thioacetate compound, compositions and their uses

专利摘要:
THIOACETATE COMPOUNDS, COMPOSITIONS AND METHODS OF USE. Described herein are compounds useful in modulating blood uric acid levels, formulations containing them and methods of their use. In some embodiments, the compounds described herein are used in the treatment or prevention of disorders related to aberrant uric acid levels.
公开号:BR112012032028B1
申请号:R112012032028-9
申请日:2011-06-15
公开日:2021-05-04
发明作者:Jean-Michel Vernier；Esmir Gunic；Samedy Ouk
申请人:Ardea Biosciences Inc；
IPC主号:

专利说明:

CROSS REFERENCE
[001] This application claims priority to U.S. Provisional Application 61/355,491, filed June 16, 2010, which is incorporated by reference in its entirety. FUNDAMENTALS OF THE INVENTION
[002] Uric acid is the result of the oxidation of xanthine. Disorders of uric acid metabolism include, without limitation, polycythemia, myeloid metaplasia, gout, a recurrent attack of gout, gouty arthritis, hyperuricemia, hypertension, a cardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome , kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, saturnism, hyperparathyroidism, psoriasis or sarcoidosis. SUMMARY OF THE INVENTION
[003] In certain embodiments, provided herein are compounds, methods and compositions, for example, for the modulation of serum uric acid (sUA) levels or for the treatment of gout or hyperuricemia in individuals in need. In some embodiments, such compositions comprise and such methods comprise administering to a subject in need thereof an effective amount of a compound of formula I:

[004] in which:
[005] Ra and Rb are selected from H, halogen, C1 to C6 alkyl; or Ra and Rb, together with the carbon atom to which they are attached, form a 3-, 4-, 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S;
[006] M is H, C1-3 alkyl or a pharmaceutically acceptable cation;
[007] X1 is N, CH, C(halogen) or C(C1-C4 alkyl);
[008] X2 is N or CH;
[009] X3 is N, CH, C(halogen) or C(C1-C4 alkyl);
[0010] X4 is N or CH; wherein at least one of X1, X2, X3 or X4 is N;
[0011] Y1 is N or CR1;
[0012] Y2 is N or CR2;
[0013] R1 is H, CF3, CH3, OCH3, F or Cl;
[0014] R2 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF3, OH, OCH3, ethoxy, SH, SCH3, SCH2CH3, CH2OH, C(CH3)2OH, Cl, F, CN , COOH, COOR2', CONH2, CONHR2' or SO2NH2; wherein R2' is H or C1-3 alkyl;
[0015] R3 is H, halogen, -CN, C1 to C6 alkyl, C1 to C6 alkoxy; and
[0016] R4 is H, halogen, -CN, C1 to C6 alkyl, C1 to C6 alkoxy; or
[0017] R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring or 6-membered can be a saturated ring, an unsaturated ring or an aromatic ring;
[0018] In specific cases: (i) if X2 and X4 are both N, then X1 cannot be C(halogen); or
[0019] if X2 and X4 are both N, then R4 cannot be Cl; or
[0020] if X2 and X4 are both N, then Y2 cannot be C-Cl; (ii) if X1 and X2 are both N, then X3 cannot be C-Cl; and (iii) the compound of formula (I) is not 1-(3-(4-cyanophenyl)pyridin-4-ylthio)cyclopropanecarboxylic acid.
Provided herein is, in certain embodiments, a compound of formula (I), wherein one of X1, X2, X3 or X4 is N. Certain specific embodiments provided herein describe a compound of formula (IA), (IB) , (IC) or (ID):

Provided herein is, in some embodiments, a compound of formula (I), wherein two of X1, X2, X3 or X4 are N. Certain specific embodiments provided herein describe a compound of formula (IE), (IF) or (IG):

[0023] Other specific embodiments provided herein describe a compound of formula (IH), (II) or (IJ):

Provided herein, in some embodiments, is a compound of formula (I), wherein R3 is H, CH3, OCH3, CF3, F or Cl; and R4 is H, CH3, OCH3, CF3, F or Cl. In certain specific embodiments, R3 and R4 are both H.
Some embodiments provided herein describe a compound of formula (I), wherein R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms. selected from O, N and S, wherein said 5- or 6-membered ring may be a saturated ring, an unsaturated ring or an aromatic ring.
Certain embodiments provided herein describe a compound of formula (I), wherein R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 6-membered aromatic ring. Certain specific embodiments provided herein describe a compound of formula (IK):

[0027] wherein n is 1, 2, 3 or 4; and
[0028] each R5 is independently selected from H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF3, OH, OCH3, ethoxy, SH, SCH3, SCH2CH3, CH2OH, C(CH3)2OH, Cl , F, CN, COOH, COOR5', CONH2, CONHR5' or SO2NH2; where R5' is H or C1-3 alkyl.
Provided herein, in certain embodiments, is a compound of formula (I), wherein Ra is H or CH3; and Rb is H or CH3. In specific modalities, Ra and Rb are both CH3. Certain specific embodiments provided herein describe a compound of formula (IL):

[0030] In additional embodiments, X1 is CH; X2 is N; X3 is CH; and X4 is CH. In yet other additional embodiments, Y1 is CR1; and Y2 is CR2.
[0031] Certain specific embodiments provided herein describe a compound of formula (IB), selected from the group consisting of:


[0032] Other specific embodiments provided herein describe a compound of formula (IM):

[0033] In certain specific embodiments, R1, R3 and R4 are all H.
[0034] Provided herein is, in some embodiments, a compound of formula (I), wherein Ra and Rb, together with the carbon atom to which they are attached, form a 3-, 4-, 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S. In certain embodiments, Ra and Rb, together with the carbon atom to which they are attached, form a 3-, 4-, 5- or 6-membered ring. In certain specific embodiments, Ra and Rb, together with the carbon atom to which they are attached, form a 3-membered ring.
[0035] Provided herein is, in certain embodiments, a compound of formula (I) where M is H. In some embodiments, provided herein is a compound of formula (I) where M is C1-C3 alkyl. In other embodiments, provided herein is a compound of formula (I), wherein M is a pharmaceutically acceptable cation. In specific embodiments, the pharmaceutically acceptable cation is Na+, Li+, K+, Ca2+, Mg2+, NH4+, tetramethylammonium, tetraethylammonium, methylamino, dimethylamino, trimethylamino or triethylamino.
Also provided herein, in some embodiments, is a method of reducing serum uric acid levels in a human, which comprises administering to the human an effective amount of a compound of formula (I). Other embodiments provided herein describe a method of treating hyperuricemia in a human with gout, which comprises administering to the human an effective amount of a compound of formula (I). Some embodiments provided herein describe a method of treating hyperuricemia in a human, which comprises administering to the human an effective amount of a compound of formula (I). Certain embodiments provided herein describe a method of treating gout in a human, which comprises administering to the human an effective amount of a compound of formula (I).
[0037] Also provided herein, in certain embodiments, is a method of treating or preventing a condition characterized by abnormal tissue or organic levels of uric acid in a subject comprising administering to the subject an effective amount of a compound of formula ( I). In specific modalities, the condition is gout, a recurrent attack of gout, gouty arthritis, hyperuricemia, hypertension, a cardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, kidney stones, kidney failure , joint inflammation, arthritis, urolithiasis, saturnism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency, or a combination of these. In certain specific modalities, the condition is gout.
[0038] In some embodiments, any of the methods described may further comprise administering a second agent effective for the treatment of gout. In certain embodiments, the second agent is an URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor, or combinations thereof. In certain specific embodiments, the second agent is allopurinol, febuxostat, FYX-051, or combinations thereof. DETAILED DESCRIPTION OF THE INVENTION
[0039] The new features of the invention are presented with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description which sets out illustrative embodiments in which the principles of the invention are utilized.
[0040] Although preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Several variations, alterations and substitutions will occur to those skilled in the art, without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein can be employed in the practice of the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents are encompassed by them.
[0041] The section headings used here are for organizational purposes only, and should not be considered as limiting the topic described. SOME CHEMICAL TERMINOLOGIES
[0042] Unless defined otherwise, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the claimed subject matter belongs. If there are multiple definitions for terms presented here, those in this section prevail.
[0043] It should be understood that the above general description and the following detailed description are exemplary and explanatory only, and are not restrictive of any claimed subject matter. In this application, the use of the singular includes the plural, unless specifically noted otherwise. It should be noted that, as used in the specification and appended claims, the singular forms “a”, “an”, “the” and “a” include plural referents, unless the context clearly dictates otherwise. It should also be noted that the use of “or” means “and/or” unless otherwise defined. Furthermore, the use of the term “which includes”, as well as of other forms, for example, “include”, “includes” and “included”, is not limiting.
[0044] Definitions of standard terms in chemistry can be found in reference works including Carey and Sundberg ADVANCED ORGANIC CHEMISTRY 4TH ED.” Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, IR and UV/Vis spectroscopy and pharmacology are employed within the skill of the art. Unless specific definitions are provided, the nomenclature used here consists of the standard definitions. Standard techniques can be used for chemical syntheses, chemical analysis, pharmaceutical preparation, formulation and release, and treatment of individuals. Reactions and purification techniques can be carried out, for example, using kits from manufacturer's specifications or as commonly obtained in the art or as described herein. The techniques and procedures cited above can generally be carried out by conventional methods well known in the art and as described in various general and more specific references which are cited and discussed throughout the present specification. Throughout the specification, groups and substituents of these may be chosen by those skilled in the field to provide stable moieties and compounds.
[0045] When substituent groups are specified by their conventional chemical formulas, written from left to right, they equally encompass the chemically identical substituents that would result when writing the structure from right to left. As a non-limiting example, -CH2O- is equivalent to -OCH2-.
[0046] Unless otherwise noted, the use of general chemical terms, eg, without limitation, "alkyl," "amine," "aryl," is equivalent to their optionally substituted forms. For example, "alkyl" as used herein includes optionally substituted alkyl.
[0047] In some embodiments, the compounds presented herein possess one or more stereocenters. In some embodiments, the stereocenter is in the R configuration, the S configuration, or combinations thereof. In some embodiments, compounds disclosed herein have one or more double bonds. In some embodiments, the compounds disclosed herein have one or more double bonds, where each double bond exists in the E (trans) or Z (cis) configuration, or combinations thereof. The presentation of a particular stereoisomer, regioisomer, diastereomer, enantiomer or epimer is intended to include all possible stereoisomers, regioisomers, diastereomers, enantiomers or epimers, and mixtures thereof. Thus, the compounds disclosed herein include all separate stereoisomeric, regioisomeric, diastereomeric, enantiomeric and epimeric configurational forms, as well as the corresponding mixtures thereof. Techniques for inverting or for leaving a particular stereocenter unchanged, and those for resolving mixtures of stereoisomers, can be found, for example, in Furniss et al. (eds.), "VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY" 5th Edition, Longman Scientific and Technical Ltd., Essex, 1991, 809-816; and Heller, Acc. Chem. Res. 1990, 23, 128.
The terms "portion", "chemical portion", "group" and "chemical group", as used herein, refer to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or attached to a molecule.
[0049] The term "reagent", as used herein, refers to a nucleophile or electrophile used to create covalent bonds.
[0050] The term "bond" or "single bond" refers to a chemical bond between two atoms, or two moieties, when the atoms joined by the bond are considered to be part of a larger substructure.
[0051] The term “optionally” or “optionally” means that the event or circumstance subsequently described may or may not occur, and that the description includes cases in which said event or circumstance occurs and cases in which it does not. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl", as defined below. In addition, an optionally substituted group may be unsubstituted (eg -CH2CH3), fully substituted (eg -CF2CF3), monosubstituted (eg -CH2CH2F) or substituted at any level between fully substituted and monosubstituted (by example, -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2 etc.). It will be understood by those of skill in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns (for example, substituted alkyl includes optionally substituted cycloalkyl groups, which, in turn, are defined as including optionally substituted alkyl groups, potentially ad infinitum) which are sterically impractical and/or synthetically unfeasible. Thus, any described substituents should generally be understood to have a maximum molecular weight of about 1,000 daltons, and more typically up to about 500 daltons (except in those cases in which macromolecular substituents are clearly intended, for example, polypeptides, polysaccharides, polyethylene glycols, DNA, RNA, and the like).
In certain non-limiting examples, "optionally substituted" indicates that the group is optionally substituted with alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, haloalkyl, haloalkenyl, haloalkynyl, perhaloalkyl, halo, cycloalkyl, cycloalkenyl, heteroalicyclyl, aryl , heteroaryl, carbocyclyl, heterocyclyl, hydroxy, alkoxy, cyano, cyanoalkyl, carboxyl, sulfhydryl, amino, an amino acid, fused cycloalkyl, spiro cycloalkyl, fused heteroaryl, fused aryl, sulfonyl, sulfinyl, sulfonamidyl, sulfamidyl, phosphonate ester, starch, ether , alkylester, or combinations thereof. In specific cases, a group designated as "optionally substituted" indicates that the group is optionally substituted with hydrogen, hydroxy, nitro, cyano, methylthiol, thiol, azido, methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert- amyl, hexyl, heptyl, octyl, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, ethynyl, 2-propynyl , 2-butynyl, 1,3-butadiinyl, fluorine, chlorine, bromine, iodine, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1-chloro-1-fluoro-1-iodoethyl, fluorethyl , bromoethyl, chloroethyl, iodoethyl, fluoropropyl, bromopropyl, chlorine propyl, iodopropyl, fluorethenyl, chloroethenyl, bromoethenyl, iodoethenyl, fluorethynyl, chloroethynyl, bromoethynyl, iodoethynyl, trifluorethenyl, trichloroethenyl, tribromoethenyl, trifluorpropynyl, trichloropropynyl, trichloropropyl, cyclopentyl, cyclopentyl, cyclopentyl and cyclopentyl , tetrahydrofuranyl, thiofuranyl, aziridinyl, oxiranil, oxaziridinyl, dioxiranil, azetidinyl, oxazil, oxetanil, tetanil, pyrrolidinyl, oxolanil, thiolanyl, oxazolidinyl, thiazolidinyl, decalinyl, tetrahydro, dipyranthylhydromanyl, hep. , tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperidinyl, oxepanyl, tiepanil, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl -pyranil, dioxanil, 1,3-dioxolanil, pyrazolinyl, dithianil, dithiolanil, dihydropyranil, dihydrothienyl, dihydride ofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, quinolizinyl, cyclohexenyl, cyclopentadienyl, bicyclo[2.2.1]hept-2-ene, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, furanyl, thienyl, acridinyl, phenyl, benzyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiazolyl, benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isoxazolyl, isoquinolinyl, indolizinyl, isothiazolyl, isoindolyloxadiazolyl, indazolyl, pyridyl, pyridazil, pyrimidyl, pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyl, quinyl quinyl, trizinyl, phthala, phthala, pyrazolyl, quinyl, hydroxy thiazolyl, triazinyl, thiadiazolyl, pyridyl-N-oxide, methyl sulfonyl, ethyl sulfonyl, aminosulfonyl, trifluoromethyl sulfonyl, phosphinic acid, carboxylic acid, starch, amino, methylamine, ethylamine, dimethylamine, diethylamine, aminoethyldimethylamine, aminoethyldiethyl amine, methylester, ethylester propylester isopropylester butylester, or combinations thereof.
[0053] As used herein, C1-Cx includes C1-C2, C1-C3 ... C1-Cx. As an example only, "C1-C4" indicates that there are one to four carbon atoms in the portion, ie groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms, as well as the ranges C1-C2 and C1-C3. Thus, just as an example, "C1-C4 alkyl" indicates that there are one to four carbon atoms in the alkyl group, that is, the alkyl group is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso -butyl, sec-butyl and t-butyl. Whenever it appears here, a numerical range such as “1 to 10” refers to each whole number in the quoted range; for example, "1 to 10 carbon atoms" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms. carbon, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
[0054] The term "lower", as used herein in combination with terms such as, for example, alkyl, alkenyl or alkynyl (i.e., "lower alkyl", "lower alkenyl" or "lower alkynyl") refers to a monoradical optionally substituted straight chain, or optionally substituted saturated branched chain hydrocarbon having one to about six carbon atoms, more preferably one to three carbon atoms. Examples include, without limitation, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2- methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl.
[0055] The term "hydrocarbon", as used herein, alone or in combination, refers to a chemical compound or group that contains only carbon and hydrogen atoms.
[0056] The terms "heteroatom" or "hetero" as used herein, alone or in combination, refer to an atom other than carbon or hydrogen. Heteroatoms can be independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, without limitation to these atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or each of all two or more heteroatoms may be different from the others.
[0057] The term "alkyl", as used herein, alone or in combination, refers to an optionally substituted straight-chain, or optionally substituted saturated branched-chain hydrocarbon monoradical having one to about ten carbon atoms, plus preferably one to six carbon atoms. Examples include, without limitation, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2- methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec- butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, for example, heptyl, octyl, and the like. Whenever a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" appears here, it means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also encompasses the occurrence of the term “alkyl” in which no numerical range is designated.
[0058] The term "alkylene", as used herein, alone or in combination, refers to a diradical derived from the monoradical defined above, alkyl. Examples include, without limitation, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like.
[0059] The term "alkenyl", as used herein, alone or in combination, refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having de two to about ten carbon atoms, more preferably two to about six carbon atoms. The group can be in either cis or trans conformation around the double bond (or bonds), and should be understood to include both isomers. Examples include, without limitation, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever it appears here, a numerical range such as "C2-C6 alkenyl" or "C2-6 alkenyl" means that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also encompasses the occurrence of the term “alkenyl” in which no numerical range is designated.
[0060] The term "alkenylene", as used herein, alone or in combination, refers to a diradical derived from the monoradical defined above, alkenyl. Examples include, without limitation, ethenylene (-CH=CH-), the propenylene isomers (for example, -CH2CH=CH- and -C(CH3)=CH-), and the like.
[0061] The term "alkynyl", as used herein, alone or in combination, refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having two up to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, without limitation, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiinyl, and the like. Wherever appearing here, a numerical range such as "C2-C6 alkynyl" or "C2-6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also encompasses the occurrence of the term “alkynyl” in which no numerical range is designated.
The term "alkynylene", as used herein, alone or in combination, refers to a diradical derived from the monoradical defined above, alkynyl. Examples include, without limitation, ethynylene (-C=C-), propargylene (-CH2-C=C-), and the like.
[0063] The term "aliphatic", as used herein, alone or in combination, refers to an optionally substituted non-aromatic hydrocarbon, straight-chain or branched-chain, non-cyclic, saturated, partially unsaturated or fully unsaturated. Thus, the term collectively includes alkyl, alkenyl and alkynyl groups.
The terms "heteroalkyl", "heteroalkenyl" and "heteroalkynyl", as used herein, alone or in combination, refer to the structures of alkyl, alkenyl and optionally substituted alkynyl, respectively, as described above, in which one or more of the chain's skeletal carbon atoms (and any associated hydrogen atoms, as appropriate) are each independently replaced with a heteroatom (i.e., a different carbon atom, eg, without limitation, oxygen, nitrogen, sulfur, silicon, phosphorus, tin, or combinations thereof), or group of heteroatoms, for example, without limitation, -OO-, -SS-, -OS-, -SO-, =NN=, -N=N-, -N =N-NH-, -P(O)2-, -OP(O)2-, -P(O)2-O-, -S(O)-, -S(O)2-, -SnH2- , and the like.
The terms "haloalkyl", "haloalkenyl" and "haloalkynyl", as used herein, alone or in combination, refer to the optionally substituted alkyl, alkenyl and alkynyl groups, respectively, as defined above, in which one or more atoms of hydrogen are replaced by atoms of fluorine, chlorine, bromine or iodine, or combinations thereof. In some embodiments, two or more hydrogen atoms can be replaced with halogen atoms that are the same as each other (eg, difluoromethyl); in other embodiments, two or more hydrogen atoms may be replaced with halogen atoms that are not the same as each other (eg, 1-chloro-1-fluor-1-iodoethyl). Non-limiting examples of haloalkyl groups are fluoromethyl and bromoethyl. A non-limiting example of a haloalkenyl group is bromoethenyl. A non-limiting example of a haloalkynyl group is chloroethynyl.
The term "perhalo", as used herein, alone or in combination, refers to groups in which all hydrogen atoms are replaced by fluorine, chlorine, bromine, iodine, or combinations thereof. Thus, by way of non-limiting example, the term "perhaloalkyl" refers to an alkyl group, as defined herein, in which all H atoms have been replaced by fluorine, chlorine, bromine or iodine atoms, or combinations thereof. A non-limiting example of a perhaloalkyl group is bromine, chlorine, fluoromethyl. A non-limiting example of a perhaloalkenyl group is trichloroethenyl. A non-limiting example of a perhaloalkynyl group is tribromopropynyl.
[0067] The term "carbon chain", as used herein, alone or in combination, refers to any alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, or heteroalkynyl group, which is linear, cyclic, or any combination thereof. If the chain is part of a linker and that linker comprises one or more rings as part of the central framework, for the purposes of calculating the length of the chain, the "chain" only includes those carbon atoms that make up the base or the top of a certain ring, not both, and when the top and bottom of the ring (or rings) are not equivalent in length, the shorter distance should be used in determining the length of the chain. If the chain contains heteroatoms as part of the scaffold, those atoms are not calculated as part of the carbon chain length.
[0068] The terms "cycle", "cyclic", "ring" and "ring members", as used herein, alone or in combination, refer to any covalently closed structure, including alicyclic, heterocyclic, aromatic, ring systems, fused or unfused heteroaromatics and polycyclics as described herein. Rings can be optionally replaced. Rings can form part of a fused ring system. The term "members" is intended to denote the number of skeletal atoms that make up the ring. Thus, just as an example, cyclohexane, pyridine, pyran and pyrimidine are six-membered rings, and cyclopentane, pyrrole, tetrahydrofuran and thiophene are five-membered rings.
[0069] The term "fused", as used herein, alone or in combination, refers to cyclic structures in which two or more rings share one or more bonds.
[0070] The term "cycloalkyl", as used herein, alone or in combination, refers to an optionally substituted saturated hydrocarbon monoradical ring containing from three to about fifteen ring carbon atoms or from three to about ten ring carbon atoms, although it may include additional carbon atoms outside the ring as substituents (eg, methylcyclopropyl). Whenever appearing here, a numerical range such as "C3-C6 cycloalkyl" or "C3-6 cycloalkyl" means that the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, ie is cyclopropyl, cyclobutyl, cyclopentyl or cycloheptyl, although the present definition also encompasses the occurrence of the term "cycloalkyl" in which no numerical range is designated. The term includes fused, unfused, bridged and spiro radicals. A fused cycloalkyl can contain from two to four fused rings, where the adhesion ring is a cycloalkyl ring, and the other individual rings can be alicyclic, heterocyclic, aromatic, heteroaromatic, or any combination thereof. Examples include, without limitation, ring systems of cyclopropyl, cyclopentyl, cyclohexyl, decalinyl, and bicyclo[2.2.1]heptyl and adamantyl. Illustrative examples include, without limitation, the following portions:

[0071] and the like.
[0072] The term "cycloalkenyl", as used herein, alone or in combination, refers to an optionally substituted non-aromatic hydrocarbon monoradical ring having one or more carbon-carbon double bonds and from three to about twenty carbon atoms. ring carbon, three to about twelve ring carbon atoms, or three to about ten ring carbon atoms. The term includes fused, unfused, bridged and spiro radicals. A cycloalkenyl fused can contain from two to four fused rings, where the adhesion ring is a cycloalkenyl ring, and the other individual rings can be alicyclic, heterocyclic, aromatic, heteroaromatic, or any combination thereof. Fused ring systems can be fused through a bond that is either a carbon-carbon single bond or a carbon-carbon double bond. Examples of cycloalkenyls include, without limitation, cyclohexenyl, cyclopentadienyl and bicyclo[2.2.1]hept-2-ene ring systems. Illustrative examples include, without limitation, the following portions:

[0073] and the like.
[0074] The terms "alicyclyl" or "alicyclic", as used herein, alone or in combination, refer to an optionally substituted, saturated, partially unsaturated or fully unsaturated non-aromatic hydrocarbon ring system containing from three to about twenty ring carbon atoms, three to about twelve ring carbon atoms, or three to about ten ring carbon atoms. Thus, the terms collectively include cycloalkyl and cycloalkenyl groups.
[0075] The terms "non-aromatic heterocyclyl" and "heteroalicyclyl", as used herein, alone or in combination, refer to non-aromatic, optionally substituted, saturated, partially unsaturated or fully unsaturated monoradicals containing from three to about twenty ring atoms, in which one or more of the ring atoms is an atom other than carbon, independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, without limitation of these atoms. In embodiments in which two or more heteroatoms are present in the ring, the two or more heteroatoms may be the same as each other, or some or each of all two or more heteroatoms may be different from each other. Terms include fused, unfused, bridged and spiro radicals. A non-aromatic fused heterocyclic radical can contain from two to four fused rings, where the adhesion ring is a non-aromatic heterocycle, and the other individual rings can be alicyclic, heterocyclic, aromatic, heteroaromatic, or any combination thereof. Fused ring systems can be fused via a single bond or a double bond, as well as via bonds that are carbon-carbon, carbon-heteroatom, or heteroatom-heteroatom. The terms also include radicals having three to about twelve ring skeleton atoms, as well as those having three to about ten ring skeleton atoms. Adhesion of a non-aromatic heterocyclic subunit to its parent molecule can be via a heteroatom or a carbon atom. Likewise, an additional substitution can be via a heteroatom or a carbon atom. As a non-limiting example, a non-aromatic imidazolidine heterocycle can be attached to a parent molecule via its N atoms (imidazolidin-1-yl or imidazolidin-3-yl) or any of its carbon atoms (imidazolidin- 2-yl, imidazolidin-4-yl or imidazolidin-5-yl). In certain embodiments, non-aromatic heterocycles contain one or more carbonyl or thiocarbonyl groups such as, for example, oxo and thio groups. Examples include, without limitation, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanil, piperazinyl, azetidinyl, oxetanyl, thiethanyl, homopiperidinyl, thiepanyl, oxepanyl, oxepanyl, diazepinyl, 2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranil, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl and quinolizinyl. Illustrative examples of heterocycloalkyl groups, also called non-aromatic heterocycles, include:

[0076] and the like. The terms also include all ring forms of carbohydrates, including, without limitation, monosaccharides, disaccharides, and oligosaccharides.
[0077] The term "aromatic", as used herein, refers to a flat, cyclic, or polycyclic ring portion that has a delocalized system of π-etetrons containing 4 n + 2 π electrons, where n is an integer . Aromatic rings can be formed from five, six, seven, eight, nine or more than nine atoms. Aromatics can be optionally substituted and can be monocyclic or polycyclic with fused rings. The term "aromatic" encompasses both all rings that contain carbon (eg, phenyl) and those rings that contain one or more heteroatoms (eg, pyridine).
[0078] The term "aryl", as used herein, alone or in combination, refers to an optionally substituted aromatic hydrocarbon radical of six to about twenty ring carbon atoms, and includes fused and unfused aryl rings. A fused aryl ring radical contains from two to four fused rings, where the adhesion ring is an aryl ring, and the other individual rings can be alicyclic, heterocyclic, aromatic, heteroaromatic, or any combination thereof. In addition, the term aryl includes fused and unfused rings containing six to about twelve ring carbon atoms, as well as those containing six to about ten ring carbon atoms. A non-limiting example of a single ring aryl group includes phenyl; a ring-fused aryl group includes naphthyl, phenantrenyl, anthracenyl, azulenyl; and an unfused biaryl group includes biphenyl.
[0079] The term "arylene", as used herein, alone or in combination, refers to a diradical derived from the monoradical defined above, aryl. Examples include, without limitation, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2-naphthylene, and the like.
[0080] The term "heteroaryl", as used herein, alone or in combination, refers to optionally substituted aromatic monoradicals containing from about five to about twenty ring skeleton atoms, wherein one or more of the atoms in the ring are a heteroatom independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but not limited to these atoms, and provided that the ring of said group does not contain two adjacent O or S atoms. In embodiments in which two or more heteroatoms are present in the ring, the two or more heteroatoms may be the same as each other, or some or each of all two or more heteroatoms may be different from each other. The term heteroaryl includes optionally substituted fused and unfused heteroaryl radicals having at least one heteroatom. The term heteroaryl also includes fused and unfused heteroaryls having five to about twelve ring skeleton atoms, as well as those having five to about ten ring skeleton atoms. Attachment to a heteroaryl group can be via a carbon atom or a heteroatom. Thus, as a non-limiting example, an imidazole group can be attached to a parent molecule via any of its carbon atoms (imidazol-2-yl, imidazol-4-yl or imidazol-5-yl), or its nitrogen atoms (imidazol-1-yl or imidazol-3-yl). Likewise, a heteroaryl group may be further substituted by any one or all of its carbon atoms, and/or any one or all of its heteroatoms. A fused heteroaryl radical can contain from two to four fused rings, where the adhesion ring is a heteroaromatic ring and the other individual rings can be alicyclic, heterocyclic, aromatic, heteroaromatic, or any combination thereof. A non-limiting example of a single ring heteroaryl group includes pyridyl; fused ring heteroaryl groups include benzimidazolyl, quinolinyl, acridinyl; and a fused biheteroaryl group includes bipyridinyl. Additional examples of heteroaryls include, without limitation, furanyl, thienyl, oxazolyl, acridinyl, phenazinyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzothiophenyl, benzoxadiazolyl, benzotriazolyl, imidazolyl, indolyl, isothiazolyl, isoxazolyl, isothiazolyl, isoxazolyl, , pyridyl, pyridazil, pyrimidyl, pyrazinyl, pyrrolyl, pyrazinyl, pyrazolyl, purinyl, phthalazinyl, pteridinyl, quinolinyl, quinazolinyl, quinoxalinyl, triazolyl, tetrazolyl, thiazolyl, triazinyl, thiadiazolyl, and the like, for example, and pyridyl oxides thereof -N-oxide. Illustrative examples of heteroaryl groups include the following portions:

[0081] and the like.
[0082] The term "heteroarylene", as used herein, alone or in combination, refers to a diradical derived from the monoradical defined above, heteroaryl. Examples include, without limitation, pyridinyl and pyrimidinyl.
[0083] The term "heterocyclyl", as used herein, alone or in combination, collectively refers to heteroalicyclyl and heteroaryl groups. Here, whenever the number of carbon atoms in a heterocycle is indicated (eg C1-C6 heterocycle), at least one atom other than carbon (the heteroatom) must be present in the ring. Designations such as "C1-C6 heterocycle" refer only to the number of carbon atoms in the ring and do not refer to the total number of atoms in the ring. Designations such as "4-6 membered heterocycle" refer to the total number of atoms that are contained in the ring (ie, a four-, five-, or six-membered ring, where at least one atom is an atom of carbon, at least one atom is a heteroatom, and the remaining two to four atoms are carbon atoms or heteroatoms). For heterocycles that have two or more heteroatoms, those two or more heteroatoms can be the same or different from each other. Heterocycles can be optionally substituted. Non-aromatic heterocyclic groups include groups that have only three ring atoms, while aromatic heterocyclic groups must have at least five ring atoms. Attachment (i.e. adhesion of a parent molecule or additional substitution) to a heterocycle can be via a heteroatom or a carbon atom.
[0084] The term "carbocyclyl", as used herein, alone or in combination, refers collectively to the alicyclyl and aryl groups; that is, all covalently closed ring structures, which may be saturated, partially unsaturated, fully unsaturated, or aromatic, are carbon. Carbocyclic rings can be formed from three, four, five, six, seven, eight, nine or more than nine carbon atoms. Carbocycles can be optionally substituted. The term distinguishes carbocyclic from heterocyclic rings, in which the ring scaffold contains at least one carbon.
The terms "halogen", "halo" or "halide", as used herein, alone or in combination, refer to fluorine, chlorine, bromine and iodine.
[0086] The term "hydroxy", as used herein, alone or in combination, refers to the monoradical -OH.
[0087] The term "cyan", as used herein, alone or in combination, refers to the monoradical -CN.
[0088] The term "cyanomethyl", as used herein, alone or in combination, refers to the monoradical -CH2CN.
[0089] The term "nitro", as used herein, alone or in combination, refers to the monoradical -NO2.
[0090] The term "oxy", as used herein, alone or in combination, refers to the diradical -O-.
[0091] The term "oxo", as used herein, alone or in combination, refers to the diradical =O.
[0092] The term "carbonyl", as used herein, alone or in combination, refers to the diradical -C(=O)-, which can also be written as -C(O)-.
The terms "carboxy" or "carboxyl", as used herein, alone or in combination, refer to the -C(O)OH moiety, which may also be written as -COOH.
The term "alkoxy", as used herein, alone or in combination, refers to an alkyl ether radical, -O-alkyl, including the -O-aliphatic and -O-carbocyclyl groups, where the alkyl groups, aliphatic and carbocyclyl may be optionally substituted, and wherein the terms alkyl, aliphatic and carbocyclyl are as defined herein. Non-limiting examples of alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.
[0095] The term "sulfinyl", as used herein, alone or in combination, refers to the diradical -S(=O)-.
[0096] The term "sulfonyl", as used herein, alone or in combination, refers to the diradical -S(=O)2-.
[0097] The terms "sulfonamide", "sulfonamido" and "sulfonamidyl", as used herein, alone or in combination, refer to the diradical groups -S(=O)2-NH- and -NH-S(=O )two-.
The terms "sulfamide", "sulfamido" and "sulfamidyl", as used herein, alone or in combination, refer to the diradical group -NH-S(=O)2-NH-.
[0099] It should be understood that in cases where two or more radicals are used in succession to define a substituent attached to a structure, the first named radical is considered to be terminal and the last named radical is considered to be attached to the structure in question. Thus, for example, the arylalkyl radical is attached to the structure in question by the alkyl group.
The term "amino acid", as used herein, refers to a group or compound consisting of an amino group, a carboxyl group, an H atom and a distinct R group (or side chain). “Amino acid” includes α-amino acids, e-amino acids, δ-amino acids and Y-amino acids. α-amino acids consist of an amino group, a carboxyl group, an H atom and a distinct R group that is attached to the α carbon atom. "Amino acid" includes natural amino acids, unnatural amino acids, amino acid analogs, amino acid mimetics, and the like.
[00101] In one aspect, the term "amino acid" refers to one of the twenty naturally occurring amino acids (ie, α-amino acids) as shown below. Amino acids consist of an amino group, a carboxyl group, an H atom and a distinct R group (or side chain), all of which are attached to an α carbon atom. As a result of containing three different groups on the α-carbon atom, amino acids contain a chiral center and therefore can exist as one of the optically active enantiomers, D- and L-. Naturally occurring acids are found as their L derivatives.

[00102] In another aspect, the amino acid is an "unnatural amino acid", "amino acid analogue", "amino acid mimetic". "Unnatural amino acid", "amino acid analogue", "amino acid mimetic", and the like, as used herein, refer to an amino acid that is not one of the 20 natural amino acids. These terms refer to amino acids in which the fundamental amino acid molecule has been modified in some way. These modifications include, but are not limited to, side chain variations; amino-CH-carboxyl scaffold substitutions or alterations; D enantiomers; combinations of these; and the like.

[00103] These terms also include, without limitation, amino acids that occur naturally, but are not naturally incorporated into a growing polypeptide chain, for example, without limitation, N-acetylglucosaminyl-L-serine, N-acetylglucosaminyl-L-threonine, O-phosphotyrosine, and the like. In addition, these terms also include, without limitation, non-naturally occurring amino acids that can be obtained synthetically or can be obtained by modification of natural, naturally occurring or unnatural amino acids.
[00104] Illustrative examples of side chain variations include, without limitation, Ot-butyl-serine, hydroxyproline, 4-chlorophenylalanine, homoserine, methionine sulfoxide, thienylalanine, and the like.

[00105] Illustrative examples of framework alterations include, without limitation, e-amino acids such as, for example, β-alanine, homoproline, amino group alkylation, substitution at the α carbon atom, thiocarboxyl, and the like.

[00106] A peptide can be natural or unnatural, and consists of amino acids that are linked together. The terms "natural peptide", "natural polypeptide", "natural protein", and the like, as used herein, refer to a polymer of natural amino acid residues linked by covalent peptide bonds, and include amino acid chains of any length, including full length proteins. The terms "unnatural peptide", "peptide mimetic", "peptide analogue", "unnatural polypeptide", "unnatural protein", and the like, as used herein, refer to a polymer of amino acid residues of any length, including full length proteins, where one or more of the amino acids is an unnatural amino acid, and/or where one or more of the amino acids are joined by chemical means other than natural peptide bonds. Illustrative examples of linking groups that can be used as alternatives to the natural peptide linkage include, without limitation, ethylene (-CH2-CH2-), ethynylene (-CH=CH-), ketomethylene (-C(=O)CH2- or -CH2C(=O)-), aminomethylene (-CH2-NH- or -NH-CH2-), methylene ether (-CH2-O- or -O-CH2-), thioether (-CH2-S- or - S-CH2-), thioamide (-C(=S)NH- or -NH-C(=S)-), ester (-C(=O)O- or , tetrazole, thiazol, and the like
[00107] "Nucleoside" is a glycosylamine consisting of a nucleobase (often simply called a base) attached to a ribose or deoxyribose sugar. A nucleoside can be a natural nucleoside or an unnatural nucleoside. The term "natural nucleoside" as used herein refers to a nucleobase attached to a ribose or deoxyribose sugar. Examples of these include cytidine, uridine, adenosine, guanosine, thymidine and inosine.

[00108] The terms "unnatural nucleoside", "nucleoside analogue", and the like, as used herein, refer to one include, without limitation, base modifications, sugar modifications, changes in linkages between base and sugar, use of alternative stereochemistry; combinations of these; and the like.
[00109] The terms "nucleotide", "polynucleotide", "oligonucleotide", "nucleic acid", "nucleic acid polymer", and the like, as used herein, refer to deoxyribonucleotides, deoxyribonucleosides, ribonucleosides or ribonucleotides, and polymers thereof , in single or double stranded form, including, without limitation, (i) naturally occurring nucleotide analogues that have binding properties similar to a reference nucleic acid and are metabolized similarly to naturally occurring nucleotides; (ii) oligonucleotide analogues including, without limitation, PNA (peptidonucleic acid), DNA analogues used in antisense technology (phosphorothioates, phosphoroamidates, and the like).
[00110] The term "lipid", as used herein, refers to any naturally occurring fat-soluble (lipophilic) molecule, for example, fats, oils, waxes, cholesterol, sterols, fat-soluble vitamins (for example, vitamins A, D, E, and K), monoglycerides, diglycerides, phospholipids, fatty acid, fatty acid esters, and the like. Lipids can be natural or unnatural. In one aspect, the lipid is a fatty acid. Fatty acids are either saturated or unsaturated. Saturated fatty acids include, without limitation, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid. Unsaturated fatty acids include, without limitation, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid.
[00111] "Phospholipid" is a type of lipid that is amphipathic. Phospholipids are a class of lipids and contain a glycerol scaffold, in which two of the glycerol scaffold hydroxy groups are esterified with fatty acid (saturated, unsaturated, natural, unnatural), and the third hydroxy is used to form an ester of phosphate with phosphoric acid. The phosphate portion of the resulting phosphatidic acid is further esterified with ethanolamine, choline or serine. Phospholipids are either natural or unnatural. Natural phospholipids include, without limitation, plasmalogen, cardiolipin, dipalmitoylphosphatidylcholine, glycerophospholipid, glycerophosphoric acid, lecithin, lysophosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol (3,4)-bisphosphate, phosphatidylinositol (3,5)-bisphosphate, phosphatidylinositol (4,5)-bisphosphate, phosphatidylinositol 3-phosphate, phosphatidylinositol 4-phosphate, phosphatidylinositol phosphate, phosphatidylmyoinositol mannosides, phosphatidylserine, platelet activating factor, sphingomyelin, sphingosyl phosphatide. “Unnatural phospholipids” contain a diglyceride, a phosphate group and a simple organic molecule such as choline, but they are prepared by nature.
[00112] "Glycoside", as used herein, refers to a group comprising any hydrophilic sugar (eg, sucrose, maltose, glucose, glucuronic acid, and the like). A glycoside is any sugar group linked through a glycosidic bond. Glycosides include natural glycosides and unnatural glycosides. Glycosides include asymmetric carbon(s) and exist in L form or D form. Natural glycosides preferably exist in D form. Glycosides include monosaccharides, disaccharides and polysaccharides. Examples of monosaccharides include, without limitation, trioses (e.g., glyceraldehyde, dihydroxyacetone), tetroses (e.g., erythrose, threose, erythrulose), pentoses (e.g., arabinose, lyse, ribose, deoxyribose, xylose, ribulosis, xylulose), hexoses (allose, altrose, galactose, glucose, gluteus, idosis, mannose, thalose, fructose, psychosis, sorbose, tagatose), heptosis (mannoheptulose, sedoheptulose); octoses (eg octolose, 2-keto-3-deoxymanoctonate), nonoses (eg sialose). Disaccharides include, without limitation, sucrose, lactose, maltose, trehalose, cellobiose, kojibiose, nigerosis, isomaltose, β,β-trehalose, sophorose, laminaribiosis, gentiobiose, turanose, maltulose, palatinose, gentiobiliosis, meliulose, manobiose rutinulose, xylobiose. Polysaccharides include glycans. Aza-sugars are also included within the term “glycoside”.
[00113] The term "polyethylene glycol" refers to linear or branched polymeric polyether polyols. PHARMACEUTICAL TERMINOLOGY
[00114] The terms "patient", "person" or "individual" are used interchangeably. As used herein, they refer to individuals suffering from a disorder, and the like, and encompass mammals and non-mammals. None of the terms require the individual to be under the care and/or supervision of a medical professional. Mammals are any member of the class Mammal, including, without limitation, humans, non-human primates such as chimpanzees, and other species of apes and apes; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals, for example, rabbits, dogs and cats; laboratory animals, including rodents, e.g., rats, mice and guinea pigs, and the like. Examples of non-mammals include, without limitation, birds, fish, and the like. In some embodiments of the methods and compositions provided herein, the subject is a mammal. In preferred embodiments, the individual is a human.
[00115] The terms "treat", "treat" or "treatment", and other grammatical equivalents, as used herein, include the alleviation, alleviation or amelioration of a disease or condition or one or more symptoms thereof, preventing further symptoms , ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, for example, stopping the development of the disease or condition, relieving the disease or condition, causing the regression of the disease or condition, alleviating a condition caused by the disease or condition, or cessation of symptoms of the disease or condition, and are intended to include prophylaxis. The terms further include obtaining a therapeutic benefit and/or a prophylactic benefit. The term “therapeutic benefit” means the eradication or amelioration of the underlying disorder being treated. Furthermore, a therapeutic benefit is obtained by eradicating or ameliorating one or more of the physical symptoms associated with the underlying disorder such that an improvement is seen in the individual even though the individual is still suffering from the underlying disorder. For prophylactic benefit, the compositions are administered to an individual at risk for the development of a particular disease, or to an individual who reports one or more of the physical symptoms of a disease, although a diagnosis of that disease has not yet been made.
[00116] The terms "administer", "administration", and the like, as used herein, refer to methods that can be used to allow the release of compounds or compositions to the desired site of biological action. These methods include, without limitation, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those skilled in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In preferred embodiments, the compounds and compositions described herein are administered orally.
[00117] The terms "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount", as used herein, refer to a sufficient amount of at least one agent or compound being administered that will relieve to some degree a or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is that amount of composition comprising a compound, as disclosed herein, necessary to provide a clinically significant decrease in a disease. An appropriate “effective” amount may differ from person to person. An appropriate “effective” amount in an individual case can be determined using techniques such as a dose escalation study.
[00118] The term "acceptable", as used herein, with respect to a formulation, composition or ingredient, means that it has no persistent detrimental effect on the general health of the individual being treated.
[00119] The term "pharmaceutically acceptable", as used herein, refers to a material, for example, a vehicle or diluent, that does not abrogate the biological activity or properties of the compounds described herein, and is relatively non-toxic, i.e., the material can be administered to an individual without causing undesirable biological effects or interacting in a deleterious way with any of the components of the composition in which it is contained.
[00120] The term "prodrug", as used herein, refers to a drug precursor that, after administration to an individual and subsequent absorption, is converted into an active, or more active, species through some process, for example, conversion via a metabolic pathway. Thus, the term encompasses any derivative of a compound, which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of this invention or a pharmaceutically active metabolite or residue thereof. Some prodrugs have a chemical group present in the prodrug that makes it less active and/or imparts solubility or some other property to the drug. After the chemical group has been cleaved and/or modified from the prodrug, the active drug is generated. Prodrugs are often helpful because, in some situations, they may be easier to administer than the parent drug. They can, for example, be bioavailable by oral administration, while the relative is not. Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when those compounds are administered to an individual (eg, by allowing an orally administered compound to be more readily absorbed into the blood) or that increase the release of the compound relative to a biological compartment (eg, the brain or lymphatic system).
The term "pharmaceutically acceptable salt", as used herein, refers to those salts which retain the biological effectiveness of the free acids and bases of the specified compound and which are not biologically or otherwise undesirable. The compounds described herein can have acidic or basic groups and therefore can be reacted with any of a variety of inorganic or organic bases and inorganic and organic acids to form a pharmaceutically acceptable salt. Such salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
[00122] The term "pharmaceutical composition", as used herein, refers to a biologically active compound, optionally mixed with at least one pharmaceutically acceptable chemical component, for example, without limitation, carriers, stabilizers, diluents, dispersing agents, cleaning agents. suspension, thickening agents, excipients, and the like.
The term "vehicle", as used herein, refers to relatively non-toxic chemical compounds or agents that facilitate the incorporation of a compound into cells or tissues.
[00124] The terms "pharmaceutical combination", "administration of an additional therapy", "administration of an additional therapeutic agent", and the like, as used herein, refer to a pharmaceutical therapy that results from mixing or combining more than one active ingredient and include both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that at least one of the compounds described herein, and at least one coagent, are both administered to a subject simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that at least one of the compounds described herein, and at least one coagent, are administered to an individual as separate entities simultaneously, concurrently or sequentially with varying intervening time limits, where such administration provides effective levels of the two or more compounds in the individual's body. These data also apply to cocktail therapies, for example, the administration of three or more active ingredients.
[00125] The terms "co-administration", "administered in combination with" and their grammatical or similar equivalents, as used herein, are intended to encompass the administration of selected therapeutic agents to a single individual, and are intended to include treatment regimens in which the agents are administered by the same route of administration or by a different route of administration or at the same time or at different times. In some embodiments, the compounds described herein will be co-administered with other agents. These terms encompass the administration of two or more agents to an animal such that both agents and/or their metabolites are present in the animal at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present. Thus, in some embodiments, the compounds of the invention and the other agent(s) are administered in a single composition. In some embodiments, the compounds of the invention and the other agent(s) are mixed in the composition.
[00126] The term "metabolite", as used herein, refers to a derivative of a compound that is formed when the compound is metabolized.
[00127] The term "active metabolite", as used herein, refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
[00128] The term "metabolized", as used herein, refers to the sum of the processes (including, without limitation, hydrolysis reactions and enzyme-catalyzed reactions) by which a particular substance is altered by an organism. Thus, enzymes can produce specific structural changes to a compound. For example, cytochrome P450 catalyzes several oxidative and reductive reactions, while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic acid molecule into aromatic alcohols, aliphatic alcohols, carboxylic acids, free amines and sulfhydryl groups. Additional information on metabolism can be found in "The Pharmacological Basis of Therapeutics", 9th Edition, McGraw-Hill (1996). COMPOUNDS
[00129] Described herein are compounds of formula (I), metabolites, pharmaceutically acceptable salts, solvates, polymorphs, esters, tautomers, or prodrugs thereof.
[00130] One modality provides a compound of formula (I):

[00131] in which:
[00132] Ra and Rb are selected from H, halogen, C1 to C6 alkyl; or Ra and Rb, together with the carbon atom to which they are attached, form a 3-, 4-, 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S;
[00133] M is H, C1-3 alkyl or a pharmaceutically acceptable cation;
[00134] X1 is N, CH, C(halogen) or C(C1-C4 alkyl);
[00135] X2 is N or CH;
[00136] X3 is N, CH, C(halogen) or C(C1-C4 alkyl);
[00137] X4 is N or CH; wherein at least one of X1, X2, X3 or X4 is N;
[00138] Y1 is N or CR1;
[00139] Y2 is N or CR2;
[00140] R1 is H, CF3, CH3, OCH3, F or Cl;
[00141] R2 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF3, OH, OCH3, ethoxy, SH, SCH3, SCH2CH3, CH2OH, C(CH3)2OH, Cl, F, CN , COOH, COOR2', CONH2, CONHR2' or SO2NH2; wherein R2' is H or C1-3 alkyl;
[00142] R3 is H, halogen, -CN, C1 to C6 alkyl, C1 to C6 alkoxy; and
[00143] R4 is H, halogen, -CN, C1 to C6 alkyl, C1 to C6 alkoxy; or
[00144] R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5-membered ring or 6-membered can be a saturated ring, an unsaturated ring or an aromatic ring.
[00145] In certain embodiments, provided herein is a compound of formula (I), wherein if X2 and X4 are both N, then X1 is not C(halogen).
In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 and X4 are both N, and X1 is N, CH, or C(C1-C4 alkyl). In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 is N, X4 is CH and X1 is N, CH, C(halogen) or C(C1-C4 alkyl). In still additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 is CH, X4 is N, and X1 is N, CH, C(halogen) or C(C1-C4 alkyl). In certain embodiments, X2 and X4 are both CH and X1 is N, CH, C(halogen) or C(C1-C4 alkyl).
[00147] In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 and X4 are both N, and X1 is N. In some embodiments, X2 and X4 are both N, and X1 is CH. In other embodiments, X2 and X4 are both N, and X1 is C(C1-C4 alkyl). In still additional or alternative embodiments, X2 is CH or N and X1 is N, CH, C(halogen) or C(C1-C4 alkyl). In still additional or alternative embodiments, provided herein is a compound of formula (I), wherein X4 is CH or N, and X1 is N, CH, C(halogen) or C(C1-C4 alkyl).
[00148] In additional or alternative embodiments, X2 and X4 are both CH and X1 is N. In some embodiments, X2 and X4 are both CH and X1 is CH. In certain embodiments, X2 and X4 are both CH and X1 is C(halogen). In other embodiments, X2 and X4 are both CH and X1 is C(C1-C4 alkyl).
[00149] In additional or alternative embodiments, X2 is CH, X4 is N, and X1 is N. In some embodiments, X2 is CH, X4 is N, and X1 is CH. In certain embodiments, X2 is CH, X4 is N, and X1 is C(halogen). In other embodiments, X2 is CH, X4 is N and X1 is C(C1-C4 alkyl).
[00150] In additional or alternative embodiments, X2 is N, X4 is CH, and X1 is N. In some embodiments, X2 is N, X4 is CH, and X1 is CH. In certain embodiments, X2 is N, X4 is CH, and X1 is C(halogen). In other embodiments, X2 is N, X4 is CH and X1 is C(C1-C4 alkyl).
[00151] In additional or alternative embodiments, X2 is N and X1 is N. In some embodiments, X2 is N and X1 is CH. In certain embodiments, X2 is N and X1 is C(halogen). In other embodiments, X2 is N and X1 is C(C1-C4 alkyl). In additional or alternative embodiments, X2 is CH and X1 is N. In some embodiments, X2 is CH and X1 is CH. In certain embodiments, X2 is CH and X1 is C(halogen). In other embodiments, X2 is CH and X1 is C(C1-C4 alkyl).
[00152] In additional or alternative embodiments, X4 is N and X1 is N. In some embodiments, X4 is N and X1 is CH. In certain embodiments, X4 is N and X1 is C(halogen). In other embodiments, X4 is N and X1 is C(C1-C4 alkyl). In additional or alternative embodiments, X4 is CH and X1 is N. In some embodiments, X4 is CH and X1 is CH. In certain embodiments, X4 is CH and X1 is C(halogen). In other embodiments, X4 is CH and X1 is C(C1-C4 alkyl).
[00153] In certain embodiments, provided herein is a compound of formula (I), wherein if X2 and X4 are both N, then R4 is not Cl.
[00154] In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 and X4 are both N, and R4 is H, halogen, -CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring members can be a saturated ring, an unsaturated ring or an aromatic ring. In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 and X4 are both CH, and R4 is H, halogen, -CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring members can be a saturated ring, an unsaturated ring or an aromatic ring. In some embodiments, X2 is CH, X4 is N, and R4 is H, halogen, -CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring members can be a saturated ring, an unsaturated ring or an aromatic ring. In other embodiments, X2 is N, X4 is CH, and R4 is H, halogen, -CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring members can be a saturated ring, an unsaturated ring or an aromatic ring.
[00155] In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 and X4 are both N, and R4 is H, fluorine, iodine, bromine, -CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring members can be a saturated ring, an unsaturated ring or an aromatic ring. In certain embodiments, X2 and X4 are both CH, and R4 is H, fluorine, chlorine, iodine, bromine, -CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring members can be a saturated ring, an unsaturated ring or an aromatic ring. In some embodiments, X2 is CH, X4 is N, and R4 is H, fluorine, chlorine, iodine, bromine, -CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring members can be a saturated ring, an unsaturated ring or an aromatic ring. In other embodiments, X2 is N, X4 is CH, and R4 is H, fluorine, chlorine, iodine, bromine, -CN, C1 to C6 alkyl, C1 to C6 alkoxy; or R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring members can be a saturated ring, an unsaturated ring or an aromatic ring.
In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 and X4 are both N, and R4 is H. In some embodiments, X2 and X4 are both N, and R4 is fluorine. In other embodiments, X2 and X4 are both N, and R4 is iodine. In certain embodiments, X2 and X4 are both N, and R4 is bromo. In some embodiments, X2 and X4 are both N, and R4 is -CN. In certain specific embodiments, X2 and X4 are both N, and R4 is C1 to C6 alkyl. In some cases, X2 and X4 are both N, and R4 is C1 to C6 alkoxy. In other embodiments, X2 and X4 are both N, and R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring may be a saturated ring, an unsaturated ring or an aromatic ring.
[00157] In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 and X4 are both CH, and R4 is H. In some embodiments, X2 and X4 are both CH, and R4 is fluorine. In some embodiments, X2 and X4 are both CH, and R4 is chlorine. In other embodiments, X2 and X4 are both CH, and R4 is iodine. In certain embodiments, X2 and X4 are both CH, and R4 is bromo. In some embodiments, X2 and X4 are both CH, and R4 is -CN. In certain specific embodiments, X2 and X4 are both CH, and R4 is C1 to C6 alkyl. In some cases, X2 and X4 are both CH, and R4 is C1 to C6 alkoxy. In other embodiments, X2 and X4 are both CH, and R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring may be a saturated ring, an unsaturated ring or an aromatic ring.
In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 is CH, X4 is N, and R4 is H. In some embodiments, X2 is CH, X4 is N, and R4 is fluorine. In some embodiments, X2 is CH, X4 is N, and R4 is chlorine. In other embodiments X2 is CH, X4 is N, and R4 is iodine. In certain embodiments, X2 is CH, X4 is N, and R4 is bromo. In some embodiments, X2 is CH, X4 is N, and R4 is -CN. In certain specific embodiments, X2 is CH, X4 is N, and R4 is C1 to C6 alkyl. In some cases, X2 is CH, X4 is N, and R4 is C1 to C6 alkoxy. In other embodiments, X2 is CH, X4 is N, and R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring may be a saturated ring, an unsaturated ring or an aromatic ring.
[00159] In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 is N, X4 is CH, and R4 is H. In some embodiments, X2 is N, X4 is CH, and R4 is fluorine. In some embodiments, X2 is N, X4 is CH, and R4 is chlorine. In other embodiments X2 is N, X4 is CH, and R4 is iodine. In certain embodiments, X2 is N, X4 is CH, and R4 is bromo. In some embodiments, X2 is N, X4 is CH, and R4 is -CN. In certain specific embodiments, X2 is N, X4 is CH, and R4 is C1 to C6 alkyl. In some cases, X2 is N, X4 is CH, and R4 is C1 to C6 alkoxy. In other embodiments, X2 is N, X4 is CH, and R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O, N and S, wherein said 5- or 6-membered ring may be a saturated ring, an unsaturated ring or an aromatic ring.
[00160] In certain embodiments, provided herein is a compound of formula (I), wherein if X2 and X4 are both N, then Y2 is not C-Cl.
[00161] In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 and X4 are both N, and Y2 is N or CR2, wherein R2 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF3, OH, OCH3, ethoxy, SH, SCH3, SCH2CH3, CH2OH, C(CH3)2OH, F, CN, COOH, COOR2', CONH2, CONHR2' or SO2NH2; where R2' is H or C1-3 alkyl. In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 and X4 are both CH, and Y2 is N or CR2, wherein R2 is H, methyl, ethyl, propyl, isopropyl, tert-butyl , cyclopropyl, cyclobutyl, CF3, OH, OCH3, ethoxy, SH, SCH3, SCH2CH3, CH2OH, C(CH3)2OH, Cl, F, CN, COOH, COOR2', CONH2, CONHR2' or SO2NH2; where R2' is H or C1-3 alkyl. In some embodiments, X2 is N, X4 is CH, and Y2 is N or CR2, where R2 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF3, OH, OCH3, ethoxy, SH , SCH3, SCH2CH3, CH2OH, C(CH3)2OH, Cl, F, CN, COOH, COOR2', CONH2, CONHR2' or SO2NH2; where R2' is H or C1-3 alkyl. In other embodiments, X2 is CH, X4 is N, and Y2 is N or CR2, where R2 is H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF3, OH, OCH3, ethoxy, SH , SCH3, SCH2CH3, CH2OH, C(CH3)2OH, Cl, F, CN, COOH, COOR2', CONH2, CONHR2' or SO2NH2; where R2' is H or C1-3 alkyl.
[00162] In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 and X4 are both N, and Y2 is N. In some embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is H. In some embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is methyl. In some embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is ethyl. In other embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is propyl. In certain embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is isopropyl. In some embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is tert-butyl. In some embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is cyclopropyl. In other embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is cyclobutyl. In some embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is CF3. In specific embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is OH. In certain embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is OCH3. In some embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is ethoxy. In other embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is SH. In some embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is SCH3. In some embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is SCH2CH3. In some embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is CH2OH. In certain embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is C(CH3)2OH. In additional embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is F. In some embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is CN. In some embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is COOH. In certain specific embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is COOR2', where R2' is H or C1-3 alkyl. In some embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is CONH2. In other embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is CONHR2', where R2' is H or C1-3 alkyl. In certain embodiments, X2 and X4 are both N, and Y2 is CR2, where R2 is SO2NH2.
In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 and X4 are both CH, and Y2 is N. In some embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is H. In some embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is methyl. In other embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is ethyl. In some embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is propyl. In certain embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is isopropyl. In some embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is tert-butyl. In other embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is cyclopropyl. In certain embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is cyclobutyl. In some embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is CF3. In other embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is OH. In some embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is OCH3. In some embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is ethoxy. In other embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is SH. In some embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is SCH3. In certain embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is SCH2CH3. In some embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is CH2OH. In certain embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is C(CH3)2OH. In some cases, X2 and X4 are both CH, and Y2 is CR2, where R2 is F. In certain embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is Cl. In some embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is CN. In other embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is COOH. In some embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is COOR2', where R2' is H or C1-3 alkyl. In certain embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is CONH2. In some embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is CONHR2', where R2' is H or C1-3 alkyl. In other embodiments, X2 and X4 are both CH, and Y2 is CR2, where R2 is SO2NH2.
[00164] In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 is CH, X4 is N, and Y2 is N. In some embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is H. In some embodiments, X2 is CH, X4 is N, and Y2 is CR2 where R2 is methyl. In other embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is ethyl. In some embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is propyl. In certain embodiments, X2 is CH, X4 is N, and Y2 is CR2 where R2 is isopropyl. In some embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is tert-butyl. In other embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is cyclopropyl. In certain embodiments, X2 is CH, X4 is N, and Y2 is CR2 where R2 is cyclobutyl. In some embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is CF3. In other embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is OH. In some embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is OCH3. In some embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is ethoxy. In other embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is SH. In some embodiments, X2 is CH, X4 is N, where R2 is SCH3. In certain embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is SCH2CH3. In some embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is CH2OH. In certain embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is C(CH3)2OH. In some cases, X2 is CH, X4 is N, and Y2 is CR2, where R2 is F. In certain embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is Cl. In some embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is CN. In other embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is COOH. In some embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is COOR2', where R2' is H or C1-3 alkyl. In certain embodiments X2 is CH, X4 is N, and Y2 is CR2, where R2 is CONH2. In some embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is CONHR2', where R2' is H or C1-3 alkyl. In other embodiments, X2 is CH, X4 is N, and Y2 is CR2, where R2 is SO2NH2.
In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X2 is N, X4 is CH, and Y2 is N. In some embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is H. In some embodiments, X2 is N, X4 is CH, and Y2 is CR2 where R2 is methyl. In other embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is ethyl. In some embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is propyl. In certain embodiments, X2 is N, X4 is CH, and Y2 is CR2 where R2 is isopropyl. In some embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is tert-butyl. In other embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is cyclopropyl. In certain embodiments, X2 is N, X4 is CH, and Y2 is CR2 where R2 is cyclobutyl. In some embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is CF3. In other embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is OH. In some embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is OCH3. In some embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is ethoxy. In other embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is SH. In some embodiments, X2 is N, X4 is CH, where R2 is SCH3. In certain embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is SCH2CH3. In some embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is CH2OH. In certain embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is C(CH3)2OH. In some cases, X2 is N, X4 is CH, and Y2 is CR2, where R2 is F. In certain embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is Cl. In some embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is CN. In other embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is COOH. In some embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is COOR2', where R2' is H or C1-3 alkyl. In certain embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is CONH2. In some embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is CONHR2', where R2' is H or C1-3 alkyl. In other embodiments, X2 is N, X4 is CH, and Y2 is CR2, where R2 is SO2NH2.
[00166] In certain embodiments, provided herein is a compound of formula (I), wherein if X1 and X2 are both N, then X3 is not C-Cl.
In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X1 and X2 are both N, and X3 is N, CH, C-F, or C(C1-C4 alkyl). In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X1 is N, X2 is CH, and X3 is N, CH, C(halogen) or C(C1-C4 alkyl). In still additional or alternative embodiments, provided herein is a compound of formula (I), wherein X1 is CH, X2 is N, and X3 is N, CH, C(halogen) or C(C1-C4 alkyl). In certain embodiments, X1 and X2 are both CH, and X3 is N, CH, C(halogen) or C(C1-C4 alkyl).
[00168] In additional or alternative embodiments, provided herein is a compound of formula (I), wherein X1 and X2 are both N, and X3 is N. In some embodiments, X1 and X2 are both N, and X3 is CH. In some modes, X1 and X2 are both N, and X3 is C-F. In some modes, X1 and X2 are both N, and X3 is C-Br. In some modes, X1 and X2 are both N, and X3 is C-I. In other embodiments, X1 and X2 are both N, and X3 is C(C1-C4 alkyl). In still additional or alternative embodiments, X1 is CH or N, and X3 is N, CH, C(halogen) or C(C1-C4 alkyl). In still additional or alternative embodiments, provided herein is a compound of formula (I), wherein X 2 is CH or N, and X 3 is N, CH, C(halogen) or C(C 1 -C 4 alkyl).
[00169] In additional or alternative embodiments, X1 and X2 are both CH, and X3 is N. In some embodiments, X1 and X2 are both CH, and X3 is CH. In certain embodiments, X1 and X2 are both CH, and X3 is C(halogen). In certain embodiments, X1 and X2 are both CH, and X3 is C-F. In certain embodiments, X1 and X2 are both CH, and X3 is C-Cl. In certain embodiments, X1 and X2 are both CH, and X3 is C-Br. In certain embodiments, X1 and X2 are both CH, and X3 is C-I. In other embodiments, X1 and X2 are both CH, and X3 is C(C1-C4 alkyl).
[00170] In additional or alternative embodiments, X1 is CH, X2 is N, and X3 is N. In some embodiments, X1 is CH, X2 is N, and X3 is CH. In certain embodiments, X1 is CH, X2 is N, and X3 is C(halogen). In certain embodiments, X1 is CH, X2 is N, and X3 is C-F. In certain embodiments, X1 is CH, X2 is N, and X3 is C-Cl. In certain embodiments, X1 is CH, X2 is N, and X3 is C-Br. In certain embodiments, X1 is CH, X2 is N, and X3 is C-I. In other embodiments, X1 is CH, X2 is N, and X3 is C(C1-C4 alkyl).
In additional or alternative embodiments, X1 is N, X2 is CH, and X3 is N. In some embodiments, X1 is N, X2 is CH, and X3 is CH. In certain embodiments, X1 is N, X2 is CH, and X3 is C(halogen). In certain embodiments, X1 is N, X2 is CH, and X3 is C-F. In certain embodiments, X1 is N, X2 is CH, and X3 is C-Cl. In certain embodiments, X1 is N, X2 is CH, and X3 is C-Br. In certain embodiments, X1 is N, X2 is CH, and X3 is C-I. In other embodiments, X1 is N, X2 is CH, and X3 is C(C1-C4 alkyl).
[00172] In additional or alternative embodiments, X1 is N and X3 is N. In some embodiments, X1 is N and X3 is CH. In certain embodiments, X1 is N and X3 is C(halogen). In certain embodiments, X1 is N and X3 is C-F. In certain embodiments, X1 is N and X3 is C-Cl. In certain embodiments, X1 is N and X3 is C-Br. In certain embodiments, X1 is N and X3 is C-I. In other embodiments, X1 is N and X3 is C(C1-C4 alkyl).
[00173] In additional or alternative embodiments, X1 is CH and X3 is N. In some embodiments, X1 is CH and X3 is CH. In certain embodiments, X1 is CH and X3 is C(halogen). In certain embodiments, X1 is CH and X3 is C-F. In certain embodiments, X1 is CH and X3 is C-Cl. In certain embodiments, X1 is CH and X3 is C-Br. In certain embodiments, X1 is CH and X3 is C-I. In other embodiments, X1 is CH and X3 is C(C1-C4 alkyl).
[00174] In additional or alternative embodiments, X1 is C(halogen) and X3 is N. In some embodiments, X1 is C(halogen) and X3 is CH. In certain embodiments, X1 is C(halogen) and X3 is C(halogen). In certain embodiments, X1 is C(halogen) and X3 is C-F. In certain embodiments, X1 is C(halogen) and X3 is C-Cl. In certain embodiments, X1 is C(halogen) and X3 is C-Br. In certain embodiments, X1 is C(halogen) and X3 is C-I. In other embodiments, X1 is C(halogen) and X3 is C(C1-C4 alkyl).
In additional or alternative embodiments, X1 is C(C1-C4 alkyl) and X3 is N. In some embodiments, X1 is C(C1-C4 alkyl) and X3 is CH. In certain embodiments, X1 is C(C1-C4 alkyl) and X3 is C(halogen). In certain embodiments, X1 is C(C1-C4 alkyl) and X3 is C-F. In certain embodiments, X1 is C(C1-C4 alkyl) and X3 is C-Cl. In certain embodiments, X1 is C(C1-C4 alkyl) and X3 is C-Br. In certain embodiments, X1 is C(C1-C4 alkyl) and X3 is C-I. In other embodiments, X1 is C(C1-C4 alkyl) and X3 is C(C1-C4 alkyl).
[00176] In additional or alternative embodiments, X2 is CH and X3 is N. In some embodiments, X2 is CH and X3 is CH. In certain embodiments, X2 is CH and X3 is C(halogen). In certain embodiments, X2 is CH and X3 is C-F. In certain embodiments, X2 is CH and X3 is C-Cl. In certain embodiments, X2 is CH and X3 is C-Br. In certain embodiments, X2 is CH and X3 is C-I. In other embodiments, X2 is CH and X3 is C(C1-C4 alkyl).
[00177] In additional or alternative embodiments, X2 is N and X3 is N. In some embodiments, X2 is N and X3 is CH. In certain embodiments, X2 is N and X3 is C(halogen). In certain embodiments, X2 is N and X3 is C-F. In certain embodiments, X2 is N and X3 is C-Cl. In certain embodiments, X2 is N and X3 is C-Br. In certain embodiments, X2 is N and X3 is C-I. In other embodiments, X2 is N and X3 is C(C1-C4 alkyl).
In certain embodiments, the compound of formula (I) is not 1-(3-(4-cyanophenyl)pyridin-4-ylthio)cyclopropanecarboxylic acid.
[00179] Another embodiment provides a compound of formula (I), wherein one of X1, X2, X3 or X4 is N.
[00180] Another embodiment provides a compound of formula (I) that has the structure of formula (IA), (IB), (IC) or (ID):

[00181] Another embodiment provides a compound of formula (I) wherein two of X1, X2, X3 or X4 are N.
[00182] Another embodiment provides a compound of formula (I) having the structure of formula (IE), (IF) or (IG):

[00183] Another embodiment provides a compound of formula (I) having the structure of formula (IH), (II) or (IJ):

[00184] Another embodiment provides a compound of formula (I) wherein R3 is H, CH3, OCH3, CF3, F or Cl; and R4 is H, CH3, OCH3, CF3, F or Cl.
[00185] Another embodiment provides a compound of formula (I) wherein R3 and R4 are both H.
[00186] Another embodiment provides a compound of formula (I) wherein R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5- or 6-membered ring, optionally containing one or two heteroatoms selected from O , N and S, wherein said 5- or 6-membered ring may be a saturated ring, an unsaturated ring or an aromatic ring.
[00187] Another embodiment provides a compound of formula (I) wherein R3 and R4, together with the carbon atoms to which they are attached, form an optionally substituted 6-membered aromatic ring.
[00188] Another embodiment provides a compound of formula (I) having the structure of formula (IK):

[00189] wherein n is 1, 2, 3 or 4; and
[00190] each R5 is independently selected from H, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, CF3, OH, OCH3, ethoxy, SH, SCH3, SCH2CH3, CH2OH, C(CH3)2OH, Cl , F, CN, COOH, COOR5', CONH2, CONHR5' or SO2NH2; where R5' is H or C1-3 alkyl.
[00191] Another embodiment provides a compound of formula (I) wherein Ra is H or CH3; and Rb is H or CH3.
[00192] Another embodiment provides a compound of formula (I) wherein Ra and Rb are both CH3.
[00193] Another embodiment provides a compound of formula (I) that has the structure of formula (IL):

[00194] Another embodiment provides a compound of formula (I-L) wherein X1 is CH; X2 is N; X3 is CH; and X4 is CH.
[00195] Another embodiment provides a compound of formula (I-L) wherein Y1 is CR1; and Y2 is CR2.
[00196] Another modality provides a compound of formula (IL) selected from:



[00197] Another embodiment provides a compound of formula (I) that has the structure of formula (IM):

[00198] Another embodiment provides a compound of formula (I-M) wherein R1, R3 and R4 are all H.
[00199] Another embodiment provides a compound of formula (I) wherein Ra and Rb, together with the carbon atom to which they are attached, form a 3-, 4-, 5- or 6-membered ring, optionally containing one or two selected heteroatoms of O, N and S.
[00200] Another embodiment provides a compound of formula (I) wherein Ra and Rb, together with the carbon atom to which they are attached, form a 3-, 4-, 5- or 6-membered ring.
[00201] Another embodiment provides a compound of formula (I) wherein Ra and Rb, together with the carbon atom to which they are attached, form a 3-membered ring.
[00202] Another embodiment provides a compound of formula (I) wherein M is H.
[00203] Another embodiment provides a compound of formula (I) wherein M is C1-C3 alkyl.
[00204] Another embodiment provides a compound of formula (I) wherein M is a pharmaceutically acceptable cation.
[00205] Another embodiment provides a compound of formula (I) wherein the pharmaceutically acceptable cation is Na+, Li+, K+, Ca2+, Mg2+, NH4+, tetramethylammonium, tetraethylammonium, methylamino, dimethylamino, trimethylamino or triethylamino. SYNTHETIC PROCEDURES
[00206] In another aspect, methods for synthesizing the compounds described herein are provided. In some embodiments, the compounds described herein can be prepared by the methods described below. The procedures and examples below are intended to illustrate those methods. Neither the procedures nor the examples are to be considered as limiting the invention in any way. In some embodiments, the compounds described herein are synthesized by any suitable method.
In some embodiments, the starting materials used for the synthesis of compounds as described herein are obtained from commercial sources, e.g., Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St. Louis, Mo. .). In some embodiments, the starting materials used for the synthesis of compounds as described herein are synthesized using techniques and materials described, for example, in March, "ADVANCED ORGANIC CHEMISTRY" 4th Edition, (Wiley 1992); Carey and Sundberg, “ADVANCED ORGANIC CHEMISTRY” 4th Edition, Vols. A and B (Plenum 2000, 2001) and Green and Wuts, "PROTECTIVE GROUPS IN ORGANIC SYNTHESIS", 3rd Edition, (Wiley 1999) (all incorporated by reference to this disclosure). In some embodiments, the following synthetic methods are used. FORMATION OF COVALENT LINKS BY REACTION OF AN ELECTROPHIL WITH A NUCLEOPHILE
[00208] The compounds described herein can be modified using various electrophiles or nucleophiles to form new functional groups or substituents. The table below entitled “Examples of Covalent Bonds and Their Precursors” lists selected examples of covalent bonds and precursor functional groups that generate and can be used as a guide for various combinations of electrophiles and nucleophiles thereof. Precursor functional groups are shown as electrophilic groups and nucleophilic groups. EXAMPLES OF COVALENT LINKS AND THEIR PRECURSORS

USE OF PROTECTION GROUPS
[00209] In some modalities of the reactions described herein, it is necessary to protect reactive functional groups, for example, hydroxy, amino, imino, thio or carboxy groups, when these are desired in the final product, to avoid their unwanted participation in the reactions. Protecting groups are used to block some or all of the reactive moieties and prevent these groups from participating in chemical reactions until the protective group is removed. It is preferred that each protection group be removable by a different means. Protecting groups that are cleaved under totally disparate reaction conditions fulfill the differential removal requirement. Protecting groups can be removed by acid, base and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid-labile and, in some embodiments, are used to protect reactive carboxy and hydroxy moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base-labile. In some embodiments, reactive carboxylic acid and hydroxy moieties are blocked with base-labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid-labile groups such as, for example, t-butyl carbamate , or with carbamates that are stable in both acid and base, but hydrolytically removable.
[00210] In some embodiments, reactive carboxylic acid and hydroxy moieties are also blocked with hydrolytically removable protecting groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base-labile groups such as , for example, Fmoc. In some embodiments, reactive carboxylic acid moieties are protected by conversion to single ester compounds, as exemplified herein, or are blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups are blocked with fluoride-labile silyl carbamates.
Allyl blocking groups are useful in the presence of acidic and basic protecting groups, as the former are stable and can subsequently be removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a Pd-catalyzed reaction in the presence of acid-labile t-butyl carbamate or base-labile amine acetate protecting groups. In some embodiments, the compounds disclosed herein, or intermediate forms thereof, are attached to a resin. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
[00212] In some modes, protection or blocking groups are selected from:

[00213] Other protective groups, in addition to a detailed description of techniques applicable to the creation of protective groups and their removal, are described in Greene and Wuts, "Protective Groups in Organic Synthesis", 3rd Edition, John Wiley & Sons, Nova York, NY, 1999, and Kocienski, "Protective Groups", Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference in connection with this disclosure. PREPARATION OF FORMULA I COMPOUNDS
Described herein are processes for preparing compounds of formula I. In some embodiments, the synthesis of compounds of the invention is carried out following the procedures described below. Generally, the thioacetic acid side chain is attached via nucleophilic substitution reactions and the biaryl bond is constructed by Pd(0)-mediated coupling of a boronic acid to an aryl bromide. The resulting biaryl compound can be processed to the desired formula (I) compounds by standard techniques. Schemes IAa to Scheme IHa illustrate some of the synthetic approaches contemplated, but are not considered to limit the scope of synthetic methods useful for preparing compounds of formula I.

[00215] Similar techniques can be employed for the synthesis of the pyridine derivatives shown below.


ADDITIONAL COMPOUND FORMS OF THE COMPOUNDS DISCLOSED HERE ISONERS
[00216] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E) and zusammen (Z) isomers, as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or the S configuration. The compounds described herein include all diastereomeric, enantiomeric and epimeric forms, in addition to the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination or interconversion, are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred (eg, crystalline diastereomeric salts). In some embodiments, diastereomers have distinct physical properties (eg melting points, boiling points, solubilities, reactivity, etc.) and are separated to benefit from these differences. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation/resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization. MARKED COMPOUNDS
[00217] In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, compounds disclosed herein include isotopically-labeled compounds that are identical to those recited herein, except that one or more atoms are replaced by an atom that has an atomic mass or mass number different from the mass. atomic or mass number normally found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chloride, eg 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P , 35S, 18F and 36Cl, respectively. The compounds described herein, and metabolites, pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds, for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavy isotopes, eg, deuterium, i.e. 2H, yields certain therapeutic advantages that result from greater metabolic stability, eg, increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically labeled compounds, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof are prepared by any suitable method.
[00218] In some embodiments, the compounds described herein are labeled by other means, including, without limitation, the use of chromophores or fluorescent moieties, bioluminescent labels or chemiluminescent labels. PHARMACEUTICALLY ACCEPTABLE SALTS
[00219] In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
[00220] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, such salts are prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt so formed.
[00221] Examples of pharmaceutically acceptable salts include those salts prepared by reacting the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycolate, hemisulphate, heptanoate, hexanoate, hexine-1,6-dioate, hydroxybenzoate, Y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methoxy methanesulfonate, methane methylbenzoate, monohydrogen phosphate, 1-naphthalene sulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, palmoate, pecti nate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, tosylate, undeconate and xylene sulfonate.
[00222] Furthermore, the compounds described herein may be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, without limitation, inorganic acids such as, for example, hydrochloric acid , hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as, for example, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, acid tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid , 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glycoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid) , 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, for example, oxalic acid, although not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
[00223] In some embodiments, those compounds described herein that comprise a free acid group react with a suitable base, for example, the hydroxide, carbonate, bicarbonate, sulfate, salts of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable primary, secondary or tertiary organic amine. Representative alkaline or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts, and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(1-4C alkyl)4, and the like.
[00224] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil soluble or dispersible products are obtained by this quaternization. The compounds described herein can be prepared as pharmaceutically acceptable salts formed when an acidic proton present in the parent compound is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or coordinates with an organic base. Base addition salts can also be prepared by reacting the free acid form of the compounds described herein with a pharmaceutically acceptable inorganic or organic base, including, without limitation, organic bases such as, for example, ethanolamine, diethanolamine, triethanolamine, tromethamine, N- methylglucamine, and the like, and inorganic bases such as, for example, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Furthermore, the salt forms of the disclosed compounds can be prepared using salts of the starting materials or intermediates. solvates
[00225] In some embodiments, the compounds described herein exist as solvates. The invention provides methods of treating disease by administering these solvates. The invention further provides methods of treating disease by administering these solvates as pharmaceutical compositions.
[00226] Solvates contain stoichiometric or non-stoichiometric amounts of a solvent and, in some embodiments, are formed during the crystallization process with pharmaceutically acceptable solvents such as, for example, water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents which include, without limitation, dioxane, tetrahydrofuran or methanol. Furthermore, the compounds provided herein can exist in unsolvated forms as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein. POLYMORPHS
[00227] In some embodiments, the compounds described herein exist as polymorphs. The invention provides methods of treating disease by administering these polymorphs. The invention further provides methods of treating disease by administering these polymorphs as pharmaceutical compositions.
[00228] Thus, the compounds described herein include all their crystalline forms, known as polymorphs. Polymorphs include the different crystal compaction arrangements of the same composition of elements in a compound. In certain cases, polymorphs have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. In certain cases, various factors such as, for example, the recrystallization solvent, the rate of crystallization and the storage temperature, cause a single crystal form to dominate. PRO-DRUGS
[00229] In some embodiments, the compounds described herein exist in prodrug form. The invention provides methods of treating disease by administering such prodrugs. The invention further provides methods of treating disease by administering these prodrugs as pharmaceutical compositions.
[00230] Prodrugs are generally precursor drugs that, after administration to an individual and subsequent absorption, are converted into an active, or more active, species through some process, for example, conversion through a metabolic pathway. Some prodrugs have a chemical group present in the prodrug that makes it less active and/or imparts solubility or some other property to the drug. After the chemical group has been cleaved and/or modified from the prodrug, the active drug is generated. Prodrugs are often helpful as, in some situations, they are easier to administer than the parent drug. They are, for example, bioavailable by oral administration, whereas the relative is not. In certain cases, the prodrug also has increased solubility in pharmaceutical compositions relative to the parent drug. An example, without limitation, of a prodrug would be a compound as described herein that is administered as an ester (the "prodrug") to facilitate transfer across a cell membrane where water solubility is detrimental to mobility, but which then it is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial. A further example of a prodrug might be a short peptide (polyamino acid) linked to an acid group where the peptide is metabolized to reveal the active moiety (see, for example, Bundgaard, “Design and Application of Prodrugs” in “A Textbook of Drug Design and Development”, Krosgaard-Larsen and Bundgaard, Ed., 1991, Chapter 5, 113-191, which is incorporated herein by reference).
[00231] In some embodiments, prodrugs are designed as reversible drug derivatives, for use as modifiers to increase drug transport to tissues at specific sites. The design of prodrugs to date has been to increase the effective water solubility of the therapeutic compound to target regions where water is the main solvent.
Additionally, prodrug derivatives of compounds described herein can be prepared by methods described herein or otherwise known in the art (for more details, see Saulnier et al., "Bioorganic and Medicinal Chemistry Letters", 1994, 4, 1985). By way of example only, suitable prodrugs may be prepared by reacting an underivatized compound with a suitable carbamylating agent, for example, without limitation, 1,1-acyloxyalkylcarbanohydrochloride, para-nitrophenyl carbonate, or the like. Prodrug forms of the compounds described herein, wherein the prodrug is metabolized in vivo to produce a derivative as shown herein, are included within the scope of the claims. In fact, some of the compounds described herein are prodrugs for another derivative or active compound.
In some embodiments, prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (for example, two, three, or four) amino acid residues, is covalently linked via an amide bond. or ester to a free amino, hydroxy or carboxylic acid group of compounds of the present invention. Amino acid residues include, without limitation, the 20 naturally occurring amino acids, and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosin, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. In other embodiments, prodrugs include compounds in which a nucleic acid residue, or an oligonucleotide of two or more (for example, two, three or four) nucleic acid residues, is covalently linked to a compound of the present invention.
Pharmaceutically acceptable prodrugs of the compounds described herein also include, without limitation, esters, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary tertiary amine derivatives, N-Mannich bases, N-acyl bases, Schiff, amino acid conjugates, phosphate esters, metal salts and sulfonate esters. Compounds that have free amino, amide, hydroxy or carboxylic groups can be converted to prodrugs. For example, free carboxyl groups can be derivatized as amides or alkyl esters. In certain cases, all such prodrug moieties incorporate groups that include, without limitation, ether, amine and carboxylic acid functionalities.
[00235] Hydroxy prodrugs include esters, for example, without limitation, acyloxyalkyl (eg acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sulfonate esters, sulfate esters and disulfide-containing esters; ethers, amides, carbamates, hemisuccinates, dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as highlighted in Advanced Drug Delivery Reviews 1996, 19, 115.
[00236] Amine-derived prodrugs include, without limitation, the following groups and combinations of groups:

[00237] in addition to sulfonamides and phosphonamides.
[00238] In certain cases, sites on any portions of the aromatic ring are susceptible to various metabolic reactions and therefore the incorporation of appropriate substituents into the aromatic ring structures can reduce, minimize or eliminate this metabolic pathway. PHARMACEUTICAL COMPOSITIONS
[00239] Pharmaceutical compositions are described herein. In some embodiments, pharmaceutical compositions comprise an effective amount of a compound of formula I, or a metabolite, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. In some embodiments, pharmaceutical compositions comprise an effective amount of a compound of formula I, or a metabolite, pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions are for treating disorders. In some embodiments, the pharmaceutical compositions are for treating disorders in a mammal. In some embodiments, the pharmaceutical compositions are for treating disorders in a human. ADMINISTRATION MODES
In some embodiments, the compounds and compositions described herein are administered alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be carried out by any method that allows the release of the compounds to the site of action. These methods include, without limitation, delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema), parenteral routes (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary , intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), by inhalation, transdermal, transmucosal, sublingual, buccal and topical administration (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal), although the most suitable route may depend, for example, on the condition and disorder of the recipient. As an example only, the compounds described herein may be administered locally to the area in need of treatment, for example, by local infusion during surgery, topical application such as, for example, creams or ointments, injection, catheter, or implant, said implant made , for example, of a porous, non-porous or gelatinous material, including membranes, for example, silastic membranes, or fibers. Administration can also be by direct injection into the site of a diseased tissue or organ.
[00241] In some embodiments, formulations suitable for oral administration are presented as separate units such as, for example, capsules, seals or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a cake, electuary or paste.
[00242] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, in addition to soft, sealed capsules made of gelatin and a plasticizer, for example, glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as, for example, a powder or granules, optionally mixed with binders, inert diluents or lubricating, surface-active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, tablets are coated or cut and are formulated to provide slow or controlled release of the active ingredient contained therein. All formulations for oral administration must be in dosages suitable for such administration. Push-fit capsules can contain the active ingredients mixed with fillers such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, for example fatty oils, liquid paraffin or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For that purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to tablets or tablet coatings for identification or to characterize different combinations of active compound doses.
[00243] In some embodiments, pharmaceutical preparations are formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations can be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in powder form or in a freeze-dried (lyophilized) condition that only requires the addition of sterile liquid vehicle, per example, sterile saline or pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
[00244] Formulations for parenteral administration include sterile aqueous and non-aqueous (oily) solutions for injection of the active compounds which may contain antioxidants, buffers, bacteriostatics and solutes which may make the formulation isotonic with the blood of the desired recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides, or liposomes. Aqueous suspensions for injection may contain substances which increase the viscosity of the suspension, for example sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
[00245] Pharmaceutical preparations can also be formulated as a depot preparation. These long-acting formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
For buccal or sublingual administration, the compositions may take the form of conventionally formulated tablets, lozenges, lozenges, or gels. These compositions may comprise the active ingredient in a flavored base such as sucrose and acacia or tragacanth.
Pharmaceutical preparations may also be formulated in rectal compositions such as, for example, suppositories or retention enemas, for example, containing conventional suppository bases such as, for example, cocoa butter, polyethylene glycol or other glycerides.
[00248] Pharmaceutical preparations can be administered topically, that is, by non-systemic administration. This includes applying a compound of the present invention externally to the epidermis or oral cavity and instilling such a compound into the ear, eye and nose such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
[00249] Pharmaceutical preparations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as, for example, gels, ointments, lotions, creams, ointments or pastes, and drops suitable for administration to the eyes, ears or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for example from 1% to 2% by weight of the formulation. It may, however, comprise up to 10% w/w, but will preferably comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the formulation.
Pharmaceutical preparations for administration by inhalation are conveniently delivered by an insufflator, pressurized nebulizer packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as, for example, lactose or starch. The powder composition may be presented in unit dosage form, in, for example, capsules, cartridges, gelatin or blister packs of which the powder may be administered with the aid of an inhaler or insufflator.
[00251] It should be understood that, in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art, in view of the type of formulation in question, for example those suitable for oral administration may include agents flavorings. FORMULATIONS
[00252] The compounds or compositions described herein can be released into a vesicle, for example, a liposome. The compounds and pharmaceutical compositions described herein can be released into a controlled release system, or a controlled release system can be placed close to the therapeutic target. In one modality, a bomb can be used.
[00253] The pharmaceutical compositions described herein may also contain the active ingredient in a form suitable for oral use, for example, as tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are optionally prepared in accordance with a known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant preparations and palatable. Tablets contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such excipients can be, for example, inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binding agents, for example starch, gelatin, polyvinylpyrrolidone or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. Tablets can be uncoated or coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thus provide a sustained action over a longer period. For example, a water-soluble taste-masking material such as, for example, hydroxypropylmethyl cellulose or hydroxypropyl cellulose, or a time delay material such as, for example, ethyl cellulose, or cellulose acetate butyrate, may be employed, as appropriate. Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient it is mixed with a water-soluble carrier such as polyethylene glycol or an oily medium, for example peanut oil, liquid paraffin or olive oil.
[00254] Aqueous suspensions contain the active material mixed with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with aliphatic chain alcohols long, for example, heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from acids hexitol fatty acids and anhydrides, for example polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, for example, sucrose, saccharin or aspartame .
[00255] Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. Pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients, and the like. Thus, for oral administration, tablets containing various excipients, for example citric acid, can be used together with various disintegrants such as starch, alginic acid and certain complex silicates, and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type can also be employed in soft and hard filled gelatin capsules. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound contained may be combined with various sweetening or flavoring agents, coloring or coloring materials and, if desired, emulsifying agents or suspending agents, together with diluents such as, for example, water, ethanol, propylene glycol, glycerin, or combinations thereof.
[00256] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as, for example, liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those mentioned above, and flavoring agents can be added to provide a palatable oral preparation. Such compositions can be preserved by the addition of an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.
[00257] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, eg sweetening, flavoring and coloring agents, may also be present. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.
[00258] Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be naturally occurring phosphatides, for example soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide , for example, polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
[00259] Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. These formulations may also contain a demulcent, a preservative, flavoring and coloring agents, and antioxidants.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may also be a sterile injectable oil-in-water microemulsion, in which the active ingredient is dissolved in the oil phase. For example, the active ingredient can first be dissolved in a mixture of soy oil and lecithin. The oily solution is then introduced into a mixture of water and glycerol and processed to form a microemulsion. Injectable solutions or microemulsions can be introduced into an individual's bloodstream by injection into a local bolus. Alternatively, it may be advantageous to administer the solution or microemulsion so as to maintain a constant circulating concentration of the present compound. In order to maintain this concentration constant, an intravenous continuous release device may be used. An example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension for intramuscular and subcutaneous administration. Such a suspension may be formulated in accordance with established technique using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butane diol. Furthermore, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any fixed oil mixture can be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
[00261] Pharmaceutical compositions can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, blends of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters.
[00262] For topical use, creams, ointments, jellies, solutions or suspensions etc., containing a compound or composition of the invention, may be used. As used herein, topical application can include mouthwashes and gargles.
[00263] Pharmaceutical compositions can be administered in intranasal form through topical use of suitable intranasal delivery vehicles and devices, or through transdermal routes, using transdermal skin patches. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof ("active ingredient") with the carrier that constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately associating the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation. DOSAGE FORMS
[00265] The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream, or for rectal administration as a suppository. The pharmaceutical composition can be in unit dosage forms suitable for the single administration of precise dosages. The pharmaceutical composition may include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. Furthermore, it can include other medicinal or pharmaceutical agents, vehicles, adjuvants etc.
Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous solutions of propylene glycol or dextrose. These dosage forms can be suitably buffered if desired. DOSES
[00267] The amount of pharmaceutical composition administered will depend primarily on the mammal being treated. In cases where the pharmaceutical compositions are administered to a human subject, the daily dosage will normally be determined by the attending physician with the dosage generally varying according to age, sex, diet, weight, general health and response. the individual, the severity of the individual's symptoms, the precise indication or condition being treated, the severity of the indication or condition being treated, the time of administration, the route of administration, the disposition of the composition, the excretion rate, combination of drugs, and at the discretion of the attending physician. Furthermore, the route of administration may vary depending on the condition and its severity. Preferably, the pharmaceutical composition is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active component, for example, an amount effective to achieve the desired purpose. Determining the proper dosage for a particular situation is within the skill of the art. Generally, treatment starts with lower dosages that are less than the optimal dose of the compound. Thereafter, the dosage is increased in small amounts until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions throughout the day, if desired. The amount and frequency of administration of the compounds described herein and, if applicable, of other therapeutic agents and/or therapies, will be regulated in accordance with the judgment of the attending physician, considering factors such as those described above. Thus, the amount of pharmaceutical composition to be administered can vary widely. Administration can be in an amount of between about 0.001 mg/kg of body weight to about 100 mg/kg of body weight per day (given in a single dose or divided doses), more preferably, at least about 0 .1 mg/kg of body weight per day. A particular therapeutic dosage can include, for example, from about 0.01 mg to about 7,000 mg of compound, and preferably includes, for example, from about 0.05 mg to about 2,500 mg. The amount of active compound in a unit dose of the preparation may be varied or adjusted from about 0.1 mg to 1000 mg, preferably from about 1 mg to 300 mg, more preferably 10 mg to 200 mg, in accordance with particular application. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases even larger doses may be employed without causing any harmful side effects, for example by dividing these larger doses into several doses small for daytime administration. The amount administered will vary depending on the particular IC50 value of the compound used. In combined applications where the compound is not the only therapy, it may be possible to administer smaller amounts of the compound and still have the therapeutic or prophylactic effect. COMBINED THERAPIES
The compounds described herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof can be administered as the sole therapy. The compounds described herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof may also be administered in combination with other therapy or therapies.
[00269] For example, the therapeutic efficacy of one of the compounds described herein can be increased by administering an adjuvant (that is, by itself the adjuvant may have only minimal therapeutic benefit, but in combination with another therapeutic agent the overall therapeutic benefit for the individual is increased). Or, just as an example, the benefit exhibited by an individual may be enhanced by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. By way of example only, in a treatment for gout which involves the administration of one of the compounds described herein, increased therapeutic benefit may result by providing the individual with another therapeutic agent for gout as well. Or, just as an example, if one of the side effects experienced by an individual upon receiving one of the compounds described herein is nausea, then it may be appropriate to administer an anti-nausea agent in combination with the compound. Or, the therapy or additional therapies may include, without limitation, physical therapy, psychotherapy, radiation therapy, applying compresses to a diseased area, rest, altered diet, and the like. Regardless of the disease, disorder, or condition being treated, the overall benefit exhibited by the individual may be additive to the two therapies or therapeutic agents, or the individual may exhibit a synergistic benefit.
[00270] In cases where the compounds described herein are administered in combination with other therapeutic agents, the compounds described herein need not be administered in the same pharmaceutical composition as the other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the compounds/compositions can be administered orally to generate and maintain good blood levels of these, while the other therapeutic agent can be administered intravenously. Thus, the compounds described herein can be administered concomitantly (e.g., simultaneously, basically simultaneously, or within the same treatment protocol), sequentially, or dosed separately from the other therapeutic agents. Initial administration can be done in accordance with established protocols known in the art, and then, based on observed effects, dosage, modes of administration and times of administration can be modified by those skilled in the art.
The particular choice of compound and other therapeutic agent will depend on the diagnosis of the attending physicians and their assessment of the individual's condition and the appropriate treatment protocol. In some embodiments, the additional agent is a URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor, a purine nucleoside phosphorylase (PNP) inhibitor, a uric acid transporter inhibitor , a glucose transporter inhibitor (GLUT), a GLUT-9 inhibitor, an inhibitor of the solute transporter family 2 (facilitated glucose transporter), member 9 (SLC2A9), an inhibitor of the organic anion transporter (OAT) , an OAT-4 inhibitor, or combinations thereof. In certain cases, URAT 1 is an ion exchanger that mediates the transport of urate. In certain cases, URAT I mediates urate transport in the proximal tubule. In certain cases, URAT I exchanges urate in a proximal tubule for lactate and nicotinate. In certain cases, xanthine oxidase oxidizes hypoxanthine to xanthine as well as uric acid. In certain cases, xanthine dehydrogenase catalyzes the conversion of xanthine, NAD+ and H2O to urate, NADH and H+. In some embodiments, the additional agent is allopurinol, febuxostat (2-(3-cyano-4-isobutoxyphenyl)-4-methyl-1,3-thiazol-5-carboxylic acid), FYX-051 (4-(5-pyridine) -4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile), probenecid, sulfinpyrazone, benzobromarone, acetaminophen, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone (ACTH) , colchicine, a glucocorticoid, an androgen, a cox-2 inhibitor, a PPAR agonist, naproxen, sevelamer, sibutramine, troglitazone, proglitazone, other uric acid reducing agent, losartan, fibric acid, benziodarone, salicylate, amlodipine, vitamin C, or combinations thereof.
ILLNESSES
Described herein are methods of treating a disease in an individual suffering from said disease comprising administering to said individual an effective amount of a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
Also described herein are methods of preventing or delaying the onset of a disease in an individual at risk for the development of said disease comprising administering to said individual an amount effective to prevent or delay the onset of said disease, from a composition comprising a compound disclosed herein or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.
Further described herein are methods for the prophylaxis or treatment of any disease or disorder in which aberrant uric acid levels play a role, including, without limitation: hyperuricemia, gout, gouty arthritis, inflammatory arthritis, kidney disease, nephrolithiasis (calculations kidney), joint inflammation, urate crystal deposition in joints, urolithiasis (stone formation in the urinary tract), urate crystal deposition in the renal parenchyma, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, gout crisis, gout tophacea, renal failure, or combinations thereof, in a human or other mammal. The methods disclosed herein extend to these cases and to the use of the compounds for the manufacture of a medicament for the treatment of these diseases or disorders. In addition, the methods disclosed herein extend to administering to a human an effective amount of a compound disclosed herein for treating any such disease or disorder.
Subjects who can be treated with the compounds described herein, or with a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative of said compounds, in accordance with the methods of this invention, include, for example, subjects who have been diagnosed as having gout, gouty arthritis, inflammatory arthritis, kidney disease, nephrolithiasis (kidney stones), joint inflammation, urate crystal deposition in joints, urolithiasis (stone formation in the urinary tract), deposition of urate crystals in the parenchyma kidney, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, gout crisis, tophaceous gout, kidney failure, or combinations of these
In some embodiments, a subject having an aberrant uric acid level is administered an amount of at least one compound disclosed herein sufficient to modulate the aberrant uric acid level (e.g., to a medically acceptable level). In some embodiments, an individual treated with the compounds disclosed herein exhibits aberrant uric acid levels where blood uric acid levels exceed a medically acceptable range (i.e., hyperuricemia). In some embodiments, an individual treated with the compounds disclosed herein exhibits aberrant uric acid levels where blood uric acid levels exceed 360 µmol/l (6 mg/dl) for a female or 400 µmol/l (6 .8 mg/dl) for a male person. In some embodiments, an individual treated with the compounds disclosed herein exhibits aberrant uric acid levels where uric acid levels in the urine exceed a medically acceptable range (ie, hyperuricosuria). In some embodiments, an individual treated with the compounds disclosed herein exhibits aberrant uric acid levels where uric acid levels in the urine exceed 800 mg/day (in a male) and exceed 750 mg/day (in a male subject). women).
[00277] In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) suffers from a cardiovascular disorder. In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) suffers from an aneurysm; angina; atherosclerosis; a stroke; cerebrovascular disease; Congestive heart failure; coronary artery disease; and/or a myocardial infarction. In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) exhibits (a) C-reactive protein (CRP) levels above about 3.0 mg/L; (b) homocysteine levels above about 15.9 mmol/l; (c) LDL levels above about 160 mg/dl; (d) HDL levels below about 40 mg/dl; and/or (e) serum creatinine levels above about 1.5 mg/dl.
[00278] In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) suffers from diabetes. In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) suffers from Type I diabetes. In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant levels of uric acid and (2) suffer from Type II diabetes. In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) suffers from a loss of islet of Langerhans beta cells in the pancreas. In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) suffers from insulin resistance and/or reduced insulin sensitivity. In some embodiments, a subject treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) exhibits (a) a fasting blood glucose level > 126 mg/dl; (b) a blood glucose level > 200 mg/dl two hours after a glucose tolerance test; and/or (c) symptoms of hyperglycemia and casual blood glucose levels > 200 mg/dl (11.1 mmol/l).
[00279] In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) suffers from metabolic syndrome. In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) suffers from (a) diabetes mellitus, impaired glucose tolerance, impaired fasting glucose and/or insulin resistance, ( b) at least two of (i) blood pressure: > 140/90 mmHg; (ii) dyslipidemia: triglycerides (TG): > 1.695 mmol/l and high-density lipoprotein cholesterol (HDL-C) < 0.9 mmol/l (men), < 1.0 mmol/l (women); (iii) central obesity: waist:hip ratio > 0.90 (men); > 0.85 (women) and/or body mass index > 30 kg/m2; and (iv) microalbuminuria: urinary albumin excretion ratio > 20 mg/min or albumin:creatinine ratio > 30 mg/g. In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) suffers from insulin resistance (ie, the top 25% of fasting insulin values among non-diabetic individuals) and (b) at least two of (i) central obesity: waist circumference > 94 cm (men), > 80 cm (women); (ii) dyslipidemia: TG > 2.0 mmol/l and/or HDL-C < 1.0 mmol/l or treated for dyslipidemia; (iii) hypertension: blood pressure > 140/90 mmHg or antihypertensive medication; and (iv) fasting glucose > 6.1 mmol/l. In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) exhibits at least three of (a) elevated waist circumference: Men > 1.016 meter (men) and >0.889 meter (women ); (b) elevated triglycerides: > 150 mg/dl; (c) reduced HDL: < 40 mg/dl (men) and < 50 mg/dl (women); (d) high blood pressure: > 130/85 mm Hg or use of medication for hypertension; and (e) elevated fasting glucose: > 100 mg/dl (5.6 mmol/l) or use of medication for hyperglycemia.
In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) suffers from kidney disease or kidney failure. In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) exhibits oliguria (decreased urine output). In some embodiments, an individual treated with the compounds disclosed herein (1) exhibits aberrant uric acid levels and (2) produces less than 400 ml per day of urine (adults), produces less than 0.5 ml/kg/h of urine (children) or produces less than 1 ml/kg/h of urine (infants). URIC ACID
[00281] In certain cases, purines (adenine, guanine), derived from food or tissue turnover (cellular nucleotides undergo continuous turnover), are catabolized in humans to their final oxidation product, uric acid. In certain cases, guanine is oxidized to xanthine, which in turn is further oxidized to uric acid by the action of xanthine oxidase; Adenosine is converted to inosine, which is further oxidized to hypoxanthine. In certain cases, xanthine oxidase oxidizes hypoxanthine to xanthine as well as uric acid. In certain cases, as part of the reverse process, the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) saves guanine and hypoxanthine.

[00282] In certain cases, the keto form of uric acid is in equilibrium with the enol form which loses a proton at physiological pH to form urate. In certain cases (eg under serum conditions (pH 7.40, 37°C)), about 98% of uric acid is ionized as the monosodium urate salt. In certain cases, urate is a strong reducing agent and a potent antioxidant. In humans, about half of plasma's antioxidant capacity comes from uric acid.

[00283] In certain cases, most uric acid dissolves in the blood and passes to the kidneys, where it is excreted by glomerular filtration and tubular secretion. In certain cases, a substantial fraction of uric acid is reabsorbed by the renal tubules. One of the peculiar characteristics of the uric acid transport system is that, although the net activity of tubular function is uric acid reabsorption, the molecule is both secreted and reabsorbed during its passage through the nephron. In certain cases, reabsorption dominates in the S1 and S3 segments of the proximal tubule and secretion dominates in the S2 segment. In certain cases, bidirectional transport results in drugs that inhibit uric acid transport, decreasing rather than increasing uric acid excretion, compromising its therapeutic utility. In certain cases, normal uric acid levels in human adults (5.1 +/- 0.93 mg/dl) are close to the solubility limits of urate (approximately 7 mg/dl at 37°C), which creates a delicate physiological balance of urate. In certain cases, the normal range of uric acid for women is approximately 1 mg/dl below the range for men. HYPERURICEMIA
[00284] In certain cases, hyperuricemia is characterized by higher-than-normal blood uric acid levels sustained over long periods of time. In certain cases, increased blood urate levels may be caused by increased uric acid production (approximately 10-20%) and/or reduced renal excretion (approximately 80-90%) of uric acid. In certain cases, causes of hyperuricemia may include: - Obesity/weight gain. - Excessive use of alcohol. - Dietary intake of excessive purine (foods such as seafood, fish roe, scallops, lentils, beans and red meat, particularly offal - brains, kidneys, tripe, liver). - Certain medications, including low-dose aspirin, diuretics, niacin, cyclosporine, pyrazinamide, ethambutol, some drugs for high blood pressure and some against cancer, immunosuppressive and cytotoxic agents. - Specific disease states, particularly those associated with a high cell turnover rate (eg, malignancy, leukemia, lymphoma or psoriasis), and also including high blood pressure, hemoglobin disorders, hemolytic anemia, sickle cell anemia, various nephropathies, disorders myeloproliferatives and lymphoproliferatives, hyperparathyroidism, kidney disease, conditions associated with insulin resistance and diabetes mellitus, and in transplant recipients and possibly heart disease. - Inherited enzymatic defects. - Abnormal renal function (eg, increased ATP turnover, reduced glomerular urate filtration). - Exposure to lead (saturnism or “saturnine drop”).
[00285] In certain cases, hyperuricemia may be asymptomatic, although it is associated with the following conditions: - Gout. - Gouty arthritis. - Uric acid stones in the urinary tract (urolithiasis). - Deposits of uric acid in soft tissue (tophus). - Uric acid deposits in the kidneys (uric acid nephropathy). - Impaired kidney function, possibly leading to chronic and acute kidney failure. PREVALENCE DROP
[00286] The incidence of gout has increased over the past two decades and, in the United States, affects up to 2.7% of the population aged 20 years and over, totaling more than 5.1 million American adults. Gout is more common in men than in women (3.8% or 3.4 million men vs. 1.6% or 1.7 million women), typically affecting men in their 40s and 50s (Although gout attacks can occur after puberty, which shows an increase in uric acid levels). An increase in the prevalence of gout from 2.9 to 5.2 per 1,000 was observed over the time period 1990 to 1999, with most of the increase occurring in patients over the age of 65. Gout attacks are more common in women after menopause. In certain cases, gout is one of the most common forms of arthritis, accounting for approximately 5% of all arthritis cases. In certain cases, renal failure and urolithiasis occur in 10-18% of individuals with gout and are common sources of disease morbidity and mortality. MAIN CAUSES
[00287] In most cases, gout is associated with hyperuricemia. In certain cases, individuals suffering from gout excrete approximately 40% less uric acid than individuals without gout at certain plasma urate concentrations. In certain cases, urate levels increase until the saturation point is reached. In certain cases, precipitation of urate crystals occurs when the saturation point is reached. In certain cases, these hardened crystallized deposits (tophus) form in the joints and on the skin, causing joint inflammation (arthritis). In certain cases, deposits are made in joint fluid (synovial fluid) and/or joint lining (synovial lining). Common areas for these deposits are the big toe, feet, ankles, and hands (less common areas include the ears and eyes). In certain cases, the skin around the affected joint becomes red and shiny, with the affected area being tender and painful to the touch. In certain cases, gout attacks increase in frequency. In certain cases, untreated acute gout attacks lead to permanent joint damage and physical disability. In certain cases, tissue urate deposition leads to: acute inflammatory arthritis, chronic arthritis, urate crystal deposition in the renal parenchyma and urolithiasis. In certain cases, the incidence of gouty arthritis increases 5-fold in individuals with serum urate levels of 7 to 8.9 mg/dl, and up to 50-fold in individuals with levels > 9 mg/dl (530 μmol/l). In certain cases, people with gout develop kidney failure and end-stage kidney disease (ie, “gouty nephropathy”). In certain cases, gouty nephropathy is characterized by chronic interstitial nephropathy, which is promoted by medullary deposition of monosodium urate.
[00288] In certain cases, gout includes painful attacks and acute monarticular inflammatory arthritis, urate crystal deposition in joints, urate crystal deposition in the renal parenchyma, urolithiasis (stone formation in the urinary tract) and nephrolithiasis (kidney stone formation ). In certain cases, secondary gout occurs in individuals with cancer, particularly leukemia, and in those with other blood disorders (eg, polycythemia, myeloid metaplasia, etc.). SYMPTOMS
[00289] In certain cases, gout attacks develop very quickly, often the first attack occurring at night. In certain cases, symptoms include sudden, severe joint pain and extreme tenderness in the joint area, joint swelling, and bright red or purple skin around the joint. In certain cases, attacks are infrequent, lasting 5-10 days, with no symptoms between episodes. In certain cases, attacks become more frequent and can last longer, especially if the disorder is not controlled. In certain cases, the episodes damage the affected joint(s), resulting in stiffness, swelling, limitation of movement and/or pain leading to persistent moderate. TREATMENT
[00290] In certain cases, gout is treated by reducing the production of uric acid. In certain cases, gout is treated by increasing the excretion of uric acid. In certain cases, gout is treated by URAT 1, xanthine oxidase, xanthine dehydrogenase, xanthine oxidoreductase, a purine nucleoside phosphorylase (PNP) inhibitor, a uric acid transporter (URAT) inhibitor, a glucose transporter inhibitor (GLUT), an inhibitor of GLUT-9, an inhibitor of the solute transporter family 2 (facilitated glucose transporter), member 9 (SLC2A9), an inhibitor of the organic anion transporter (OAT), an inhibitor of OAT-4 , or combinations thereof. In general, the goals of gout treatment are: i) to reduce pain, swelling, and duration of an acute attack, and ii) to prevent future attacks and joint damage. In certain cases gout attacks are successfully treated using a combination of treatments. In certain cases, gout is one of the most treatable forms of arthritis. i) Treatment of gout attack. In certain cases, the pain and swelling associated with an acute gout attack can be treated with medications such as acetaminophen, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), adrenocorticotropic hormone (ACTH), or colchicine. In some cases, proper medication controls gout within 12 to 24 hours, and treatment is stopped after a few days. In certain cases, the medication is used in conjunction with rest, increased fluid intake, cold compresses, elevation and/or protection of the affected area(s). In certain cases, the treatments mentioned above do not prevent recurrent attacks and do not affect the underlying disorders of abnormal uric acid metabolism. ii) Prevention of future attacks. In certain cases, lowering serum uric acid levels below the saturation level is the goal for preventing further gout attacks. In some cases, this is achieved by decreasing uric acid production (eg, allopurinol), or by increasing uric acid excretion with uricosuric agents (eg, probenecid, sulfinpyrazone, benzobromarone).
[00291] In certain cases, allopurinol inhibits uric acid formation, resulting in a reduction in both serum and urinary uric acid levels and becomes fully effective after 2 to 3 months.

[00292] In certain cases, allopurinol is a structural analogue of hypoxanthine, (differing only in the transposition of carbon and nitrogen atoms in positions 7 and 8), which inhibits the action of xanthine oxidase, the enzyme responsible for converting hypoxanthine into xanthine, and xanthine in uric acid. In certain cases, it is metabolized to the corresponding xanthine analogue, alloxanthine (oxypurinol), which is also a xanthine oxidase inhibitor. In certain cases, alloxanthine, although more potent in inhibiting xanthine oxidase, is less pharmaceutically acceptable due to its low oral bioavailability. In certain cases, fatal reactions due to hypersensitivity, bone marrow suppression, hepatitis and vasculitis have been reported with allopurinol. In certain cases, the incidence of side effects can total 20% of all individuals treated with the drug. Treatment for uric acid metabolism disorders has not evolved significantly in the two decades since the introduction of allopurinol.
[00293] In certain cases, uricosuric agents (eg, probenecid, sulfinpyrazone, and benzobromarone) increase uric acid excretion. In certain cases, probenecid causes an increase in the secretion of uric acid by the renal tubules and, when used chronically, mobilizes the body's urate stores. In certain cases, 25-50% of individuals treated with probenecid fail to achieve a reduction in serum uric acid levels < 6 mg/dl. In certain cases, insensitivity to probenecid results from intolerance to the drug, concomitant ingestion of salicylate, and renal impairment. In certain cases, a third of individuals develop intolerance to probenecid. In certain cases, administration of uricosuric agents also results in urinary calculi, gastrointestinal obstruction, jaundice, and anemia. PLUMBISM OR "DROP SATURNINE"
[00294] In certain cases, excessive lead exposure (lead poisoning or saturnism) results in “saturnine gout”, a lead-induced hyperuricemia due to lead's inhibition of tubular urate transport causing decreased renal excretion of uric acid. In certain cases, more than 50% of individuals with lead nephropathy suffer from gout. In certain cases, acute attacks of Saturnine gout occur in the knee more often than in the big toe. In certain cases, kidney disease is more frequent and more severe in saturnine gout than in primary gout. In certain cases, treatment consists of excluding the individual from further exposure to lead, the use of chelating agents to remove lead, and management of acute gouty arthritis and hyperuricemia. In certain cases, Saturnine gout is characterized by less frequent attacks than primary gout. In certain cases, lead-associated gout occurs in premenopausal women, an unusual occurrence in non-lead-associated gout. LESCH-NYHAN SYNDROME
[00295] In certain cases, Lesch-Nyhan syndrome (LNS or Nyhan syndrome) affects about 1 in 100,000 live births. In certain cases, LNS is caused by a genetic deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). In certain cases, LNS is an X-linked recessive disease. In certain cases, LNS is present at birth in boys. In certain cases, the disorder leads to severe gout, poor muscle control, and moderate mental retardation, which appears in the first year of life. In certain cases, the disorder also results in self-injurious behaviors (eg, biting the lips and fingers, banging the head) that begin in the second year of life. In certain cases, the disorder also results in gout-like swelling in the joints and severe kidney problems. In certain cases, the disorder leads to neurological symptoms that include facial grimacing, involuntary twists, and repetitive movements of the arms and legs similar to those seen in Huntington's disease. The prognosis for individuals with LNS is poor. In certain cases, the life expectancy of an individual not treated with LNS is less than about 5 years. In certain cases, the life expectancy of an individual treated with LNS is greater than about 40 years of age. HYPERURICEMIA AND OTHER DISEASES
In certain cases, hyperuricemia is found in individuals with cardiovascular disease (CVD) and/or kidney disease. In certain cases, hyperuricemia is found in individuals with pre-hypertension, hypertension, increased proximal sodium reabsorption, microalbuminuria, proteinuria, renal disease, obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, arterial disease peripheral, carotid and coronary artery, atherosclerosis, congestive heart failure, stroke, tumor lysis syndrome, endothelial dysfunction, oxidative stress, elevated renin levels, elevated endothelin levels and/or elevated C-reactive protein levels. In certain cases, hyperuricemia is found in individuals with obesity (eg, central obesity), high blood pressure, hyperlipidemia, and/or impaired fasting glucose. In certain cases, hyperuricemia is found in individuals with metabolic syndrome. In certain cases, gouty arthritis is indicative of an increased risk of acute myocardial infarction. In some embodiments, administration of the compounds described herein to an individual is useful for decreasing the likelihood of a clinical event associated with a disease or condition linked to hyperuricemia, including, without limitation, prehypertension, hypertension, increased proximal sodium reabsorption, microalbuminuria , proteinuria, kidney disease, obesity, hypertriglyceridemia, low high-density lipoprotein cholesterol, hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, peripheral arterial, carotid and coronary disease, atherosclerosis, congestive heart failure, stroke, tumor lysis syndrome, endothelial dysfunction, oxidative stress, high levels of renin, high levels of endothelin and/or high levels of C-reactive protein.
[00297] An modality provides a method of treating or preventing a condition characterized by abnormal tissue or organic levels of uric acid in a subject comprising administering to the subject an effective amount of a compound of formula (I). Another modality provides the method where the condition is gout, a recurrent attack of gout, gouty arthritis, hyperuricemia, hypertension, a cardiovascular disease, coronary heart disease, Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, kidney disease, kidney stones , renal failure, joint inflammation, arthritis, urolithiasis, saturnism, hyperparathyroidism, psoriasis, sarcoidosis, hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency or a combination of these. Another modality provides the method in which the condition is gout.
[00298] In another embodiment, the method further comprises administering a second agent effective for the treatment of gout. Another embodiment provides the method wherein the second agent is a URAT 1 inhibitor, a xanthine oxidase inhibitor, a xanthine dehydrogenase, a xanthine oxidoreductase inhibitor, or combinations thereof. Another embodiment provides the method where the second agent is allopurinol, febuxostat, FYX-051, or combinations thereof.
In some embodiments, the compounds described herein are administered to an individual suffering from a disease or condition that requires treatment with a compound that is a diuretic. In some embodiments, the compounds described herein are administered to an individual suffering from a disease or condition that requires treatment with a compound that is a diuretic, wherein the diuretic causes renal retention of urate. In some modalities, the disease or condition is congestive heart failure or essential hypertension.
[00300] In some embodiments, administration of the compounds described herein to an individual is useful to improve motility or improve quality of life.
[00301] In some embodiments, administration of the compounds described herein to an individual is useful for treating or lessening the side effects of cancer treatment.
[00302] In some embodiments, administration of the compounds described herein to an individual is useful for decreasing the renal toxicity of cisplatin. KITS
The compounds, compositions and methods described herein provide kits for the treatment of disorders such as those described herein. Kits comprise a compound, compounds or compositions described herein in a container and, optionally, instructions that teach use of the kit in accordance with the various methods and approaches described herein. These kits may also include information, for example, references to scientific literature, package inserts, clinical trial results and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or describe the dosage, administration, side effects, drug interactions or other information useful to the healthcare professional. This information can be based on the results of various studies, for example, studies using experimental animals that involve in vivo models and studies based on human clinical trials. The kits described herein can be provided, marketed and/or promoted to healthcare professionals, including physicians, nurses, pharmacists, drug formulation professionals, and the like. Kits can also, in some modalities, be sold directly to the consumer.
The compounds described herein can be used for diagnostics and as research reagents. For example, the compounds described herein, alone or in combination with other compounds, can be used as tools in differential and/or combinatorial analysis to elucidate expression patterns of genes expressed within cells and tissues. As a non-limiting example, expression patterns within cells or tissues treated with one or more compounds are compared to control cells or tissues not treated with compounds, and the patterns produced are analyzed for differential levels of gene expression to see if they belong. , for example, to the association of disease, signaling pathway, cell location, expression level, size, structure or function of the genes examined. This analysis can be performed on stimulated or unstimulated cells, and in the presence or absence of other compounds that affect expression patterns.
In addition to being useful for human treatment, the compounds and formulations of the present invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. Most preferred animals include horses, dogs and cats.
[00306] The examples and preparations provided below illustrate and further exemplify the compounds of the present invention and methods of preparing those compounds. It should be understood that the scope of the present invention is in no way limited by the scope of the following examples and preparations. In the following examples, molecules with a single chiral center, unless otherwise noted, exist as a racemic mixture. Those molecules with two or more chiral centers, unless noted differently, exist as a racemic mixture of diastereomers. Single enantiomers/diastereomers can be obtained by methods known to those skilled in the art. EXAMPLES I. Chemical syntheses Example 1: Preparation of compounds of formula (I-A)
[00307] Compounds of formula (IA) can be prepared according to below:

[00308] A mixture of 2-bromo-3-fluoropyridine (1.05 g, 6.0 mmol), 4-cyanophenylboronic acid (0.882 g, 6.0 mmol), Pd(PPh3)4 (0.138 g, 0, 12 mmol) and aqueous solution of sodium carbonate (2 M, 6 ml) in dioxane (6 ml) was degassed for 15 minutes. The mixture was sealed, heated to 80°C for 12 hours, washed with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated and purified by chromatography to give 4-(3-fluoropyridin-2-yl)benzonitrile (1.16 g, 89%). Step B: 4-(3-Mercaptopyridin-2-yl)benzonitrile
A mixture of 4-(3-fluoropyridin-2-yl)benzonitrile (0.198 g, 1.0 mmol), Na2S (0.39 g, 5 mmol), N-methylmorpholine (0.5 ml) and DMF (2 ml) was heated to 160°C under microwave irradiation for 30 minutes. After completion of the reaction, the mixture was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and purified by chromatography to give 4-(3-mercaptopyridin-2-yl)benzonitrile (0.18 g, 85%). Step C: Ethyl 2-(2-(4-cyanophenyl)pyridin-3-ylthio)-2-methylpropanoate
A mixture of 4-(3-mercaptopyridin-2-yl)benzonitrile (0.18 g, 0.85 mmol), ethyl 2-bromo-2-methylpropanoate (0.195 g, 1 mmol) and K2CO3 (0.138 g , 1.0 mmol) in DMF (2 ml) was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and purified by chromatography to give ethyl 2-(2-(4-cyanophenyl)pyridin-3-ylthio)-2-methylpropanoate (0.137 g, 49%). Step D: 2-(2-(4-Cyanophenyl)pyridin-3-ylthio)-2-methylpropanoic acid
A mixture of ethyl 2-(2-(4-cyanophenyl)pyridin-3-ylthio)-2-methylpropanoate (0.137 g, 0.42 mmol), aqueous sodium hydroxide solution (1 M, 1 ml) and methanol (2 ml) was stirred at 60°C for 12 hours. The reaction mixture was concentrated to remove methanol, acidified and filtered to obtain 2-(2-(4-cyanophenyl)pyridin-3-ylthio)-2-methylpropanoic acid as a white powder (0.121 g, 96%).
[00312] 1H-NMR (400 MHz, DMSO-d6, 25°C) 12.72 (bs, COOH), 8.71 ((d, J = 3.2 Hz, 1H), 8.04 (d, J = 6.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 8.04 (dd, J = 6.4, 3.2 Hz, 1H), 1.22 (s, 6H).
[00313] m/z (M+1) 298.99. Examples 1B-1V
[00314] The compounds in the table below are prepared according to the procedures described in example 1A.


Example 2: Preparation of compounds of formula (IB)
[00315] Compounds of formula (IB) can be prepared according to the general schemes shown below:


A mixture of 3-bromo-4-chloropyridine (10.0 g, 52 mmol) and sodium sulfide (12.2 g, 156 mmol) in DMF (100 ml) was stirred at 130°C for 2 hours . While the reaction was cooled in an ice-water bath, aqueous HCl (6N, 45 ml) was added dropwise with rigorous stirring. The resulting yellow slurry was concentrated using rotary evaporation in a water bath (80°C) to dryness. The resulting yellow solid was extracted with methanol (4 x 50 ml), and the combined extracts concentrated to give a yellow solid (9.5 g, 96%). Step B: Ethyl 2-(3-bromopyridin-4-ylthio)-2-methylpropanoate
A mixture of 3-bromopyridine-4-thiol (step A, 4.75 g, 25 mmol), ethyl 2-bromoisobutyrate (9.75 g, 50 mmol) and sodium carbonate (7.95 g, 75 mmol) in DMF (50 ml) was stirred at 60°C for 1 hour. The reaction mixture was partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was washed with water (2 x 100 ml) and saturated sodium chloride (100 ml). The aqueous washes were back-extracted with ethyl acetate (2 x 100 ml). The combined organic layers were dried over sodium sulfate, concentrated and purified by normal phase chromatography (a gradient of 0-25% ethyl acetate in hexane) to give ethyl 2-(3-bromopyridin-4-ylthio)-2- methylpropanoate as a pale yellow oil (6.6 g, 88%). Step C: Ethyl 2-(3-(4-cyanophenyl)pyridin-4-ylthio)-2-methylpropanoate
[00318] To a mixture of 4-cyanophenylboronic acid (49 mg, 0.33 mmol) and Pd(dppf)Cl2 (9 mg, 5% mol), a solution of ethyl 2-(3-bromopyridin-4-) was added freshly purified ylthio)-2-methylpropanoate from step B (67 mg, 0.22 mmol) in THF (1 ml), acetonitrile (0.5 ml) and sodium carbonate (1 M aqueous, 0.5 ml). The resulting mixture was degassed by bubbling nitrogen for 1 minute, and then heated to 150 °C for 30 minutes under microwave irradiation. The mixture was loaded onto a 5 g ISCO loading cartridge and eluted with a gradient of 0-100% ethyl acetate in hexane onto a 12 g ISCO column to give ethyl 2-(3-(4-cyanophenyl)pyridin-4 -ylthio)-2-methylpropanoate (0.049 g, 70%). Step D: 2-(3-(4-Cyanophenyl)pyridin-4-ylthio)-2-methylpropanoic acid
To ethyl 2-(3-(4-cyanophenyl)pyridin-4-ylthio)-2-methylpropanoate (step C, 49 mg, 0.15 mmol) were added methanol (0.8 ml) and sodium hydroxide (2 M aqueous, 0.8 ml). The resulting mixture was stirred at room temperature for 2 hours. The volume was reduced (approximately 0.8 ml) by rotary evaporation. To the residue, HCl (6N aqueous) was added with stirring until the pH reached 6, resulting in the formation of a white precipitate, which was isolated by filtration. The solid was washed with water (6 x 1 ml), air dried for 1 hour and dried under vacuum (P2O5) overnight to give a white powder (28 mg, 64%).
[00320] 1H-NMR (400 MHz, DMSO-d6) δppm 1.46 (s, 6H), 7.44 (d, J = 5.39 Hz, 1H), 7.60-7.70 (m , 2H), 7.98 (d, J = 8.29 Hz, 2H), 8.44 (s, 1H), 8.56 (d, J = 5.18 Hz, 1H), 13.14 (br s., 1H).
[00321] MS (m/z), M+1, 299. Examples 2B-2JJJ
The compounds in the table below were prepared according to the procedure described in example 2A.








Example 3: Preparation of compounds of formula (IC)
[00323] Compounds of formula (IC) can be prepared according to the general scheme shown below:

[00324] Example 3A: 2-(4-(4-Cyanophenyl)pyridin-3-ylthio)-2-methylpropanoic acid
Step A: 4-(3-Fluorpyridin-4-yl)benzonitrile
[00325] 4-Cyanophenylboronic acid (1.77 g, 12 mmol) and Pd(dppf)Cl2 (400 mg, 5% mol) were weighed into a 20 ml microwave reaction flask. A solution of 4-chloro-3-fluoropyridine (1.31 g, 10 mmol) in THF (6 ml), acetonitrile (6 ml) and aqueous sodium carbonate solution (2M, 0.8 ml) was added. The resulting suspension was degassed by bubbling in N2 for 1 min. The mixture was then heated to 150 °C for 30 minutes under microwave irradiation. The mixture was loaded onto a 5 g ISCO loading cartridge and eluted with a gradient of 0-80% ethyl acetate in hexane onto a 40 g ISCO column to give ethyl 2-(4-(4-cyanophenyl)pyridin-3 -ylthio)-2-methylpropanoate as a white powder (1.08 g, 54%). Step B: 4-(3-Mercaptopyridin-4-yl)benzonitrile
[00326] A mixture of 4-(3-fluoropyridin-4-yl)benzonitrile (1.08 g, 5.4 mmol) and sodium sulfide (0.84 g, 10.8 mmol) in DMF (20 ml) was stirred at 130°C for 0.5 hours. While the reaction was cooled in an ice-water bath, aqueous HCl (6N, 2.5 ml) was added dropwise with rigorous stirring. The resulting yellow slurry was concentrated using rotary evaporation in a water bath (80°C) to dryness. The resulting yellow solid was extracted with methanol (4 x 20 ml). The combined extracts were concentrated to dryness to give a yellow solid (1.1 g, 96%). Step C: Ethyl 2-(4-(4-cyanophenyl)pyridin-3-ylthio)-2-methylpropanoate
[00327] A mixture of 4-(3-mercaptopyridin-4-yl)benzonitrile (1.1 g, 5.2 mmol), ethyl 2-bromoisobutyrate (2.0 g, 10.4 mmol) and sodium carbonate ( 1.6 g, 15.5 mmol) in DMF (20 ml) was stirred at 60°C for 1 hour. The reaction mixture was partitioned between water (20ml) and ethyl acetate (20ml). The organic layer was washed with water (2 x 20 ml) and brine (20 ml). The aqueous washes were back-extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were dried over sodium sulfate, concentrated and purified by normal phase chromatography using a gradient of 0-25% ethyl acetate in hexane to give ethyl 2-(3-bromopyridin-4-ylthio)-2-methylpropanoate as a pale yellow oil (0.25 g, 15%). Step D: 2-(4-(4-Cyanophenyl)pyridin-3-ylthio)-2-methylpropanoic acid
[00328] Methanol (1 ml) and aqueous sodium hydroxide solution (2 M, 1 ml) were added to ethyl 2-(4-(4-cyanophenyl)pyridin-3-ylthio)-2-methylpropanoate (0.25 g, 0.77 mmol) and stirred at room temperature for 2 hours. The volume was reduced (approximately 1 ml) by rotary evaporation and the resulting residue treated with aqueous HCl (6N) with stirring to pH 6, resulting in the formation of a white precipitate, which was isolated by filtration. The solid was washed with water (6 x 1 ml), air dried for 1 hour and dried under vacuum over P2O5 overnight to give a white powder (0.072 g, 32%).
[00329] 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.17 (s, 6H), 7.50 (d, J = 4.98 Hz, 1H), 7.67 (d, J = 8 .29 Hz, 2H), 7.97 (d, J = 8.29 Hz, 2H), 8.69 (d, J = 4.98 Hz, 1H), 8.73 (s, 1H) 12.65 (br, 1H).
[00330] MS (m/z), M+1, 299. Examples 3B-3Z
[00331] The compounds in the table below are prepared according to the procedures described in example 3A.



Example 4: Preparation of compounds of formula (ID)
[00332] Compounds of formula (ID) can be prepared according to the general schemes shown below:

A mixture of 1,4-dibromonaphthalene (24.06 g, 84 mmol) and copper cyanide (6.02 g, 67 mmol) in DMF (85 ml) was heated to 125 °C overnight. other. The mixture was partially concentrated to remove DMF and the resulting residue washed with aqueous ammonium hydroxide and extracted with ethyl acetate. The organic layer was concentrated and purified by chromatography to give 4-bromo-1-naphtonitrile (5.13 g, 26%). Step B: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphtonitrile
A mixture of 4-bromo-1-naphtonitrile (4.58 g, 19.7 mmol), bis(pinacol)diboron (5.00 g, 19.7 mmol), Pd(dppf)Cl2 (0, 49 g, 0.6 mmol) and potassium acetate (5.78 g, 59.1 mmol) in DMSO was heated to 80°C for 5 hours. The reaction mixture was washed with 1M aqueous HCl, extracted with ethyl acetate and purified by chromatography to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 -naphtonitrile (2.00 g, 36%). Step C: 3-bromopyridine-2-thiol
A mixture of 3-bromo-2-chloropyridine (0.769 g, 4 mmol) and sodium sulfide (0.336 g, 6 mmol) in DMF (3 ml) was heated under microwave irradiation at 130°C for 0. 5 hours. Water (50 ml) and ethyl acetate (20 ml) were added and the layers separated. The aqueous layer was acidified to pH 6 resulting in the formation of a precipitate, which was isolated by filtration and dried under vacuum to give the product as a yellow solid (0.42 g, 55%). Step D: Ethyl 2-(3-bromopyridin-2-ylthio)-2-methylpropanoate
A mixture of 3-bromopyridine-2-thiol (189 mg, 1 mmol), ethyl-2-bromoisobutyrate (390 mg, 2 mmol) and sodium carbonate (159 mg, 1.5 mmol) in DMF (2 ml) was heated to 70°C for 1 hour. The reaction mixture was neutralized with 1M aqueous HCl and extracted with ethyl acetate. The organic layer was dried over Mg2SO4, concentrated and purified by chromatography to give ethyl 2-(3-bromopyridin-2-ylthio)-2-methylpropanoate (0.271 g, 89%). Step E: Ethyl 2-(3-(4-cyanonaphthalen-1-yl)pyridin-2-ylthio)-2-methylpropanoate
A mixture of ethyl 2-(3-bromopyridin-2-ylthio)-2-methylpropanoate (271 mg, 0.89 mmol), 4-(4,4,5,5-tetramethyl-1,3,2 - dioxaborolan-2-yl)-1-naphtonitrile (248 mg, 0.89 mmol), palladium tetrakis triphenylphosphine (51 mg, 0.044 mmol) and aqueous sodium carbonate solution (2 M, 1.5 ml, 3 mmol) in dioxane (3 ml) was degassed and heated to 80°C for 5 hours. The mixture was washed with water and extracted with ethyl acetate. The organic layer was dried with Mg2SO4, concentrated and purified by chromatography to give ethyl 2-(3-(4-cyanonaphthalen-1-yl)pyridin-2-ylthio)-2-methylpropanoate (0.121 g, 36%). Step F: 2-(3-(4-Cyonaphthalen-1-yl)pyridin-2-ylthio)-2-methylpropanoic acid
[00338] Ethyl 2-(3-(4-cyanonaphthalen-1-yl)pyridin-2-ylthio)-2-methylpropanoate (121 mg, 0.32 mmol) in a mixture of aqueous sodium hydroxide solution (1 M , 2 ml) and methanol (5 ml) was stirred at room temperature for 5 hours. Methanol was partially removed and the resulting residue acidified causing precipitation of the product 2-(3-(4-cyanonaphthalen-1-yl)pyridin-2-ylthio)-2-methylpropanoic acid. The solid product was isolated by filtration and dried under vacuum (0.065 g, 0.187 mmol, 60%).
[00339] 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.47 (s, 1H), 8.56 (d, J = 4.8 Hz, 1H), 8.29 (d, J = 7 .2 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 7.88 (dd, J = 7.6, 7.6 Hz, 1H), 7.72 (dd, J = 7.6, 7.6 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.50 (d , J = 8.8 Hz, 1H), 7.35 (dd, J = 4.8, 7.6 Hz, 1H), 1.49 (s, 6H). MS (m/z), M+1, 349.08. Examples 4B, 4C
The compounds in the table below were prepared according to the procedure described in example 4A.
4D-4Z Examples
[00341] The compounds in the table below are prepared according to the procedures described in example 4A.



Example 5: Preparation of compounds of formula (IE)
[00342] Compounds of formula (IE) can be prepared according to the general schemes shown below:

A mixture of 2,3-dichloropyrazine (2.98 g, 2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphtonitrile (0.558 mmol, 2 mmol) palladium tetrakis triphenylphosphine (0.069 g, 0.06 mmol) and aqueous solution of sodium carbonate (2 M, 3 ml, 6 mmol) in dioxane (7 ml) was heated to 80°C for 12 hours. The reaction mixture was cooled to room temperature, washed with water, extracted with ethyl acetate and purified by chromatography to give 4-(3-chloropyrazin-2-yl)-1-naphtonitrile (0.36 g, 68%) . Step B: Methyl 2-(3-(4-cyanonaphthalen-1-yl)pyrazin-2-ylthio)acetate
[00344] A mixture of 4-(3-chloropyrazin-2-yl)-1-naphtonitrile (0.16 g, 0.6 mmol), methyl thioglycolate (0.127 g, 1.2 mmol) and sodium carbonate (0.082 g, 0.78 mmol) in DMF (1 ml) was heated under microwave irradiation to 130°C for 1 hour. The mixture was washed with water, extracted with ethyl acetate and purified by chromatography to give methyl 2-(3-(4-cyanonaphthalen-1-yl)pyrazin-2-ylthio)acetate (0.127 g, 63%). Step C: 2-(3-(4-cyanonaphthalen-1-yl)pyrazin-2-ylthio)acetic acid
A mixture of methyl 2-(3-(4-cyanonaphthalen-1-yl)pyrazin-2-ylthio)acetate (0.125 g, 0.37 mmol), aqueous sodium hydroxide solution (1 M, 0, 5 ml) and methanol (1 ml) was stirred at room temperature for 12 hours. Methanol was removed and the mixture was washed with water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to dryness. The solid residue was recrystallized from ethyl acetate and hexanes to give 2-(3-(4-cyanonaphthalen-1-yl)pyrazin-2-ylthio)acetic acid (0.102 g, 86%).
[00346] 1H-NMR (400 MHz, DMSO-d6, 25°C) 12.60 (bs, OH), 8.70 (d, J = 2.4 Hz, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 7.6 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.90 (dd, J = 7 .6, 7.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.71 (dd, J = 7.6, 7.6 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 3.95 (s, 2H).
[00347] MS (m/z), M+1 = 322.08. Examples 5B-5Z
[00348] The compounds in the table below are prepared according to the procedures described in example 5A.



Example 6: Preparation of compounds of formula (IF)
[00349] Compounds of formula (IF) can be prepared according to the general schemes shown below:


A mixture of 4-chloro-5-bromopyrimidine (0.193 g, 1.0 mmol), methyl 2-mercaptoacetate (0.116 g, 1.1 mmol) and sodium carbonate (0.159 g, 1.5 mmol) in DMF (0.7 ml) was heated under microwave irradiation to 150 °C for 20 minutes. The mixture was washed with water, extracted with ethyl acetate and purified by chromatography to give methyl 2-(5-bromopyrimidin-4-ylthio)acetate (0.22 g, 84%). Step B: 2-(5-(4-cyanonaphthalen-1-yl)pyrimidin-4-ylthio)acetic acid
A mixture of methyl 2-(5-bromopyrimidin-4-ylthio) acetate (220 mg, 0.84 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1-naphtonitrile (237 mg, 0.85 mmol) palladium tetrakis triphenylphosphine (46 mg, 0.04 mmol) and aqueous sodium carbonate solution (2M, 1.5 ml, 3 mmol) in dioxane (3 ml) was heated to 100°C for 5 hours. The reaction mixture was allowed to cool to room temperature and aqueous sodium hydroxide solution (1 M, 30 ml) was added. The mixture was washed with ethyl acetate (2 x 20 ml), and the aqueous layer acidified to pH 4 resulting in the formation of a precipitate which was isolated by filtration and dried under vacuum to give 2-(5-(4-acid) cyanonaphthalen-1-yl)pyrimidin-4-ylthio)acetic (143 mg, 53%).
[00352] 1H-NMR (400 MHz, DMSO-d6) 12.80 (bs, OH), 9.15 (s, 1H), 8.56 (s, 1H), 8.35 (d, J = 7 .2 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.91 (dd, J = 7.6, 7.6 Hz, 1H), 7.75 (dd, J = 7.6, 7.6 Hz, 1H), 7.71 (d, J = 7.6, Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 3.99 ( s, 2H).
[00353] MS (m/z), M+1, 322.08. Example 6B: 2-(5-(4-cyanonaphthalen-1-yl) pyrimidin-4-ylthio)-2-methylpropanoic acid

2-(5-(4-cyanonaphthalen-1-yl)pyrimidin-4-ylthio)-2-methylpropanoic acid was prepared according to the procedures described in example 6A, using methyl 2-mercapto-2-methylpropanoate in place of methyl 2-mercaptoacetate, in step A.
[00355] 1H-NMR (400 MHz, DMSO-d6) 12.70 (bs, OH), 9.07 (s, 1H), 8.53 (s, 1H), 8.33 (d, J = 7 0.6 Hz, 1H), 8.27 (d, J = 7.6 Hz, 1H), 7.91 (dd, J = 7.6, 7.6 Hz, 1H), 7.75 (dd, J = 7.6, 7.6 Hz, 1H), 7.71 (d, J = 7.6, Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 3.99 ( s, 2H).
[00356] MS (m/z), M+1, 350.08.

Examples 6G-5Z
[00357] The compounds in the table below are prepared according to the procedures described in example 6A.



Example 7: Preparation of compounds of formula (IG)
[00358] Compounds of formula (IG) can be prepared according to the general schemes shown below:

Step A: 4-(5-Bromopyrimidin-4-yl)-1-naphtonitrile
A mixture of 4-chloro-5-bromopyrimidine (193 mg, 1 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphtonitrile (279mg, 1mmol) palladium tetrakis triphenylphosphine (0.023g, 0.02mmol) and aqueous solution of sodium carbonate (2M, 1.5ml, 3mmol) in dioxane (3ml) was heated to 80°C for 12 hours. The reaction mixture was cooled to room temperature, washed with water, extracted with ethyl acetate and purified by chromatography to give 4-(5-bromopyrimidin-4-yl)-1-naphtonitrile (214 mg, 69%). Step B: Methyl 2-(4-(4-cyanonaphthalen-1-yl)pyrimidin-5-ylthio)acetate
[00360] A mixture of 4-(5-bromopyrimidin-4-yl)-1-naphtonitrile (45 mg, 0.14 mmol), methyl thioglycolate (74 mg, 0.7 mmol) and potassium carbonate (27 mg, 0.2 mmol) in DMF (0.6 ml) was heated under microwave irradiation to 160°C for 0.5 hour. The mixture was washed with water, extracted with ethyl acetate and purified by chromatography to give methyl 2-(4-(4-cyanonaphthalen-1-yl)pyrimidin-5-ylthio)acetate (22mg, 47%). Step C: 2-(4-(4-Cyonaphthalen-1-yl)pyrimidin-5-ylthio)acetic acid
A mixture of methyl 2-(4-(4-cyanonaphthalen-1-yl) pyrimidin-5-ylthio)acetate (22 mg, 0.065 mmol), aqueous sodium hydroxide solution (1 M, 0.5 ml ) and methanol (1 ml) was stirred at room temperature for 2 hours. Methanol was removed and aqueous sodium hydroxide solution (1M, 1ml) and ethyl acetate (3ml) were added. The aqueous layer was removed, acidified and extracted with ethyl acetate. The second organic layer was concentrated to dryness to give 2-(4-(4-cyanonaphthalen-1-yl)pyrimidin-5-ylthio)acetic acid (19 mg, 91%).
[00362] 1H-NMR (400 MHz, CDCl3, 25°C) 9.26 (s, 1H), 9.03 (s, 1H), 8.71 (bs, 1H), 8.39 (d, J = 8.0 Hz, 1H), 8.50 (d, J = 8.4 Hz, 1H), 7.79 (dd, J = 7.2, 7.2 Hz, 1H), 7.55-7 .66 (m, 2H), 7.61 (d, J = 8.4 Hz, 1H), 3.99 (s, 2H).
[00363] MS (m/z), M+1 = 322.08. Examples 7B-7Z
[00364] The compounds in the table below are prepared according to the procedures described in example 7A.



II. Biological evaluation Example 8: Evaluation with URAT1 model test
[00365] Human embryonic kidney cells HEK293 (ATCC # CRL-1573) were propagated in EMEM tissue culture medium as described by ATCC in an atmosphere of 5% CO2 and 95% air. Transfections of HEK293 cells with an URAT1 template construct were performed using L2000 transfection reagent (Invitrogen) as described by the manufacturer. After 24 h the transfected cells were split into 10 cm cell culture dishes and grown for 1 day after which the medium was replaced with fresh growth medium containing G418 (Gibco) at 0.5 mg/ml final concentration. Drug resistant colonies were selected after approximately 8 days and then tested for 14C-uric acid transport activity. HEK293/model URAT1 cells are plated in Poly-D-Lysine coated 96-well plates at a density of 125,000 cells per well.
Cells were grown overnight (20-26 hours) at 37°C in an incubator. The plates were brought to room temperature and the medium was washed with a 250 µl wash of wash buffer (125 mM Na gluconate, 10 mM Hepes pH 7.3). Compound or vehicle is added in assay buffer with 14 C-uric acid to a final concentration of 125 µM uric acid with a specific activity of 54 mCi/mmol. Assay buffer is 125 mM Sodium Gluconate, 4.8 mM Potassium Gluconate, 1.2 mM Potassium Phosphate, monobasic, 1.2 mM Magnesium Sulfate, 1.3 mM Ca Gluconate, 5 0.6 mM glucose, 25 mM HEPES, pH 7.3. Plates were incubated at room temperature for 10 minutes then washed 3 times with 50 μl wash buffer and 3 times with 250 μl wash buffer. Microscint 20 scintillation fluid was added and the plates were incubated overnight at room temperature to equilibrate. Plates are then read on the TopCount plate reader and an EC50 value is generated. (See Enomoto et al., Nature, 2002, 417, 447-451 and Anzai et al., J. Biol. Chem., 2004, 279, 45.942-45.950.)
[00367] Compounds as described herein were tested according to the protocol described above against model URAT-1; the results are shown in the table below where: - A represents an EC50 value in the range of ≤ 10 µM to > 0.5 µM; - B represents an EC50 value in the range of ≤ 0.5 µM to > 0.05 µM; and - C represents an EC50 value in the range of ≤ 0.05 µM to > 0.001 µM.










[00368] The examples and embodiments described herein are for illustrative purposes only and various modifications or changes suggested to those skilled in the art are to be included in the spirit and scope of this application and scope of the appended claims.

权利要求:
Claims (23)
[0001]
1. Compound characterized by having the formula:
[0002]
2. Compound according to claim 1, characterized in that it is
[0003]
3. Pharmaceutical composition characterized by the fact that it comprises a compound of the formula:
[0004]
4. Pharmaceutical composition characterized by the fact that it comprises a compound of the formula:
[0005]
5. Pharmaceutical composition according to claim 3, characterized in that it additionally comprises a xanthine oxidase inhibitor.
[0006]
6. Pharmaceutical composition according to claim 5, characterized in that the xanthine oxidase inhibitor is febuxostat.
[0007]
7. Pharmaceutical composition according to claim 5, characterized in that the xanthine oxidase inhibitor is allopurinol.
[0008]
8. Pharmaceutical composition according to claim 4, characterized in that it additionally comprises a xanthine oxidase inhibitor.
[0009]
9. Pharmaceutical composition according to claim 8, characterized in that the xanthine oxidase inhibitor is febuxostat.
[0010]
10. Pharmaceutical composition according to claim 8, characterized in that the xanthine oxidase inhibitor is allopurinol.
[0011]
11. Use of a compound of formula:
[0012]
12. Use of a compound of formula:
[0013]
13. Use of a compound of formula:
[0014]
14. Use of a compound of formula:
[0015]
15. Use of a compound of formula:
[0016]
16. Use of a compound of formula:
[0017]
17. Use of a compound of formula:
[0018]
18. Use of a compound of formula:
[0019]
19. Use of a compound of formula:
[0020]
20. Use of a compound of formula:
[0021]
21. Use according to any one of claims 11 to 20, characterized in that the drug additionally comprises a xanthine oxidase inhibitor.
[0022]
22. Use according to claim 21, characterized in that the xanthine oxidase inhibitor is febuxostat.
[0023]
23. Use according to claim 21, characterized in that the xanthine oxidase inhibitor is allopurinol.

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法律状态:
2017-10-10| B25G| Requested change of headquarter approved|Owner name: ARDEA BIOSCIENCES INC. (US) |

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2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-10| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-07-24| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-02-05| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2021-03-30| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-05-04| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/06/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US35549110P| true| 2010-06-16|2010-06-16|

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US61/355,491|2010-06-16|

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PCT/US2011/040585|WO2011159839A2|2010-06-16|2011-06-15|Thioacetate compounds, compositions and methods of use|

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