MYST inhibitors

Abstract

Provided herein are compounds that are MYST inhibitors, and pharmaceutically acceptable derivatives thereof. Also provided are pharmaceutical compositions containing the compounds and methods of using the compounds for treating a subject with a hyperproliferative disease including cancer.

Description

ATTY DKT. NO. ISTX 104 WO MYST INHIBITORS RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. provisional patent application nos.63 / 585,817, filed September 27, 2023, 63 / 558,419, filed February 27, 2024, and 63 / 655,961, filed June 4, 2024, the disclosures of which are incorporated herein by reference in their entireties. SEQUENCE LISTING

[0002] This application contains a sequence listing, which is being submitted herewith as an XML filed named “ISTX104WO_SL.xml”, created on September 11, 2024, size 5406 bytes, which is incorporated by reference herein in its entirety. FIELD

[0003] Provided herein are compounds and compositions for inhibiting the MYST family of lysine acetyltransferases (KATs). In one embodiment, provided are methods of treating diseases, including hyperproliferative diseases, with the compounds and compositions provided herein. In another embodiment, the hyperproliferative disease is cancer. BACKGROUND

[0004] The MYST family of enzymes are KATs and include KAT6A (also known as MOZ or MYST3), KAT6B (also known as MORF or MYST4), KAT5 (also known as Tip60), KAT7 (also known as, HBO1 or MYST2) and KAT8 (also known as, MOF or MYST1) (see, e.g., Wiesel-Motiuk, et al., Drug Resistance Updates 2020, 53, 100729; Wapenaar, et al., Clinical Epigenetics 2016, 8(59), 1 (DOI 10.1186 / s13148-016-0225-2)). The MYST family of KATs is particularly important in regulation of the cell cycle (Carrozza, et al., Trends in Genetics 2003, 19, 321-329).

[0005] Dysregulation of the expression of KAT6 proteins supports tumor progression (see, e.g., Trisciuoglio et al., Stem Cells Int.2018, Article ID 8908751 (https: / / doi.org / 10.1155 / 2018 / 8908751)). Dysregulation through gene amplification, overexpression or mutation of KAT6A has been documented in multiple cancer types including breast, lung adenocarcinoma, ovarian, colon and rectal adenocarcinoma, and uterine cervix (see, e.g., Huang, et al., Molecular and Cellular Biology 2016, 63, 1900-1907; Zack, et al., Nature Genetics 2013, 45, 1134-1140). It is reported that the locus that contains the gene for KAT6A (8p11-p12 amplicon) is the 12thmost commonly amplified region of theATTY DKT. NO. ISTX 104 WO genome across all cancer types (see, e.g., Zack, et al., 2013, supra). In acute myeloid leukemia (AML), recurrent oncogenic fusions of KAT6A have been documented that can drive transformation to a malignant state (see, e.g., Sheikh, et al., Blood 2015, 125, 1910- 1921). Translocation of KAT6A and fusion to a partner such as CBP, p300, TIF2 and NCOA3 are known to lead to aggressive forms of AML (see, e.g., Sheikh, et al., 2015, supra).

[0006] In addition to the role that KATs play in epigenetic regulation, KATs also acetylate non-histone proteins. Through modification of the acetylation state of non-histone proteins, KATs are involved modulating protein function and stability, protein-protein and protein- DNA interactions, and regulation of enzyme activity (see, e.g., Glozak, et al., Gene 2005, 363, 15-23; Das, et al., IUBMB Life 2005, 57, 137-148).

[0007] Thus, there is a need for MYST inhibitors for treatment of hyperproliferative diseases, including cancer. SUMMARY

[0008] Provided herein is a compound of Formula I: wher1 4 6 7e R -R , R , R , a, Het, X and Z1-Z6are as defined elsewhere herein.

[0010] Also provided herein is a compound of Formula II:where R1-R4, R6, R7, a, Het, X and Z1-Z6are as defined elsewhere herein.

[0012] Also provided herein is a compound of Formula III:ATTY DKT. NO. ISTX 104 WO where R1-R4, R6, R7, a, Het, X

[0014] Pharmaceutical compositions containing a compound of Formula I, II or III and a pharmaceutically acceptable excipient are also provided.

[0015] In one embodiment, the compounds of Formula I, II or III provided herein inhibit one or more of the MYST family of lysine acetyl transferases. In another embodiment, the compounds provided herein inhibit KAT6A. In another embodiment, the compounds provided herein are covalent inhibitors of KAT6A. Without being bound by any theory, in one embodiment, the compounds provided herein inhibit KAT6A through covalent modification of a cysteine residue at or near the Ac-CoA binding site. In another embodiment, the compounds provided herein are non-covalent inhibitors of KAT6A.

[0016] In other embodiments, provided are methods of treatment of a hyperproliferative disease by administering a compound or composition provided herein. In one embodiment, the hyperproliferative disease is cancer. In another embodiment, the cancer is breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, uterine / cervical cancer or leukemia. In another embodiment of the methods provided herein, the compounds of Formula I are used as single agents or in combination with a standard of care treatment for a particular cancer.

[0017] In another embodiment, provided are methods of inhibiting a MYST enzyme by contacting the MYST enzyme or a composition containing a MYST enzyme with a compound or composition provided herein. In another embodiment, provided are methods of inhibiting KAT6A by contacting KAT6A or a composition containing KAT6A with a compound or composition provided herein. DETAILED DESCRIPTION I. DEFINITIONS

[0018] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.ATTY DKT. NO. ISTX 104 WO

[0019] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0020] The singular forms "a," "an," and "the" include plural references, unless the context clearly dictates otherwise.

[0021] As used herein "subject" is an animal, such as a mammal, including human, such as a patient.

[0022] As used herein, biological activity refers to the in vivo activities of a compound or physiological responses that result upon in vivo administration of a compound, composition or other mixture. Biological activity, thus, encompasses therapeutic effects and pharmacokinetic behavior of such compounds, compositions and mixtures. Biological activities can be observed in in vitro systems designed to test for such activities.

[0023] As used herein, pharmaceutically acceptable derivatives of a compound include, but are not limited to, salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, clathrates, solvates or hydrates thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization. The compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and inorganic salts, such as but not limited to, sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, mesylates, and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids,ATTY DKT. NO. ISTX 104 WO sulfonic acids, sulfinic acids and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of formula C=C(OR) where R is alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of formula C=C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.

[0024] As used herein, treatment means any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as use for treating a hyperproliferative disease.

[0025] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or pharmaceutical composition.

[0026] As used herein, and unless otherwise indicated, the terms "manage," "managing" and "management" encompass preventing the recurrence of the specified disease or disorder in a subject who has already suffered from the disease or disorder, and / or lengthening the time that a subject who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and / or duration of the disease or disorder, or changing the way that a subject responds to the disease or disorder.

[0027] Where moieties are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical moieties that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0028] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain saturated hydrocarbon radical, which can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0029] The term "alkenyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain hydrocarbon radical having one or more carbon-carbon double bonds, which can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons).ATTY DKT. NO. ISTX 104 WO Examples of alkenyl groups include, but are not limited to, vinyl (i.e., ethenyl), 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), and the higher homologs and isomers.

[0030] The term "alkynyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain hydrocarbon radical having one or more carbon-carbon triple bonds, which can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C1-C10 means one to ten carbons). Examples of alkynyl groups include, but are not limited to, ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers.

[0031] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, including those groups having 10 or fewer carbon atoms. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having six or fewer carbon atoms.

[0032] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.

[0033] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, consisting of a heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atom may have an alkyl substituent to fulfill valency and / or may optionally be quaternized. The heteroatom(s) O, N, P, Si and S may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2- CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive, such as, for example, - CH2-NH-OCH3and –CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and –CH2-S-CH2-CH2-NH-CH2-. For alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula – C(O)2R'- represents both –C(O)2R'- and –R'C(O)2-.

[0034] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" andATTY DKT. NO. ISTX 104 WO "heteroalkyl", respectively, including bicyclic, tricyclic, spirocyclic and bridged bicyclic groups. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornanyl, bicyclo[2.2.2]octanyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, 1- or 2-azabicyclo[2.2.2]octanyl, and the like.

[0035] The terms "halo," by itself or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1- C4)alkyl" is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobutyl, 3-bromopropyl, and the like. Similarly, the terms "cycloalkenyl", “cycloalkynyl”, “heterocycloalkenyl” and "heterocycloalkynyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkenyl", “alkynyl”, “heteroalkenyl” and "heteroalkynyl", respectively, including bicyclic, tricyclic, spirocyclic and bridged bicyclic groups.

[0036] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (in one embodiment from 1 to 3 rings) which are fused together or linked covalently. The term "heteroaryl" refers to aryl groups that contain from one to four heteroatoms selected from N, O, and S in the ring(s), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2- thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5- quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituent moieties for aryl and heteroaryl ring systems may be selected from the group of acceptable substituent moieties described herein. The term "heteroarylium" refers to a heteroaryl group that is positively charged on one or more of the heteroatoms.ATTY DKT. NO. ISTX 104 WO

[0037] The term "oxo" as used herein means an oxygen atom that is double bonded to a carbon atom.

[0038] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl" and "heteroaryl") are meant to include both substituted and unsubstituted forms of the indicated radical. Non- limiting examples of substituent moieties for each type of radical are provided below.

[0039] Substituent moieties for alkyl, heteroalkyl, alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups are, in one embodiment, selected from, deuterium, -OR', =O, =NR', =N-OR', -NR'R", -SR', halo, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R'")=NR"", -NR- C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -NRSO2NR'R'', -CN and –NO2 in a number ranging from zero to the number of hydrogen atoms in such radical. In one embodiment, substituent moieties for cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups also include substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl. R', R", R"' and R"" each in one embodiment independently are hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound provided herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituent moieties, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3and –CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).

[0040] Substituent moieties for aryl and heteroaryl groups are, in one embodiment, selected from deuterium, halo, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl, -OR', -NR'R", -SR', -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR-C(NR'R"R'")=NR"", -NR-C(NR'R")=NR'", -S(O)R', -S(O)2R', -S(O)2NR'R", -NRSO2R', -CN and –NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, andATTY DKT. NO. ISTX 104 WO fluoro(C1-C4)alkyl, in a number ranging from zero to the total number of hydrogens on the aromatic ring system; and where R', R", R"' and R"" are, in one embodiment, independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound provided herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.

[0041] Two of the substituent moieties on adjacent atoms of an aryl or heteroaryl ring may optionally form a ring of the formula -Q'-C(O)-(CRR')q-Q''-, wherein Q' and Q'' are independently –NR-, -O-, -CRR'- or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituent moieties on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently –CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituent moieties on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula –(CRR')s-X'-(CR''R''')d-, where s and d are independently integers of from 0 to 3, and X' is –O-, -NR'-, -S-, -S(O)-, -S(O)2-, or –S(O)2NR'-. The substituent moieties R, R', R" and R'" are, in one embodiment, independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0042] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0043] As used herein, a prodrug is a compound that upon in vivo administration is metabolized, or otherwise undergoes chemical changes under physiological conditions, by one or more steps or processes or otherwise converted to a biologically, pharmaceutically or therapeutically active form of the compound. Additionally, prodrugs can be converted to a biologically, pharmaceutically or therapeutically active form of the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.ATTY DKT. NO. ISTX 104 WO

[0044] Certain compounds provided herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds provided herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure.

[0045] Certain compounds provided herein possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, tautomers, geometric isomers and individual isomers are encompassed within the scope of the present disclosure. The compounds provided herein do not include those which are known in the art to be too unstable to synthesize and / or isolate.

[0046] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds provided herein, whether radioactive or not, are encompassed within the scope of the present disclosure. II. COMPOUNDS FOR USE IN COMPOSITIONS AND METHODS

[0047] In one embodiment, provided is a compound of Formula I for use in the compositions and methods provided herein:wherein:

[0049] a is 0-2;

[0050] R1and R2together form alkylene;

[0051] R3is -O-(CH2)b-R8;

[0052] b is 1-4;

[0053] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);ATTY DKT. NO. ISTX 104 WO

[0054] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0055] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0056] R12is alkyl or NR14R15;

[0057] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0058] R4is H or alkoxy;

[0059] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0060] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0061] (ii) Z1is NH or O, and Z2and Z3are C, or

[0062] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0063] Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv):

[0064] (i) Z4is N, Z5is CR5, and Z6is CH,

[0065] (ii) Z4is CR16, Z5is N, and Z6is CH,

[0066] (iii) Z4is CR16, Z5is CR5, and Z6is N, or

[0067] (iv) Z4is CR16, Z5is CR5, and Z6is CH;

[0068] R5and R16are selected from (i) or (ii):

[0069] (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or

[0070] (ii) R5and R16together form alkylene or heteroalkylene;

[0071] X is O, S(O)xor CH2, where x is 0-2;

[0072] Het and R6are selected from (i) or (ii):

[0073] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0074] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0075] R7is -C(O)R17, -S(O)R18or -SO2R18;

[0076] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19ATTY DKT. NO. ISTX 104 WO is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0077] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR20R21.

[0078] In one embodiment, provided is a compound of Formula Ia for use in the compositions and methods provided herein:

[0080] a is 0-2;

[0081] R1and R2together form alkylene;

[0082] R3is -O-(CH2)b-R8;

[0083] b is 1-4;

[0084] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0085] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0086] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0087] R12is alkyl or NR14R15;

[0088] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0089] R4is H or alkoxy;

[0090] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0091] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0092] (ii) Z1is NH or O, and Z2and Z3are C, or

[0093] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0094] Z4is N or CR16;ATTY DKT. NO. ISTX 104 WO

[0095] R5and R16are selected from (i) or (ii):

[0096] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl or haloalkyl, or

[0097] (ii) R5and R16together form alkylene or heteroalkylene;

[0098] X is O, S(O)x or CH2, where x is 0-2;

[0099] Het and R6are selected from (i) or (ii):

[0100] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0101] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0102] R7is -C(O)R17or -SO2R18;

[0103] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0104] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR20R21.

[0105] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0106] R8is H, CN, OH, alkoxy, aryl, heteroaryl, NR9R10or C(O)R11;

[0107] R9is H and R10is H or C(O)R13; where R13is alkyl or alkoxy; and

[0108] R11is alkyl or alkoxy;

[0109] R5and R16are selected from (i) or (ii):

[0110] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl or alkynyl, or

[0111] (ii) R5and R16together form alkylene;

[0112] X is O or CH2;ATTY DKT. NO. ISTX 104 WO

[0113] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0114] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0115] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0116] R8is H, CN, OH, alkoxy, aryl, NR9R10or C(O)R11;

[0117] R9is H and R10is C(O)R13; where R13is alkyl; and

[0118] R11is alkoxy;

[0119] R5and R16are selected from (i) or (ii):

[0120] (i) R5is H, cyano, alkoxy or alkyl, and R16is H, alkyl, alkoxy, halo or alkynyl, or

[0121] (ii) R5and R16together form alkylene;

[0122] X is O or CH2;

[0123] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0124] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0125] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein R1and R2together form C2-4alkylene.

[0126] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein R1and R2together form propylene.

[0127] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I:wherein:

[0129] a is 0-2;

[0130] R1and R2are selected from (i) or (ii):

[0131] (i) R1is H, alkyl, haloalkyl or halo; and R2is alkyl, cycloalkyl or haloalkyl, or

[0132] (ii) R1and R2together form alkylene;ATTY DKT. NO. ISTX 104 WO

[0133] R3is -O-(CH2)b-R8;

[0134] b is 1-4;

[0135] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0136] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0137] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0138] R12is alkyl or NR14R15;

[0139] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0140] R4is H or alkoxy;

[0141] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0142] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0143] (ii) Z1is NH or O, and Z2and Z3are C, or

[0144] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0145] Z4is CR16;

[0146] Z5is CR5;

[0147] Z6is N or CH;

[0148] R5and R16together form alkylene or heteroalkylene;

[0149] X is O, S(O)x or CH2, where x is 0-2;

[0150] Het and R6are selected from (i) or (ii):

[0151] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0152] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0153] R7is -C(O)R17, -S(O)R18or -SO2R18;

[0154] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; andATTY DKT. NO. ISTX 104 WO

[0155] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0156] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula Ia:a

[0159] R1and R2are selected from (i) or (ii):

[0160] (i) R1is H, alkyl, haloalkyl or halo; and R2is alkyl, cycloalkyl or haloalkyl, or

[0161] (ii) R1and R2together form alkylene;

[0162] R3is -O-(CH2)b-R8;

[0163] b is 1-4;

[0164] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0165] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0166] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0167] R12is alkyl or NR14R15;

[0168] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0169] R4is H or alkoxy;

[0170] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0171] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0172] (ii) Z1is NH or O, and Z2and Z3are C, or

[0173] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0174] Z4is CR16;

[0175] R5and R16together form alkylene or heteroalkylene;ATTY DKT. NO. ISTX 104 WO

[0176] X is O, S(O)x or CH2, where x is 0-2;

[0177] Het and R6are selected from (i) or (ii):

[0178] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0179] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0180] R7is -C(O)R17or -SO2R18;

[0181] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0182] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0183] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0184] R1and R2are selected from (i) or (ii):

[0185] (i) R1is H; and R2is alkyl, cycloalkyl or haloalkyl, or

[0186] (ii) R1and R2together form alkylene;

[0187] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[0188] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[0189] R11is alkyl or alkoxy;

[0190] R5and R16together form alkylene;

[0191] X is O or CH2;

[0192] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0193] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.ATTY DKT. NO. ISTX 104 WO

[0194] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0195] R1and R2are selected from (i) or (ii):

[0196] (i) R1is H; and R2is alkyl or haloalkyl, or

[0197] (ii) R1and R2together form alkylene;

[0198] R8is H, CN, OH, aryl, NR9R10or C(O)R11;

[0199] R9and R10are each independently H or C(O)R13; where R13is alkyl;

[0200] R11is alkoxy;

[0201] R5and R16together form alkylene;

[0202] X is O or CH2;

[0203] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0204] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0205] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein R5and R16together form C3-5alkylene.

[0206] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein R5and R16together form propylene.

[0207] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein X is O or S(O)x, where x is 0-2. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein X is O or S.

[0208] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I: R3NZ1wherein:

[0210] a is 0-2;

[0211] R1and R2are selected from (i) or (ii):ATTY DKT. NO. ISTX 104 WO

[0212] (i) R1is H, alkyl, haloalkyl or halo; and R2is alkyl, cycloalkyl or haloalkyl, or

[0213] (ii) R1and R2together form alkylene;

[0214] R3is -O-(CH2)b-R8;

[0215] b is 1-4;

[0216] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0217] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0218] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0219] R12is alkyl or NR14R15;

[0220] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0221] R4is H or alkoxy;

[0222] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0223] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0224] (ii) Z1is NH or O, and Z2and Z3are C, or

[0225] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0226] Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv):

[0227] (i) Z4is N, Z5is CR5, and Z6is CH,

[0228] (ii) Z4is CR16, Z5is N, and Z6is CH,

[0229] (iii) Z4is CR16, Z5is CR5, and Z6is N, or

[0230] (iv) Z4is CR16, Z5is CR5, and Z6is CH;

[0231] R5and R16are selected from (i) or (ii):

[0232] (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or

[0233] (ii) R5and R16together form alkylene or heteroalkylene;

[0234] X is O or S(O)x, where x is 0-2;

[0235] Het and R6are selected from (i) or (ii):

[0236] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0237] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0238] R7is -C(O)R17, -S(O)R18or -SO2R18;ATTY DKT. NO. ISTX 104 WO

[0239] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0240] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0241] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula Ia:wherein:

[0243] a is 0-2;

[0244] R1and R2are selected from (i) or (ii):

[0245] (i) R1is H, alkyl, haloalkyl or halo; and R2is alkyl, cycloalkyl or haloalkyl, or

[0246] (ii) R1and R2together form alkylene;

[0247] R3is -O-(CH2)b-R8;

[0248] b is 1-4;

[0249] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0250] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0251] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0252] R12is alkyl or NR14R15;ATTY DKT. NO. ISTX 104 WO

[0253] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0254] R4is H or alkoxy;

[0255] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0256] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0257] (ii) Z1is NH or O, and Z2and Z3are C, or

[0258] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0259] Z4is N or CR16;

[0260] R5and R16are selected from (i) or (ii):

[0261] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl or haloalkyl, or

[0262] (ii) R5and R16together form alkylene or heteroalkylene;

[0263] X is O or S(O)x, where x is 0-2;

[0264] Het and R6are selected from (i) or (ii):

[0265] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0266] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0267] R7is -C(O)R17or -SO2R18;

[0268] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0269] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0270] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0271] R1and R2are selected from (i) or (ii):ATTY DKT. NO. ISTX 104 WO

[0272] (i) R1is H; and R2is alkyl, cycloalkyl or haloalkyl, or

[0273] (ii) R1and R2together form alkylene;

[0274] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[0275] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[0276] R11is alkyl or alkoxy;

[0277] R5and R16are selected from (i) or (ii):

[0278] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl or alkynyl, or

[0279] (ii) R5and R16together form alkylene;

[0280] X is O;

[0281] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0282] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0283] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0284] R1and R2are selected from (i) or (ii):

[0285] (i) R1is H; and R2is alkyl or haloalkyl, or

[0286] (ii) R1and R2together form alkylene;

[0287] R8is H, CN, OH, aryl, NR9R10or C(O)R11;

[0288] R9and R10are each independently H or C(O)R13; where R13is alkyl;

[0289] R11is alkoxy;

[0290] R5and R16are selected from (i) or (ii):

[0291] (i) R5is H, cyano, alkoxy or alkyl, and R16is H, alkyl, alkoxy, halo or alkynyl, or

[0292] (ii) R5and R16together form alkylene;

[0293] X is O;

[0294] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0295] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0296] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula Ia:ATTY DKT. NO. ISTX 104 WO

[0299] R1and R2are selected from (i) or (ii):

[0300] (i) R1is H, alkyl, haloalkyl or halo; and R2is alkyl, cycloalkyl or haloalkyl, or

[0301] (ii) R1and R2together form alkylene;

[0302] R3is -O-(CH2)b-R8;

[0303] b is 1-4;

[0304] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0305] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0306] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0307] R12is alkyl or NR14R15;

[0308] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0309] R4is H or alkoxy;

[0310] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0311] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0312] (ii) Z1is NH or O, and Z2and Z3are C, or

[0313] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0314] Z4is N or CR16, where R16is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl;

[0315] R5is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl;

[0316] X is O, S(O)x or CH2, where x is 0-2;

[0317] Het and R6are selected from (i) or (ii):

[0318] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, orATTY DKT. NO. ISTX 104 WO

[0319] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0320] R7is -C(O)R17or -SO2R18;

[0321] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0322] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0323] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0324] R1and R2are selected from (i) or (ii):

[0325] (i) R1is H; and R2is alkyl, cycloalkyl or haloalkyl, or

[0326] (ii) R1and R2together form alkylene;

[0327] R5is alkenyl or alkynyl;

[0328] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[0329] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[0330] R11is alkyl or alkoxy;

[0331] X is O or CH2;

[0332] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0333] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0334] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0335] R1and R2are selected from (i) or (ii):

[0336] (i) R1is H; and R2is alkyl or haloalkyl, orATTY DKT. NO. ISTX 104 WO

[0337] (ii) R1and R2together form alkylene;

[0338] R5is alkynyl;

[0339] R8is H, CN, OH, aryl, NR9R10or C(O)R11;

[0340] R9and R10are each independently H or C(O)R13; where R13is alkyl;

[0341] R11is alkoxy;

[0342] X is O or CH2;

[0343] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0344] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0345] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I:wherein:

[0347] a is 0-2;

[0348] R1is H, alkyl, haloalkyl or halo;

[0349] R2and R4together form heteroalkylene;

[0350] R3is -O-(CH2)b-R8;

[0351] b is 1-4;

[0352] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0353] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0354] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0355] R12is alkyl or NR14R15;

[0356] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0357] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0358] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,ATTY DKT. NO. ISTX 104 WO

[0359] (ii) Z1is NH or O, and Z2and Z3are C, or

[0360] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0361] Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv):

[0362] (i) Z4is N, Z5is CR5, and Z6is CH,

[0363] (ii) Z4is CR16, Z5is N, and Z6is CH,

[0364] (iii) Z4is CR16, Z5is CR5, and Z6is N, or

[0365] (iv) Z4is CR16, Z5is CR5, and Z6is CH;

[0366] R5and R16are selected from (i) or (ii):

[0367] (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or

[0368] (ii) R5and R16together form alkylene or heteroalkylene;

[0369] X is O, S(O)xor CH2, where x is 0-2;

[0370] Het and R6are selected from (i) or (ii):

[0371] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0372] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0373] R7is -C(O)R17, -S(O)R18or -SO2R18;

[0374] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0375] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0376] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula Ia:ATTY DKT. NO. ISTX 104 WO

[0379] R1is H, alkyl, haloalkyl or halo;

[0380] R2and R4together form heteroalkylene;

[0381] R3is -O-(CH2)b-R8;

[0382] b is 1-4;

[0383] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0384] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0385] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0386] R12is alkyl or NR14R15;

[0387] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0388] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0389] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0390] (ii) Z1is NH or O, and Z2and Z3are C, or

[0391] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0392] Z4is N or CR16;

[0393] R5and R16are selected from (i) or (ii):

[0394] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl or haloalkyl, or

[0395] (ii) R5and R16together form alkylene or heteroalkylene;

[0396] X is O, S(O)x or CH2, where x is 0-2;

[0397] Het and R6are selected from (i) or (ii):

[0398] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, orATTY DKT. NO. ISTX 104 WO

[0399] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0400] R7is -C(O)R17or -SO2R18;

[0401] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0402] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0403] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0404] R1is H;

[0405] R2and R4together form -O-(CH2)r- or -O-(CH2)1-3-O-(CH2)1-3-, where r is an integer from 2 to 5 and the terminal O is attached to the R4position of Formula I;

[0406] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[0407] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[0408] R11is alkyl or alkoxy;

[0409] R5and R16are selected from (i) or (ii):

[0410] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl or alkynyl, or

[0411] (ii) R5and R16together form alkylene;

[0412] X is O or CH2;

[0413] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0414] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.ATTY DKT. NO. ISTX 104 WO

[0415] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0416] R1is H;

[0417] R2and R4together form -O-(CH2)r- or -O-(CH2)1-3-O-(CH2)1-3-, where r is an integer from 2 to 5 and the terminal O is attached to the R4position of Formula I;

[0418] R8is H, CN, OH, aryl, NR9R10or C(O)R11;

[0419] R9and R10are each independently H or C(O)R13; where R13is alkyl;

[0420] R11is alkoxy;

[0421] R5and R16are selected from (i) or (ii):

[0422] (i) R5is H, cyano, alkoxy or alkyl, and R16is H, alkyl, alkoxy, halo or alkynyl, or

[0423] (ii) R5and R16together form alkylene;

[0424] X is O or CH2;

[0425] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0426] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0427] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I:wherein:

[0429] a is 0-2;

[0430] R1is H, alkyl, haloalkyl or halo;

[0431] R2is alkyl, cycloalkyl or haloalkyl;

[0432] R3is -O-(CH2)b-R8;

[0433] b is 1-4;

[0434] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0435] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;ATTY DKT. NO. ISTX 104 WO

[0436] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0437] R12is alkyl or NR14R15;

[0438] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0439] R4is H or alkoxy;

[0440] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0441] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0442] (ii) Z1is NH or O, and Z2and Z3are C, or

[0443] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0444] Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv):

[0445] (i) Z4is N, Z5is CR5, and Z6is CH,

[0446] (ii) Z4is CR16, Z5is N, and Z6is CH,

[0447] (iii) Z4is CR16, Z5is CR5, and Z6is N, or

[0448] (iv) Z4is CR16, Z5is CR5, and Z6is CH;

[0449] R5and R16are selected from (i) or (ii):

[0450] (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or

[0451] (ii) R5and R16together form alkylene or heteroalkylene;

[0452] X is CR22R23, where R22and R23are each independently H or alkyl;

[0453] Het and R6are selected from (i) or (ii):

[0454] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0455] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0456] R7is -C(O)R17; and

[0457] R17is alkoxy, alkenyloxy, alkynyloxy or -O-(CH2)2-R19; where R19is -OR9or - NR9R10.

[0458] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula Ia:ATTY DKT. NO. ISTX 104 WO

[0461] R1is H, alkyl, haloalkyl or halo;

[0462] R2is alkyl, cycloalkyl or haloalkyl;

[0463] R3is -O-(CH2)b-R8;

[0464] b is 1-4;

[0465] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0466] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0467] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0468] R12is alkyl or NR14R15;

[0469] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0470] R4is H or alkoxy;

[0471] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0472] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0473] (ii) Z1is NH or O, and Z2and Z3are C, or

[0474] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0475] Z4is N or CR16;

[0476] R5and R16are selected from (i) or (ii):

[0477] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl or haloalkyl, or

[0478] (ii) R5and R16together form alkylene or heteroalkylene;

[0479] X is CR22R23, where R22and R23are each independently H or alkyl;

[0480] Het and R6are selected from (i) or (ii):

[0481] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, orATTY DKT. NO. ISTX 104 WO

[0482] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0483] R7is -C(O)R17; and

[0484] R17is alkoxy, alkenyloxy, alkynyloxy or -O-(CH2)2-R19; where R19is -OR9or - NR9R10.

[0485] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0486] R1is H;

[0487] R2is alkyl, cycloalkyl or haloalkyl;

[0488] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[0489] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[0490] R11is alkyl or alkoxy;

[0491] X is CH2; and

[0492] R17is alkoxy.

[0493] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0494] R1is H;

[0495] R2is alkyl or haloalkyl;

[0496] R8is H, CN, OH, aryl, NR9R10or C(O)R11;

[0497] R9and R10are each independently H or C(O)R13; where R13is alkyl;

[0498] R11is alkoxy;

[0499] X is CH2; and

[0500] R17is alkoxy.

[0501] In one embodiment, provided is a compound of Formula II for use in the compositions and methods provided herein:wherein:

[0503] a is 0-2;ATTY DKT. NO. ISTX 104 WO

[0504] R1and R2together form alkylene;

[0505] R3is -O-(CH2)b-R8;

[0506] b is 1-4;

[0507] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0508] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0509] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0510] R12is alkyl or NR14R15;

[0511] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0512] R4is H or alkoxy;

[0513] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0514] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0515] (ii) Z1is NH or O, and Z2and Z3are C, or

[0516] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0517] Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv):

[0518] (i) Z4is N, Z5is CR5, and Z6is CH,

[0519] (ii) Z4is CR16, Z5is N, and Z6is CH,

[0520] (iii) Z4is CR16, Z5is CR5, and Z6is N, or

[0521] (iv) Z4is CR16, Z5is CR5, and Z6is CH;

[0522] R5and R16are selected from (i) or (ii):

[0523] (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or

[0524] (ii) R5and R16together form alkylene or heteroalkylene;

[0525] X is O, S(O)x or CH2, where x is 0-2;

[0526] Het and R6are selected from (i) or (ii):

[0527] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0528] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0529] R7is -C(O)R17, -S(O)R18or -SO2R18;

[0530] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl,ATTY DKT. NO. ISTX 104 WO aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0531] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR20R21.

[0532] In one embodiment, provided is a compound of Formula IIa for use in the compositions and methods provided herein:wherein:

[0534] a is 0-2;

[0535] R1and R2together form alkylene;

[0536] R3is -O-(CH2)b-R8;

[0537] b is 1-4;

[0538] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0539] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0540] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0541] R12is alkyl or NR14R15;

[0542] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0543] R4is H or alkoxy;

[0544] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0545] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,ATTY DKT. NO. ISTX 104 WO

[0546] (ii) Z1is NH or O, and Z2and Z3are C, or

[0547] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0548] Z4is N or CR16;

[0549] R5and R16are selected from (i) or (ii):

[0550] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl or haloalkyl, or

[0551] (ii) R5and R16together form alkylene or heteroalkylene;

[0552] X is O, S(O)xor CH2, where x is 0-2;

[0553] Het and R6are selected from (i) or (ii):

[0554] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0555] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0556] R7is -C(O)R17or -SO2R18;

[0557] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0558] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR20R21.

[0559] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein:

[0560] R8is H, CN, OH, alkoxy, aryl, heteroaryl, NR9R10or C(O)R11;

[0561] R9is H and R10is H or C(O)R13; where R13is alkyl or alkoxy; and

[0562] R11is alkyl or alkoxy;

[0563] R5and R16are selected from (i) or (ii):

[0564] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl or alkynyl, orATTY DKT. NO. ISTX 104 WO

[0565] (ii) R5and R16together form alkylene;

[0566] X is O or CH2;

[0567] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0568] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0569] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein:

[0570] R8is H, CN, OH, alkoxy, aryl, NR9R10or C(O)R11;

[0571] R9is H and R10is C(O)R13; where R13is alkyl; and

[0572] R11is alkoxy;

[0573] R5and R16are selected from (i) or (ii):

[0574] (i) R5is H, cyano, alkoxy or alkyl, and R16is H, alkyl, alkoxy, halo or alkynyl, or

[0575] (ii) R5and R16together form alkylene;

[0576] X is O or CH2;

[0577] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0578] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0579] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein R1and R2together form C2-4alkylene.

[0580] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein R1and R2together form propylene.

[0581] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II:wherein:

[0583] a is 0-2;

[0584] R1and R2are selected from (i) or (ii);ATTY DKT. NO. ISTX 104 WO

[0585] (i) R1is alkyl, cycloalkyl or haloalkyl; and R2is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo, or

[0586] (ii) R1and R2together form alkylene;

[0587] R3is -O-(CH2)b-R8;

[0588] b is 1-4;

[0589] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0590] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0591] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0592] R12is alkyl or NR14R15;

[0593] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0594] R4is H or alkoxy;

[0595] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0596] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0597] (ii) Z1is NH or O, and Z2and Z3are C, or

[0598] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0599] Z4is CR16;

[0600] Z5is CR5;

[0601] Z6is N or CH;

[0602] R5and R16together form alkylene or heteroalkylene;

[0603] X is O, S(O)xor CH2, where x is 0-2;

[0604] Het and R6are selected from (i) or (ii):

[0605] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0606] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0607] R7is -C(O)R17, -S(O)R18or -SO2R18;

[0608] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy,ATTY DKT. NO. ISTX 104 WO haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0609] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0610] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula IIa: wherein:

[0612] a is 0-2;

[0613] R1and R2are selected from (i) or (ii):

[0614] (i) R1is alkyl, cycloalkyl or haloalkyl; and R2is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo; or

[0615] (ii) R1and R2together form alkylene;

[0616] R3is -O-(CH2)b-R8;

[0617] b is 1-4;

[0618] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0619] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0620] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0621] R12is alkyl or NR14R15;

[0622] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0623] R4is H or alkoxy;

[0624] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0625] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,ATTY DKT. NO. ISTX 104 WO

[0626] (ii) Z1is NH or O, and Z2and Z3are C, or

[0627] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0628] Z4is CR16;

[0629] R5and R16together form alkylene or heteroalkylene;

[0630] X is O, S(O)x or CH2, where x is 0-2;

[0631] Het and R6are selected from (i) or (ii):

[0632] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0633] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0634] R7is -C(O)R17or -SO2R18;

[0635] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0636] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0637] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein:

[0638] R1and R2are selected from (i) or (ii):

[0639] (i) R1is alkyl, cycloalkyl or haloalkyl, and R2is H or alkoxy, or

[0640] (ii) R1and R2together form alkylene;

[0641] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[0642] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[0643] R11is alkyl or alkoxy;

[0644] R5and R16together form alkylene;

[0645] X is O or CH2;ATTY DKT. NO. ISTX 104 WO

[0646] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0647] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0648] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein:

[0649] R1and R2are selected from (i) or (ii):

[0650] (i) R1is alkyl or haloalkyl, and R2is H or alkoxy, or

[0651] (ii) R1and R2together form alkylene;

[0652] R8is H, CN, OH, aryl, NR9R10or C(O)R11;

[0653] R9and R10are each independently H or C(O)R13; where R13is alkyl;

[0654] R11is alkoxy;

[0655] R5and R16together form alkylene;

[0656] X is O or CH2;

[0657] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0658] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0659] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein R5and R16together form C3-5alkylene.

[0660] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein R5and R16together form propylene.

[0661] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein X is O or S(O)x, where x is 0-2. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein X is O or S.

[0662] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II:ATTY DKT. NO. ISTX 104 WO wherein:

[0665] R1and R2are selected from (i) or (ii):

[0666] (i) R1is alkyl, cycloalkyl or haloalkyl, and R2is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo, or

[0667] (ii) R1and R2together form alkylene;

[0668] R3is -O-(CH2)b-R8;

[0669] b is 1-4;

[0670] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0671] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0672] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0673] R12is alkyl or NR14R15;

[0674] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0675] R4is H or alkoxy;

[0676] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0677] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0678] (ii) Z1is NH or O, and Z2and Z3are C, or

[0679] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0680] Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv):

[0681] (i) Z4is N, Z5is CR5, and Z6is CH,

[0682] (ii) Z4is CR16, Z5is N, and Z6is CH,

[0683] (iii) Z4is CR16, Z5is CR5, and Z6is N, or

[0684] (iv) Z4is CR16, Z5is CR5, and Z6is CH;

[0685] R5and R16are selected from (i) or (ii):ATTY DKT. NO. ISTX 104 WO

[0686] (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or

[0687] (ii) R5and R16together form alkylene or heteroalkylene;

[0688] X is O or S(O)x, where x is 0-2;

[0689] Het and R6are selected from (i) or (ii):

[0690] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0691] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0692] R7is -C(O)R17, -S(O)R18or -SO2R18;

[0693] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0694] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0695] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula IIa:

[0697] a is 0-2;

[0698] R1and R2are selected from (i) or (ii):ATTY DKT. NO. ISTX 104 WO

[0699] (i) R1is alkyl, cycloalkyl or haloalkyl, and R2is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo, or

[0700] (ii) R1and R2together form alkylene;

[0701] R3is -O-(CH2)b-R8;

[0702] b is 1-4;

[0703] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0704] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0705] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0706] R12is alkyl or NR14R15;

[0707] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0708] R4is H or alkoxy;

[0709] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0710] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0711] (ii) Z1is NH or O, and Z2and Z3are C, or

[0712] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0713] Z4is N or CR16;

[0714] R5and R16are selected from (i) or (ii):

[0715] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl or haloalkyl, or

[0716] (ii) R5and R16together form alkylene or heteroalkylene;

[0717] X is O or S(O)x, where x is 0-2;

[0718] Het and R6are selected from (i) or (ii):

[0719] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0720] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0721] R7is -C(O)R17or -SO2R18;

[0722] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl,ATTY DKT. NO. ISTX 104 WO aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0723] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0724] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein:

[0725] R1and R2are selected from (i) or (ii):

[0726] (i) R1is alkyl, cycloalkyl or haloalkyl, and R2is H or alkoxy, or

[0727] (ii) R1and R2together form alkylene;

[0728] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[0729] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[0730] R11is alkyl or alkoxy;

[0731] R5and R16are selected from (i) or (ii):

[0732] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl or alkynyl, or

[0733] (ii) R5and R16together form alkylene;

[0734] X is O;

[0735] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0736] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0737] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein:

[0738] R1and R2are selected from (i) or (ii):

[0739] (i) R1is alkyl or haloalkyl, and R2is H or alkoxy, or

[0740] (ii) R1and R2together form alkylene;

[0741] R8is H, CN, OH, aryl, NR9R10or C(O)R11;

[0742] R9and R10are each independently H or C(O)R13; where R13is alkyl;

[0743] R11is alkoxy;

[0744] R5and R16are selected from (i) or (ii):ATTY DKT. NO. ISTX 104 WO

[0745] (i) R5is H, cyano, alkoxy or alkyl, and R16is H, alkyl, alkoxy, halo or alkynyl, or

[0746] (ii) R5and R16together form alkylene;

[0747] X is O;

[0748] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0749] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0750] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula IIa:

[0752] a is 0-2;

[0753] R1and R2are selected from (i) or (ii):

[0754] (i) R1is alkyl, cycloalkyl or haloalkyl, and R2is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo, or

[0755] (ii) R1and R2together form alkylene;

[0756] R3is -O-(CH2)b-R8;

[0757] b is 1-4;

[0758] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0759] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0760] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0761] R12is alkyl or NR14R15;

[0762] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0763] R4is H or alkoxy;

[0764] Z1, Z2and Z3are selected from (i), (ii) or (iii):ATTY DKT. NO. ISTX 104 WO

[0765] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0766] (ii) Z1is NH or O, and Z2and Z3are C, or

[0767] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0768] Z4is N or CR16, where R16is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl;

[0769] R5is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl;

[0770] X is O, S(O)xor CH2, where x is 0-2;

[0771] Het and R6are selected from (i) or (ii):

[0772] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0773] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0774] R7is -C(O)R17or -SO2R18;

[0775] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0776] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0777] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein:

[0778] R1and R2are selected from (i) or (ii):

[0779] (i) R1is alkyl, cycloalkyl or haloalkyl, and R2is H or alkoxy, or

[0780] (ii) R1and R2together form alkylene;

[0781] R5is alkenyl or alkynyl;

[0782] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[0783] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[0784] R11is alkyl or alkoxy;

[0785] X is O or CH2;ATTY DKT. NO. ISTX 104 WO

[0786] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0787] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0788] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein:

[0789] R1and R2are selected from (i) or (ii):

[0790] (i) R1is alkyl or haloalkyl, and R2is H or alkoxy, or

[0791] (ii) R1and R2together form alkylene;

[0792] R5is alkynyl;

[0793] R8is H, CN, OH, aryl, NR9R10or C(O)R11;

[0794] R9and R10are each independently H or C(O)R13; where R13is alkyl;

[0795] R11is alkoxy;

[0796] X is O or CH2;

[0797] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0798] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0799] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I:wherein:

[0801] a is 0-2;

[0802] R1is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo;

[0803] R2and R4together form heteroalkylene;

[0804] R3is -O-(CH2)b-R8;

[0805] b is 1-4;

[0806] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);ATTY DKT. NO. ISTX 104 WO

[0807] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0808] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0809] R12is alkyl or NR14R15;

[0810] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0811] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0812] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0813] (ii) Z1is NH or O, and Z2and Z3are C, or

[0814] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0815] Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv):

[0816] (i) Z4is N, Z5is CR5, and Z6is CH,

[0817] (ii) Z4is CR16, Z5is N, and Z6is CH,

[0818] (iii) Z4is CR16, Z5is CR5, and Z6is N, or

[0819] (iv) Z4is CR16, Z5is CR5, and Z6is CH;

[0820] R5and R16are selected from (i) or (ii):

[0821] (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or

[0822] (ii) R5and R16together form alkylene or heteroalkylene;

[0823] X is O, S(O)x or CH2, where x is 0-2;

[0824] Het and R6are selected from (i) or (ii):

[0825] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0826] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0827] R7is -C(O)R17, -S(O)R18or -SO2R18;

[0828] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; andATTY DKT. NO. ISTX 104 WO

[0829] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0830] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula Ia:a

[0833] R1is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo;

[0834] R2and R4together form heteroalkylene;

[0835] R3is -O-(CH2)b-R8;

[0836] b is 1-4;

[0837] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0838] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0839] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0840] R12is alkyl or NR14R15;

[0841] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0842] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0843] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0844] (ii) Z1is NH or O, and Z2and Z3are C, or

[0845] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0846] Z4is N or CR16;

[0847] R5and R16are selected from (i) or (ii):ATTY DKT. NO. ISTX 104 WO

[0848] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl or haloalkyl, or

[0849] (ii) R5and R16together form alkylene or heteroalkylene;

[0850] X is O, S(O)xor CH2, where x is 0-2;

[0851] Het and R6are selected from (i) or (ii):

[0852] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0853] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0854] R7is -C(O)R17or -SO2R18;

[0855] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0856] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[0857] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0858] R1is H or alkoxy;

[0859] R2and R4together form -O-(CH2)r- or -O-(CH2)1-3-O-(CH2)1-3-, where r is an integer from 2 to 5 and the terminal O is attached to the R4position of Formula I;

[0860] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[0861] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[0862] R11is alkyl or alkoxy;

[0863] R5and R16are selected from (i) or (ii):

[0864] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl or alkynyl, or

[0865] (ii) R5and R16together form alkylene;ATTY DKT. NO. ISTX 104 WO

[0866] X is O or CH2;

[0867] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0868] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0869] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein:

[0870] R1is H or alkoxy;

[0871] R2and R4together form -O-(CH2)r- or -O-(CH2)1-3-O-(CH2)1-3-, where r is an integer from 2 to 5 and the terminal O is attached to the R4position of Formula I;

[0872] R8is H, CN, OH, aryl, NR9R10or C(O)R11;

[0873] R9and R10are each independently H or C(O)R13; where R13is alkyl;

[0874] R11is alkoxy;

[0875] R5and R16are selected from (i) or (ii):

[0876] (i) R5is H, cyano, alkoxy or alkyl, and R16is H, alkyl, alkoxy, halo or alkynyl, or

[0877] (ii) R5and R16together form alkylene;

[0878] X is O or CH2;

[0879] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[0880] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[0881] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II:wherein:

[0883] a is 0-2;

[0884] R1is alkyl, cycloalkyl or haloalkyl;

[0885] R2is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo;

[0886] R3is -O-(CH2)b-R8;ATTY DKT. NO. ISTX 104 WO

[0887] b is 1-4;

[0888] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0889] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0890] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0891] R12is alkyl or NR14R15;

[0892] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0893] R4is H or alkoxy;

[0894] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0895] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0896] (ii) Z1is NH or O, and Z2and Z3are C, or

[0897] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0898] Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv):

[0899] (i) Z4is N, Z5is CR5, and Z6is CH,

[0900] (ii) Z4is CR16, Z5is N, and Z6is CH,

[0901] (iii) Z4is CR16, Z5is CR5, and Z6is N, or

[0902] (iv) Z4is CR16, Z5is CR5, and Z6is CH;

[0903] R5and R16are selected from (i) or (ii):

[0904] (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or

[0905] (ii) R5and R16together form alkylene or heteroalkylene;

[0906] X is CR22R23, where R22and R23are each independently H or alkyl;

[0907] Het and R6are selected from (i) or (ii):

[0908] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0909] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0910] R7is -C(O)R17; and

[0911] R17is alkoxy, alkenyloxy, alkynyloxy or -O-(CH2)2-R19; where R19is -OR9or - NR9R10.

[0912] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula IIa:ATTY DKT. NO. ISTX 104 WO

[0915] R1is alkyl, cycloalkyl or haloalkyl;

[0916] R2is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo;

[0917] R3is -O-(CH2)b-R8;

[0918] b is 1-4;

[0919] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0920] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0921] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0922] R12is alkyl or NR14R15;

[0923] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0924] R4is H or alkoxy;

[0925] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0926] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0927] (ii) Z1is NH or O, and Z2and Z3are C, or

[0928] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0929] Z4is N or CR16;

[0930] R5and R16are selected from (i) or (ii):

[0931] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl or haloalkyl, or

[0932] (ii) R5and R16together form alkylene or heteroalkylene;

[0933] X is CR22R23, where R22and R23are each independently H or alkyl;

[0934] Het and R6are selected from (i) or (ii):

[0935] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, orATTY DKT. NO. ISTX 104 WO

[0936] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0937] R7is -C(O)R17; and

[0938] R17is alkoxy, alkenyloxy, alkynyloxy or -O-(CH2)2-R19; where R19is -OR9or - NR9R10.

[0939] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein:

[0940] R1is alkyl, cycloalkyl or haloalkyl;

[0941] R2is H or alkoxy;

[0942] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[0943] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[0944] R11is alkyl or alkoxy;

[0945] X is CH2; and

[0946] R17is alkoxy.

[0947] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein:

[0948] R1is alkyl or haloalkyl;

[0949] R2is H or alkoxy;

[0950] R8is H, CN, OH, aryl, NR9R10or C(O)R11;

[0951] R9and R10are each independently H or C(O)R13; where R13is alkyl;

[0952] R11is alkoxy;

[0953] X is CH2; and

[0954] R17is alkoxy.

[0955] In one embodiment, provided is a compound of Formula III for use in the compositions and methods provided herein:wherein:ATTY DKT. NO. ISTX 104 WO

[0957] a is 0-2;

[0958] R1and R2together form alkylene;

[0959] R3is -O-(CH2)b-R8;

[0960] b is 1-4;

[0961] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0962] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0963] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0964] R12is alkyl or NR14R15;

[0965] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[0966] R4is H or alkoxy;

[0967] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0968] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[0969] (ii) Z1is NH or O, and Z2and Z3are C, or

[0970] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[0971] Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv):

[0972] (i) Z4is N, Z5is CR5, and Z6is CH,

[0973] (ii) Z4is CR16, Z5is N, and Z6is CH,

[0974] (iii) Z4is CR16, Z5is CR5, and Z6is N, or

[0975] (iv) Z4is CR16, Z5is CR5, and Z6is CH;

[0976] R5and R16are selected from (i) or (ii):

[0977] (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or

[0978] (ii) R5and R16together form alkylene or heteroalkylene;

[0979] X is O, S(O)xor CH2, where x is 0-2;

[0980] Het and R6are selected from (i) or (ii):

[0981] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[0982] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[0983] R7is -C(O)R17, -S(O)R18or -SO2R18;ATTY DKT. NO. ISTX 104 WO

[0984] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[0985] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR20R21.

[0986] In one embodiment, provided is a compound of Formula IIIa for use in the compositions and methods provided herein: R3 NZ1O2

[0988] a is 0-2;

[0989] R1and R2together form alkylene;

[0990] R3is -O-(CH2)b-R8;

[0991] b is 1-4;

[0992] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[0993] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[0994] R11is hydroxy, alkyl, alkoxy or NR14R15;

[0995] R12is alkyl or NR14R15;

[0996] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;ATTY DKT. NO. ISTX 104 WO

[0997] R4is H or alkoxy;

[0998] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[0999] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[1000] (ii) Z1is NH or O, and Z2and Z3are C, or

[1001] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[1002] Z4is N or CR16;

[1003] R5and R16are selected from (i) or (ii):

[1004] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl or haloalkyl, or

[1005] (ii) R5and R16together form alkylene or heteroalkylene;

[1006] X is O, S(O)x or CH2, where x is 0-2;

[1007] Het and R6are selected from (i) or (ii):

[1008] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[1009] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[1010] R7is -C(O)R17or -SO2R18;

[1011] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[1012] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR20R21.

[1013] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein:

[1014] R8is H, CN, OH, alkoxy, aryl, heteroaryl, NR9R10or C(O)R11;

[1015] R9is H and R10is H or C(O)R13; where R13is alkyl or alkoxy; and

[1016] R11is alkyl or alkoxy;ATTY DKT. NO. ISTX 104 WO

[1017] R5and R16are selected from (i) or (ii):

[1018] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl or alkynyl, or

[1019] (ii) R5and R16together form alkylene;

[1020] X is O or CH2;

[1021] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[1022] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[1023] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein:

[1024] R8is H, CN, OH, alkoxy, aryl, NR9R10or C(O)R11;

[1025] R9is H and R10is C(O)R13; where R13is alkyl; and

[1026] R11is alkoxy;

[1027] R5and R16are selected from (i) or (ii):

[1028] (i) R5is H, cyano, alkoxy or alkyl, and R16is H, alkyl, alkoxy, halo or alkynyl, or

[1029] (ii) R5and R16together form alkylene;

[1030] X is O or CH2;

[1031] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[1032] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[1033] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein R1and R2together form C1-4alkylene optionally substituted with one or more halo or methyl.

[1034] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein R1and R2together form methylene or ethylene each optionally substituted with one or two halo or methyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein R1and R2together form unsubstituted methylene or ethylene.

[1035] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III:ATTY DKT. NO. ISTX 104 WO

[1038] R1and R2are selected from (i) or (ii):

[1039] (i) R1and R2are each independently alkyl, cycloalkyl or haloalkyl, or

[1040] (ii) R1and R2together form alkylene;

[1041] R3is -O-(CH2)b-R8;

[1042] b is 1-4;

[1043] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[1044] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[1045] R11is hydroxy, alkyl, alkoxy or NR14R15;

[1046] R12is alkyl or NR14R15;

[1047] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[1048] R4is H or alkoxy;

[1049] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[1050] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[1051] (ii) Z1is NH or O, and Z2and Z3are C, or

[1052] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[1053] Z4is CR16;

[1054] Z5is CR5;

[1055] Z6is N or CH;

[1056] R5and R16together form alkylene or heteroalkylene;

[1057] X is O, S(O)x or CH2, where x is 0-2;

[1058] Het and R6are selected from (i) or (ii):

[1059] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, orATTY DKT. NO. ISTX 104 WO

[1060] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[1061] R7is -C(O)R17, -S(O)R18or -SO2R18;

[1062] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[1063] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[1064] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula IIIa: R3NZ1

[1066] a is 0-2;

[1067] R1and R2are selected from (i) or (ii):

[1068] (i) R1and R2are each independently alkyl, cycloalkyl or haloalkyl, or

[1069] (ii) R1and R2together form alkylene;

[1070] R3is -O-(CH2)b-R8;

[1071] b is 1-4;

[1072] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);ATTY DKT. NO. ISTX 104 WO

[1073] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[1074] R11is hydroxy, alkyl, alkoxy or NR14R15;

[1075] R12is alkyl or NR14R15;

[1076] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[1077] R4is H or alkoxy;

[1078] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[1079] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[1080] (ii) Z1is NH or O, and Z2and Z3are C, or

[1081] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[1082] Z4is CR16;

[1083] R5and R16together form alkylene or heteroalkylene;

[1084] X is O, S(O)xor CH2, where x is 0-2;

[1085] Het and R6are selected from (i) or (ii):

[1086] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[1087] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[1088] R7is -C(O)R17or -SO2R18;

[1089] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[1090] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[1091] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein:ATTY DKT. NO. ISTX 104 WO

[1092] R1and R2are selected from (i) or (ii):

[1093] (i) R1and R2are each alkyl, or

[1094] (ii) R1and R2together form alkylene optionally substituted with one or more halo or methyl;

[1095] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[1096] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[1097] R11is alkyl or alkoxy;

[1098] R5and R16together form alkylene;

[1099] X is O or CH2;

[1100] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[1101] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[1102] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein R5and R16together form C3-5alkylene.

[1103] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein R5and R16together form propylene.

[1104] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein X is O or S(O)x, where x is 0-2. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein X is O or S.

[1105] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III:wherein:

[1107] a is 0-2;

[1108] R1and R2are selected from (i) or (ii):

[1109] (i) R1and R2are each independently alkyl, cycloalkyl or haloalkyl, orATTY DKT. NO. ISTX 104 WO

[1110] (ii) R1and R2together form alkylene;

[1111] R3is -O-(CH2)b-R8;

[1112] b is 1-4;

[1113] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[1114] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[1115] R11is hydroxy, alkyl, alkoxy or NR14R15;

[1116] R12is alkyl or NR14R15;

[1117] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[1118] R4is H or alkoxy;

[1119] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[1120] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[1121] (ii) Z1is NH or O, and Z2and Z3are C, or

[1122] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[1123] Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv):

[1124] (i) Z4is N, Z5is CR5, and Z6is CH,

[1125] (ii) Z4is CR16, Z5is N, and Z6is CH,

[1126] (iii) Z4is CR16, Z5is CR5, and Z6is N, or

[1127] (iv) Z4is CR16, Z5is CR5, and Z6is CH;

[1128] R5and R16are selected from (i) or (ii):

[1129] (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or

[1130] (ii) R5and R16together form alkylene or heteroalkylene;

[1131] X is O or S(O)x, where x is 0-2;

[1132] Het and R6are selected from (i) or (ii):

[1133] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[1134] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[1135] R7is -C(O)R17, -S(O)R18or -SO2R18;

[1136] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl,ATTY DKT. NO. ISTX 104 WO aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[1137] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[1138] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula IIIa:

[1140] a is 0-2;

[1141] R1and R2are selected from (i) or (ii):

[1142] (i) R1and R2are each independently alkyl, cycloalkyl or haloalkyl, or

[1143] (ii) R1and R2together form alkylene;

[1144] R3is -O-(CH2)b-R8;

[1145] b is 1-4;

[1146] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[1147] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[1148] R11is hydroxy, alkyl, alkoxy or NR14R15;

[1149] R12is alkyl or NR14R15;

[1150] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;ATTY DKT. NO. ISTX 104 WO

[1151] R4is H or alkoxy;

[1152] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[1153] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[1154] (ii) Z1is NH or O, and Z2and Z3are C, or

[1155] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[1156] Z4is N or CR16;

[1157] R5and R16are selected from (i) or (ii):

[1158] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl or haloalkyl, or

[1159] (ii) R5and R16together form alkylene or heteroalkylene;

[1160] X is O or S(O)x, where x is 0-2;

[1161] Het and R6are selected from (i) or (ii):

[1162] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[1163] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[1164] R7is -C(O)R17or -SO2R18;

[1165] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[1166] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[1167] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein:

[1168] R1and R2are selected from (i) or (ii):

[1169] (i) R1and R2are each alkyl, orATTY DKT. NO. ISTX 104 WO

[1170] (ii) R1and R2together form alkylene optionally substituted with one or more halo or methyl;

[1171] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[1172] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[1173] R11is alkyl or alkoxy;

[1174] R5and R16are selected from (i) or (ii):

[1175] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl or alkynyl, or

[1176] (ii) R5and R16together form alkylene;

[1177] X is O;

[1178] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[1179] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[1180] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein:

[1181] R1and R2are selected from (i) or (ii):

[1182] (i) R1and R2are each alkyl, or

[1183] (ii) R1and R2together form alkylene optionally substituted with one or more halo or methyl;

[1184] R8is H, CN, OH, aryl, NR9R10or C(O)R11;

[1185] R9and R10are each independently H or C(O)R13; where R13is alkyl;

[1186] R11is alkoxy;

[1187] R5and R16are selected from (i) or (ii):

[1188] (i) R5is H, cyano, alkoxy or alkyl, and R16is H, alkyl, alkoxy, halo or alkynyl, or

[1189] (ii) R5and R16together form alkylene;

[1190] X is O;

[1191] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[1192] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[1193] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula IIIa:ATTY DKT. NO. ISTX 104 WO

[1196] R1and R2are selected from (i) or (ii):

[1197] (i) R1and R2are each independently alkyl, cycloalkyl or haloalkyl, or

[1198] (ii) R1and R2together form alkylene;

[1199] R3is -O-(CH2)b-R8;

[1200] b is 1-4;

[1201] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[1202] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[1203] R11is hydroxy, alkyl, alkoxy or NR14R15;

[1204] R12is alkyl or NR14R15;

[1205] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[1206] R4is H or alkoxy;

[1207] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[1208] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[1209] (ii) Z1is NH or O, and Z2and Z3are C, or

[1210] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[1211] Z4is N or CR16, where R16is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl;

[1212] R5is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl;

[1213] X is O, S(O)xor CH2, where x is 0-2;

[1214] Het and R6are selected from (i) or (ii):

[1215] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, orATTY DKT. NO. ISTX 104 WO

[1216] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[1217] R7is -C(O)R17or -SO2R18;

[1218] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[1219] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[1220] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein:

[1221] R1and R2are selected from (i) or (ii):

[1222] (i) R1and R2are each independently alkyl, cycloalkyl or haloalkyl, or

[1223] (ii) R1and R2together form alkylene optionally substituted with one or more halo or methyl;

[1224] R5is alkenyl or alkynyl;

[1225] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[1226] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[1227] R11is alkyl or alkoxy;

[1228] X is O or CH2;

[1229] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[1230] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[1231] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein:

[1232] R1and R2are selected from (i) or (ii):ATTY DKT. NO. ISTX 104 WO

[1233] (i) R1and R2are each independently alkyl or haloalkyl, or

[1234] (ii) R1and R2together form alkylene optionally substituted with one or more halo or methyl;

[1235] R5is alkynyl;

[1236] R8is H, CN, OH, aryl, NR9R10or C(O)R11;

[1237] R9and R10are each independently H or C(O)R13; where R13is alkyl;

[1238] R11is alkoxy;

[1239] X is O or CH2;

[1240] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[1241] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[1242] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III:wherein:

[1244] a is 0-2;

[1245] R1is alkyl or haloalkyl;

[1246] R2and R4together form heteroalkylene;

[1247] R3is -O-(CH2)b-R8;

[1248] b is 1-4;

[1249] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[1250] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[1251] R11is hydroxy, alkyl, alkoxy or NR14R15;

[1252] R12is alkyl or

[1253] R14and R15are eachalkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;ATTY DKT. NO. ISTX 104 WO

[1254] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[1255] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[1256] (ii) Z1is NH or O, and Z2and Z3are C, or

[1257] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[1258] Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv):

[1259] (i) Z4is N, Z5is CR5, and Z6is CH,

[1260] (ii) Z4is CR16, Z5is N, and Z6is CH,

[1261] (iii) Z4is CR16, Z5is CR5, and Z6is N, or

[1262] (iv) Z4is CR16, Z5is CR5, and Z6is CH;

[1263] R5and R16are selected from (i) or (ii):

[1264] (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or

[1265] (ii) R5and R16together form alkylene or heteroalkylene;

[1266] X is O, S(O)xor CH2, where x is 0-2;

[1267] Het and R6are selected from (i) or (ii):

[1268] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or

[1269] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[1270] R7is -C(O)R17, -S(O)R18or -SO2R18;

[1271] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[1272] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[1273] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula IIIa:ATTY DKT. NO. ISTX 104 WO

[1276] R1is alkyl or haloalkyl;

[1277] R2and R4together form heteroalkylene;

[1278] R3is -O-(CH2)b-R8;

[1279] b is 1-4;

[1280] R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12);

[1281] R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15;

[1282] R11is hydroxy, alkyl, alkoxy or NR14R15;

[1283] R12is alkyl or NR14R15;

[1284] R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl;

[1285] Z1, Z2and Z3are selected from (i), (ii) or (iii):

[1286] (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N,

[1287] (ii) Z1is NH or O, and Z2and Z3are C, or

[1288] (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N;

[1289] Z4is N or CR16;

[1290] R5and R16are selected from (i) or (ii):

[1291] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl or haloalkyl, or

[1292] (ii) R5and R16together form alkylene or heteroalkylene;

[1293] X is O, S(O)xor CH2, where x is 0-2;

[1294] Het and R6are selected from (i) or (ii):

[1295] (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, orATTY DKT. NO. ISTX 104 WO

[1296] (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;

[1297] R7is -C(O)R17or -SO2R18;

[1298] R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and

[1299] R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

[1300] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein:

[1301] R1is alkyl;

[1302] R2and R4together form -O-(CH2)r- or -O-(CH2)1-3-O-(CH2)1-3-, where r is an integer from 2 to 5 and the terminal O is attached to the R4position of Formula III or IIIa;

[1303] R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11;

[1304] R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy;

[1305] R11is alkyl or alkoxy;

[1306] R5and R16are selected from (i) or (ii):

[1307] (i) R5and R16are each independently H, cyano, halo, alkoxy, alkyl, alkenyl or alkynyl, or

[1308] (ii) R5and R16together form alkylene;

[1309] X is O or CH2;

[1310] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[1311] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.ATTY DKT. NO. ISTX 104 WO

[1312] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula III or IIIa, wherein:

[1313] R1is alkyl;

[1314] R2and R4together form -O-(CH2)r- or -O-(CH2)1-3-O-(CH2)1-3-, where r is an integer from 2 to 5 and the terminal O is attached to the R4position of Formula III or IIIa;

[1315] R8is H, CN, OH, aryl, NR9R10or C(O)R11;

[1316] R9and R10are each independently H or C(O)R13; where R13is alkyl;

[1317] R11is alkoxy;

[1318] R5and R16are selected from (i) or (ii):

[1319] (i) R5is H, cyano, alkoxy or alkyl, and R16is H, alkyl, alkoxy, halo or alkynyl, or

[1320] (ii) R5and R16together form alkylene;

[1321] X is O or CH2;

[1322] R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and

[1323] R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

[1324] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein X is O. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein X is CH2.

[1325] In another embodiment, a is 0. In another embodiment, a is 1. In another embodiment, a is 2. In another embodiment, a is 0 or 1.

[1326] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein R2is alkyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein R2is methyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein R2is haloalkyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein R2is fluoromethyl, difluoromethyl or trifluoromethyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I or Ia, wherein R2is difluoromethyl.

[1327] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein R2is H. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa,ATTY DKT. NO. ISTX 104 WO wherein R2is alkoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein R2is methoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein R2is haloalkoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein R2is fluoromethoxy, difluoromethoxy or trifluoromethoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula II or IIa, wherein R2is difluoromethoxy.

[1328] In another embodiment, b is 1. In another embodiment, b is 2. In another embodiment, b is 3. In another embodiment, b is 4. In another embodiment, b is 1 or 2.

[1329] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R8is H, phenyl, 4- fluorophenyl, morpholinyl, COOH, COOMe, C(=NH)NHOH, tetrazolyl, oxadiazolyl, triazolyl, pyridyl, imidazolyl, oxazolidinyl, NHC(O)OMe, cyano, hydroxy, amino or acetylamino. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R8is H, phenyl, COOMe, hydroxy, cyano, amino or acetylamino. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R8is hydrogen. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein b is 1 and R8is hydrogen.

[1330] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R4is alkoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R4is methoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R4is H.

[1331] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein Z1is NH or O, and Z2and Z3are C. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein Z1is O, and Z2and Z3are C.

[1332] In another embodiment, Z4is N. In another embodiment, Z4is CR16.

[1333] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R5is H, cyano, alkoxy or alkyl,ATTY DKT. NO. ISTX 104 WO and R16is H, alkyl, alkoxy, halo or alkynyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R5is H, cyano, methoxy or methyl, and R16is H, methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, fluoro, ethynyl or propynyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R5is H, cyano, methoxy or methyl, and R16is H, methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, ethynyl or propynyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R5is H and R16is H, methyl, ethyl, isopropyl, tert-butyl or methoxy.

[1334] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein Het is a 5- or 6-membered heteroaryl, and R6is H or alkyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein Het is a 5-membered heteroaryl, and R6is H or methyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein Het is pyrazolyl, oxazolyl, thiazolyl or pyridyl, and R6is H or methyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein Het is pyrazolyl, and R6is H or methyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein Het is a 5-membered heteroaryl, R6is –(CH2)–, and R6and Het together with the atoms to which they are attached form a 5,5-bicyclic ring system. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein Het is a pyrazolyl, R6is –(CH2)–, and R6and Het together with the atoms to which they are attached form a 5,5-bicyclic ring system.

[1335] In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R7is -C(O)R17. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R7is -S(O)R18. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R7is -SO2R18. In another embodiment, the compounds for use in theATTY DKT. NO. ISTX 104 WO compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R17is alkyl, alkoxy, alkenyl, haloalkenyl, alkynyl, NR20R21or hydroxyalkynyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R17is alkyl, alkoxy, alkenyl, haloalkenyl, alkynyl or hydroxyalkynyl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R17is methyl, methoxy, NHMe, ethenyl, 1-fluoro-1-ethenyl, ethynyl or 1-propyn-1-yl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R17is methyl, methoxy, ethenyl, 1-fluoro-1-ethenyl, ethynyl or 1-propyn-1-yl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R17is methyl or methoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R17is methoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R17is ethenyl, 1-fluoro-1-ethenyl, ethynyl or 1- propyn-1-yl. In another embodiment, the compounds for use in the compositions and methods provided herein have Formula I, Ia, II, IIa, III or IIIa, wherein R18is methyl or tert-butyl.

[1336] In another embodiment, the compounds for use in the compositions and methods provided herein are selected from: O O O O OOO ONFOO O O SNO NHATTY DKT. NO. ISTX 104 WO

[1337] In another embodiment, the compounds for use in the compositions and methods provided herein are selected from:

[1338] In another embodiment, the compounds for use in the compositions and methods provided herein are selected from: O O O O O ONO O O O ONF SONH ONONH FATTY DKT. NO. ISTX 104 WOOprovided herein are selected from:ATTY DKT. NO. ISTX 104 WO ,ATTY DKT. NO. ISTX 104 WOATTY DKT. NO. ISTX 104 WO , , ,ATTY DKT. NO. ISTX 104 WO F F .provided herein is: O OOO O O N ,ATTY DKT. NO. ISTX 104 WO , .,provided herein is:ATTY DKT. NO. ISTX 104 WO . compound for use in the compositions and methods, ,methods provided herein is:ATTY DKT. NO. ISTX 104 WO O O O .by any method apparent to those of skill in the art. Compounds provided herein can be prepared according to the Exemplary Preparation Schemes provided below. Reaction conditions, steps, and reactants not provided in the Exemplary Preparation Schemes would be apparent to, and known by, those skilled in the art.

[1347] Additional steps and reagents not provided in the Exemplary Preparation Schemes would be known to those of skill in the art. Exemplary methods of preparation are described in detail in the Examples herein.

[1348] General Scheme 1 describes the preparation of a compound of Formula I where Z1is O and Z2and Z3are C; and all other groups are as defined in the Summary or in any embodiments described herein. General Scheme 1 R5R3O C)benzo[d]isoxazole compounds provided herein where in Step 1, an appropriately substituted 2-fluorobenzonitrile is converted to a benzo[d]isoxazol-3-amine scaffold by reacting with N- hydroxyacetamide in presence of a base such as potassium t-butoxide. In Step 2, the free amine is reacted with an aryl or heteroaryl sulfonyl chloride in presence of a base such as sodium tert-pentoxide, triethylamine, pyridine or sodium hydride. This can be accomplishedATTY DKT. NO. ISTX 104 WO at 0oC, but may need to be done at room temperature or at an elevated temperature such as 60oC. The final steps involve deprotection of the amine (Step 3) followed by amide formation (either via a reaction with an appropriately substituted acid chloride or via activation of an acid using a coupling agent such as HATU, HBTU, T3P, EDCI / HOBt or other agents known to those skilled in the art) or sulfonamide formation with a sulfonyl chloride in the presence of a base such as triethyl amine in Step 4. For preparing a carbamate or a urea derivative, an appropriately substituted carbonochloridate or isocyanate can be reacted with the free amine, in the presence of a base such as triethyl amine.

[1350] General Scheme 2 describes the preparation of a compound of Formula I where Z1and Z3are N and Z2is C; and all other groups are as defined in the Summary or in any embodiments described herein.prepared by starting with an appropriately substituted 2-chloropyridine which can be converted to the corresponding 2-hydrazinopyridine by heating in presence of hydrazine hydrate (Step 1). In Step 2, reaction with cyanogen bromide leads to the assembly of the [1,2,4]triazolo[4,3-a]pyridin-3-amine scaffold. Steps 3, 4 and 5 follow protocols detailed above for General Scheme 1 (steps 2, 3 and 4) leading to the synthesis of compounds of Formula I, where Z1and Z3are N and Z2is C.

[1352] General Scheme 3 describes the preparation of a compound of Formula I where Z1and Z2are N and Z3is C; and all other groups are as defined in the Summary or in any embodiments described herein.ATTY DKT. NO. ISTX 104 WO

[1353] An appropriately substituted 2-cyano pyridine is converted to a 1-amino 2-cyano pyridine by reacting with a sulfonylated hydroxyl amine or (aminooxy)sulfonic acid (Step 1, condition A or B), followed by cyclization in the presence of hydroxylamine and acetic anhydride (Step 2). Steps 3, 4 and 5 follow protocols detailed above for General Scheme 1 (steps 2, 3 and 4) leading to the synthesis of compounds of Formula I, where Z1and Z2are N and Z3is C.

[1354] General Scheme 4 describes the preparation of a compound of Formula I where Z1is NH and Z2and Z3are C; and all other groups are as defined in the Summary or in any embodiments described herein.to the 3-aminobenzopyrazole (Step 1), using hydrazine in the presence of a base such as potassium carbonate, as shown above. Steps 2, 3 and 4 follow protocols detailed above for General Scheme 1 (steps 2, 3 and 4) leading to the synthesis of compounds of Formula I, where Z1is NH and Z2and Z3are C.ATTY DKT. NO. ISTX 104 WO

[1356] General Scheme 5 describes the preparation of a compound of Formula I where Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N; and all other groups are as defined in the Summary or in any embodiments described herein.reduced in Step 1 with LAH in a solvent such as THF. Treatment of the resulting 2- aminomethyl pyridine intermediate with cyanogen bromide in toluene (Step 2) affords the imidazo[1,5-a]pyridin-3-amine Intermediate A. In General scheme 5(B), an appropriately substituted 2-cyanopyridine is reduced to the corresponding 2-aminomethyl pyridine (Step 1 as in Scheme 5A above), then subjected to Steps 2 and 3 which involve N-formylation followed by refluxing in phosphorus oxychloride to construct the imidazo[1,5-a]pyridine ring. Nitration and reduction with the reagents in Step 4 leads to the substituted imidazo[1,5- a]pyridin-1-amine, Intermediate B. In the final steps, Intermediate A and B follow protocols detailed above for General Scheme 1 (steps 2, 3 and 4) leading to the synthesis of compounds of Formula I, where Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N.

[1358] General Scheme 6 describes the preparation of a compound of Formula I where R2and R4together form heteroalkylene; and all other groups are as defined in the Summary or in any embodiments described herein.ATTY DKT. NO. ISTX 104 WO

[1359] The synthesis of the macrocyclic compounds is accomplished by assembling starting materials using general methods described above. In General Scheme 6(A), R4is a phenoxy or heteroaryloxy group with a terminal leaving group which reacts with a hydroxy group at R2in the presence of a base such as NaH or K2CO3. Alternatively, in General Scheme 6(B), R4is a phenoxy or heteroaryloxy group with a terminal alkene which reacts with a terminal alkene at R2in a ring closing metathesis (RCM) reaction in the presence of Grubb’s catalyst. The resulting alkene is a feature of the final molecule or is reduced to a saturated heterocycle. Steps 2 and 3 follow protocols detailed above for General Scheme 1 (steps 2, 3 and 4) leading to the synthesis of compounds of Formula I, where R2and R4form a heteroalkylene. IV. PHARMACEUTICAL COMPOSITIONS

[1360] The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of compounds provided herein and a pharmaceutically acceptable carrier, diluent or excipient.

[1361] The compounds can be formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for ophthalmic or parenteral administration, as well as transdermal patch preparation and dryATTY DKT. NO. ISTX 104 WO powder inhalers. Typically, the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

[1362] In the compositions, effective concentrations of one or more compounds or pharmaceutically acceptable salts is (are) mixed with a suitable pharmaceutical carrier or vehicle. In certain embodiments, the concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms and / or progression of a disease or disorder disclosed herein.

[1363] Typically, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

[1364] In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. Liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as known in the art. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS.

[1365] The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the subject treated. The therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in vivo systems described herein and then extrapolated therefrom for dosages for humans. In some embodiments, the active compound is administered in a method to achieve a therapeutically effective concentration of the drug. In some embodiments, a companion diagnostic (see, e.g., Olsen D and Jorgensen J T, Front. Oncol., 2014 May 16, 4:105, doi: 10.3389 / fonC.2014.00105) is used to determineATTY DKT. NO. ISTX 104 WO the therapeutic concentration and safety profile of the active compound in specific subjects or subject populations.

[1366] The concentration of active compound in the pharmaceutical composition will depend on absorption, tissue distribution, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of a disease or disorder disclosed herein.

[1367] In certain embodiments, a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng / mL to about 50-100 µg / mL. In one embodiment, the pharmaceutical compositions provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg and in certain embodiments, from about 10 to about 500 mg of the essential active ingredient or a combination of essential ingredients per dosage unit form.

[1368] The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[1369] Thus, effective concentrations or amounts of one or more of the compounds described herein or pharmaceutically acceptable salts thereof are mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions. Compounds are included in an amount effective for ameliorating one or more symptoms of, or for treating, retarding progression, or preventing. The concentration of active compound in the composition will depend on absorption, tissue distribution, inactivation, excretion rates of the active compound, the dosage schedule,ATTY DKT. NO. ISTX 104 WO amount administered, particular formulation as well as other factors known to those of skill in the art.

[1370] The compositions are intended to be administered by a suitable route, including but not limited to oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, mucosal, dermal, transdermal, buccal, rectal, topical, local, nasal or inhalation. For oral administration, capsules and tablets can be formulated. The compositions are in liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration.

[1371] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerin, propylene glycol, dimethyl acetamide or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampules, pens, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material.

[1372] In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN®, or dissolution in aqueous sodium bicarbonate.

[1373] Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined.

[1374] The pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable salts thereof. The pharmaceutically therapeutically active compounds and salts thereof are formulated and administered in unit dosage forms or multiple dosage forms. Unit dose forms as used herein refer to physically discrete units suitable for human and animal subjects andATTY DKT. NO. ISTX 104 WO packaged individually as is known in the art. Each unit dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dose forms include ampules and syringes and individually packaged tablets or capsules. Unit dose forms may be administered in fractions or multiples thereof. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container to be administered in segregated unit dose form. Examples of multiple dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit doses which are not segregated in packaging.

[1375] Sustained-release preparations can also be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound provided herein, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include iontophoresis patches, polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L-glutamate, non- degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated compound remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37° C., resulting in a loss of biological activity and possible changes in their structure. Rational strategies can be devised for stabilization depending on the mechanism of action involved. For example, if the aggregation mechanism is discovered to be intermolecular S--S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

[1376] Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium croscarmellose, glucose, sucrose, magnesium carbonate or sodiumATTY DKT. NO. ISTX 104 WO saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain about 0.001%-100% active ingredient, in certain embodiments, about 0.1-85% active ingredient, or, in other embodiments, about 75-95% active ingredient.

[1377] The active compounds or pharmaceutically acceptable salts may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings.

[1378] The compositions may include other active compounds to obtain desired combinations of properties. The compounds provided herein, or pharmaceutically acceptable salts thereof as described herein, may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinabove, such as diseases related to oxidative stress. It is to be understood that such combination therapy constitutes a further aspect of the compositions and methods of treatment provided herein.

[1379] Lactose-free compositions provided herein can contain excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) SP (XXI) / NF (XVI). In general, lactose-free compositions contain an active ingredient, a binder / filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose-free dosage forms contain an active ingredient, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate.

[1380] Further encompassed are anhydrous pharmaceutical compositions and dosage forms containing a compound provided herein. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp.379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and / or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment and use of formulations.ATTY DKT. NO. ISTX 104 WO

[1381] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected.

[1382] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs and strip packs. A. ORAL DOSAGE FORMS

[1383] Oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric coated, sugar coated or film coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.

[1384] In certain embodiments, the formulations are solid dosage forms, such as capsules or tablets. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent.

[1385] Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include croscarmellose sodium, sodium starch glycolate, crospovidone, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water-soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasantATTY DKT. NO. ISTX 104 WO sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

[1386] If oral administration is desired, the compound could be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.

[1387] When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

[1388] The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound or pharmaceutically acceptable salt thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included.

[1389] Pharmaceutically acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. Enteric coated tablets, because of the enteric coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. Sugar coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are applied. Film coated tablets are compressed tablets which have been coated with a polymer or other suitable coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned. Coloring agents may also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed tablets, sugar coated, multiple compressed andATTY DKT. NO. ISTX 104 WO chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.

[1390] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil in-water or water in oil. In some embodiments, the suspension is a suspension of microparticles or nanoparticles. In some embodiments, the emulsion is an emulsion of microparticles or nanoparticles.

[1391] Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non- effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms.

[1392] Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic adds include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water-soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation.ATTY DKT. NO. ISTX 104 WO

[1393] For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration.

[1394] Alternatively, liquid or semi solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550- dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[1395] Other formulations include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal. Alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.

[1396] In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate. B. INJECTABLES, SOLUTIONS AND EMULSIONS

[1397] Parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. In someATTY DKT. NO. ISTX 104 WO embodiments, the suspension is a suspension of microparticles or nanoparticles. In some embodiments, the emulsion is an emulsion of microparticles or nanoparticles. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. Implantation of a slow release or sustained release system, such that a constant level of dosage is maintained is also contemplated herein. Briefly, a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, that is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject.

[1398] Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous.ATTY DKT. NO. ISTX 104 WO

[1399] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.

[1400] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances.

[1401] Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment.

[1402] The concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the subject or animal as is known in the art.

[1403] The unit dose parenteral preparations are packaged in an ampule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art.

[1404] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.ATTY DKT. NO. ISTX 104 WO

[1405] Injectables are designed for local and systemic administration. Typically, a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w / w up to about 90% w / w or more, such as more than 1% w / w of the active compound to the treated tissue(s). The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations.

[1406] The compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined. C. LYOPHILIZED POWDERS

[1407] Of interest herein are also lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels.

[1408] The sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable salt thereof, in a suitable solvent. The solvent may contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, in one embodiment, about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Generally, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dosage (including but not limited to 10-1000ATTY DKT. NO. ISTX 104 WO mg or 100-500 mg) or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4° C. to room temperature.

[1409] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, about 1-50 mg, about 5- 35 mg, or about 9-30 mg of lyophilized powder, is added per mL of sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such amount can be empirically determined. D. TOPICAL ADMINISTRATION

[1410] Topical mixtures are prepared as described for the local and systemic administration. The resulting mixture may be a solution, suspension, emulsion or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration.

[1411] The compounds or pharmaceutically acceptable salts thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Pat. Nos.4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will have diameters of less than 50 microns or less than 10 microns.

[1412] The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.

[1413] These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01%-10% isotonic solutions, pH about 5-7, with appropriate salts. E. COMPOSITIONS FOR OTHER ROUTES OF ADMINISTRATION

[1414] Other routes of administration, such as topical application, transdermal patches, and rectal administration are also contemplated herein.ATTY DKT. NO. ISTX 104 WO

[1415] For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono, di and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. An exemplary weight of a rectal suppository is about 2 to 3 grams.

[1416] Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration. F. SUSTAINED RELEASE COMPOSITIONS

[1417] Active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; and U.S. Pat. Nos.4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500 and 6,740,634, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[1418] All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. In one embodiment, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. In certain embodiments, advantages of controlled-ATTY DKT. NO. ISTX 104 WO release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects.

[1419] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[1420] In certain embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (see, Sefton, CRC Crit. Ref. Biomed. Eng.14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med.321:574 (1989). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol.2, pp.115-138 (1984).

[1421] In some embodiments, a controlled release device is introduced into a subject in proximity of the site of inappropriate immune activation or a tumor. Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990). The active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene,ATTY DKT. NO. ISTX 104 WO ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer, that is insoluble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject. G. TARGETED FORMULATIONS

[1422] The compounds provided herein, or pharmaceutically acceptable salts thereof, may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non- limiting examples of targeting methods, see, e.g., U.S. Pat. Nos.6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874.

[1423] In one embodiment, the antibody-based delivery system is an antibody-drug conjugate ("ADC"), e.g., as described in Hamilton G S, Biologicals, 2015 September, 43(5):318-32; Kim E G and Kim K M, Biomol. Ther. (Seoul), 2015 November, 23(6):493- 509; and Peters C and Brown S, Biosci. Rep., 2015 Jun.12, 35(4) pii: e00225, each of which is incorporated herein by reference.

[1424] In one embodiment, liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Pat. No.4,522,811. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS. H. ARTICLES OF MANUFACTURE

[1425] The compounds or pharmaceutically acceptable salts can be packaged as articles of manufacture containing packaging material, a compound or pharmaceutically acceptable salt thereof provided herein, which is used for treatment, prevention or amelioration of one orATTY DKT. NO. ISTX 104 WO more symptoms or progression of a disease or disorder disclosed herein, and a label that indicates that the compound or pharmaceutically acceptable salt thereof is used for treatment, prevention or amelioration of one or more symptoms or progression of a disease or disorder disclosed herein.

[1426] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, pens, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions provided herein are contemplated.

[1427] In certain embodiments, provided herein also are kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[1428] In certain embodiments, the kit includes a container comprising a dosage form of the compound provided herein, including a single enantiomer or a mixture of diastereomers thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in a container comprising one or more other therapeutic agent(s) described herein.

[1429] Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle- less injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.

[1430] Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection,ATTY DKT. NO. ISTX 104 WO and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. V. DOSING

[1431] The compounds and pharmaceutical compositions provided herein may be dosed in certain therapeutically or prophylactically effective amounts, certain time intervals, certain dosage forms, and certain dosage administration methods as described below.

[1432] In certain embodiments, a therapeutically or prophylactically effective amount of the compound is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day, from about 0.05 to about 10 mg per day, from about 0.05 to about 5 mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 to about 5 mg per day.

[1433] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day.

[1434] In one embodiment, the recommended daily dose range of the compound provided herein, or a derivative thereof, for the conditions described herein lie within the range of from about 0.5 mg to about 50 mg per day, in one embodiment given as a single once-a-day dose, or in divided doses throughout a day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage ranges from about 0.5 to about 5 mg per day. Specific doses per day include 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day.

[1435] In a specific embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4, or 5 mg per day. The dose may be escalated to 15, 20, 25, 30, 35, 40, 45 and 50 mg / day. In a specific embodiment, the compound can be administered in an amount of about 25 mg / day. In a particular embodiment, the compound can be administeredATTY DKT. NO. ISTX 104 WO in an amount of about 10 mg / day. In a particular embodiment, the compound can be administered in an amount of about 5 mg / day. In a particular embodiment, the compound can be administered in an amount of about 4 mg / day. In a particular embodiment, the compound can be administered in an amount of about 3 mg / day.

[1436] In certain embodiments, the therapeutically or prophylactically effective amount is from about 0.001 to about 100 mg / kg / day, from about 0.01 to about 50 mg / kg / day, from about 0.01 to about 25 mg / kg / day, from about 0.01 to about 10 mg / kg / day, from about 0.01 to about 9 mg / kg / day, 0.01 to about 8 mg / kg / day, from about 0.01 to about 7 mg / kg / day, from about 0.01 to about 6 mg / kg / day, from about 0.01 to about 5 mg / kg / day, from about 0.01 to about 4 mg / kg / day, from about 0.01 to about 3 mg / kg / day, from about 0.01 to about 2 mg / kg / day, from about 0.01 to about 1 mg / kg / day, or from about 0.01 to about 0.05 mg / kg / day.

[1437] The administered dose can also be expressed in units other than mg / kg / day. For example, doses for parenteral administration can be expressed as mg / m2 / day. One of ordinary skill in the art would readily know how to convert doses from mg / kg / day to mg / m2 / day to given either the height or weight of a subject or both (see, www.fda.gov / cder / cancer / animalframe.htm). For example, a dose of 1 mg / kg / day for a 65 kg human is approximately equal to 38 mg / m2 / day.

[1438] In certain embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 0.001 to about 500 µM, about 0.002 to about 200 µM, about 0.005 to about 100 µM, about 0.01 to about 50 µM, from about 1 to about 50 µM, about 0.02 to about 25 µM, from about 0.05 to about 20 µM, from about 0.1 to about 20 µM, from about 0.5 to about 20 µM, or from about 1 to about 20 µM.

[1439] In other embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 5 to about 100 nM, about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM or from about 50 to about 100 nM.

[1440] As used herein, the term "plasma concentration at steady state" is the concentration reached after a period of administration of a compound provided herein, or a derivative thereof. Once steady state is reached, there are minor peaks and troughs on the time dependent curve of the plasma concentration of the compound.

[1441] In certain embodiments, the amount of the compound administered is sufficient to provide a maximum plasma concentration (peak concentration) of the compound, rangingATTY DKT. NO. ISTX 104 WO from about 0.001 to about 50 µM, about 0.002 to about 200 µM, about 0.005 to about 100 µM, about 0.01 to about 50 µM, from about 1 to about 50 µM, about 0.02 to about 25 µM, from about 0.05 to about 20 µM, from about 0.1 to about 20 µM, from about 0.5 to about 20 µM, or from about 1 to about 20 µM.

[1442] In certain embodiments, the amount of the compound administered is sufficient to provide a minimum plasma concentration (trough concentration) of the compound, ranging from about 0.001 to about 500 µM, about 0.002 to about 200 µM, about 0.005 to about 100 µM, about 0.01 to about 50 µM, from about 1 to about 50 µM, about 0.01 to about 25 µM, from about 0.01 to about 20 µM, from about 0.02 to about 20 µM, from about 0.02 to about 20 µM, or from about 0.01 to about 20 µM.

[1443] In certain embodiments, the amount of the compound administered is sufficient to provide an area under the curve (AUC) of the compound, ranging from about 100 to about 100,000 ng*hr / mL, from about 1,000 to about 50,000 ng*hr / mL, from about 5,000 to about 25,000 ng*hr / mL, or from about 5,000 to about 10,000 ng*hr / mL.

[1444] The methods provided herein encompass treating a patient regardless of subject's age, although some diseases or disorders are more common in certain age groups.

[1445] Depending on the disease to be treated and the subject's condition, the compound provided herein, or a derivative thereof, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. The compound provided herein, or a derivative thereof, may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration.

[1446] In one embodiment, the compound provided herein, or a derivative thereof, is administered orally. In another embodiment, the compound provided herein, or a derivative thereof, is administered parenterally. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered intravenously.

[1447] The compound provided herein, or a derivative thereof, can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time, such as, e.g., continuous infusion over time or divided bolus doses over time. The compound can be administered repeatedly if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity. For example, stable disease for solid tumors generally means that the perpendicular diameterATTY DKT. NO. ISTX 104 WO of measurable lesions has not increased by 25% or more from the last measurement. Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3): 205216 (2000). Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.

[1448] The compound provided herein, or a derivative thereof, can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID). In addition, the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug). As used herein, the term "daily" is intended to mean that a therapeutic compound, such as the compound provided herein, or a derivative thereof, is administered once or more than once each day, for example, for a period of time. The term "continuous" is intended to mean that a therapeutic compound, such as the compound provided herein or a derivative thereof, is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The term "intermittent" or "intermittently" as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of the compound provided herein or a derivative thereof is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days. The term "cycling" as used herein is intended to mean that a therapeutic compound, such as the compound provided herein or a derivative thereof, is administered daily or continuously but with a rest period. In some such embodiments, administration is once a day for two to six days, then a rest period with no administration for five to seven days.

[1449] In some embodiments, the frequency of administration is in the range of about a daily dose to about a monthly dose. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the compound provided herein, or a derivative thereof, is administered once a day. In another embodiment, the compound provided herein, or a derivative thereof, is administered twice a day. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered three times a day. In still another embodiment, the compound provided herein, or a derivative thereof, is administered four times a day.ATTY DKT. NO. ISTX 104 WO

[1450] In certain embodiments, the compound provided herein, or a derivative thereof, is administered once per day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks. In certain embodiments, the compound provided herein, or a derivative thereof, is administered once per day for one week, two weeks, three weeks, or four weeks. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 4 days. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 5 days. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 6 days. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for one week. In another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for two weeks. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for three weeks. In still another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for four weeks. VI. METHODS OF TREATMENT

[1451] Inhibitors of post-translational lysine acetylation mediated by KATs of the MYST family are promising anti-neoplastic agents and therefore are useful therapeutic agents, e.g., for use in the treatment of cancer. Such agents are also useful as therapeutic agents for the treatment of cancers which exhibit overexpression of MYST proteins.

[1452] In another embodiment, provided is a method of treating a subject with cancer by administering a compound or composition provided herein. In another embodiment, provided herein is a method of treating a condition, disease, or disorder by inhibiting MYST family of lysine acetyl transferases, including KAT6A and KAT6B, comprising administering a therapeutically effective amount of a compound or composition provided herein.

[1453] In another embodiment, provided is a method of treating a condition, disease, or disorder, where the condition, disease, or disorder is a hyperproliferative disease, such as cancer. In some embodiments, the cancer is selected from: lymphoma, melanoma, carcinoma (e.g. adenocarcinoma, hepatocellular carcinoma, medullary carcinoma, papillary carcinoma, squamous cell carcinoma), astrocytoma, glioma, medulloblastoma, myeloma, meningioma, neuroblastoma, and sarcoma (e.g. angiosarcoma, chrondrosarcoma, osteosarcoma). In some embodiments, the cancer is a MYST overexpressing cancer. In another embodiment, the cancer over-expresses MYST protein relative to non-cancerous tissue. In some embodiments, the cancer overproduces MYST mRNA relative to non-cancerous tissue. In anotherATTY DKT. NO. ISTX 104 WO embodiment, the cancer is a MYST overexpressing cancer where the overexpressed MYST protein or MYST mRNA is any one of KATs of the MYST family, e.g., KAT6A. In some embodiments, the cancer is leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin's lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, breast ductal carcinoma, colon and rectal cancer, colon cancer, squamous cell carcinoma, gastric cancer, adrenocortical cancer, anal cancer, bladder cancer, blood cancer, bone cancer, brain tumor, cancer of the female genital system, cancer of the male genital system (including testicular cancer and penile cancer), central nervous system lymphoma, cervical cancer, childhood rhabdomyosarcoma, childhood sarcoma, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal tract cancer, hairy cell leukemia, head and neck cancer, hepatocellular cancer, hypopharyngeal cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer, malignant fibrous histiocytoma, malignant thymoma, mesothelioma, multiple myeloma, myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nervous system cancer, neuroblastoma, oral cavity cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm, primary CNS lymphoma, rectal cancer, respiratory system, retinoblastoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thyroid cancer, urinary system cancer, uterine cancer, uterine sarcoma, vaginal cancer, endocrine, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, glioblastoma, brain stem glioma, pituitary adenoma, vascular system, Waldenstrom's macroglobulinemia or Wilms' tumor. In some embodiments, the cancer is breast cancer, including ER positive breast cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer, ovarian cancer, or blood cancer (including a leukemia or lymphoma). In one embodiment, the cancer is breast cancer, lung cancer, ovarian cancer, colon cancer, prostate cancer, uterine / cervical cancer or leukemia.

[1454] In another embodiment, provided is a method of inhibiting the activity of a MYST KAT by contacting the MYST KAT or a composition comprising the MYST KAT with a compound or composition provided herein. In one embodiment, the MYST KAT is a KAT6 lysine acetyl transferase. In another embodiment, the MYST KAT is KAT6A.

[1455] Without wishing to be bound by any theory, one aspect of the catalytic mechanism of the KAT family of enzymes is the acetylation of lysine residues using the cofactor Ac- CoA as an acetyl donor. One possible catalytic mechanism is the stepwise transfer of theATTY DKT. NO. ISTX 104 WO acetyl group from acetyl co-enzyme A (Ac-CoA) to transiently form an acetyl-enzyme intermediate. This acetyl-enzyme intermediate subsequently is the source of the acetyl group that is transferred to the substrate, typically a lysine on a histone (Wapenaar et al., 2016, supra). In the MYST family of KATs there is a conserved cysteine that is acylated transiently as part of the catalytic cycle, as indicated by the bold C in the sequences below. Amino Acid Sequence Alignment near the Ac-CoA binding site of the MYST Family of KATs KAT5 ESTEDYNVACILTLPPYQRR (SEQ ID NO: 1) KAT8 ESPDGNNVACILTLPPYQRR (SEQ ID NO: 2) KAT7 NSFLNYNVSCILTMPQYMRQ (SEQ ID NO: 3) KAT6A HCQQKYNVSCIMILPQYQRK (SEQ ID NO: 4) KAT6B LCQQKYNVSCIMIMPQHQRQ (SEQ ID NO: 5)

[1456] Thus, in one embodiment, provided is a method of inhibiting a MYST KAT by covalent modification of this conserved cysteine residue with a compound or composition provided herein. In another embodiment, provided is a method of covalent modification of this conserved MYST KAT cysteine residue by contacting the MYST KAT or a composition containing the MYST KAT with a compound or composition provided herein.

[1457] In another embodiment, it is known in the art that histone acetyltransferases or HATs, including KAT6, have a key role in facilitating myc-driven transcriptional regulation. Myc is a transcriptional regulator that is known to recruit HATs to target chromatin facilitating chromatin remodeling, resulting in transcription, proliferation, and tumor growth. Myc is a transcriptional regulator with many protein interactors in a series of complexes, which mediate this transcriptional activity. One such interacting protein known as transformation / transcription domain associated protein or TRRAP, is a member of several HAT containing protein complexes where it serves as bridging protein between transcription factors like myc and HATs. Myc has been documented to recruit histone acetylation through a TRRAP complex facilitating acetylation of nucleosomes at histone H4 through HATs that include but may not be limited to KAT2A and KAT5 and Tip60 / p400. This myc-associated HAT activity enables the opening of chromatin structurally facilitating transcription (see, e.g., Laurenco, et al. Nature Reviews Cancer 2021, 21, 579-591). Myc recruits HATs to target chromatin and locally promote acetylation of multiple specific lysines on both H3 and H4 some of which are known targets of KAT6A acetylation, resulting in transcriptional activation (see, e.g., Martinato et al. PLoS ONE 2008, 3(11), e3650, doi:10.1371 / journal.pone.0003650). KAT6A, as a recruitable HAT, plays a role in specificATTY DKT. NO. ISTX 104 WO cancers and cell types and may be a key mediator of HAT activity recruited to myc-driven transcriptional activation sites in some tumors.

[1458] Furthermore, hallmark targets of myc-induced transcriptional regulation (myc pathway targets) are reduced through the use of KAT6A inhibitors. This includes the myc pathway in KAT6A-amplified breast cancer cell lines following administration of a KAT6 inhibitor (See, e.g., Sharma et al. Cell Chemical Biology 2023, doi.org / 10.1016 / j.chembiol.2023.07.005).

[1459] Indeed, there is direct evidence that KAT6 may be a HAT that has a key role in myc-driven transcriptional regulation and that loss of KAT6 activity could disrupt myc- driven transcriptional programming. Myc-driven growth of a lymphoma cell line in vivo is inhibited by systemic administration of KAT6 inhibitors. Specifically, two small molecule inhibitors of KAT6A and KAT6B lead to anti-tumor activity in MYC-driven models of lymphoma (see, e.g., Baell, et al. Nature 2018, 560, 253–257; Priebbenow et al. J. Med. Chem.2020, 63, 4655–4684)

[1460] Finally, MYC is amplified in approximately 30% of solid tumors, including lung, ovarian, esophagus, breast, stomach, pancreas and liver cancer. There are a number of overlapping solid tumor types with characterized myc activity which also contain KAT6 genomic amplifications. Therefore, inhibition of KAT6A activity is expected to reduce transcriptional activity and tumorigenicity in solid tumors in which myc is a key transcriptional regulator.

[1461] Thus, in another embodiment, provided is a method of treating a myc-driven cancer in a subject by administering a compound or composition provided herein to the subject. In another embodiment, the myc-driven cancer is lung, ovarian, esophageal , breast, stomach, pancreatic or liver cancer. In another embodiment, the myc-driven cancer is a cancer in which myc is amplified. In another embodiment, provided is a method of treating a cancer in which myc is amplified in a subject by administering a compound or composition provided herein to the subject.

[1462] KAT6A is an acetyltransferase of p53 at K120 and K382 and colocalizes with p53 in promyelocytic leukemia (PML) nuclear bodies following cellular stress (Rokudai, et al. PNAS 2013, 110(10), 3895-3900). This ternary complex enhances p53-dependent p21 expression. KAT6A acetylation of p53, affecting complex formation or stability and altering its downstream activity, is thus involved in pathogenesis of tumors and leukemia. Therefore, KAT6A inhibitors can be used in the treatment of hematological cancers. Thus, in anotherATTY DKT. NO. ISTX 104 WO embodiment, provided is a method of treating a hematological cancer in a subject by administering a compound or composition provided herein to the subject.

[1463] KAT6A acetylation of SMAD3 regulates myeloid-derived suppressor cell recruitment, metastasis, and immunotherapy in triple-negative breast cancer (TNBC) (Yu, et al. Adv. Sci.2021, 8, 2100014). Therefore, KAT6A inhibitors can be used in the treatment of TNBC. In another embodiment, provided is a method of treating TNBC in a subject by administering a compound or composition provided herein to the subject. VII. COMBINATION THERAPY WITH OTHER ACTIVE AGENT(S)

[1464] The compound provided herein, or a derivative thereof, can also be combined or used in combination with other therapeutic agents useful in the treatment and / or prevention of hyperproliferative diseases including cancer.

[1465] In one embodiment, provided herein is a method of treating, preventing, or managing hyperproliferative diseases including cancer, comprising administering to a subject a compound provided herein, or a derivative thereof; in combination with one or more second active agents.

[1466] As used herein, the term "in combination" includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject with a disease or disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein, or a derivative thereof) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein.

[1467] Administration of the compound provided herein, or a derivative thereof and one or more other active agents to a subject can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease or disorder being treated.ATTY DKT. NO. ISTX 104 WO

[1468] The route of administration of the compound provided herein, or a derivative thereof, is independent of the route of administration of a second therapy. In one embodiment, the compound provided herein, or a derivative thereof, is administered orally. In another embodiment, the compound provided herein, or a derivative thereof, is administered intravenously. Thus, in accordance with these embodiments, the compound provided herein, or a derivative thereof, is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, the compound provided herein, or a derivative thereof, and a second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, the compound provided herein, or a derivative thereof, is administered by one mode of administration, e.g., by IV, whereas the second agent is administered by another mode of administration, e.g., orally.

[1469] In one embodiment, the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount of the compound provided herein, or a derivative thereof, and any optional additional active agents concurrently administered to the subject.

[1470] One or more other active ingredients or agents can be used together with the compound provided herein, or a derivative thereof, in the methods and compositions provided herein. Other active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules).

[1471] Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, immune- based therapeutic agents in classification known as immunoncology which improve immune- mediated recognition of tumors, particularly, therapeutic antibodies to cancer antigens. Typical large molecule active agents are biological molecules, such as naturally occurring or synthetic or recombinant proteins.

[1472] In one embodiment, the compound provided herein, or a derivative thereof, are administered in an amount ranging from about 0.1 to about 150 mg, from about 1 to about 25ATTY DKT. NO. ISTX 104 WO mg, or from about 2 to about 10 mg orally and daily alone, or in combination with a second active agent, prior to, during, or after the use of conventional therapy.

[1473] In another embodiment, the choice of other active agent depends on the disease to be treated. Examples of second active agents for a particular cancer are well known to those of skill in the art. For example, if the disease is breast cancer, then the second active agent may be an aromatase inhibitor, a CDK4 / 6 inhibitor or an ER antagonist. Other examples of agents that can be used in combination with a KAT6 inhibitor for treatment of breast cancer are selective inhibitors of Cyclin Dependent Kinases such as CDK2 or CDK4 inhibitors and Selective Estrogen Receptor Degraders (SERDs). PIK3CA is a frequently mutated oncogene in breast cancer. The H1047R mutation of PIK3CA is highly prevalent in breast cancers and other solid tumors. KAT6 inhibitors can be combined with mutant-selective PI3Kα inhibitors for the treatment of breast and other cancers.

[1474] Another example of a solid tumor type which harbors KAT6A genomic and mRNA amplifications is ovarian cancer. Ovarian cancers are treated with platinum-based chemotherapeutics such as cisplatin, which have a high level of toxicity that often limits dosing and achieving maximal efficacious exposures. In some cases, PARP inhibitors or CDK2 inhibitors are used to treat ovarian cancers. KAT6 inhibitors can be used in combination with these agents, but not limited to these agents, to treat ovarian cancers.

[1475] KAT6 epigenetic activity has been shown to be involved in the development of resistance to menin pathway inhibitors and has been demonstrated to play a role in chromatin remodeling by the menin-MLL / KMT2 complex in solid tumors as well as AML. KAT6 inhibitors can be applied in the treatment of hematological cancers such as AML and in tumors where the menin-MLL / KMT2 complex drives tumors growth, alone and in combination with menin and menin pathway inhibitors. VIII. EXAMPLES

[1476] The examples below are meant to illustrate certain embodiments provided herein, and not to limit the scope of this disclosure.

[1477] As used herein, the symbols and conventions used in these processes, schemes, and examples, regardless of whether a particular abbreviation is specifically defined, are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, but without limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); µL (microliters); mM (millimolar); µM (micromolar); Hz (Hertz); MHz (megahertz); mmol (millimoles); h, hr orATTY DKT. NO. ISTX 104 WO hrs (hours); min (minutes); MS (mass spectrometry); ESI (electrospray ionization); rt (room temperature); Rf (retention factor); TLC (thin-layer chromatography); LCMS (liquid chromatography-mass spectrometry); HPLC (high performance liquid chromatography); AcOH (acetic acid); n-BuLi (n-Butyl lithium); tBuOK (potassium tert butoxide); CDCl3(Chloroform-d); CH3CN (acetonitrile); Cs2CO3 (cesium carbonate); DMF (N,N- Dimethylformamide); DCM (dichloromethane); DEA (diethylamine); DIPEA (diisopropyl ethylamine); DMSO (dimethylsulfoxide); DMSO-d6 (dimethyl sulfoxide-d6); EtOAc or EA (ethyl acetate); Et3N (triethylamine); EtOH (ethanol); HCl (hydrochloric acid); H2SO4(sulphuric acid); K2CO3 (potassium carbonate); LiOH (lithium hydroxide); MsCl (methane sulphonyl chloride); MeI (methyl iodide); MeOH (Methanol); MeOH-d4(Methanol-d4); NaBH4 (sodium borohydride); NaH (sodium hydride); NaHCO3 (sodium bicarbonate); NaNO2(sodium nitrite); NaOH (sodium hydroxide); NaOMe (sodium methoxide); Na2SO4(sodium sulphate); K3FeCN6 (potassium ferricyanide); Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0)); SO2(sulphur dioxide); SO2Cl2(sulfuryl chloride); T3P (propanephosphonic acid anhydride); THF (tetrahydrofuran); TMEDA (1,2 bis(dimethylamino)ethane); Zn (zinc); ZnCN2 (zinc cyanide).

[1478] For all the following examples, standard work-up and purification methods known to those skilled in the art can be utilized. Unless otherwise indicated, all temperatures are expressed in ºC (degrees Celsius). All reactions are conducted at room temperature unless otherwise noted. Synthetic methodologies illustrated herein are intended to exemplify the applicable chemistry through the use of specific examples and are not indicative of the scope of the disclosure. EXAMPLES 1-2

[1479] Scheme 1: Synthesis of 5-chloro-2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6- dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.1) and 5-chloro-2-methoxy-N-(4-methoxy-6-((5- propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.2)ATTY DKT. NO. ISTX 104 WOadded NaOMe (14.86 g, 275.22 mmol) and the reaction mixture was allowed to stir at 0oC for 2 h. After completion (monitored by TLC), the mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure to afford the title compound 2 (55 g) as a yellow solid. LCMS Calculated for C8H5BrFNO: 228.95; Found: 229.5 (M+1).

[1482] Synthesis of methyl 4-cyano-3-fluoro-5-methoxybenzoate (3)

[1483] To a solution of compound 2 (13 g, 56.511 mmol) in methanol (140 mL) in steel bomb wad added triethylamine (1.58 mL, 11.303 mmol) and purged with nitrogen for 5 min. Palladium(II) acetate (634 mg, 2.823 mmol) and DPPP (1,3-Bis(diphenylphosphino)propane) (2.33 g, 5.59 mmol) were added and reaction mixture was heated at 80°C in presence of CO gas (110 psi) for 16 h. After completion (monitored by TLC), the mixture was cooled to room temperature and filtered through a celite bed. The filtrate was concentrated in vacuo and purified by combi flash chromatography using 14% EtOAc / Hexane to afford methyl 4- cyano-3-fluoro-5-methoxy-benzoate 3 (10 g, 47.81%) as a white solid. TLC: 20% EtOAc / Heptane (Rf: 0.5). LCMS Calculated form C10H8FNO3: 209.05; Found: 210.0 (M+1).

[1484] Synthesis of 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile (4)

[1485] To a stirred solution of LiBH4(2.08 g, 95.611 mmol in THF (100 mL) at 0oC was added compound 3 (10 g, 47.80 mmol) in THF (600 mL) dropwise. The reaction mixture was stirred at 80oC for 4h. After completion (monitored by TLC), the mixture was cooled to RT and quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure toATTY DKT. NO. ISTX 104 WO afford the title compound 4 (6 g, 69.27%) as a white solid. TLC: 50% EtOAc / Heptane (Rf: 0.25). LCMS Calculated for C9H8FNO2: 181.05; Found: 182.0 (M+1).

[1486] Synthesis of 4-(bromomethyl)-2-fluoro-6-methoxybenzonitrile (5)

[1487] To a stirred solution of compound 4 (7 g, 38.637 mmol) in ACN (70 mL) was added and PPh3 (16.82 g, 64.138 mmol) followed by Br2 (3.08 mL, 64.137 mmol) at 0oC. The reaction mixture was stirred at 60°C for 2h. After completion (monitored by TLC), the mixture was quenched with sodium thiosulphate (110 mL) and extracted with EtOAc (3 x 60mL). The combined organic layer was dried over anhydrous Na2SO4and concentrated invacuo. The crude was purified by combi-flash chromatography (15% EtOAc in Heptane) to afford the title compound 5 (4 g, 16.389 mmol, 42.46%) as a white solid. TLC: 30% EtOAc / Heptane (Rf: 0.6). LCMS Calculated for C9H7BrFNO: 242.97; Found: 244.2 (M+2).

[1488] Synthesis of tert-butyl 2-(4-cyano-3-fluoro-5-methoxybenzyl)-2,6- dihydropyrrolo[3,4-c] pyrazole-5(4H)-carboxylate and tert-butyl 2-(4-cyano-3-fluoro-5- methoxybenzyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (6)

[1489] To a stirred solution of compound 5 (1.0 g, 4.097 mmol) in acetonitrile (5 mL) was added DIPEA (2.146 mL, 12.292 mmol) followed by tert-butyl 2,6-dihydropyrrolo[3,4- c]pyrazole-5(4H)-carboxylate (1.02 g, 4.916 mmol). The reaction mixture was heated at 70 °C for 6 h. After completion (monitored by TLC), the reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude was purified by silica gel (100-200 mesh) column chromatography using a gradient method of 0-50% EtOAc / Heptane to afford the title compound 6 (1.0 g, 48.65%, isolated as inseparable mixture regioisomers) as a yellow solid. TLC: 80% EtOAc / Heptane (Rf: 0.45). LCMS Calculated for C19H21FN4O3: 372.16; Found: 373.40 (M+1).

[1490] Synthesis of tert-butyl 1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl)methyl)- 4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate and tert-butyl 2-((3-amino-4- methoxybenzo[d]isoxazol-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)- carboxylate (7)

[1491] To a stirred solution of compound 6 (mixture of regioisomers) (0.50 g, 1.34 mmol) in DMF (7 mL) was added acetohydroxamic acid (0.31 g, 4.02 mmol) followed by K2CO3 (0.56 g, 4.02 mmol). The reaction mixture was allowed to stir at 65 °C for 16 h. After completion (monitored by TLC), the mixture was cooled to room temperature and quenched with ice water. The aqueous layer was extracted with ethyl acetate. The organic layer wasATTY DKT. NO. ISTX 104 WO washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by silica gel (100-200 mesh) column chromatography using a gradient method of 0-50% EtOAc / Heptane to afford the title compound 7 (mixture of isomers) (0.20 g, 38.64%, isolated as inseparable mixture of regioisomers) as an off-white solid. TLC: 70% EtOAc / Heptane (Rf: 0.40). LCMS Calculated for C19H23N5O4: 385.42; Found: 386.00 (M+1).1H NMR is complicated and indicates a regioisomeric mixture.

[1492] Synthesis of tert-butyl 1-((3-((5-chloro-2-methoxyphenyl) sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl) methyl)-4,6-dihydropyrrolo[3,4-c] pyrazole-5(1H)- carboxylate and tert-butyl 2-((3-((5-chloro-2-methoxyphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)- carboxylate (8)

[1493] To a stirred solution of compound 7 (0.75 g, 1.945 mmol) in THF (20 mL) was added 1M solution of KOtBu in THF (5.8 mL, 5.838 mmol) at 0 °C. The reaction mixture was stirred for 10 min. at 0 °C followed by the addition of 5-chloro-2- methoxybenzenesulfonyl chloride (0.70 g, 2.919 mmol). The reaction mixture was stirred at room temperature for 16h. After completion (monitored by TLC), the mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by combi flash column chromatography by using 50-60% EA in Heptane to afford title compound 8 (mixture of regioisomers) (0.50 g, 43.55%) as an off-white solid. TLC: 50% EtOAc / Heptane (Rf: 0.5). LCMS calculated for C26H28ClN5O7S: 589.14; found: 590.20 (M+1).

[1494] Synthesis of 5-chloro-N-(6-((5,6-dihydropyrrolo[3,4-c] pyrazol-1(4H)-yl) methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide hydrochloride and 5-chloro-N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4- methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide hydrochloride (9)

[1495] To a stirred solution of compound 8 (0.50 g, 0.8475 mmol) in DCM (10 mL) was added 4M HCl in 1,4-dioxane (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. After completion (monitored by TLC), the mixture was concentrated under reduced pressure. The residue was washed with Et2O and dried under reduced pressure to afford title compound 9 (mixture of regioisomers) (0.42 g, 94.17%) as an off-white solid. TLC: 10% MeOH / DCM (Rf: 0.3). LCMS calculated for C21H20ClN5O5S: 489.09; found: 490.10 (M+1).

[1496] Synthesis of 5-chloro-2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6- dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3-ATTY DKT. NO. ISTX 104 WO yl)benzenesulfonamide (Syn. Ex.1) and 5-chloro-2-methoxy-N-(4-methoxy-6-((5- propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.2)

[1497] To a stirred solution of compound 9 (0.20 g, 0.379 mmol) in DMF (5 mL) was added propiolic acid (0.032 g, 0.455 mmol), DIPEA (0.198 mL, 1.137 mmol) and 50%solution of T3P in EtOAc (0.36 g, 1.139 mmol) at 0°C under N2 atmosphere. The reactionmixture was stirred at room temperature for 2 h. After completion (monitored by TLC), the reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by combi flash column chromatography by using 5% MeOH in DCM to afford a mixture of regioisomers which was further purified by chiral HPLC to get 5-chloro-2- methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)- yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide (Syn. Ex.1; 35 mg, 16.15%) as an off white solid and 5-chloro-2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4- c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide (Syn. Ex.2; 15 mg, 7.28%) as an off white solid. TLC: 10% MeOH / DCM (Rf: 0.3), (See Table 1 for analytical data). EXAMPLE 3

[1498] Scheme 2: Synthesis of 2-methoxy-N-(4-methoxy-6-((5-propionyl-5,6- dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.3)benzo[d]isoxazol-6-yl) methyl)-4,6-dihydropyrrolo[3,4-c] pyrazole-5(1H)-carboxylateATTY DKT. NO. ISTX 104 WO and tert-butyl 2-((4-methoxy-3-((2-methoxyphenyl)sulfonamido)benzo[d]isoxazol-6- yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (10)

[1500] To a stirred solution of compound 7 (0.3 g, 0.77 mmol) in THF (5 mL) was added 2-methoxybenzenesulfonyl chloride (0.320 g, 1.55 mmol) and NaOtPn (0.428 g, 3.89 mmol). The reaction mixture was allowed to stir at room temperature for 16 h. After completion (monitored by TLC), the mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by combi flash using gradient of 70-80% ethyl acetate to afford the title compound 10 (mixture of regioisomers) (310 mg, 71.75 %) as brown solid. TLC: 5% MeOH / DCM (Rf: 0.6). LCMS Calculated for C26H29N5O7S: 555.18; Found: 556.20 (M+1).

[1501] Synthesis of 2-methoxy-N-(4-methoxy-6-((5-(2,2,2-trifluoroacetyl)-5,6-dihydro- 5l4-pyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide and 2-methoxy-N-(4-methoxy-6-((5-(2,2,2-trifluoroacetyl)-5,6-dihydro-5l4-pyrrolo[3,4- c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide (11)

[1502] To a stirred solution of compound 10 (mixture of regioisomers) (0.4 g, 0.68 mmol) in DCM (4 mL) was added TFA (0.52 mL, 6.83 mmol) at 0 °C. The reaction was allowed to stir at the room temperature for 2 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure, triturated with ether, and dried on vacuum to afford the title compound 11 (mixture of regioisomers) (410 mg, crude) as a brown olid.TLC:10% MeOH / DCM (Rf:0.5). LCMS Calculated for C21H21N5O5S: 455.13: Found: 454.3(M-1).

[1503] Synthesis of 2-methoxy-N-(4-methoxy-6-((5-propionyl-5,6-dihydropyrrolo[3,4- c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide (Syn. Ex.3)

[1504] To a stirred solution of compound 11 (260 mg, 0.570 mmol) in DMF (3 mL) was added propionic acid (63 mg, 0.856 mmol), DIPEA (0.398 mL, 2.28 mmol) and 50% solutionof T3P in EtOAc (0.867 mL, 1.141 mmol) at 0oC. The reaction mixture was stirred at roomtemperature for 2h. After completion (monitored by TLC), the mixture was quenched with ice-cold water and extracted with EtOAc (2 x 50 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was triturated with Et2O and purified by chiral HPLC purification to get 2-methoxy-N-(4- methoxy-6-((5-propionyl-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)- yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide (Syn. Ex.3; 50 mg, 17.18%) as an offATTY DKT. NO. ISTX 104 WO white solid. The other regioisomer was not isolated in pure form from the mixture TLC: 5% MeOH / DCM (Rf: 0.4). (See Table 1 for analytical data) EXAMPLES 4-5

[1505] Scheme 3: Synthesis of 2,5-dimethoxy-N-(4-methoxy-6-((5-propioloyl-5,6- dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.4) and 2,5-dimethoxy-N-(4-methoxy-6-((5-propioloyl- 5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.5)methoxybenzo[d]isoxazol-6-yl)methyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)- carboxylate and tert-butyl 2-((3-((2,5-dimethoxyphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)- carboxylate (12)

[1507] To a stirred solution of compound 7 (mixture of regioisomers) (750 mg, 1.945 mmol) in THF (20 mL) was added at 1M solution of KOtBu in THF (5.8 mL, 5.837 mmol) 0°C. The reaction mixture was stirred for 10 min followed by addition of 2,5- dimethoxybenzenesulfonyl chloride (0.69 g, 2.917 mmol) at 0°C. The reaction was stirred at room temperature for 16 h. After completion (monitored by TLC), the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by combi flash column chromatography using 80-90% EA / Heptane to afford title compound 12 (mixture of regioisomers) (450 mg, 39.50%) as an off-white solid. TLC: 50% EA / Heptane (Rf: 0.5). LCMS Calculated for C27H31N5O8S: 585.19; Found: 586.2 (M+H).ATTY DKT. NO. ISTX 104 WO

[1508] Synthesis of N-(6-((5,6-dihydropyrrolo[3,4-c] pyrazol-1(4H)-yl)methyl)-4- methoxybenzo[d]isoxazol-3-yl)-2,5-dimethoxybenzenesulfonamide hydrochloride and N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3- yl)-2,5-dimethoxybenzenesulfonamide hydrochloride (13)

[1509] To a stirred solution of compound 12 (450 mg, 0.768 mmol) in DCM (5mL) was added 4M HCl in 1,4 Dioxane (4 mL) at 0°C. The reaction mixture was stirred at room temperature for 4h. After completion (monitored by TLC), the mixture was concentrated in vacuo. The residue was washed with diethyl ether and dried in vacuo to afford the title compound 13 (mixture of regioisomers) (350 mg, 87.28%) as an off-white solid (HCl salt). TLC: 10% MeOH / DCM (Rf: 0.2). LCMS Calculated for C22H23N5O6S: 485.14; Found: 486.30(M+1).

[1510] Synthesis of 2,5-dimethoxy-N-(4-methoxy-6-((5-propioloyl-5,6- dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.4) and 2,5-dimethoxy-N-(4-methoxy-6-((5-propioloyl- 5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)benzo[d]isoxazol-3-yl)benze nesulfonamide (Syn. Ex.5)

[1511] To a stirred solution of compound 13 (200 mg, 0.383 mmol) in DMF (5 mL) was added DIPEA (0.2 mL, 1.149 mmol), propiolic acid (32 mg, 0.459 mmol) and 50% solution of T3P in EtOAc (0.87 mL, 1.149 mmol) at 0oC. The reaction mixture was stirred at room temperature for 2h. After completion (monitored by TLC), the mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was washed with Diethyl ether to afford a mixture of regioisomers which was further purified by chiral HPLC to get 2,5- dimethoxy-N-(4-methoxy- 6((5propioloyl5,6dihydropyrrolo[3,4c]pyrazol1(4H)yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.4; 35 mg, 15.02%) as off-white and 2,5-dimethoxy-N-(4- methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)- yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide (Syn. Ex.5; 15 mg) as an off-white solid. TLC: 10% MeOH / DCM (Rf: 0.4). (See Table 1 for analytical data). EXAMPLES 6-7

[1512] Scheme 4: Synthesis of 2-methoxy-N-(4-methoxy-6-((4- (methylsulfonamidomethyl)-1H-pyrazol-1-yl) methyl) benzo[d]isoxazol-3-yl) benzenesulfonamide (Syn. Ex.6) & Synthesis of methyl ((1-((4-methoxy-3-((2-ATTY DKT. NO. ISTX 104 WO methoxyphenyl) sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl) carbamate (Syn. Ex.7)

[1514] To a stirred solution of compound 18 (5 g, 53.711 mmol) in methanol (400 mL) was added NiCl2.6H2O (5.01 g, 38.671 mmol) followed by addition of sodium borohydride (21.00 g, 549.5 mmol) at 0oC. The reaction mixture was stirred at room temperature for 2h followed by addition of Di-tert-butyl dicarbonate (24 mL, 107.422). The mixture was stirred at room temperature for 48h. After completion (monitored by TLC), the mixture was quenched with H2O (50mL) and evaporated under reduced pressure. The aqueous layer was extracted with EtOAc (5 x 30 mL). The combined organic layer was filtered through a CelitePad, dried over anhydrous Na2SO4and concentrated in vacuo to afford the title compound19 (2.5 g, 24%) as a blue solid. TLC: 5% MeOH / DCM (Rf: 0.30). LCMS Calculated for C9H15N3O2: 197.12; Found: 198.20 (M+1).ATTY DKT. NO. ISTX 104 WO

[1515] Synthesis of tert-butyl ((1-(4-cyano-3-fluoro-5-methoxybenzyl)-1H-pyrazol-4-yl) methyl) carbamate (14)

[1516] To a stirred solution of compound 5 (15 g, 61.460 mmol) in DMF (15 mL) was added DIPEA (21.46 mL, 122.92 mmol) and compound 19 (14.54 g, 73.752 mmol) at the room temperature. The resulting reaction mixture was heated at 70 °C for 12 h. After completion (monitored by TLC), the mixture was cooled to room temperature, quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude compound was purified by Combi-flash chromatography using a gradient method of 40-70% EtOAc / Heptane to afford the title compound 14 (12 g, 33.30%) as a colourless semi solid. TLC: 60% EtOAc / Heptane (Rf: 0.45). LCMS Calculated for C18H21FN4O3: 360.39; Found: 361.00 (M+1).

[1517] Synthesis of tert-butyl ((1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl) methyl)- 1H-pyrazol-4-yl)methyl)carbamate (15)

[1518] To a stirred solution of compound 14 (0.2 g, 0.55 mmol) in a 6:1 mixture of DMF: H2O (7 mL) was added acetohydroxamic acid (0.112 g, 1.50 mmol) and K2CO3 (0.414 g, 3.0 mmol) at room temperature. The reaction mixture was allowed to stir at 60 °C for 16 h. After completion (monitored by TLC), the mixture was cooled to room temperature, quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by Combi flash chromatography using a gradient method of 40-60% EtOAc / Heptane to afford the title compound 15 (0.1 g, 48.25%) as a brown semi-solid. TLC: 80% EtOAc / Heptane (Rf: 0.40). LCMS Calculated for C18H23N5O4: 373.41; Found: 374.05 (M+1).

[1519] Synthesis tert-butyl ((1-((4-methoxy-3-((2-methoxyphenyl) sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl) carbamate (16)

[1520] To a stirred solution of compound 15 (0.45 g, 1.20 mmol) in THF (5 mL) was added 2-methoxybenzenesulfonyl chloride (0.49 g, 2.41 mmol) followed by NaOtPn (0.396 g, 3.60 mmol). The resulting reaction mixture was allowed to stir at 60 °C for 16 h. After completion (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated under reduced pressure. The crude compound was purified by Combi flash chromatography using a gradient method of 60-80% ethyl acetate / Heptane to afford the titleATTY DKT. NO. ISTX 104 WO compound 16 (0.130 g, 19.9 %) as a brown gummy solid. TLC: 5% MeOH / DCM (Rf: 0.6). LCMS Calculated for C25H29N5O7S: 543.60; Found: 542.1 (M-1).

[1521] Synthesis of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl) methyl)-4- methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide hydrochloride (17)

[1522] To a stirred solution of compound 16 (0.13 g, 0.239 mmol) in DCM (3 mL) was added 4M HCl in 1,4 Dioxane (0.5 mL, 2.39 mmol) at 0 °C. The reaction was allowed to stir at the room temperature for 2 h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure to afford the title compound 17 (0.1 g, 94.3% HCl salt) as a brown semi solid. TLC: 10% MeOH / DCM (Rf: 0.5). LCMS Calculated for C20H22ClN5O5S: 479.10: Found: 442.4(M-1).

[1523] Synthesis of 2-methoxy-N-(4-methoxy-6-((4-(methylsulfonamidomethyl)-1H- pyrazol-1-yl) methyl) benzo[d]isoxazol-3-yl) benzenesulfonamide (Syn. Ex.6)

[1524] To a stirred solution of compound 17 (0.13 g, 0.270 mmol) in DCM (5 mL) were added Et3N (0.11 mL, 0.812 mmol) followed by MsCl (0.037 g, 0.324 mmol) in DCM (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1h. After completion (monitored by TLC), the mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by prep-HPLC to afford title compound 2-methoxy-N-(4-methoxy-6-((4- (methylsulfonamidomethyl)-1H-pyrazol-1-yl) methyl) benzo[d]isoxazol-3-yl) benzenesulfonamide (Syn. Ex.6; 30 mg, 21.24%) as an off-white solid. TLC: 40% EtOAc / Heptane (Rf: 0.5). (See Table 1 for analytical data).

[1525] Synthesis of methyl ((1-((4-methoxy-3-((2-methoxyphenyl) sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl) carbamate (Syn. Ex.7)

[1526] To a solution of compound 17 (0.12 g, 0.250 mmol) in DCM (10 mL) was added Et3N (0.1 mL, 0.750 mmol) followed by methyl chloroformate (0.028 g, 0.300 mmol) in DCM (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 30 min. After completion (monitored by TLC), the mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified using prep HPLC to afford title compound methyl ((1-((4-methoxy-3-((2-methoxyphenyl) sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H- pyrazol-4-yl) methyl) carbamate (Syn. Ex.7; 25 mg, 20%) as an off-white solid. TLC: 50% EtOAc / Heptane (Rf: 0.5). (See Table 1 for analytical data).ATTY DKT. NO. ISTX 104 WO EXAMPLE 8

[1527] Scheme 5: Synthesis of N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)acetamide (Syn. Ex.8)methoxybenzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl) carbamate (20)

[1529] To a stirred solution of compound 15 (0.150 g, 0.401 mmol) in THF (3 mL) was added 1M solution of tBuOK in THF (1.2 mL, 1.20 mmol) followed by 5-ethyl-2- methoxybenzenesulfonyl chloride (185 mg, 0.898 mmol) at 0 °C. The reaction mixture was allowed to stir at 0 °C for 3 h. After completion (monitored by TLC), the mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by Combi flash column chromatography using a gradient method of 40-60% EtOAc / Heptane to afford the title compound 20 (130 mg, 56.76%) as an off-white solid. TLC: 80% EtOAc / Heptane (Rf: 0.35). LCMS Calculated for C27H33N5O7S: 571.21; Found: 572.03 (M+1).

[1530] Synthesis of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl) methyl)-4- methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide hydrochloride (21)

[1531] To a stirred solution of compound 20 (130 mg, 0.227 mmol) in DCM (2 mL) was added 4M HCl in 1,4-dioxane (2 mL) at 0 °C. The reaction mixture was allowed to stir at room temperature for 2 h. After completion (monitored by TLC), the mixture was evaporated under reduced pressure. The crude was triturated with DCM / Heptane to afford the title compound 21 (100 mg, salt) as an off-white solid. TLC: 5% MeOH / DCM (Rf: 0.3). LCMS Calculated for C22H25N5O5S: 471.16; Found: 472.30.ATTY DKT. NO. ISTX 104 WO

[1532] Synthesis of N-((1-((3-((5-ethyl-2-methoxyphenyl) sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl) acetamide (Syn. Ex.8)

[1533] To a stirred solution of compound 21 (100 mg, 0.196 mmol) in DCM (3 mL) was added triethylamine (0.082 mL, 0.590 mmol) at 0 °C. The reaction mixture was stirred for 10 min. followed by addition of Ac2O (0.022 mL, 0.235 mmol) in DCM (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1h. After completion (monitored by TLC), the mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to get crude. The crude was purified using prep. HPLC to afford N-((1-((3-((5-ethyl-2-methoxyphenyl) sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl) acetamide (Syn. Ex.8; 45 mg, 44.55%) as an off-white solid. TLC: 10% MeOH / DCM (Rf: 0.5). (See Table 1 for analytical data). EXAMPLE 9

[1534] Scheme 6: Synthesis of 5-ethyl-2-methoxy-N-(4-methoxy-6-((6-propioloyl- 5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-1(4H)-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.9)tetrahydropyrazolo[3,4-d] azepine-6(1H)-carboxylate and tert-butyl 2-(4-cyano-3- fluoro-5-methoxybenzyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (22)

[1536] To a stirred solution of compound 5 (0.75 g, 3.073 mmol) in DMF (7 mL) was added DIPEA (1.6 mL, 9.219 mmol) followed by tert-butyl 4,5,7,8-tetrahydropyrazolo[3,4-d] azepine-6(1H)-carboxylate (0.729 g, 3.073 mmol). The reaction mixture was stirred at 60°C for 16 h. After completion (monitored by TLC), the mixture was quenched with water andATTY DKT. NO. ISTX 104 WO extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound 22 (1.2 g, crude) as a brown liquid. TLC: 40% EtOAc / Heptane (Rf: 0.4). LCMS Calculated for C21H25FN4O3: 400.19; Found: 400.30

[1537] Synthesis of tert-butyl 1-((3-amino-4-methoxybenzo[d]isoxazol-6-yl) methyl)- 4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(1H)-carboxylate and tert-butyl 2-((3-amino- 4-methoxybenzo[d]isoxazol-6-yl)methyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine- 6(2H)-carboxylate (23)

[1538] To a solution of compound 22 (1.2 g, 2.996 mmol) in a mixture of DMF: H2O (48 mL, 6:1 ratios) was added K2CO3(2.48 g, 17.979 mmol) and N-hydroxy acetamide (0.674 g, 8.988 mmol). The reaction mixture was stirred at 70°C for 16h. After completion (monitored by TLC), the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound 23 (750 mg, 60.53%) as a yellow solid. TLC: 40% EtOAc / Heptane (Rf: 0.4). LCMS Calculated for C21H27N5O4: 413.21; Found: 414.5 (M+1).

[1539] Synthesis of tert-butyl 1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(1H)- carboxylate and tert-butyl 2-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)- carboxylate (24)

[1540] To a stirred solution of compound 23 (750 mg, 1.813 mmol) in THF (8 mL) was added NaOtBu (0.87 g, 9.069 mmol) followed by 5-ethyl-2-methoxybenzenesulfonyl chloride (0.510 g, 2.175 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16h. After completion (monitored by TLC), the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4,and concentrated under reduced pressure to offer the title compound 24 (1.1 g, 99.18%) as a brown gummy oil. The crude was carried forward to the next step without further purification. TLC: 40% EtOAc / Heptane (Rf: 0.4). LCMS Calculated for C30H37N5O7S: 611.24; Found: 612.5(M+1).

[1541] Synthesis of 5-ethyl-2-methoxy-N-(4-methoxy-6-((5,6,7,8- tetrahydropyrazolo[3,4-d]azepin-1(4H)-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide hydrochloride and 5-ethyl-2-methoxy-N-(4-methoxy-6-((5,6,7,8- tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide hydrochloride (25)ATTY DKT. NO. ISTX 104 WO

[1542] To a solution of compound 24 (1.0 g, 1.63 mmol) in DCM (10 mL) was added 4M HCl in 1,4 Dioxane (5 mL) at 0°C and the reaction mixture was stirred at room temperature for 4h. After completion (reaction monitored by TLC), the mixture was concentrated under reduced pressure. The residue was washed diethyl ether 3 times and dried in vacuo to afford the title compound 25 (750 mg, HCl salt) as an off-white solid. The crude has been carried forward in next reaction. It was taken to the next step with no further purification. TLC: 40% EtOAc / Heptane (Rf: 0.4). LCMS Calculated for C25H29N5O5S: 511.19; Found: 512.30.

[1543] Synthesis of 5-ethyl-2-methoxy-N-(4-methoxy-6-((6-propioloyl-5,6,7,8- tetrahydropyrazolo[3,4-d]azepin-1(4H)-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.9)

[1544] To a stirred solution of compound 25 (0.750 g, 1.368 mmol) and prop-2-ynoic acid (0.143 g, 2.052 mmol) in DMF (7.5 mL) were added DIPEA (0.716 mL, 4.104 mmol) and 50% solution of T3P in EtOAc (5.22 mL, 8.208 mmol) at 0oC. The reaction mixture was stirred at room temperature for 2h. After completion (monitored by TLC), the mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by combi-flash chromatography (5% MeOH in DCM) followed by prep-HPLC to get the desired compound as a mixture of regioisomers. The desired regioisomer (Syn. Ex.9) was obtained by subjecting this mixture to prep-SFC to afford 5-ethyl-2-methoxy-N-(4-methoxy-6-((6- propioloyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-1(4H)-yl)methyl)benzo[d]isoxazol-3-yl) benzenesulfonamide (Syn. Ex.9; 55 mg, 7.13%) as an off-white solid. The other regioisomer was not isolated. TLC: 10% MeOH / DCM (Rf: 0.5). (See analytical data in Table 1). EXAMPLE 10

[1545] Scheme 7: Synthesis of 2,4-dimethoxy-N-(4-methoxy-6-((4- (methylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.10)ATTY DKT. NO. ISTX 104 WO-

[1547] To a stirred solution of compound 15 (500 mg, 1.339 mmol) in THF (15 mL) was added 1M solution of KOtBu solution in THF (4 mL, 4.017 mmol) at 0°C. The reaction mixture was stirred for 10 min at 0°C followed by addition of 2,4-dimethoxybenzenesulfonyl chloride (0.475 g, 2.008 mmol) in THF (1 mL). The reaction was stirred at room temperature for 16h. After completion (monitored by TLC), the mixture was quenched with 1N HCl and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by combi flash chromatography using (neutral alumina) gradient 30-50% EA / Heptane to afford the title compound 26 (140 mg, 18.22%) as a pale-yellow solid. TLC: 10% MeOH / DCM (Rf: 0.6). LCMS Calculated for C26H31N5O8S: 573.62; Found: 574.06 (M+1).

[1548] Synthesis of N-(6-((4-(amino methyl)-1H-pyrazol-1-yl) methyl)-4- methoxybenzo[d]isoxazol-3-yl)-2,4-dimethoxybenzenesulfonamide hydrochloride (27)

[1549] To a stirred solution of compound 26 (140 mg, 0.274 mmol) in DCM (3 mL) was added 4M HCl in 1,4 Dioxane (2 mL) at 0°C. The reaction mixture was stirred at room temperature for 4h. After completion (monitored by TLC), the mixture was concentrated under reduced pressure. The residue was washed with diethyl ether to afford the title compound 27 (110 mg, 74.24%) as an off-white solid (HCl salt). TLC: 10% MeOH / DCM (Rf: 0.6). LCMS Calculated for C21H23N5O6S: 473.14; found: 474.20.

[1550] Synthesis of 2,4-dimethoxy-N-(4-methoxy-6-((4-(methylsulfonamidomethyl)- 1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide (Syn. Ex.10)

[1551] To a stirred solution of compound 27 (110 mg, 0.2157 mmol) in DCM (3 mL) was added triethylamine (0.09 mL, 0.647 mmol) followed by methanesulfonyl chloride (0.029 g, 0.2588 mmol) in DCM (1 mL) at 0°C. The reaction was mixture was stirred at roomATTY DKT. NO. ISTX 104 WO temperature for 15 min. After completion (monitored by TLC), the mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4,and concentrated under reduced pressure. The crude was purified by using prep-HPLC to afford 2,4-dimethoxy-N-(4-methoxy-6-((4-(methylsulfonamidomethyl)-1H-pyrazol-1- yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide (Syn. Ex.10; 29 mg, 24.57%) as an off-white solid. TLC: 10% MeOH / DCM (Rf: 0.5). (See Table 1 for analytical data). EXAMPLES 11-13

[1552] Scheme 8: Synthesis of N-(6-((5-(but-2-ynoyl)-5,6-dihydropyrrolo[3,4- c]pyrazol-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2- methoxybenzenesulfonamide (Syn. Ex.11), N-(6-((5-(but-2-ynoyl)-5,6- dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5- ethyl-2-methoxybenzenesulfonamide (Syn. Ex.12) and 5-ethyl-N-(6-((5-(2- fluoroacryloyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)-4- methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide (Syn. Ex.13)methoxybenzo[d]isoxazol-6-yl)methyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)- carboxylate and tert-butyl 2-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)- carboxylate (28)ATTY DKT. NO. ISTX 104 WO

[1554] To a stirred solution of compound 15 (mixture of isomers) (1.3 g, 3.372 mmol) in THF (20 mL) was added NaOtPn (2.22 g, 20.237 mmol) followed by 5-ethyl-2- methoxybenzenesulfonyl chloride (1.58 g, 6.744 mmol) at 0 °C. The reaction was allowed to stir at 60 °C for 16 h. After completion (monitored by TLC), the mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4,and concentrated under reduced pressure. The crude was purified by Combi flash using a gradient method of 20-60% EtOAc / Heptane to afford the title compound 28 (mixture of isomers) (1.0 g, 51.02%) as a pale-yellow solid. TLC: 100% EtOAc (Rf: 0.5). LCMS Calculated for: C28H33N5O7S: 583.21; Found: 584.5 (M+1).

[1555] Synthesis of N-(6-((5,6-dihydropyrrolo[3,4-c] pyrazol-1(4H)-yl) methyl)-4- methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide hydrochloride and N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4- methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide hydrochloride (29)

[1556] To a stirred solution of compound 28 (mixture of isomers) (1 g, 1.713 mmol) in DCM (5 mL) was added 4M HCl in 1,4 Dioxane (4.28 mL, 17.133 mmol) at 0°C. The reaction was allowed to stir at room temperature for 2h. After completion (monitored by TLC), the mixture was concentrated under reduced pressure and triturated with Et2O to afford the title compound 29 (mixture of isomers) (750 mg, HCl salt) as a gummy off-white solid. TLC: 5% MeOH / DCM (Rf: 0.2). LCMS Calculated for: C23H25N5O5S: 483.16; Found: 484.20.

[1557] Synthesis of N-(6-((5-(but-2-ynoyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)- yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide (Syn. Ex.11) and N-(6-((5-(but-2-ynoyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)- yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide (Syn. Ex.12)

[1558] To a stirred solution of compound 29 (mix. of isomers) (350 mg, 0.673 mmol) in DMF (3 mL) was added DIPEA (0.352 mL, 2.019 mmol), but-2-ynoic acid (67 mg, 0.807 mmol) followed by 50% solution of T3P in EtOAc (1.28 mL, 2.019 mmol) at 0oC. The reaction mixture was allowed to stir at room temperature for 16h. After completion (monitored by TLC), the mixture was concentrated under reduced pressure. The crude was purified by Chiral HPLC purification to afford the 2 isomers N-(6-((5-(but-2-ynoyl)-5,6- dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2- methoxybenzenesulfonamide (Syn. Ex.11; 45 mg, 11.31%) as an off white solid and N-(6-ATTY DKT. NO. ISTX 104 WO ((5-(but-2-ynoyl)-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4- methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide (Syn. Ex.12; 14 mg, 5.31% yield) as an off white solid. TLC: 5% MeOH / DCM (Rf: 0.5). (See Table 1 for analytical data).

[1559] Synthesis of 5-ethyl-N-(6-((5-(2-fluoroacryloyl)-5,6-dihydropyrrolo[3,4- c]pyrazol-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-2- methoxybenzenesulfonamide (Syn. Ex.13)

[1560] To a stirred solution of compound 29 (mix. of isomers) (200 mg, 0.384 mmol) in DMF (3 mL) was added DIPEA (0.2 mL, 1.153 mmol), 2-fluoroacrylic acid (41 mg, 0.460 mmol) followed by 50% solution of T3P in EtOAc (0.733 mL, 1.153 mmol) at 0oC. The reaction mixture was allowed to stir at room temperature for 1h. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure. The crude was purified by Chiral HPLC purification to afford the title compound N-(6-((5-(but-2-ynoyl)-5,6- dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2- methoxybenzenesulfonamide (Syn. Ex.13; 15 mg, 6.52% yield) as an off white solid. TLC: 5% MeOH / DCM (Rf: 0.5) (See Table 1 for analytical data). The other isomer was not isolated. EXAMPLES 14-18

[1561] Scheme 9: N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)-2-fluoroacrylamide (Syn. Ex.14), N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)but-2-ynamide (Syn. Ex. 15), ethyl ((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6- yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (Syn. Ex.16), methyl ((1-((3-((5-ethyl-2- methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4- yl)methyl)carbamate (Syn. Ex.17) and 5-ethyl-2-methoxy-N-(4-methoxy-6-((4-(((2- methoxyethyl)sulfonamido)methyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.18)ATTY DKT. NO. ISTX 104 WO O HO O F OMe NO N NFmethoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)-2-fluoroacrylamide (Syn. Ex.14)

[1563] To a stirred solution of compound 21 (0.12 g, 0.236 mmol) in DMF (2 mL) was added 2-fluoroacrylic acid (0.042 g, 0.472 mmol) and DIPEA (0.20 mL, 1.181 mmol) at 0oC. The reaction mixture was stirred at 0 °C for 10 min followed by the addition of 50% solution of T3P in EtOAc (0.375 mL, 0.590 mmol) at 0 °C. The mixture was allowed to stir at room temperature for 3h. After completion (monitored by TLC), the mixture was quenched with ice water (10 mL). The solid precipitate was filtered, washed with heptane, and dried under reduced pressure. The crude was purified by prep HPLC to afford the title compound N-((1- ((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H- pyrazol-4-yl)methyl)-2-fluoroacrylamide (Syn. Ex.14; 3.8 mg, 2.96%) as an off-white solid. (See Table 1 for analytical data).ATTY DKT. NO. ISTX 104 WO

[1564] Synthesis of N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)but-2-ynamide (Syn. Ex. 15)

[1565] To a stirred solution of compound 21 (0.12 g, 0.236 mmol) in DMF (2 mL) was added but-2-ynoic acid (0.039 g, 0.472 mmol) and DIPEA (0.20, 1.181 mmol) at 0oC. The reaction mixture was stirred for 10 min followed by the addition of 50% solution of T3P in EtOAc (0.36 mL, 0.590 mmol) at 0oC. The mixture was allowed to stir at room temperature for 3 h. After completion (monitored by TLC), the mixture was quenched with ice cold water (20 mL). The solid precipitate was filtered, washed with heptane, and dried under reduced pressure. The crude was purified by prep HPLC to afford title compound N-((1-((3-((5-ethyl- 2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4- yl)methyl)but-2-ynamide (Syn. Ex.15; 5.4 mg, 4.28%) as an off-white solid. (See Table 1 for analytical data)

[1566] Synthesis of ethyl ((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (Syn. Ex.16)

[1567] To a stirred solution of compound 21 (150 mg, 0.295 mmol) in DCM (2 mL) was added TEA (0.12 mL, 0.885 mmol) followed by ethyl chloroformate (48 mg, 0.442 mmol) in DCM (1mL) at 0oC. The reaction mixture was allowed to stir at 0oC for 1h. After completion (monitored by TLC and LCMS), the mixture was quenched with ice-water (20mL) and extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the crude which was purified using prep-HPLC to afford ethyl ((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6- yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (Syn. Ex.16; 14 mg, 8.75%) as an off-white solid. (See Table 1 for analytical data).

[1568] Synthesis of methyl ((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (Syn. Ex.17)

[1569] To a stirred solution of compound 21 (120 mg, 0.236 mmol) in DCM (2 mL) was added TEA (0.09 mL, 0.708 mmol) followed by methyl chloroformate (26 mg, 0.283 mmol) in DCM (1mL) at 0oC. The reaction mixture was allowed to stir at 0oC for 1h. After completion (monitored by TLC and LCMS), the reaction mixture was quenched with ice cold water (30mL) and extracted with ethyl acetate (100 mL x 2). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the crude which was purified using prep-HPLC to afford methyl ((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-ATTY DKT. NO. ISTX 104 WO 4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (Syn. Ex.17; 9 mg, 6.834%) as an off-white solid. (See Table 1 for analytical data).

[1570] Synthesis of 5-ethyl-2-methoxy-N-(4-methoxy-6-((4-(((2- methoxyethyl)sulfonamido)methyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.18)

[1571] To a stirred solution of compound 21 (120 mg, 0.236 mmol) in DCM (2 mL) was added TEA (0.09 mL, 0.708 mmol) followed by 2-methoxyethane-1-sulfonyl chloride (44 mg, 0.283 mmol) in DCM (1mL) at 0oC. The reaction mixture was allowed to stir at 0oC to room temperature for 16h. After completion (monitored by TLC and LCMS), the mixture was quenched with 1N HCl (10 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by prep-HPLC purification to afford 5-ethyl- 2-methoxy-N-(4-methoxy-6-((4-(((2-methoxyethyl)sulfonamido)methyl)-1H-pyrazol-1- yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide (Syn. Ex.18; 4.5 mg, 3.04%) as an off-white solid. (See Table 1 for analytical data). EXAMPLES 19-20

[1572] Scheme 10: Synthesis of N-((1-((4-methoxy-3-((2-methoxy-4,5- dimethylphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4- yl)methyl)propiolamide (Syn. Ex.19) and Synthesis of 2-methoxy-N-(4-methoxy-6-((4- (methylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)-4,5- dimethylbenzenesulfonamide (Syn. Ex.20)ATTY DKT. NO. ISTX 104 WO

[1573] Synthesis of tert-butyl ((1-((4-methoxy-3-((2-methoxy-4,5-dimethylphenyl) sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl) carbamate (30)

[1574] To a stirred solution of compound 15 (1.0 g, 2.678 mmol) in THF (10 mL) was added 1.0 M KOtBu in THF (8.0 mL, 8.034 mmol) at 0 °C. The reaction mixture was stirred at 0°C for 10 min followed by the addition of 2-methoxy-4,5-dimethylbenzenesulfonyl chloride (0.628 g, 3.213 mmol). The mixture was stirred at room temperature for 16h. After completion (monitored by TLC), the mixture was quenched with water (50 mL) and extracted with 10% MeOH in DCM (3 x 50 mL). The organic layer was dried over anhydrous Na2SO4,filtered and concentrated under reduced pressure. The crude was purified by combi flash column chromatography (neutral silica gel) using 80-90% EtOAc in Heptane to afford title compound 30 (0.23 g, 15.03%) as an off-white solid. LCMS calculated for C27H33N5O7S: 571.21; found: 572.46 (M+1).

[1575] Synthesis of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4- methoxybenzo[d]isoxazol-3-yl)-2-methoxy-4,5-dimethylbenzenesulfonamide hydrochloride (31)

[1576] To a solution of compound 30 (0.31 g, 0.542 mmol) in dioxane (3 mL) was added 4M HCl in dioxane (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 4h. After completion (monitored by TLC), the mixture was concentrated under reduced pressure. The residue was triturated with Et2O (3 x 20 mL) and dried under reduced pressure to afford the title compound 31 (0.28 g, HCl salt) as an off-white solid. LCMS calculated for C22H26ClN5O5S: 471.16; found: 472.42 (M+1).

[1577] Synthesis of N-((1-((4-methoxy-3-((2-methoxy-4,5- dimethylphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4- yl)methyl)propiolamide (Syn. Ex.19)

[1578] To a stirred solution of compound 31 (0.10 g, 0.196 mmol) in DMF (1 mL) was added DIPEA (0.10 mL, 0.590 mmol), propiolic acid (0.027 g, 0.393 mmol) and 50% solution of T3P in EtOAc (0.373 mL, 0.588 mmol) at 0oC. The reaction mixture was stirred at room temperature for 4h. After completion (monitored by TLC), the mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer waswashed with brine (10 mL), dried over anhydrous Na2SO4,and concentrated under reducedpressure. The crude was purified by prep HPLC to afford the title compound N-((1-((4- methoxy-3-((2-methoxy-4,5-dimethylphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-ATTY DKT. NO. ISTX 104 WO 1H-pyrazol-4-yl)methyl)propiolamide (Syn. Ex.19; 24 mg, 23.30%) as an off-white solid. (See Table 1 for analytical data).

[1579] Synthesis of 2-methoxy-N-(4-methoxy-6-((4-(methylsulfonamidomethyl)-1H- pyrazol-1-yl) methyl) benzo[d]isoxazol-3-yl)-4,5-dimethylbenzenesulfonamide (Syn. Ex. 20)

[1580] To a stirred solution of compound 31 (0.10 g, 0.196 mmol) in DCM (2 mL) was added Et3N (0.08 mL, 0.588 mmol) and methane sulfonyl chloride (0.020 g, 0.176 mmol) in DCM (1 mL) at 0oC. The reaction mixture was stirred at room temperature for 2h. After completion (monitored by TLC), the mixture was quenched with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layer was washed with brine (10 mL), driedover anhydrous Na2SO4,and concentrated under reduced pressure. The crude was purifiedby prep HPLC to afford the title compound 2-methoxy-N-(4-methoxy-6-((4- (methylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)-4,5- dimethylbenzenesulfonamide (Syn. Ex.20; 25 mg, 23.14% Yield) as an off-white solid. (See Table 1 for analytical data) EXAMPLES 21-22

[1581] Scheme 11: N-((1-((3-((5-chloro-2-methoxy-4-methylphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide (Syn. Ex. 21) & 5-chloro-2-methoxy-N-(4-methoxy-6-((4-(methylsulfonamidomethyl)-1H-pyrazol- 1-yl)methyl)benzo[d]isoxazol-3-yl)-4-methylbenzenesulfonamide (Syn. Ex.22)ATTY DKT. NO. ISTX 104 WO

[1582] Synthesis of tert-butyl ((1-((3-((5-chloro-2-methoxy-4- methylphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4- yl)methyl)carbamate (32)

[1583] To a stirred solution of compound 15 (0.50 g, 1.339 mmol) in THF (5 mL) was added 1.0 M solution of KOtBu in THF (4.45 mL, 4.017 mmol) at 0oC. The reaction mixture was stirred for 10 min followed by the addition of 5-chloro-2-methoxy-4-methyl- benzenesulfonyl chloride (0.512 g, 2.008 mmol) at 0oC. The reaction mixture was stirred at room temperature for 16h. After completion (monitored by TLC), the mixture was quenched with ice cold water and extracted with EtOAc (3 x 80 mL). The combined organic layer waswashed with brine, dried over anhydrous Na2SO4,and concentrated under reduced pressureto afford title compound 32 (0.38 g, 47.97%) as a brown solid. LCMS calculated for C26H30ClN5O7S: 591.16; found: 592.63 (M+1).

[1584] Synthesis of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl)methyl)-4- methoxybenzo[d]isoxazol-3-yl)-5-chloro-2-methoxy-4-methylbenzenesulfonamide hydrochloride (33)

[1585] To a stirred solution of compound 32 (0.38 g, 0.641 mmol) in DCM (5 mL) was added 4M HCl in Dioxane (1.6 mL, 6.418 mmol) at 0oC. The reaction mixture was stirred at room temperature for 2h. After completion (monitored by TLC), the mixture was concentrated under reduced pressure. The crude was triturated with Et2O (2 x 5 mL) to afford title compound 33 (0.30 g, HCl salt) as a brown semi solid. LCMS calculated for C21H22ClN5O5S: 491.10; found: 493.00 (M+2).

[1586] Synthesis of N-((1-((3-((5-chloro-2-methoxy-4-methylphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide (Syn. Ex. 21)

[1587] To a stirred solution of compound 33 (0.10 g, 0.189 mmol) in DMF (3 mL) was added DIPEA (0.13 mL, 0.756 mmol) at 0 °C. The reaction mixture was stirred for 5 min followed by the addition of propiolic acid (0.015 g, 0.226 mmol) and 50% solution of T3P in EtOAc (0.360 mL, 0.567 mmol) at 0 °C. The mixture was stirred at room temperature for 1h. After completion (monitored by TLC), the mixture was quenched with ice cold water and extracted with EtOAc (3 x 20 mL). The combined organic layer was dried over anhydrousNa2SO4and concentrated under reduced pressure to afford the crude. The crude was purifiedby combi flash chromatography using with 95-100% EA / Heptane to afford the title compound N-((1-((3-((5-chloro-2-methoxy-4-methylphenyl)sulfonamido)-4-ATTY DKT. NO. ISTX 104 WO methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide (Syn. Ex.21; 19 mg, 18.46%) as an off-white solid. (See Table 1 for analytical data)

[1588] Synthesis of 5-chloro-2-methoxy-N-(4-methoxy-6-((4- (methylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)-4- methylbenzenesulfonamide (Syn. Ex.22)

[1589] To a stirred solution of compound 33 (0.12 g, 0.227 mmol) in DCM (5 mL) were added Et3N (0.095 mL, 0.681 mmol) and methane sulfonyl chloride (0.031 g, 0.272 mmol) in DCM (0.5 mL) at 0oC. After completion (monitored by TLC), the mixture was quenched with ice-cold water and extracted with DCM (3 x 20 mL). The combined organic layer wasdried over anhydrous Na2SO4and concentrated under reduced pressure to afford the crudewhich was purified by prep. HPLC to afford the title compound 5-chloro-2-methoxy-N-(4- methoxy-6-((4-(methylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)- 4-methylbenzenesulfonamide (Syn. Ex.22; 73 mg, 56.41%) as an off-white solid. (See Table 1 for analytical data) EXAMPLES 23-25

[1590] Scheme 12: N-((1-((4-methoxy-3-((6-methoxy-2,3-dihydro-1H-indene)-5- sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide (Syn. Ex.23), 6-methoxy-N-(4-methoxy-6-((4-(methylsulfonamidomethyl)-1H-pyrazol-1- yl)methyl)benzo[d]isoxazol-3-yl)-2,3-dihydro-1H-indene-5-sulfonamide (Syn. Ex.24) and methyl ((1-((4-methoxy-3-((6-methoxy-2,3-dihydro-1H-indene)-5- sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (Syn. Ex.25)ATTY DKT. NO. ISTX 104 WO- 5-sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl) carbamate (34)

[1592] To a stirred solution of compound 15 (0.35 g, 0.937 mmol) in THF (40 mL) was added 1M solution of KOtBu in THF (2.81 mL, 2.812 mmol) and 6-methoxy-2,3-dihydro- 1H-indene-5-sulfonyl chloride (0.30 g, 1.219 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16h. After completion (monitored by TLC), the mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by combi flash column chromatography using 70-75% EA:Heptane to afford title compound 34 (0.20 g, 36.55%) as an off-white solid. LCMS calculated for C28H33N5O7S: 583.21; found: 584.49 (M+1).

[1593] Synthesis of N-(6-((4-(amino methyl)-1H-pyrazol-1-yl) methyl)-4- methoxybenzo [d]isoxazol-3-yl)-6-methoxy-2,3-dihydro-1H-indene-5-sulfonamide hydrochloride (35)ATTY DKT. NO. ISTX 104 WO

[1594] To a solution of compound 34 (0.20 g, 0.342 mmol) in DCM (2 mL) was added 4M HCl in 1,4 dioxane (2 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2h. After completion (monitored by TLC), the mixture was concentrated under reduced pressure. The residue was washed with Et2O and dried under reduced pressure to afford title compound 35 (0.16 g, 89.88%) as an off-white solid. LCMS calculated for C23H25N5O5S: 483.16; found: 484.76 (M+1).

[1595] Synthesis of N-((1-((4-methoxy-3-((6-methoxy-2,3-dihydro-1H-indene)-5- sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide (Syn. Ex.23)

[1596] To a stirred solution of compound 35 (0.13 g, 0.250 mmol) in DMF (5 mL) was added DIPEA (0.18 mL, 1.075 mmol) at 0 °C. The reaction mixture was stirred for 5 min followed by addition of propiolic acid (0.026 g, 0.375 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphorinane-2,4,6-trioxide (0.23 g, 0.750 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1h. After completion (monitored by TLC), the mixture was quenched with ice cold water and extracted with EtOAc (3 x 20 mL). The combined organiclayer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crudewas purified by combi flash chromatography using 95-100% EA / PE to afford title compound N-((1-((4-methoxy-3-((6-methoxy-2,3-dihydro-1H-indene)-5-sulfonamido)benzo[d]isoxazol- 6-yl)methyl)-1H-pyrazol-4-yl)methyl)propiolamide (Syn. Ex.23; 30 mg, 22.42%) as an off- white solid. (See Table 1 for analytical data)

[1597] Synthesis of 6-methoxy-N-(4-methoxy-6-((4-(methylsulfonamidomethyl)-1H- pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)-2,3-dihydro-1H-indene-5-sulfonamide (Syn. Ex.24)

[1598] To a stirred solution of compound 35 (100 mg, 0.192 mmol) in DCM (3 mL) was added Et3N (0.08 mL, 0.576 mmol) followed by methane sulfonyl chloride (0.018 mL, 0.230 mmol) in DCM (1 mL) at 0oC. After completion (monitored by TLC), the mixture was quenched with ice-cold water and extracted with DCM (3 x 100 mL). The combined organiclayer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crudewas purified by prep. HPLC to afford the title compound 6-methoxy-N-(4-methoxy-6-((4- (methylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)-2,3-dihydro-1H- indene-5-sulfonamide (Syn. Ex.24; 21 mg, 19.44%) as an off-white solid. (See Table 1 for analytical data)ATTY DKT. NO. ISTX 104 WO

[1599] Synthesis of methyl ((1-((4-methoxy-3-((6-methoxy-2,3-dihydro-1H-indene)-5- sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate (Syn. Ex.25)

[1600] To a stirred solution of compound 35 (80 mg, 0.153 mmol) in DCM (3 mL) was added triethylamine (0.064 mL, 0.461 mmol) and methyl chloroformate (0.015 mL, 0.1836 mmol) in DCM (0.5 mL) at 0oC. After completion (monitored by TLC), the mixture was quenched with ice-cold water and extracted with DCM (3 x 20 mL). The combined organiclayer was dried over anhydrous Na2SO4and concentrated in vacuo to afford the crude whichwas purified by prep HPLC purification to get methyl ((1-((4-methoxy-3-((6-methoxy-2,3- dihydro-1H-indene)-5-sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4- yl)methyl)carbamate (Syn. Ex.25; 16 mg, 19.20%) as an off-white solid. (See Table 1 for analytical data) EXAMPLE 26

[1601] Scheme 13: Synthesis of 4-cyano-2-methoxy-N-[4-methoxy-6-[(5-prop-2-ynoyl- 4,6-dihydropyrrolo[3,4-c]pyrazol-1-yl)methyl]-1,2-benzoxazol-3-yl]benzenesulfonamide (Syn. Ex.26)

[1603] To a solution of compound 36 (1 g, 4.715 mmol) in 1,4-Dioxane (10 mL) was added KSAc (0.646 g, 5.658 mmol), DIPEA (2.46 mL, 14.145 mmol) and followed by XantPhos (0.554 g, 0.943 mmol) at room temperature. The reaction mixture was purged with nitrogen for 10 min. followed by addition of Pd2(dba)3(0.431 g, 0.47161 mmol). The mixture was stirred in sealed tube at 110°C for 16 h. After completion (monitored by TLC and LCMS), the mixture was cooled to room temperature and filtered through a celite bed. The filtrate was diluted with H2O (30 mL) and extracted with EtOAc (3 x 20mL). The combined organicATTY DKT. NO. ISTX 104 WO layer dried over anhydrous Na2SO4 and concentrated in vacuo. The crude was purified by column chromatography (neutral silica gel) using 10% EtOAc in Heptane to afford the title compound 37 (300 mg, 30.70%) as a pale-yellow solid. TLC: 20% EtOAc in Hexane (Rf; 0.5), LCMS Calculated for: C10H9NO2S: 207.04; Found: 208.5 (M+1).

[1604] Synthesis of 4-cyano-2-methoxybenzenesulfonyl chloride (38)

[1605] A solution of compound 37 (0.35 g, 1.688 mmol) in ACN (14 mL) was added AcOH (0.6 mL) and water (0.35 mL) followed by 1,3-Dichloro-5,5-dimethylhydantoin (0.665 g, 3.376 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1h. After completion (monitored by TLC), the reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (3 x 20 mL). The organic layer dried over anhydrousNa2SO4and concentrated in vacuo to afford the title compound 38 (650 mg, crude) as an off-white solid. TLC: 60% EtOAc in Heptane (Rf; 0.4). LCMS Calculated for: C8H6ClNO3S: 230.98; Found: 231.2 (M+1).

[1606] Synthesis of tert-butyl 1-((3-((4-cyano-2-methoxyphenyl) sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl) methyl)-4,6-dihydropyrrolo[3,4-c] pyrazole-5(1H)- carboxylate and tert-butyl 2-((3-((4-cyano-2-methoxyphenyl)sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)- carboxylate (39)

[1607] To a solution of compound 7 (mixture of isomers) (0.350 g, 0.908 mmol) in THF (10 mL) was added 1M solution of KOtBu in THF (2.7 mL, 2.724 mmol) at 0 °C. The reaction mixture was stirred for 10 minutes followed by addition of 4-cyano-2-methoxy- benzenesulfonyl chloride 38 (0.631 g, 2.724 mmol) in THF (2 mL) at 0°C. The mixture was stirred at room temperature for 16h. After completion (monitored by TLC and LCMS), thereaction mixture was poured into ice-cold H2O (30 mL) and extracted with EtOAc (30 mL x3). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude was triturated with diethyl ether (2 x 10 mL) to get title compound 39 (200 mg, 37.95%) as a pale-yellow solid. TLC: 60% EtOAc in Heptane. LCMS Calculated for: C27H28N6O7S:580.17; Found: 581.2 (M+1).

[1608] Synthesis of 4-cyano-N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazol-1(4H)-yl)methyl)- 4-methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide hydrochloride and 4- cyano-N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-4- methoxybenzo[d]isoxazol-3-yl)-2-methoxybenzenesulfonamide hydrochloride (40)ATTY DKT. NO. ISTX 104 WO

[1609] To a solution of compound 39 (200 mg, 0.3445 mmol) in 1,4-Dioxane (2 mL) was added 4M HCl in 1,4 Dioxane (0.4 mL, 1.722 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16h. After completion (monitored by TLC), the mixture was concentrated in vacuo. The crude was triturated with Diethyl ether (2 x 10 mL) and dried in vacuo to afford the title compound 40 (180 mg, HCl salt) as a pale-yellow solid. TLC: 10% MeOH in DCM (Rf; 0.3). LCMS Calculated for: C22H20N6O5S: 480.12 Found: 480.20 (M+1).

[1610] Synthesis of 4-cyano-2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6- dihydropyrrolo[3,4-c] pyrazol-1(4H)-yl) methyl) benzo[d]isoxazol-3-yl) benzenesulfonamide (Syn. Ex.26)

[1611] To a stirred solution of compound 40 (180 mg, 0.348 mmol) in DMF (2 mL) was added DIPEA (0.18mL, 1.044 mmol), prop-2-ynoic acid (48 mg, 0.696 mmol) followed by 50% solution of T3P in EtOAc (0.66 mL, 1.044 mmol) at 0oC. The reaction mixture was stirred at room temperature for 1h. After completion (monitored by TLC), the mixture was quenched with H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organiclayer was dried over anhydrous Na2SO4and concentrated in vacuo. The crude was purifiedby chiral prep-HPLC to afford the title compound 4-cyano-2-methoxy-N-[4-methoxy-6-[(5- prop-2-ynoyl-4,6-dihydropyrrolo[3,4-c]pyrazol-1-yl)methyl]-1,2-benzoxazol-3- yl]benzenesulfonamide (Syn. Ex.26; 26 mg, 13.97%) as an off-white solid. TLC: 10% MeOH in DCM (Rf; 0.5). (See Table 1 for analytical data). The other regioisomer was not isolated. EXAMPLES 27-28

[1612] Scheme 14: Synthesis of N-((1-((4-methoxy-3-((2-methoxy-4,5- dimethylphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl) but-2-ynamide (Syn. Ex.27) and 2-fluoro-N-((1-((4-methoxy-3-((2-methoxy-4,5- dimethylphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4- yl)methyl)acrylamide (Syn. Ex.28)ATTY DKT. NO. ISTX 104 WO- yl)methyl)but-2-ynamide (Syn. Ex.27)

[1614] To a stirred solution of compound 31 (0.11 g, 0.216 mmol) in DMF (3 mL) was added DIPEA (0.11 mL, 0.649 mmol), but-2-ynoic acid (0.036 g, 0.432 mmol) and 50% solution of T3P in EtOAc (0.40 mL, 0.649 mmol) at 0oC. The reaction mixture was stirred at room temperature for 1h. After completion (monitored by TLC), the mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was dried overanhydrous Na2SO4and concentrated under reduced pressure. The crude obtained waspurified by combi flash chromatography (neutral silica) with 80% EtOAc in Heptane to afford title compound N-((1-((4-methoxy-3-((2-methoxy-4,5- dimethylphenyl)sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)but-2- ynamide (Syn. Ex.27; 45 mg, 38.79%) as an off-white solid. TLC: 10% MeOH in DCM. (See analytical data in Table 1).

[1615] Synthesis of 2-fluoro-N-((1-((4-methoxy-3-((2-methoxy-4,5-dimethylphenyl) sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)acrylamide (Syn. Ex.28)

[1616] To a stirred solution of compound 31 (0.1 g, 0.196 mmol) in DMF (3 mL) was added DIPEA (0.1 mL, 0.590 mmol), 2-fluoroprop-2-enoic acid (0.035 g, 0.392 mmol) and50% solution of T3P in EtOAc (0.375 mL, 0.590 mmol) at 0°C. The reaction mixture wasstirred at room temperature for 1h. After completion (monitored by TLC), the mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organiclayer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crudeATTY DKT. NO. ISTX 104 WO was purified by combi flash chromatography (neutral silica) using 80% EtOAc in Heptane to afford title compound 2-fluoro-N-((1-((4-methoxy-3-((2-methoxy-4,5- dimethylphenyl)sulfonamido) benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4- yl)methyl)acrylamide (Syn. Ex.28; 30 mg, 28.03%) as an off white solid. (See analytical data in Table 1). EXAMPLES 29-30

[1617] Scheme 15: Synthesis of N-((1-((4-methoxy-3-((6-methoxy-2, 3-dihydro-1H- indene)-5-sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl)methyl)but-2- ynamide (Syn. Ex.29) and 2-fluoro-N-((1-((4-methoxy-3-((6-methoxy-2,3-dihydro-1H- indene)-5-sulfonamido) benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4- yl)methyl)acrylamide (Syn. Ex.30)sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl) but-2-ynamide (Syn. Ex.29)

[1619] To a stirred solution of compound 35 (0.1 g, 0.192 mmol) in DMF (3 mL) was added DIPEA (0.1 mL, 0.576 mmol), but-2-ynoic acid (0.032, 0.384 mmol) and 50% solution of T3P in EtOAc (0.366 mL, 0.576 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1h. After completion (monitored by TLC), the mixture was diluted with ice- cold water (20 mL) and extracted with EtOAc (3 x 20 mL). The organic layer was dried overanhydrous Na2SO4and concentrated in vacuo. The crude was purified by prep HPLC toafford title compound N-((1-((4-methoxy-3-((6-methoxy-2,3-dihydro-1H-indene)-5- sulfonamido) benzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl) but-2-ynamide (Syn.ATTY DKT. NO. ISTX 104 WO Ex.29; 23 mg, 21.90%) as an off-white solid. TLC: 10% MeOH in DCM. (See analytical data in Table 1).

[1620] Synthesis of 2-fluoro-N-((1-((4-methoxy-3-((6-methoxy-2,3-dihydro-1H- indene)-5-sulfonamido)benzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4- yl)methyl)acrylamide (Syn. Ex.30)

[1621] To a stirred solution of compound 35 (0.10 g, 0.192 mmol) in DMF (2 mL) was added DIPEA (0.10 mL, 0.576 mmol), 2-fluoroprop-2-enoic acid (0.034 g, 0.384 mmol) and 50% solution of T3P in EtOAc (0.366 mL, 0.576 mmol) at 0oC. The reaction mixture was stirred at room temperature for 1h. After completion (monitored by TLC), the mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (3 x 20 mL). The combinedorganic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure.The crude was purified by prep HPLC to afford title compound 2-fluoro-N-((1-((4-methoxy- 3-((6-methoxy-2,3-dihydro-1H-indene)-5-sulfonamido)benzo[d]isoxazol-6-yl) methyl)-1H- pyrazol-4-yl)methyl)acrylamide (Syn. Ex.30; 40 mg, 37.73%) as an off-white solid. TLC: 10% MeOH in DCM. (See analytical data in Table 1). EXAMPLES 31-32

[1622] Scheme 16: Synthesis of 2-((tert-butoxycarbonyl) amino) ethyl ((1-((3-((5-ethyl- 2-methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1Hpyrazol4yl) methyl) carbamate (Syn. Ex.31) and 2-aminoethyl ((1-((3-((5-ethyl-2-methoxyphenyl) sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl) carbamate (Syn. Ex.32)(42)ATTY DKT. NO. ISTX 104 WO

[1624] To a stirred solution of compound 41 (2.0 g, 12.406 mmol) in DCM (20 mL) was added Et3N (3.48 mL, 24.813 mmol) and 4-nitrophenyl carbonochloridate (3.75 g, 18.609 mmol) at 0 °C. The reaction mixture was stirred at 80 °C for 24h. After completion (monitored by TLC), the mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude was purified by combi flash with 20-25% ethyl acetate in heptane to afford title compound 42 (1.50 g, 28.30%) as a pale-yellow semi-solid.1H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.26 (m, 2H), 7.69 - 7.48 (m, 2H), 7.14 - 7.02 (m, 1H), 4.22 (br t, J = 5.4 Hz, 2H), 3.30 - 3.26 (m, 2H), 1.45 - 1.34 (m, 9H).

[1625] Synthesis of 2-((tert-butoxycarbonyl)amino)ethyl ((1-((3-((5-ethyl-2- methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4- yl)methyl)carbamate (Syn. Ex.31)

[1626] To a stirred solution of compound 21 (0.25 g, 0.492 mmol) in DMF (3 mL) was added Et3N (0.2 mL, 1.476 mmol) followed by compound 42 (0.24 g, 0.738 mmol) in DMF (2 mL) drop wise at 0oC. The reaction mixture was stirred at room temperature for 3h. After completion (monitored by TLC), the mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by combi flash chromatography with 4% MeOH in DCM to afford title compound 2-((tert-butoxycarbonyl)amino)ethyl ((1-((3-((5-ethyl-2- methoxyphenyl)sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4- yl)methyl)carbamate (Syn. Ex.31; 0.24 g, 74.07%) as an off-white solid. (See analytical data in Table 1).

[1627] Synthesis of 2-aminoethyl ((1-((3-((5-ethyl-2-methoxyphenyl) sulfonamido)-4- methoxybenzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl) carbamate (Syn. Ex. 32)

[1628] To a stirred solution of Syn. Ex.31 (0.13 g, 0.197 mmol) in DCM (1.5 mL) was added 4M HCl in 1,4-dioxane (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2h. After completion (monitored by TLC), the mixture was concentrated under reduced pressure. The residue was washed with Et2O and dried under reduced pressure to afford title compound 2-aminoethyl((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamido)-4- methoxybenzo[d] isoxazol-6-yl)methyl)-1H-pyrazol-4-yl)methyl)carbamate hydrochloride (Syn. Ex.32; 96 mg, 82.05%) as an off-white solid. (See analytical data in Table 1).ATTY DKT. NO. ISTX 104 WO EXAMPLE 33

[1629] Scheme 17: 5-(tert-butyl)-2-methoxy-N-(4-methoxy-6-((4- (methylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.33) -4-methoxybenzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4-yl) methyl) carbamate (43)

[1631] To a solution of compound 15 (0.40 g, 1.071 mmol) in THF (15 mL) was added 1M solution of KOtBu in THF (3.2mL, 3.213 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min. followed by the addition of 5-(tert-butyl)-2-methoxybenzenesulfonyl chloride (0.36 g, 1.392 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 16h. After completion (monitored by TLC), the mixture was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by combi flash chromatography using 0-72% EA in Heptane to afford title compound 43 (0.22 g, 34.26%) as an off-white solid. LCMS calculated for C29H37N5O7S: 599.24; Found: 600.79 (M+1).

[1632] Synthesis of N-(6-((4-(aminomethyl)-1H-pyrazol-1-yl) methyl)-4-methoxybenzo [d] isoxazol-3-yl)-5-(tert-butyl)-2-methoxybenzenesulfonamide hydrochloride (44)

[1633] To a stirred solution of compound 43 (0.22 g, 0.366 mmol) in DCM (3 mL) was added 4M HCl in 1,4-Dioxane (2 mL) at 0oC. The reaction mixture was stirred at room temperature for 4h. After completion (monitored by TLC), the mixture was concentrated under reduced pressure. The residue was washed with Et2O and dried under reduced pressure to afford title compound 44 (0.17 g, 86.73%) as an off-white solid. LCMS calculated for C24H29N5O5S: 499.19; Found: 500.78 (M+1).ATTY DKT. NO. ISTX 104 WO

[1634] Synthesis of 5-(tert-butyl)-2-methoxy-N-(4-methoxy-6-((4- (methylsulfonamidomethyl)-1H-pyrazol-1-yl)methyl)benzo[d]isoxazol-3- yl)benzenesulfonamide (Syn. Ex.33)

[1635] To a solution of compound 44 (0.15 g, 0.279 mmol) in DCM (1 mL) was added TEA (0.11 g, 0.839 mmol) followed by methane sulfonyl chloride 5 (0.041 g, 0.362 mmol) in DCM (1mL) drop-wise at 0 °C. The reaction mixture was stirred at room temperature for 30 min. After completion (monitored by TLC), the mixture was quenched with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by prep HPLC to afford title compound 5-(tert-butyl)-2-methoxy-N-(4-methoxy-6-((4-(methylsulfonamidomethyl)-1H- pyrazol-1-yl)methyl)benzo[d]isoxazol-3-yl)benzenesulfonamide (Syn. Ex. 33; 85 mg, 52.79%) as an off-white solid. (See analytical data in Table 1). EXAMPLE 34

[1636] Scheme 18: Synthesis of 2-hydroxyethyl ((1-((3-((5-ethyl-2-methoxyphenyl) sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl)methyl)-1H-pyrazol-4- yl)methyl)carbamate (Syn. Ex.34)(46)

[1638] To a stirred solution of compound 45 (0.50 g, 2.835 mmol) in DCM (5 mL) was added Et3N (1 mL, 7.087 mmol) and (4-nitrophenyl) carbonochloridate (0.56 g, 2.835 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16h. After completion (monitored by TLC), the mixture was quenched with ice-cold water (20 mL), extracted with EtOAc (3 x 50 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4,ATTY DKT. NO. ISTX 104 WO filtered, and concentrated under reduced pressure. The crude was purified by combi flash chromatography using 7-12% of EA in Heptane to afford title compound 46 (0.32 g, 33.05%) as a brown oil. LCMS calculated for C15H23NO6Si: 341.13; Found: the expected product from the reaction was not ionised as evidenced from LCMS.

[1639] Synthesis of 2-((tert-butyldimethylsilyl) oxy) ethyl ((1-((3-((5-ethyl-2- methoxyphenyl) sulfonamido)-4-methoxybenzo[d]isoxazol-6-yl) methyl)-1H-pyrazol-4- yl) methyl) carbamate (47)

[1640] To a stirred solution of compound 21 (0.25 g, 0.492 mmol) in DMF (3 mL) was added Et3N (0.2 mL, 1.476 mmol) followed by of compound 46 (0.251 g, 0.738 mmol) at 0°C. The reaction mixture was stirred at room temperature for 4h. After completion (monitored by TLC), the mixture was quenched with ice-cold water (5...

Claims

ATTY DKT. NO. ISTX 104 WO WHAT IS CLAIMED IS:

1. A compound of Formula I:R1and R2together form alkylene; R3is -O-(CH2)b-R8; b is 1-4; R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12); R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15; R11is hydroxy, alkyl, alkoxy or NR14R15; R12is alkyl or NR14R15; R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl; R4is H or alkoxy; Z1, Z2and Z3are selected from (i), (ii) or (iii): (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N, (ii) Z1is NH or O, and Z2and Z3are C, or (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N; Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv): (i) Z4is N, Z5is CR5, and Z6is CH, (ii) Z4is CR16, Z5is N, and Z6is CH, (iii) Z4is CR16, Z5is CR5, and Z6is N, or (iv) Z4is CR16, Z5is CR5, and Z6is CH; R5and R16are selected from (i) or (ii): (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, orATTY DKT. NO. ISTX 104 WO (ii) R5and R16together form alkylene or heteroalkylene; X is O, S(O)xor CH2, where x is 0-2; Het and R6are selected from (i) or (ii): (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system; R7is -C(O)R17, -S(O)R18or -SO2R18; R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR20R21.

2. A compound of Formula I:a is 0-2; R1and R2are selected from (i) or (ii): (i) R1is H, alkyl, haloalkyl or halo; and R2is alkyl, cycloalkyl or haloalkyl, or (ii) R1and R2together form alkylene; R3is -O-(CH2)b-R8; b is 1-4;ATTY DKT. NO. ISTX 104 WO R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12); R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15; R11is hydroxy, alkyl, alkoxy or NR14R15; R12is alkyl or NR14R15; R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl; R4is H or alkoxy; Z1, Z2and Z3are selected from (i), (ii) or (iii): (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N, (ii) Z1is NH or O, and Z2and Z3are C, or (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N; Z4is CR16; Z5is CR5; Z6is N or CH; R5and R16together form alkylene or heteroalkylene; X is O, S(O)x or CH2, where x is 0-2; Het and R6are selected from (i) or (ii): (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system; R7is -C(O)R17, -S(O)R18or -SO2R18; R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl,ATTY DKT. NO. ISTX 104 WO aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

3. A compound of Formula I: R3NZ1O2R1and R2are selected from (i) or (ii): (i) R1is H, alkyl, haloalkyl or halo; and R2is alkyl, cycloalkyl or haloalkyl, or (ii) R1and R2together form alkylene; R3is -O-(CH2)b-R8; b is 1-4; R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12); R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15; R11is hydroxy, alkyl, alkoxy or NR14R15; R12is alkyl or NR14R15; R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl; R4is H or alkoxy; Z1, Z2and Z3are selected from (i), (ii) or (iii): (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N, (ii) Z1is NH or O, and Z2and Z3are C, or (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N; Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv): (i) Z4is N, Z5is CR5, and Z6is CH, (ii) Z4is CR16, Z5is N, and Z6is CH, (iii) Z4is CR16, Z5is CR5, and Z6is N, orATTY DKT. NO. ISTX 104 WO (iv) Z4is CR16, Z5is CR5, and Z6is CH; R5and R16are selected from (i) or (ii): (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or (ii) R5and R16together form alkylene or heteroalkylene; X is O or S(O)x, where x is 0-2; Het and R6are selected from (i) or (ii): (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system; R7is -C(O)R17, -S(O)R18or -SO2R18; R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

4. A compound of Formula I:a is 0-2; R1is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo; R2and R4together form heteroalkylene;ATTY DKT. NO. ISTX 104 WO R3is -O-(CH2)b-R8; b is 1-4; R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12); R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15; R11is hydroxy, alkyl, alkoxy or NR14R15; R12is alkyl or NR14R15; R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl; Z1, Z2and Z3are selected from (i), (ii) or (iii): (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N, (ii) Z1is NH or O, and Z2and Z3are C, or (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N; Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv): (i) Z4is N, Z5is CR5, and Z6is CH, (ii) Z4is CR16, Z5is N, and Z6is CH, (iii) Z4is CR16, Z5is CR5, and Z6is N, or (iv) Z4is CR16, Z5is CR5, and Z6is CH; R5and R16are selected from (i) or (ii): (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or (ii) R5and R16together form alkylene or heteroalkylene; X is O, S(O)x or CH2, where x is 0-2; Het and R6are selected from (i) or (ii): (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system; R7is -C(O)R17, -S(O)R18or -SO2R18; R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy,ATTY DKT. NO. ISTX 104 WO haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

5. A compound of Formula I:a is 0-2; R1is H, alkyl, haloalkyl or halo; R2is alkyl, cycloalkyl or haloalkyl; R3is -O-(CH2)b-R8; b is 1-4; R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12); R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15; R11is hydroxy, alkyl, alkoxy or NR14R15; R12is alkyl or NR14R15; R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl; R4is H or alkoxy; Z1, Z2and Z3are selected from (i), (ii) or (iii): (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N, (ii) Z1is NH or O, and Z2and Z3are C, or (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N; Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv):ATTY DKT. NO. ISTX 104 WO (i) Z4is N, Z5is CR5, and Z6is CH, (ii) Z4is CR16, Z5is N, and Z6is CH, (iii) Z4is CR16, Z5is CR5, and Z6is N, or (iv) Z4is CR16, Z5is CR5, and Z6is CH; R5and R16are selected from (i) or (ii): (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or (ii) R5and R16together form alkylene or heteroalkylene; X is CR22R23, where R22and R23are each independently H or alkyl; Het and R6are selected from (i) or (ii): (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system; R7is -C(O)R17; and R17is alkoxy, alkenyloxy, alkynyloxy or -O-(CH2)2-R19; where R19is -OR9or -NR9R10.

6. The compound of any one of claims 1-5 that has Formula Ia:

7. The compound of any one of claims 1-6, wherein: R1is H; R2is alkyl, cycloalkyl or haloalkyl; R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11; R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy; R11is alkyl or alkoxy; X is CH2; and R17is alkoxy.

8. The compound of any one of claims 1-7, wherein: R1is H; R2is alkyl or haloalkyl;ATTY DKT. NO. ISTX 104 WO R8is H, CN, OH, aryl, NR9R10or C(O)R11; R9and R10are each independently H or C(O)R13; where R13is alkyl; R11is alkoxy; X is CH2; and R17is alkoxy.

9. A compound of Formula II:a R1and R2together form alkylene; R3is -O-(CH2)b-R8; b is 1-4; R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12); R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15; R11is hydroxy, alkyl, alkoxy or NR14R15; R12is alkyl or NR14R15; R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl; R4is H or alkoxy; Z1, Z2and Z3are selected from (i), (ii) or (iii): (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N, (ii) Z1is NH or O, and Z2and Z3are C, or (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N; Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv): (i) Z4is N, Z5is CR5, and Z6is CH, (ii) Z4is CR16, Z5is N, and Z6is CH, (iii) Z4is CR16, Z5is CR5, and Z6is N, orATTY DKT. NO. ISTX 104 WO (iv) Z4is CR16, Z5is CR5, and Z6is CH; R5and R16are selected from (i) or (ii): (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or (ii) R5and R16together form alkylene or heteroalkylene; X is O, S(O)xor CH2, where x is 0-2; Het and R6are selected from (i) or (ii): (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system; R7is -C(O)R17, -S(O)R18or -SO2R18; R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR20R21.

10. A compound of Formula II:a is 0-2; R1and R2are selected from (i) or (ii);ATTY DKT. NO. ISTX 104 WO (i) R1is alkyl, cycloalkyl or haloalkyl; and R2is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo, or (ii) R1and R2together form alkylene; R3is -O-(CH2)b-R8; b is 1-4; R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12); R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15; R11is hydroxy, alkyl, alkoxy or NR14R15; R12is alkyl or NR14R15; R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl; R4is H or alkoxy; Z1, Z2and Z3are selected from (i), (ii) or (iii): (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N, (ii) Z1is NH or O, and Z2and Z3are C, or (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N; Z4is CR16; Z5is CR5; Z6is N or CH; R5and R16together form alkylene or heteroalkylene; X is O, S(O)xor CH2, where x is 0-2; Het and R6are selected from (i) or (ii): (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system; R7is -C(O)R17, -S(O)R18or -SO2R18; R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19ATTY DKT. NO. ISTX 104 WO is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

11. A compound of Formula II:a is 0-2; R1and R2are selected from (i) or (ii): (i) R1is alkyl, cycloalkyl or haloalkyl, and R2is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo, or (ii) R1and R2together form alkylene; R3is -O-(CH2)b-R8; b is 1-4; R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12); R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15; R11is hydroxy, alkyl, alkoxy or NR14R15; R12is alkyl or NR14R15; R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl; R4is H or alkoxy; Z1, Z2and Z3are selected from (i), (ii) or (iii): (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N, (ii) Z1is NH or O, and Z2and Z3are C, orATTY DKT. NO. ISTX 104 WO (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N; Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv): (i) Z4is N, Z5is CR5, and Z6is CH, (ii) Z4is CR16, Z5is N, and Z6is CH, (iii) Z4is CR16, Z5is CR5, and Z6is N, or (iv) Z4is CR16, Z5is CR5, and Z6is CH; R5and R16are selected from (i) or (ii): (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or (ii) R5and R16together form alkylene or heteroalkylene; X is O or S(O)x, where x is 0-2; Het and R6are selected from (i) or (ii): (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system; R7is -C(O)R17, -S(O)R18or -SO2R18; R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

12. A compound of Formula II:ATTY DKT. NO. ISTX 104 WOR1is alkyl, cycloalkyl or haloalkyl; R2is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo; R3is -O-(CH2)b-R8; b is 1-4; R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12); R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15; R11is hydroxy, alkyl, alkoxy or NR14R15; R12is alkyl or NR14R15; R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl; R4is H or alkoxy; Z1, Z2and Z3are selected from (i), (ii) or (iii): (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N, (ii) Z1is NH or O, and Z2and Z3are C, or (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N; Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv): (i) Z4is N, Z5is CR5, and Z6is CH, (ii) Z4is CR16, Z5is N, and Z6is CH, (iii) Z4is CR16, Z5is CR5, and Z6is N, or (iv) Z4is CR16, Z5is CR5, and Z6is CH; R5and R16are selected from (i) or (ii): (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or (ii) R5and R16together form alkylene or heteroalkylene;ATTY DKT. NO. ISTX 104 WO X is CR22R23, where R22and R23are each independently H or alkyl; Het and R6are selected from (i) or (ii): (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system; R7is -C(O)R17; and R17is alkoxy, alkenyloxy, alkynyloxy or -O-(CH2)2-R19; where R19is -OR9or -NR9R10.

13. A compound of any one of claims 9-12, wherein the compound has Formula IIa:

14. The compound of any one of claims 9-13, wherein: R1is alkyl, cycloalkyl or haloalkyl; R2is H; R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11; R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy; R11is alkyl or alkoxy; X is CH2; and R17is alkoxy.

15. The compound of any one of claims 9-13, wherein: R1is alkyl or haloalkyl; R2is H; R8is H, CN, OH, aryl, NR9R10or C(O)R11; R9and R10are each independently H or C(O)R13; where R13is alkyl; R11is alkoxy; X is CH2; and R17is alkoxy.

16. A compound of Formula III:ATTY DKT. NO. ISTX 104 WOR1and R2together form alkylene; R3is -O-(CH2)b-R8; b is 1-4; R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12); R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15; R11is hydroxy, alkyl, alkoxy or NR14R15; R12is alkyl or NR14R15; R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl; R4is H or alkoxy; Z1, Z2and Z3are selected from (i), (ii) or (iii): (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N, (ii) Z1is NH or O, and Z2and Z3are C, or (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N; Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv): (i) Z4is N, Z5is CR5, and Z6is CH, (ii) Z4is CR16, Z5is N, and Z6is CH, (iii) Z4is CR16, Z5is CR5, and Z6is N, or (iv) Z4is CR16, Z5is CR5, and Z6is CH; R5and R16are selected from (i) or (ii): (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or (ii) R5and R16together form alkylene or heteroalkylene;ATTY DKT. NO. ISTX 104 WO X is O, S(O)x or CH2, where x is 0-2; Het and R6are selected from (i) or (ii): (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system; R7is -C(O)R17, -S(O)R18or -SO2R18; R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR20R21.

17. A compound of Formula III:a is 0-2; R1and R2are selected from (i) or (ii): (i) R1and R2are each independently alkyl, cycloalkyl or haloalkyl, or (ii) R1and R2together form alkylene; R3is -O-(CH2)b-R8; b is 1-4;ATTY DKT. NO. ISTX 104 WO R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12); R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15; R11is hydroxy, alkyl, alkoxy or NR14R15; R12is alkyl or NR14R15; R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl; R4is H or alkoxy; Z1, Z2and Z3are selected from (i), (ii) or (iii): (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N, (ii) Z1is NH or O, and Z2and Z3are C, or (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N; Z4is CR16; Z5is CR5; Z6is N or CH; R5and R16together form alkylene or heteroalkylene; X is O, S(O)x or CH2, where x is 0-2; Het and R6are selected from (i) or (ii): (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system; R7is -C(O)R17, -S(O)R18or -SO2R18; R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl,ATTY DKT. NO. ISTX 104 WO aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

18. A compound of Formula III:R1and R2are selected from (i) or (ii): (i) R1and R2are each independently alkyl, cycloalkyl or haloalkyl, or (ii) R1and R2together form alkylene; R3is -O-(CH2)b-R8; b is 1-4; R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12); R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15; R11is hydroxy, alkyl, alkoxy or NR14R15; R12is alkyl or NR14R15; R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl; R4is H or alkoxy; Z1, Z2and Z3are selected from (i), (ii) or (iii): (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N, (ii) Z1is NH or O, and Z2and Z3are C, or (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N; Z4, Z5and Z6are selected from (i), (ii), (iii) or (iv): (i) Z4is N, Z5is CR5, and Z6is CH, (ii) Z4is CR16, Z5is N, and Z6is CH, (iii) Z4is CR16, Z5is CR5, and Z6is N, orATTY DKT. NO. ISTX 104 WO (iv) Z4is CR16, Z5is CR5, and Z6is CH; R5and R16are selected from (i) or (ii): (i) R5and R16are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or (ii) R5and R16together form alkylene or heteroalkylene; X is O or S(O)x, where x is 0-2; Het and R6are selected from (i) or (ii): (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system; R7is -C(O)R17, -S(O)R18or -SO2R18; R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

19. The compound of any one of claims 16-18, wherein the compound has Formula IIIa: .ATTY DKT. NO. ISTX 104 WOR1and R2are selected from (i) or (ii): (i) R1and R2are each independently alkyl, cycloalkyl or haloalkyl, or (ii) R1and R2together form alkylene; R3is -O-(CH2)b-R8; b is 1-4; R8is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR9R10, C(O)R11, C(=NH)(R12) or C(=N-O-R9)(R12); R9and R10are each independently H, alkyl or C(O)R13; where R13is alkyl, alkoxy or NR14R15; R11is hydroxy, alkyl, alkoxy or NR14R15; R12is alkyl or NR14R15; R14and R15are each independently H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached form heterocyclyl; R4is H or alkoxy; Z1, Z2and Z3are selected from (i), (ii) or (iii): (i) Z1is N, one of Z2and Z3is C and the other of Z2and Z3is N, (ii) Z1is NH or O, and Z2and Z3are C, or (iii) Z1is CH, one of Z2and Z3is C and the other of Z2and Z3is N; Z4is N or CR16, where R16is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl; R5is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl; X is O, S(O)xor CH2, where x is 0-2; Het and R6are selected from (i) or (ii): (i) Het is a 5- or 6-membered heteroaryl, and R6is H, alkyl or haloalkyl, or (ii) Het is a 5- or 6-membered heteroaryl, R6is –(CH2)1-2–, and R6and Het together with the atoms to which they are attached form a 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring system;ATTY DKT. NO. ISTX 104 WO R7is -C(O)R17or -SO2R18; R17is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, methylaminomethylalkenyl, dimethylaminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, methylaminomethylalkynyl, dimethylaminomethylalkynyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, -NH-(CH2)2-R19, -O-(CH2)2-R19or -NR20R21; where R19is -OR9or -NR9R10, and R20and R21are each independently H, alkyl, cycloalkyl or haloalkyl; and R18is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR9R10.

21. The compound of any one of claims 16-20, wherein: R1and R2are selected from (i) or (ii): (i) R1and R2are each alkyl, or (ii) R1and R2together form alkylene; R8is H, CN, OH, aryl, heteroaryl, NR9R10or C(O)R11; R9and R10are each independently H or C(O)R13; where R13is alkyl or alkoxy; R11is alkyl or alkoxy; R5and R16together form alkylene; X is O or CH2; R17is alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl; and R18is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

22. The compound of any one of claims 1-4, 6, 9-11, 13 and 16-21, wherein X is O.

23. The compound of any one of claims 1, 2, 4-10 and 11-21, wherein X is CH2.

24. The compound of any one of claims 1-23, wherein a is 0 or 1.

25. The compound of any one of claims 1-8, wherein R2is alkyl.

26. The compound of any one of claims 1-8, wherein R2is haloalkyl.

27. The compound of any one of claims 1-8, wherein R2is difluoromethyl.

28. The compound of any one of claims 9-15, wherein R1is alkyl.

29. The compound of any one of claims 9-15, wherein R1is haloalkyl.ATTY DKT. NO. ISTX 104 WO 30. The compound of any one of claims 9-15, wherein R1is difluoromethyl.

31. The compound of any one of claims 1-6, wherein R1is H.

32. The compound of any one of claims 9-15, wherein R2is H.

33. The compound of any one of claims 16-21, wherein R1and R2together form C1-4alkylene optionally substituted with one or more halo or methyl.

34. The compound of any one of claims 1-33, wherein b is 1 or 2.

35. The compound of any one of claims 1-6, 9-13 and 16-21, wherein R8is H, phenyl, 4-fluorophenyl, mopholinyl, COOH, COOMe, C(=NH)NHOH, tetrazolyl, oxadiazolyl, triazolyl, pyridyl, imidazolyl, oxazolidinyl, NHC(O)OMe, cyano, hydroxy, amino or acetylamino.

36. The compound of any one of claims 1-35, wherein R8is hydrogen.

37. The compound of any one of claims 1-36, wherein R4is H.

38. The compound of any one of claims 1-37, wherein R4is methoxy.

39. The compound of any one of claims 1-38, wherein Z1is NH or O, and Z2and Z3are C.

40. The compound of any one of claims 1-39, wherein Z1is O, and Z2and Z3are C.

41. The compound of any one of claims 1-40, wherein Z4is N.

42. The compound of any one of claims 1-40, wherein Z4is CR16.

43. The compound of any one of claims 1-42, wherein R5is H, cyano, alkoxy or alkyl, and R16is H, alkyl, alkoxy, halo or alkynyl.

44. The compound of any one of claims 1-43, wherein R5is H, cyano, methoxy or methyl, and R16is H, methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, fluoro, ethynyl or propynyl.

45. The compound of any one of claims 1-44, wherein Het is a 5- or 6-membered heteroaryl, and R6is H or alkyl.

46. The compound of any one of claims 1-45, wherein Het is a 5-membered heteroaryl, and R6is H or methyl.

47. The compound of any one of claims 1-46, wherein Het is pyrazolyl, oxazolyl, thiazolyl or pyridyl, and R6is H or methyl.

48. The compound of any one of claims 1-47, wherein Het is pyrazolyl, and R6is H or methyl.

49. The compound of any one of claims 1-48, wherein R7is -C(O)R17.

50. The compound of any one of claims 1-48, wherein R7is -S(O)R18.

51. The compound of any one of claims 1-48, wherein R7is -SO2R18.ATTY DKT. NO. ISTX 104 WO 52. The compound of any one of claims 1-6, 9-13 and 16-21, wherein R17is alkyl, alkoxy, alkenyl, haloalkenyl, alkynyl, NR20R21or hydroxyalkynyl.

53. The compound of any one of claims 1-6, 9-13 and 16-21, wherein R17is methyl, methoxy, NHMe, ethenyl, 1-fluoro-1-ethenyl, ethynyl or 1-propyn-1-yl.

54. The compound of any one of claims 1-53, wherein R18is methyl or tert-butyl.

55. The compound of any one of claims 1-54, wherein the compound is any one of the compounds disclosed herein.

56. A pharmaceutical composition, comprising the compound of any one of claims 1-55 and a pharmaceutically acceptable carrier.

57. A method of treating a subject having cancer, comprising administering to the subject the compound of any one of claims 1-55 or the pharmaceutical composition of claim 56.

58. A method of treating a subject having a myc-driven cancer, comprising administering to the subject the compound of any one of claims 1-55 or the pharmaceutical composition of claim 56.

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