ₍i_ast) and AUC _(inf) were calculated from plasma concentration-time profiles using the linear trapezoidal rule. The oral bioavailability (F) was calculated using the following equation; F=(AUC₍o-_inf),po x Div)/(AUC(o-_inf),iv x D_PO)* 100% [0305] The PK evaluation in mice utilized the same procedures described above except the number of mice was three per time point per dosed group and the blood samples were collected by cardiac puncture.

[0306] Table 2 provides data from a mouse PK model with IV and PO arms.

Table 2

Example 99: Protocol for ocular exposure following topical instillation

[0307] Twenty male mice were given one 10 μL drop of the 1% formulation of test compound. Composite sampling was employed to generate tissue concentration-time profiles for compound over the following a certain defined time course for sampling post-instillation.

Both eyes were removed from each mouse and dissected to obtain the cornea, retina and eye cup (sclera and choroid). Plasma samples were also obtained from each mouse at the time of euthanasia. Determinations of amounts of compounds in various eye tissues were made by LC/MS/MS. (Z)-5-((4-(Thiophen-2-yl)quinolin-6-yl)methylene)thiazolidine-2,4-dione was evaluated in an ocular PK and showed levels well above cell EC₅₀ in the back of the eye tissues.

Example 100: Ocular PK

[0308] Table 3 shows ocular PK data for selected compounds with low oral availability Table 3

Example 101: Murine model of ocular edema and neovascularization [0309] A murine model of ocular edema and neovasularization was used to assess compound activity. Laser energy is used to rupture the Bruch's membrane, after which edema and neovascularization develop within the choroid. (Tobe T. et al. (1998) Am J Pathol 153:1641-1646). Optical coherence tomography (OCT) was then used 7-9 days post-lasering to quantify the area of laser lesion sites, as a measure of edema and neovascularization. Topical application of a 0.3% formulation of 5-[4-(5-hydroxymethyl-thiophen-2-yl)-quinolin-6- ylmethylene]-thiazolidine-2,4-dione (twice daily as a 10 μL eyedrop) reduced laser lesion area by 24% vs. vehicle-treated animals (P= 0.02):

Example 102: Cell data against for selected compounds against various cancer cell lines

Table 4a

Compound # PTEN deleted as identified in tumor lines

Table 1 Breast Glioblastoma Multiple Myeloma

BT549 U87 MG I Multiple lines

EC50, nM

502 1370

References

[0310] 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

[0311] 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.

[0312] 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 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, - CH₂OH, -CH₂CH₂OH, CH₃, -CONH₂, -CONH₂, -C(O)NH-phenyl, phenyl, -alkynyl-phenyl, F, Cl, CO₂H, — C(O)NCH₂CH₂-pyrrolidine, or dimethylisoxazole, wherein the phenyl is optionally substituted by one or two substitutents selected from the group consisting of halo, cyano, hydroxyl, alkyl, alkoxy, N-alkylsulphamoyl, sulphamoyl, 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 NR₁₂, and R₁₂ is phenyl optionally substituted by one or two halogen moieties.

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

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

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

8. The compound of claim 5, wherein R₃ is phenyl optionally substituted by a substituent chosen from hydroxyl, alkyl, N-alkylsulphamoyl, alkoxy, or alkylmorpholino.

9. A compound 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, CRb, NH, N-alkyl, N-aryl, N-heterocycle, N-

C(O)-alkyl, N-C(O)-heterocycle, N-C(O)-N-alkyl, N-C(O)-N-heterocycle, O, or S;

R₁ is H or alkyl;

R₇ is H or alkyl;

Rg 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; Rn 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.

10. The compound of claim 9, wherein X is O.

11. The compound of claim 9, wherein m is 0.

12. The compound of claim 9, wherein m is an integer from 1 to 3, inclusive.

13. The compound claim of 12, wherein m is 2.

14. The compound of claim 9, wherein R_1O at each occurrence is H.

15. The compound of claim 9, wherein one of R₇ or Rg is H and one of R₇ or Rg is

; wherein R₁₁ is chosen from: pyrrolindyl, phenyl, or isoxazole.

16. The compound of claim 15, wherein m is 0.

17. The compound of claim 9, wherein R₁₁ is phenyl.

18. The compound claim 17, wherein R₁₁ is substituted at one or two positions by methyl.

19. The compound of claim 9, wherein R₇ is H.

20. The compound of claim 9, wherein R₇ is methyl.

21. The compound of claim 9, wherein R₈ is methyl.

22. The compound of claim 20, wherein R₈ is H.

23. The compound of claim 19, wherein R₈ is methyl.

24. The compound of claim 9, wherein R₉ is chosen from: H, Cl, phenyl, CO₂H, or 3,5- dimethyl-isoxazol-4-yl.

25. The compound of claim 9, wherein R₁₃ is alkynylene.

26. A compound selected from: 5-(4-Thiophen-2-yl-quinolin-6-ylmethylene)-thiazolidine-2,4- dione; 5-(4-Benzo[b]thiophen-3-yl-quinolin-6-ylmethylene)-thiazolidine-2,4-dione; 5-[4-(5- Hydroxymethyl-thiophen-2-yl)-quinolin-6-ylmethylene]-thiazolidine-2,4-dione; 5-(4-Furan-2- yl-quinolin-6-ylmethylene)-thiazolidine-2,4-dione; 5-(4-Benzofuran-2-yl-quinolin-6- ylmethylene)-thiazolidine-2,4-dione; 5-[4-(5-Chloro-thiophen-2-yl)-quinolin-6-ylmethylene]- thiazolidine-2,4-dione; 5-[4-(5-Phenyl-thiophen-2-yl)-quinolin-6-ylmethylene]-thiazolidine- 2,4-dione; 5-{4-[5-(3,5-Dimethyl-isoxazol-4-yl)-thiophen-2-yl]-quinolin-6-ylmethylene}- thiazolidine-2,4-dione; 5-[4-(4-Methyl-thiophen-2-yl)-quinolin-6-ylmethylene]-thiazolidine- 2,4-dione; 5-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4-yl]-thiophene-2- carboxylic acid; 5-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4-yl]-thiophene-2- carboxylic acid (2-pyrrolidin-l-yl-ethyl)-amide; 5-[4-(3-Methyl-thiophen-2-yl)-quinolin-6- ylmethylene]-thiazolidine-2,4-dione; 5-(4-Benzo[b]thiophen-2-yl-quinolin-6-ylmethylene)- thiazolidine-2,4-dione; 5-[4-(2,3-Dihydro-thieno[3,4-b][l,4]dioxin-5-yl)-quinolin-6- ylmethylene]-thiazolidine-2,4-dione; 5-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4- yl]-thiophene-2-carboxylic acid amide; 5-(4-Furan-2-yl-quinazolin-6-ylmethylene)- thiazolidine-2,4-dione; 2-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4-yl]- benzo[b]thiophene-6-carbonitrile; N-tert-Butyl-3-{5-[6-(2,4-dioxo-thiazolidin-5- ylidenemethyl)-quinolin-4-yl]-thiophen-2-yl}-benzenesulfonamide; 5-{4-[5-(3-Isopropyl- phenyl)-thiophen-2-yl]-quinolin-6-ylmethylene}-thiazolidine-2,4-dione; 5-{4-[5-(3- Isopropoxy-phenyl)-thiophen-2-yl]-quinolin-6-ylmethylene}-thiazolidine-2,4-dione; 5- {4- [5- (2,6-Dimethoxy-phenyl)-thiophen-2-yl]-quinolin-6-ylmethylene}-thiazolidine-2,4-dione; 2-[6- (2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4-yl]-benzo[b]thiophene-4-carbonitrile; 5- [4-(4-Methyl-thiophen-3-yl)-quinolin-6-ylmethylene]-thiazolidine-2,4-dione; 5-[6-(2,4-Dioxo- thiazolidin-5-ylidenemethyl)-quinolin-4-yl]-thiophene-2-carboxylic acid (3-methoxy-phenyl)- amide; 5-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4-yl]-thiophene-2-carboxylic acid (3-hydroxy-phenyl)-amide; 5-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4-yl]- thiophene-2-carboxylic acid (4-hydroxy-phenyl)-amide; 5-[6-(2,4-Dioxo-thiazolidin-5- ylidenemethyl)-quinolin-4-yl] -thiophene-2-carboxylic acid (4-morpholin-4-ylmethyl-phenyl)- amide; 5-[4-(4,5,6,7-Tetrahydro-thieno[3,2-c]pyridin-2-yl)-quinolin-6-ylmethylene]- thiazolidine-2,4-dione; 5-[4-(4,5,6,7-Tetrahydro-thieno[3,2-c]pyridin-2-yl)-quinazolin-6- ylmethylene] thiazolidine-2,4-dione; 2-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4- yl]-benzo[b]thiophene-6-carbonitrile; 2-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4- yl]-benzo[b]thiophene-4-carbonitrile; 2-[6-(2,4-Dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4- yl]-benzo[b]thiophene-7-carbonitrile; (Z)-2-(6-((2,4-Dioxothiazolidin-5- ylidene)methyl)quinolin-4-yl)-3-methylbenzo[b]thiophene-6-carbonitrile; (Z)-2-(6-((2,4- Dioxothiazolidin-5-ylidene)methyl)quinolin-4-yl)-3-methylbenzo[b]thiophene-4-carbonitrile; N-fer?-Butyl-3-{5-[6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-quinolin-4-yl]-thiophen-2-yl}- benzenesulfonamide; (Z)-5-((4-(4-Methylthiophen-3-yl)quinolin-6-yl)methylene)thiazolidine- 2,4-dione; (Z)-5-((4-(4,5,6,7-Tetrahydrothieno[J,2-c]pyridin-2-yl)quinolin-6-yl)methylene) thiazolidine-2,4-dione; 3-Methyl-5-(6-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)quinolin-4- yl)thiophene-2-carbonitrile; (Z)-5-((4-(5-(3-Isopropylphenyl)thiophen-2-yl)quinolin-6- yl)methylene)thiazolidine-2,4-dione; (Z)-5-((4-(5-(3-Isopropoxyphenyl)thiophen-2-yl)quinolin- 6-yl)methylene)thiazolidine-2,4-dione; (Z)-5-((4-(5-(2,6-Dimethoxyphenyl)thiophen-2- yl)quinolin-6-yl)methylene)thiazolidine-2,4-dione; (Z)-5-(6-((2,4-Dioxothiazolidin-5- ylidene)methyl)quinolin-4-yl)-N-(3-hydroxyphenyl)thiophene-2-carboxamide; (Z)-5-(6-((2,4- Dioxothiazolidin-5-ylidene)methyl)quinolin-4-yl)-N-(4-hydroxyphenyl)thiophene-2- carboxamide; (Z)-5-(6-((2,4-Dioxothiazolidin-5-ylidene)methyl)quinolin-4-yl)-N-(4- (morpholinomethyl)phenyl)thiophene-2-carboxamide; (Z)-5-(6-((2,4-Dioxothiazolidin-5- ylidene)methyl)quinolin-4-yl)-N-(3-(moφholinomethyl)phenyl)thiophene-2-carboxamide; (Z)- 5-((5-(6-((Z)-(2,4-Dioxothiazolidin-5-ylidene)methyl)quinolin-4-yl)thiophen-2- yl)methylene)thiazolidine-2,4-dione; (Z)-5-((4-(5-(3-Methoxyphenyl)thiophen-2-yl)quinolin-6- yl)methylene)thiazolidine-2,4-dione; 5-{4-[5-(3-Hydroxy-phenylethynyl)-thiophen-2-yl]- quinolin-6-ylmethylene}-thiazolidine-2,4-dione; 2-(2-Chloro-5-fluoro-phenylimino)-5-(4- thiophen-2-yl-quinolin-6-ylmethylene)-thiazolidin-4-one and 2-Phenylimino-5-(4-thiophen-2- yl-quinolin-6-ylmethylene)-thiazolidin-4-one and pharmaceutically acceptable salts, prodrugs, N-oxides, and hydrates thereof.

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

28. A composition comprising a compound of claim 9, and a pharmaceutically acceptable carrier.

29. The composition of claim 28, wherein the composition is formulated for one of: oral administration, intraveneous administration, injectable administration, topical application, as a suppository, inhalation administration, or systemic administration.

30. The composition of claim 29 wherein the composition is formulated for use in the eye.

31. The composition of claim 29 wherein the composition is formulated as an eye drop.

32. A method of treating an respiratory or ocular disorder, comprising administering to a patient in need thereof an effective amount of a compound of claim 9.

33. 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 claim 9.

34. A method of treating pain, diabetes, inflammation, platelet aggregation, ischemic heart disease, sclerosis, restenosis, immune-mediated disease, rheumatoid arthritis, HIV, bone resorption, cancer, non-small cell lung cancer, or brain cancer, comprising administering to a patient in need thereof an effective amount of a compound of claim 9.

35. The method of claim 34, wherein the cancer is breast or prostate cancer, or multiple myeloma.