MYST inhibitors

Abstract

Compounds that are MYST inhibitors and pharmaceutically acceptable derivatives thereof are provided herein. Pharmaceutical compositions containing the compounds and methods for using the compounds to treat subjects having hyperproliferative diseases, including cancer, are also provided.

Description

Related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 585,817 filed on 27 September 2023, U.S. Provisional Patent Application No. 63 / 558,419 filed on 27 February 2024, and U.S. Provisional Patent Application No. 63 / 655,961 filed on 4 June 2024, the disclosures of which are incorporated herein by reference in their entirety.

[0002] Sequence List This application includes a sequence listing submitted with this specification as an XML file named "ISTX104WO_SL.xml" with a size of 5406 bytes, created on September 11, 2024, which is incorporated herein by reference in its entirety. [Technical Field]

[0003] Compounds and compositions for inhibiting the MYST family of lysine acetyltransferases (KATs) are provided herein. In one embodiment, a method is provided for treating a disease, including a hyperproliferative disease, using the compounds and compositions provided herein. In another embodiment, the hyperproliferative disease is cancer. [Background technology]

[0004] The MYST family of enzymes are KATs, including 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 cell cycle regulation (Carrozza, et al., Trends in Genetics 2003, 19, 321-329).

[0005] Dysregulation of KAT6 protein expression supports tumor progression (see, e.g., Trisciusglio et al., Stem Cells Int. 2018, Article ID 8908751 (https: / / doi.org / 10.1155 / 2018 / 8908751)). Dysregulation of KAT6A due to gene amplification, overexpression, or mutation has been demonstrated in multiple cancer types, including breast, lung, ovarian, colorectal, and cervical adenocarcinomas (see, e.g., Huang, et al., Molecular and Cellular Biology 2016, 63, 1900-1907; Zack, et al., Nature Genetics 2013, 45, 1134-1140). The locus containing the KAT6A gene (8p11-p12 amplicon) is located in 12 parts of the genome across all cancer types. 番目It has been reported that this is the most commonly amplified region (see, e.g., Zack, et al., 2013 above). In acute myeloid leukemia (AML), relapsed oncogenic fusions of KAT6A have been demonstrated to drive transformation to malignant states (see, e.g., Sheikh, et al., Blood 2015, 125, 1910-1921). Translocations of KAT6A and fusions to partners such as CBP, p300, TIF2, and NCOA3 are known to result in aggressive forms of AML (see, e.g., Sheikh, et al., 2015 above).

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

[0007] Therefore, MYST inhibitors are needed for the treatment of hyperproliferative diseases, including cancer. [Overview of the Initiative]

[0008] Formula I: TIFF2026534467000001.tif43170

[0009] Compounds of or pharmaceutically acceptable derivatives thereof are provided herein, where R 1 ~R 4 , R 6 , R 7 a, Het, X and Z 1 ~Z 6 This is defined elsewhere in this specification.

[0010] Also, Equation II: TIFF2026534467000002.tif43170

[0011] A compound or a pharmaceutically acceptable derivative thereof of is provided herein, wherein R 1 to R 4 , R 6 , R 7 , a, Het, X and Z 1 to Z 6 are as defined elsewhere in the present specification.

[0012] Also provided is Formula III: TIFF2026534467000003.tif43170

[0013] A compound or a pharmaceutically acceptable derivative thereof of is provided herein, wherein R 1 to R 4 , R 6 , R 7 , a, Het, X and Z 1 to Z 6 are as defined elsewhere in the present specification.

[0014] Also provided is a pharmaceutical composition comprising a compound of Formula I, II or III and a pharmaceutically acceptable excipient.

[0015] In one embodiment, the compounds of Formula I, II or III provided herein inhibit one or more members of the MYST family of lysine acetyltransferases. 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 by covalently modifying 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, a method for treating hyperproliferative disorders by administering compounds or compositions provided herein is provided. In one embodiment, the hyperproliferative disorder 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 method provided herein, the compound of formula I is used as a monotherapy or in combination with standard care treatment for a particular cancer.

[0017] Another embodiment provides a method for inhibiting the MYST enzyme by contacting the MYST enzyme or a composition containing the MYST enzyme with a compound or composition provided herein. Another embodiment provides a method for inhibiting KAT6A by contacting the KAT6A or a composition containing KAT6A with a compound or composition provided herein. [Modes for carrying out the invention]

[0018] I. Definition To facilitate understanding of the disclosures contained herein, several terms are defined below.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. All patents, applications, published applications, and other publications are incorporated in their entirety by reference. If a term in this specification has multiple definitions, the definition in this section shall prevail unless otherwise specified.

[0020] The singular forms "a," "an," and "the" include multiple references unless the context explicitly indicates otherwise.

[0021] As used herein, "subject" refers to animals, including mammals, and humans such as patients.

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

[0023] When used herein, pharmaceutically acceptable derivatives of the compounds include, but are not limited to, their salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, clathrates, solvates, or hydrates. Such derivatives can be readily prepared by those skilled in the art using known methods for such derivatization. The resulting compounds may be administered to animals or humans without substantial toxicity and may be pharmaceutically active or prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidine-1'-ylmethylbenzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; but are not limited to lithium, potassium and sodium Alkali metal salts such as ammonium; alkaline earth metal salts such as barium, calcium, and magnesium, but not limited to these; transition metal salts such as zinc, but not limited to these; inorganic salts such as sodium hydrogen phosphate and disodium phosphate, but not limited to these; salts of mineral acids, but not limited to these, including hydrochloride and sulfate salts, but not limited to these; and salts of organic acids, such as acetate, lactate, malate, tartrate, citrate, ascorbate, succinate, butyrate, valerate, mesylate, and fumarate, but not limited to these. Pharmaceutically acceptable esters include, but not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups (including, but not limited to, carboxylic acids, phosphoric acid, phosphinic acid, sulfonic acid, sulfinic acid, and boronic acid). Pharmaceutically acceptable enol ethers include, but not limited to, derivatives of the 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 the 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 with 1 to about 100, or 1 to about 10, or 1 to about 2, 3, or 4 solvent or water molecules.

[0024] As used herein, treatment means any method by which one or more symptoms of a disease or disorder are improved or otherwise beneficially altered. Treatment also includes any pharmaceutically acceptable use of the compositions herein, such as for treating hyperproliferative diseases.

[0025] As used herein, improvement of symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition means any relief, whether permanent or temporary, sustained or transient, that may be caused by or related to the administration of the compound or pharmaceutical composition.

[0026] As used herein, unless otherwise indicated, the terms “manage,” “managing,” and “management” include preventing a relapse of a particular disease or disorder in a subject who has previously suffered from the disease or disorder, and / or extending the time that a subject with the disease or disorder maintains a state of remission. This term also includes modulating the threshold, development, and / or duration of the disease or disorder, or altering the way in which a subject responds to the disease or disorder.

[0027] If parts are identified by those conventional chemical formulas written from left to right, they equally encompass chemically identical parts resulting from writing the structure from right to left; for example, -CH2O- is equivalent to -OCH2-.

[0028] The term "alkyl" means a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon radical (i.e., C1-C) which, unless otherwise specified, may include divalent and polyvalent radicals having a specified number of carbon atoms, either by itself or as part of another substituent. 10 (where ∫ means 1 to 10 carbon atoms). Examples of alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, and sec-butyl; and groups such as homologs and isomers of n-pentyl, n-hexyl, n-heptyl, and n-octyl, but are not limited to these.

[0029] The term "alkenyl" means a straight-chain (i.e., unbranched) or branched-chain hydrocarbon radical having one or more carbon-carbon double bonds, which, unless otherwise specified, may include divalent and polyvalent radicals having a specified number of carbon atoms, either by itself or as part of another substituent (i.e., C1-C 10 (where ∫ means 1 to 10 carbon atoms). Examples of alkenyl groups include, but are not limited to, vinyl (i.e., ethenyl), 2-propenyl, clotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), as well as their higher homologs and isomers.

[0030] The term "alkynyl" means a straight-chain (i.e., unbranched) or branched-chain hydrocarbon radical having one or more carbon-carbon triple bonds, which, unless otherwise specified, may include divalent and polyvalent radicals having a specified number of carbon atoms, either by itself or as part of another substituent (i.e., C1-C 10 (where 1 means 1 to 10 carbon atoms). Examples of alkynyl groups include, but are not limited to, ethynyl, 1- and 3-propynyl, 3-butynyl, and their higher congeners and isomers.

[0031] The term "alkylene" refers to a divalent radical derived from an alkyl group, exemplified but not limited to -CH2CH2CH2CH2-, either by itself or as part of another substituent. Typically, alkyl (or alkylene) groups have 1 to 24 carbon atoms, including groups with 10 or fewer carbon atoms. "Lower alkyl" or "lower alkylene" are shorter-chain alkyl or alkylene groups, generally having 6 or fewer carbon atoms.

[0032] The terms “alkoxy,” “alkylamino,” and “alkylthio” (or thioalkoxy) are used in their traditional sense to refer to alkyl groups bonded to the rest of a molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.

[0033] The term "heteroalkyl," either by itself or in combination with other terms, means a linear or branched hydrocarbon radical containing a heteroatom selected from the group consisting of O, N, P, Si, and S, unless otherwise specified, wherein the nitrogen and sulfur atoms are optionally oxidized, the nitrogen atom may have alkyl substituents that satisfy its valence, and / or may be optionally quaternized. The heteroatoms O, N, P, Si, and S can be located at any internal 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. For example, up to two heteroatoms may be consecutive, such as -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Similarly, the term “heteroalkylene” means a divalent radical derived from heteroalkyls, either by itself or as part of another substituent, but not limited to those exemplified by -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For alkylene and heteroalkylene bonding groups, the orientation of the bonding group is not implied by the direction in which the formula of the bonding 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," either by themselves or in combination with other terms, refer to the cyclic versions of "alkyl" and "heteroalkyl," respectively, including bicyclic, tricyclic, spirocyclic, and bridging bicyclic groups, unless otherwise specified. Furthermore, in the case of heterocycloalkyls, the heteroatom can occupy a position where the heterocycle is bonded to the rest of the molecule. Examples of cycloalkyls include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornanyl, and bicyclo[2.2.2]octanyl. Examples of heterocycloalkyls 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, and 1- or 2-azabicyclo[2.2.2]octanyl.

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

[0036] The term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent that can be monocyclic or polycyclic (one to three rings in one embodiment) that is condensed or covalently bonded, unless otherwise specified. The term "heteroaryl" refers to an aryl group containing one to four heteroatoms selected from N, O, and S in the ring, where the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. Heteroaryl groups can be bonded to the rest of the molecule via carbon or heteroatoms. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrzolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, and 2-thiazolyl. These include 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. The substituents of the aryl ring system and heteroaryl ring system may be selected from the group of acceptable substituents described herein. The term "heteraryllium" refers to a heteroaryl group that is positively charged on one or more heteroatoms.

[0037] As used herein, the term "oxo" refers to an oxygen atom double-bonded to a carbon atom.

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

[0039] The substituents of alkyl, heteroalkyl, alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl groups are, in one embodiment, 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, selected from -NR”C(O)R', -NR”C(O)2R', -S(O)2NR'R”, -NRSO2R', -NRSO2NR'R”, -CN and -NO2, and a number ranging from 0 to the number of hydrogen atoms in such radicals. In one embodiment, cycloalkyl, heterocycloalkyl, Substituent portions of cycloalkenyl and heterocycloalkenyl groups also include substituted and unsubstituted alkyls, substituted and unsubstituted alkenyls, and substituted and unsubstituted alkynyls. In one embodiment, each of R', R'', R''', and R'''' is independently a hydrogen atom, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group (e.g., an aryl group substituted with 1 to 3 halogens), a substituted or unsubstituted alkyl group, an alkoxy or thioalkoxy group, or an arylalkyl group. If the compounds provided herein contain two or more R groups, each of these R groups is independently selected, for example, each R', R'', R''', and R'''' group (if there are two or more groups). If R' and R'' are bonded to the same nitrogen atom, they can bond to the nitrogen atom to form a 4-membered, 5-membered, 6-membered, or 7-membered ring. For example, -NR'R'' means including, but not limited to, 1-pyrrolidinyl and 4-morpholinyl.From the above discussion of substituents, those skilled in the art will understand that the term "alkyl" includes groups containing carbon atoms bonded to groups other than hydrogen groups, such as haloalkyls (e.g., -CF3 and -CH2CF3) and acyls (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, etc.).

[0040] The substituents of the aryl and heteroaryl groups are, in one embodiment, deuterium, halo, substituted and unsubstituted alkyls, substituted and unsubstituted alkenyls, and substituted and unsubstituted alkynyls, -OR', -NR'R'', -SR', -SiR'R''R''', -C(O)R', -C(O)R', -CO2R', -CONR'R'', -C(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', - R' is selected from S(O)2NR'R'', -NRSO2R', -CN and -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy and fluoro(C1-C4)alkyl, and is a number ranging from 0 to the total number of hydrogens on the aromatic ring system; wherein one embodiment, R', R'', R''' and R''' are 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. If the compounds provided herein contain two or more R groups, each of these R groups is independently selected, for example, each R', R'', R''' and R''' group (if there are two or more groups).

[0041] Two of the substituent groups on adjacent atoms of an aryl ring or heteroaryl ring are given by the formula -Q'-C(O)-(CRR') qA ring of the form -Q”- (wherein Q' and Q” are independently -NR-, -O-, -CRR'- or a single bond, and q is an integer from 0 to 3) may be arbitrarily formed. Alternatively, two of the substituents on adjacent atoms of an aryl ring or heteroaryl ring may be of the form -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 from 1 to 4) substituents can be optionally replaced by substituents of the formula -(CRR') s -X'-(CR"R"') d -(wherein s and d are independently integers from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2-, or -S(O)2NR'-) substituents may be optionally replaced. The substituent parts 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 terms “heteroatom” or “ring heteroatom” mean including 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 under physiological conditions by one or more steps or processes, or otherwise undergoes chemical modification, or is otherwise converted into a biologically, pharmaceutically, or therapeutically active form of the compound. Furthermore, a prodrug can be converted into a biologically, pharmaceutically, or therapeutically active form of the compound by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be converted into the compound of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0044] Certain compounds provided herein may exist in solvated forms, including non-solvated and hydrated forms. Generally, solvated forms are equivalent to non-solvated forms and are included within the scope of this disclosure. Certain compounds provided herein may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses intended herein and are intended within the scope of this disclosure.

[0045] Certain compounds provided herein have an asymmetric carbon atom (optical center) or a double bond; racemates, diastereomers, tautomers, geometric isomers, and individual isomers are included within the scope of this disclosure. The compounds provided herein do not include any known in the art to be too unstable to be synthesized and / or isolated.

[0046] The compounds provided herein may also contain atomic isotopes in proportions not found in nature in one or more of the atoms constituting such compounds. For example, a compound may contain tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 They can be radiolabeled with radioactive isotopes such as C). All isotopic variations of the compounds provided herein, whether radioactive or not, are included within the scope of this disclosure.

[0047] II. Compounds for use in compositions and methods In one embodiment, Formula I: for use in compositions and methods provided herein TIFF2026534467000004.tif42170

[0048] A compound or a pharmaceutically acceptable derivative thereof is provided, in the formula:

[0049] a is between 0 and 2;

[0050] R1 and R 2 They combine to form alkylenes;

[0051] R 3 is -O-(CH2) b -R 8 and;

[0052] b is 1 to 4;

[0053] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0054] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0055] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0056] R 12 is alkyl or NR 14 R 15 and;

[0057] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0058] R 4 is H or alkoxy;

[0059] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0060] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0061] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0062] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0063] Z 4 , Z 5 and Z 6 The following is selected from (i), (ii), (iii), or (iv):

[0064] (i)Z 4 is N, Z 5 CR 5 Z 6 CH is

[0065] (ii)Z 4 CR 16 Z 5 is N, Z 6 CH is

[0066] (iii)Z 4 CR 16 And Z 5 CR 5 Z 6 is N, or

[0067] (iv) Z 4 is CR 16 , and Z 5 is CR 5 , and Z 6 is CH;

[0068] R 5 and R 16 are selected from the following (i) or (ii):

[0069] (i) R 5 and R 16 are each independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl or haloalkyl, or

[0070] (ii) R 5 and R 16 together form an alkylene or heteroalkylene;

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

[0072] Het and R 6 are selected from the following (i) or (ii):

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

[0074] (ii) Het is a 5-membered or 6-membered heteroaryl, and R 6 is -(CH₂) 1-2 -, and R 6 and 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] R 7 is -C(O)R17 ,-S(O)R 18 or -SO2R 18 and;

[0076] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0077] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 20 R 21 That is the case.

[0078] In one embodiment, Formula Ia is used in the compositions and methods provided herein: TIFF2026534467000005.tif48170

[0079] A compound or a pharmaceutically acceptable derivative thereof is provided, in the formula:

[0080] a is between 0 and 2;

[0081] R 1 and R 2 They combine to form alkylenes;

[0082] R 3 is -O-(CH2) b -R 8 and;

[0083] b is 1 to 4;

[0084] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0085] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0086] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0087] R 12 is alkyl or NR 14 R 15 and;

[0088] R 14 and R15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0089] R 4 is H or alkoxy;

[0090] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0091] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0092] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0093] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0094] Z 4 is N or CR 16 and;

[0095] R 5 and R 16 The following is selected from (i) or (ii):

[0096] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl, or haloalkyl,

[0097] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0098] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[0099] Het and R 6 The following is selected from (i) or (ii):

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

[0101] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0102] R 7 is -C(O)R 17 or -SO2R 18 and;

[0103] R 17 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-R 19 -O-(CH2)2-R 19or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0104] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 20 R 21 That is the case.

[0105] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, wherein:

[0106] R 8 H, CN, OH, alkoxy, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[0107] R 9 H is R 10 is H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[0108] R 11 is alkyl or alkoxy;

[0109] R 5 and R 16 The following is selected from (i) or (ii):

[0110] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, or alkynyl,

[0111] (ii)R 5 and R 16 They combine to form alkylenes;

[0112] X is either O or CH2;

[0113] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0114] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0115] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, wherein:

[0116] R 8 H, CN, OH, alkoxy, aryl, NR 9 R 10 or C(O)R 11 and;

[0117] R 9 H is R 10 is C(O)R 13 And; in the formula, R 13 is alkyl;

[0118] R 11 It is an alkoxy;

[0119] R 5 and R 16 The following is selected from (i) or (ii):

[0120] (i)R 5 is H, cyano, alkoxy, or alkyl, and R 16 is H, alkyl, alkoxy, halo or alkynyl, or

[0121] (ii)R 5 and R 16 They combine to form alkylenes;

[0122] X is either O or CH2;

[0123] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0124] R 18 These are 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 R 1 and R 2 They are together C 2-4 Forms alkylenes.

[0126] In another embodiment, the compounds for use in the compositions and methods provided herein have formula I or Ia, wherein R 1 and R 2 They combine to form propylene.

[0127] In another embodiment, the compound for use in the compositions and methods provided herein is of formula I: TIFF2026534467000006.tif43170

[0128] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0129] a is between 0 and 2;

[0130] R 1 and R 2 The following is selected from (i) or (ii):

[0131] (i)R 1 is H, alkyl, haloalkyl or halo; and R 2 is alkyl, cycloalkyl or haloalkyl, or

[0132] (ii)R 1 and R 2 They combine to form alkylenes;

[0133] R 3 is -O-(CH2) b -R 8 and;

[0134] b is 1 to 4;

[0135] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0136] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0137] R 11 is hydroxy, alkyl, alkoxy or NR14 R 15 and;

[0138] R 12 is alkyl or NR 14 R 15 and;

[0139] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0140] R 4 is H or alkoxy;

[0141] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0142] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0143] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0144] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0145] Z 4 CR 16 and;

[0146] Z 5 CR 5 and;

[0147] Z 6 is N or CH;

[0148] R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0149] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[0150] Het and R 6 The following is selected from (i) or (ii):

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

[0152] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0153] R 7 is -C(O)R 17 ,-S(O)R 18 or -SO2R 18 and;

[0154] R 17Alkyl, 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0155] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0156] In another embodiment, the compound for use in the compositions and methods provided herein is of formula Ia: TIFF2026534467000007.tif42170

[0157] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0158] a is between 0 and 2;

[0159] R 1 and R 2 The following is selected from (i) or (ii):

[0160] (i)R 1 is H, alkyl, haloalkyl or halo; and R 2 is alkyl, cycloalkyl or haloalkyl, or

[0161] (ii)R 1 and R 2 They combine to form alkylenes;

[0162] R 3 is -O-(CH2) b -R 8 and;

[0163] b is 1 to 4;

[0164] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0165] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0166] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0167] R 12 is alkyl or NR 14 R 15 and;

[0168] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0169] R 4 is H or alkoxy;

[0170] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0171] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0172] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0173] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0174] Z 4 CR 16 and;

[0175] R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0176] X is O, S(O)x Alternatively, it is CH2, where x is between 0 and 2;

[0177] Het and R 6 The following is selected from (i) or (ii):

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

[0179] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0180] R 7 is -C(O)R 17 or -SO2R 18 and;

[0181] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0182] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0183] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, wherein:

[0184] R 1 and R 2 The following is selected from (i) or (ii):

[0185] (i)R 1 H is R 2 is alkyl, cycloalkyl or haloalkyl, or

[0186] (ii)R 1 and R 2 They combine to form alkylenes;

[0187] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[0188] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[0189] R 11 is alkyl or alkoxy;

[0190] R 5 and R 16 They combine to form alkylenes;

[0191] X is either O or CH2;

[0192] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0193] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0194] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, wherein:

[0195] R 1 and R 2 The following is selected from (i) or (ii):

[0196] (i)R 1 H is R 2 is alkyl or haloalkyl, or

[0197] (ii)R 1 and R 2 They combine to form alkylenes;

[0198] R 8 H, CN, OH, aryl, NR 9 R 10 or C(O)R 11 and;

[0199] R 9and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl;

[0200] R 11 It is an alkoxy;

[0201] R 5 and R 16 They combine to form alkylenes;

[0202] X is either O or CH2;

[0203] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0204] R 18 These are 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 R 5 and R 16 They are together C 3-5 Forms alkylenes.

[0206] In another embodiment, the compounds for use in the compositions and methods provided herein have formula I or Ia, wherein R 5 and R 16 They combine to form propylene.

[0207] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, where X is O or S(O) xIn another embodiment, the compounds for use in the compositions and methods provided herein have formula I or Ia, where X is O or S.

[0208] In another embodiment, the compound for use in the compositions and methods provided herein is of formula I: TIFF2026534467000008.tif44170

[0209] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0210] a is between 0 and 2;

[0211] R 1 and R 2 The following is selected from (i) or (ii):

[0212] (i)R 1 is H, alkyl, haloalkyl or halo; and R 2 is alkyl, cycloalkyl or haloalkyl, or

[0213] (ii)R 1 and R 2 They combine to form alkylenes;

[0214] R 3 is -O-(CH2) b -R 8 and;

[0215] b is 1 to 4;

[0216] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0217] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0218] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0219] R 12 is alkyl or NR 14 R 15 and;

[0220] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0221] R 4 is H or alkoxy;

[0222] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0223] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0224] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0225] (iii)Z 1CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0226] Z 4 , Z 5 and Z 6 The following is selected from (i), (ii), (iii), or (iv):

[0227] (i)Z 4 is N, Z 5 CR 5 Z 6 CH is

[0228] (ii)Z 4 CR 16 Z 5 is N, Z 6 CH is

[0229] (iii)Z 4 CR 16 Z 5 CR 5 Z 6 is N, or

[0230] (iv)Z 4 CR 16 Z 5 CR 5 Z 6 is CH;

[0231] R 5 and R 16 The following is selected from (i) or (ii):

[0232] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl,

[0233] (ii)R5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0234] X is O or S(O) x And in the equation x is between 0 and 2;

[0235] Het and R 6 The following is selected from (i) or (ii):

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

[0237] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0238] R 7 is -C(O)R 17 ,-S(O)R 18 or -SO2R 18 and;

[0239] R 17 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-R 19 -O-(CH2)2-R19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0240] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0241] In another embodiment, the compound for use in the compositions and methods provided herein is of formula Ia: TIFF2026534467000009.tif42170

[0242] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0243] a is between 0 and 2;

[0244] R 1 and R 2 The following is selected from (i) or (ii):

[0245] (i)R 1 is H, alkyl, haloalkyl or halo; and R 2 is alkyl, cycloalkyl or haloalkyl, or

[0246] (ii)R 1 and R 2They combine to form alkylenes;

[0247] R 3 is -O-(CH2) b -R 8 and;

[0248] b is 1 to 4;

[0249] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0250] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0251] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0252] R 12 is alkyl or NR 14 R 15 and;

[0253] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0254] R 4 is H or alkoxy;

[0255] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0256] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0257] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0258] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0259] Z 4 is N or CR 16 and;

[0260] R 5 and R 16 The following is selected from (i) or (ii):

[0261] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl, or haloalkyl,

[0262] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0263] X is O or S(O) x And in the equation x is between 0 and 2;

[0264] Het and R6 The following is selected from (i) or (ii):

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

[0266] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0267] R 7 is -C(O)R 17 or -SO2R 18 and;

[0268] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0269] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0270] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, wherein:

[0271] R 1 and R 2 The following is selected from (i) or (ii):

[0272] (i)R 1 H is R 2 is alkyl, cycloalkyl or haloalkyl, or

[0273] (ii)R 1 and R 2 They combine to form alkylenes;

[0274] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[0275] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[0276] R 11 is alkyl or alkoxy;

[0277] R 5 and R 16 The following is selected from (i) or (ii):

[0278] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, or alkynyl,

[0279] (ii)R 5 and R 16 They combine to form alkylenes;

[0280] X is O,

[0281] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0282] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0283] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, wherein:

[0284] R 1 and R 2 The following is selected from (i) or (ii):

[0285] (i)R 1 H is R 2 is alkyl or haloalkyl, or

[0286] (ii)R 1 and R 2 They combine to form alkylenes;

[0287] R8 H, CN, OH, aryl, NR 9 R 10 or C(O)R 11 and;

[0288] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl;

[0289] R 11 It is an alkoxy;

[0290] R 5 and R 16 The following is selected from (i) or (ii):

[0291] (i)R 5 is H, cyano, alkoxy, or alkyl, and R 16 is H, alkyl, alkoxy, halo or alkynyl, or

[0292] (ii)R 5 and R 16 They combine to form alkylenes;

[0293] X is O,

[0294] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0295] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0296] In another embodiment, the compound for use in the compositions and methods provided herein is of formula Ia: TIFF2026534467000010.tif45170

[0297] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0298] a is between 0 and 2;

[0299] R 1 and R 2 The following is selected from (i) or (ii):

[0300] (i)R 1 is H, alkyl, haloalkyl or halo; and R 2 is alkyl, cycloalkyl or haloalkyl, or

[0301] (ii)R 1 and R 2 They combine to form alkylenes;

[0302] R 3 is -O-(CH2) b -R 8 and;

[0303] b is 1 to 4;

[0304] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0305] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0306] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0307] R 12 is alkyl or NR 14 R 15 and;

[0308] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0309] R 4 is H or alkoxy;

[0310] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0311] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0312] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0313] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0314] Z 4 is N or CR 16 And in the formula R16 is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl;

[0315] R 5 is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl;

[0316] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[0317] Het and R 6 The following is selected from (i) or (ii):

[0318] (i) Het is a 5-membered or 6-membered heteroaryl, R 6 is H, alkyl or haloalkyl, or

[0319] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0320] R 7 is -C(O)R 17 or -SO2R 18 and;

[0321] R 17Alkyl, 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0322] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0323] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, wherein:

[0324] R 1 and R 2 The following is selected from (i) or (ii):

[0325] (i)R1 H is R 2 is alkyl, cycloalkyl or haloalkyl, or

[0326] (ii)R 1 and R 2 They combine to form alkylenes;

[0327] R 5 is alkenyl or alkinyl;

[0328] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[0329] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[0330] R 11 is alkyl or alkoxy;

[0331] X is either O or CH2;

[0332] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0333] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0334] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, wherein:

[0335] R 1 and R 2 The following is selected from (i) or (ii):

[0336] (i)R 1 H is R 2 is alkyl or haloalkyl, or

[0337] (ii)R 1 and R 2 They combine to form alkylenes;

[0338] R 5 is Alkinnil;

[0339] R 8 H, CN, OH, aryl, NR 9 R 10 or C(O)R 11 and;

[0340] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl;

[0341] R 11 It is an alkoxy;

[0342] X is either O or CH2;

[0343] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0344] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0345] In another embodiment, the compound for use in the compositions and methods provided herein is of formula I: TIFF2026534467000011.tif43170

[0346] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0347] a is between 0 and 2;

[0348] R 1 is H, alkyl, haloalkyl or halo;

[0349] R 2 and R 4 They form heteroalkylenes together;

[0350] R 3 is -O-(CH2) b -R 8 and;

[0351] b is 1 to 4;

[0352] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0353] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0354] R 11 is hydroxy, alkyl, alkoxy or NR 14 R15 and;

[0355] R 12 is alkyl or NR 14 R 15 and;

[0356] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0357] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0358] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0359] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0360] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0361] Z 4 , Z 5 and Z 6 The following is selected from (i), (ii), (iii), or (iv):

[0362] (i)Z 4 is N, Z 5 CR 5 Z 6 CH is

[0363] (ii)Z 4 CR 16 Z 5 is N, Z 6 CH is

[0364] (iii)Z 4 CR 16 Z 5 CR 5 Z 6 is N, or

[0365] (iv)Z 4 CR 16 Z 5 CR 5 Z 6 is CH;

[0366] R 5 and R 16 The following is selected from (i) or (ii):

[0367] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl,

[0368] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0369] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[0370] Het and R 6 The following is selected from (i) or (ii):

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

[0372] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0373] R 7 is -C(O)R 17 ,-S(O)R 18 or -SO2R 18 and;

[0374] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0375] R 18Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0376] In another embodiment, the compound for use in the compositions and methods provided herein is of formula Ia: TIFF2026534467000012.tif44170

[0377] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0378] a is between 0 and 2;

[0379] R 1 is H, alkyl, haloalkyl or halo;

[0380] R 2 and R 4 They form heteroalkylenes together;

[0381] R 3 is -O-(CH2) b -R 8 and;

[0382] b is 1 to 4;

[0383] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0384] R 9 and R 10 each independently are H, alkyl or C(O)R 13 ; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 ;

[0385] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 ;

[0386] R 12 is alkyl or NR 14 R 15 ;

[0387] R 14 and R 15 each independently are H, OH, alkoxy or alkyl, or together with the nitrogen atom to which they are attached, form a heterocyclyl;

[0388] Z 1 , Z 2 and Z 3 are selected from the following (i), (ii) or (iii):

[0389] (i) Z 1 is N, one of Z 2 and Z 3 is C, and the other of Z 2 and Z 3 is N,

[0390] (ii) Z 1 is NH or O, and Z 2 and Z 3 are C, or

[0391] (iii) Z 1 is CH, one of Z 2 and Z 3 is C, and Z 2 and Z 3the other is N;

[0392] Z 4 is N or CR 16 ;

[0393] R 5 and R 16 are selected from the following (i) or (ii):

[0394] (i) R 5 and R 16 are each independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl or haloalkyl, or

[0395] (ii) R 5 and R 16 together form an alkylene or heteroalkylene;

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

[0397] Het and R 6 are selected from the following (i) or (ii):

[0398] (i) Het is a 5-membered or 6-membered heteroaryl, and R 6 is H, alkyl or haloalkyl, or

[0399] (ii) Het is a 5-membered or 6-membered heteroaryl, and R 6 is -(CH2) 1-2 -, and R 6 and 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] R 7 is -C(O)R 17 or -SO2R 18 ;

[0401] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0402] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0403] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, wherein:

[0404] R 1 H is;

[0405] R 2 and R4 Together, -O-(CH2) r -or -O-(CH2) 1-3 -O-(CH2) 1-3 - forms the R of equation I, where r is an integer between 2 and 5, and terminal O is R of equation I. 4 It is linked to the position;

[0406] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[0407] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[0408] R 11 is alkyl or alkoxy;

[0409] R 5 and R 16 The following is selected from (i) or (ii):

[0410] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, or alkynyl,

[0411] (ii)R 5 and R 16 They combine to form alkylenes;

[0412] X is either O or CH2;

[0413] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0414] R 18 is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl or hydroxymethylalkynyl.

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

[0416] R 1 is H;

[0417] R 2 and R 4 together 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 bonded to the R 4 position of Formula I;

[0418] R 8 is H, CN, OH, aryl, NR 9 R 10 or C(O)R 11 ;

[0419] R 9 and R 10 are each independently H or C(O)R 13 , where R 13 is alkyl;

[0420] R 11 is alkoxy;

[0421] R 5 and R 16 are selected from the following (i) or (ii):

[0422] (i) R 5 is H, cyano, alkoxy or alkyl, and R 16 is H, alkyl, alkoxy, halo or alkynyl, or

[0423] (ii)R 5 and R 16 They combine to form alkylenes;

[0424] X is either O or CH2;

[0425] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0426] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0427] In another embodiment, the compound for use in the compositions and methods provided herein is of formula I: TIFF2026534467000013.tif42170

[0428] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0429] a is between 0 and 2;

[0430] R 1 is H, alkyl, haloalkyl or halo;

[0431] R 2 These are alkyl, cycloalkyl, or haloalkyl;

[0432] R 3 is -O-(CH2) b -R 8 and;

[0433] b is 1 to 4;

[0434] R 8H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0435] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0436] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0437] R 12 is alkyl or NR 14 R 15 and;

[0438] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0439] R 4 is H or alkoxy;

[0440] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0441] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3The other side is N.

[0442] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0443] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0444] Z 4 , Z 5 and Z 6 The following is selected from (i), (ii), (iii), or (iv):

[0445] (i)Z 4 is N, Z 5 CR 5 Z 6 CH is

[0446] (ii)Z 4 CR 16 Z 5 is N, Z 6 CH is

[0447] (iii)Z 4 CR 16 Z 5 CR 5 Z 6 is N, or

[0448] (iv)Z 4 CR 16 Z 5 CR 5 Z 6 is CH;

[0449] R 5 and R 16 The following is selected from (i) or (ii):

[0450] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl,

[0451] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0452] X is CR 22 R 23 And in the formula R 22 and R 23 Each of these is independently either H or alkyl;

[0453] Het and R 6 The following is selected from (i) or (ii):

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

[0455] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0456] R 7 -C(O)R 17 and;

[0457] R 17 These are alkoxy, alkenyloxy, alkynyloxy or -O-(CH2)2-R 19 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 That is the case.

[0458] In another embodiment, the compound for use in the compositions and methods provided herein is of formula Ia: TIFF2026534467000014.tif43170

[0459] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0460] a is between 0 and 2;

[0461] R 1 is H, alkyl, haloalkyl or halo;

[0462] R 2 These are alkyl, cycloalkyl, or haloalkyl;

[0463] R 3 is -O-(CH2) b -R 8 and;

[0464] b is 1 to 4;

[0465] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0466] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0467] R 11is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0468] R 12 is alkyl or NR 14 R 15 and;

[0469] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0470] R 4 is H or alkoxy;

[0471] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0472] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0473] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0474] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0475] Z 4 is N or CR 16 and;

[0476] R 5 and R16 The following is selected from (i) or (ii):

[0477] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl, or haloalkyl,

[0478] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0479] X is CR 22 R 23 And in the formula R 22 and R 23 Each of these is independently either H or alkyl;

[0480] Het and R 6 The following is selected from (i) or (ii):

[0481] (i) Het is a 5-membered or 6-membered heteroaryl, R 6 is H, alkyl or haloalkyl, or

[0482] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0483] R 7 -C(O)R 17 and;

[0484] R 17 These are alkoxy, alkenyloxy, alkynyloxy or -O-(CH2)2-R 19 And; in the formula, R 19 is -OR 9or -NR 9 R 10 That is the case.

[0485] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, wherein:

[0486] R 1 H is;

[0487] R 2 These are alkyl, cycloalkyl, or haloalkyl;

[0488] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[0489] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[0490] R 11 is alkyl or alkoxy;

[0491] X is CH2;

[0492] R 17 It is an alkoxy.

[0493] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, wherein:

[0494] R 1 H is;

[0495] R 2 is alkyl or haloalkyl;

[0496] R 8H, CN, OH, aryl, NR 9 R 10 or C(O)R 11 and;

[0497] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl;

[0498] R 11 It is an alkoxy;

[0499] X is CH2;

[0500] R 17 It is an alkoxy.

[0501] In one embodiment, Formula II is used in the compositions and methods provided herein: TIFF2026534467000015.tif41170

[0502] A compound of or a pharmaceutically acceptable derivative thereof, wherein the formula is:

[0503] a is between 0 and 2;

[0504] R 1 and R 2 They combine to form alkylenes;

[0505] R 3 is -O-(CH2) b -R 8 and;

[0506] b is 1 to 4;

[0507] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11, C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0508] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0509] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0510] R 12 is alkyl or NR 14 R 15 and;

[0511] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0512] R 4 is H or alkoxy;

[0513] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0514] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0515] (ii)Z 1 is NH or O, Z 2 and Z3 is C, or

[0516] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0517] Z 4 , Z 5 and Z 6 The following is selected from (i), (ii), (iii), or (iv):

[0518] (i)Z 4 is N, Z 5 CR 5 Z 6 CH is

[0519] (ii)Z 4 CR 16 Z 5 is N, Z 6 CH is

[0520] (iii)Z 4 CR 16 Z 5 CR 5 Z 6 is N, or

[0521] (iv)Z 4 CR 16 Z 5 CR 5 Z 6 is CH;

[0522] R 5 and R 16 The following is selected from (i) or (ii):

[0523] (i)R 5 and R 16Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl,

[0524] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0525] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[0526] Het and R 6 The following is selected from (i) or (ii):

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

[0528] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0529] R 7 is -C(O)R 17 ,-S(O)R 18 or -SO2R 18 and;

[0530] R 17Alkyl, 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0531] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 20 R 21 That is the case.

[0532] In one embodiment, Formula IIa for use in compositions and methods provided herein: TIFF2026534467000016.tif40170

[0533] A compound of or a pharmaceutically acceptable derivative thereof, wherein the formula is:

[0534] a is between 0 and 2;

[0535] R 1 and R 2 They combine to form alkylenes;

[0536] R 3 is -O-(CH2) b -R 8 and;

[0537] b is 1 to 4;

[0538] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0539] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0540] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0541] R 12 is alkyl or NR 14 R 15 and;

[0542] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0543] R 4 is H or alkoxy;

[0544] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0545] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0546] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0547] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0548] Z 4 is N or CR 16 and;

[0549] R 5 and R 16 The following is selected from (i) or (ii):

[0550] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl, or haloalkyl,

[0551] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0552] X is O, S(O)x Alternatively, it is CH2, where x is between 0 and 2;

[0553] Het and R 6 The following is selected from (i) or (ii):

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

[0555] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0556] R 7 is -C(O)R 17 or -SO2R 18 and;

[0557] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0558] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 20 R 21 That is the case.

[0559] In another embodiment, the compound for use in the compositions and methods provided herein has formula II or IIa, wherein:

[0560] R 8 H, CN, OH, alkoxy, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[0561] R 9 H is R 10 is H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[0562] R 11 is alkyl or alkoxy;

[0563] R 5 and R 16 The following is selected from (i) or (ii):

[0564] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, or alkynyl,

[0565] (ii)R 5 and R 16 They combine to form alkylenes;

[0566] X is either O or CH2;

[0567] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0568] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0569] In another embodiment, the compound for use in the compositions and methods provided herein has formula II or IIa, wherein:

[0570] R 8 H, CN, OH, alkoxy, aryl, NR 9 R 10 or C(O)R 11 and;

[0571] R 9 H is R 10 is C(O)R 13 And; in the formula, R 13 is alkyl;

[0572] R 11 It is an alkoxy;

[0573] R 5 and R 16 The following is selected from (i) or (ii):

[0574] (i)R 5 is H, cyano, alkoxy, or alkyl, and R 16is H, alkyl, alkoxy, halo or alkynyl, or

[0575] (ii)R 5 and R 16 They combine to form alkylenes;

[0576] X is either O or CH2;

[0577] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0578] R 18 These are 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 R 1 and R 2 They are together C 2-4 Forms alkylenes.

[0580] In another embodiment, the compounds for use in the compositions and methods provided herein have formula II or IIa, wherein R 1 and R 2 They combine to form propylene.

[0581] In another embodiment, the compound for use in the compositions and methods provided herein is Formula II: TIFF2026534467000017.tif41170

[0582] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0583] a is between 0 and 2;

[0584] R 1 and R 2 (i) or (ii) below is selected;

[0585] (i)R 1 R is alkyl, cycloalkyl, or haloalkyl; 2 is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo,

[0586] (ii)R 1 and R 2 They combine to form alkylenes;

[0587] R 3 is -O-(CH2) b -R 8 and;

[0588] b is 1 to 4;

[0589] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0590] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0591] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0592] R 12is alkyl or NR 14 R 15 and;

[0593] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0594] R 4 is H or alkoxy;

[0595] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0596] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0597] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0598] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0599] Z 4 CR 16 and;

[0600] Z 5 CR 5 and;

[0601] Z 6 is N or CH;

[0602] R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0603] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[0604] Het and R 6 The following is selected from (i) or (ii):

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

[0606] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0607] R 7 is -C(O)R 17 ,-S(O)R 18 or -SO2R 18 and;

[0608] R 17 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-R 19-O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0609] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0610] In another embodiment, the compound for use in the compositions and methods provided herein is of formula IIa: TIFF2026534467000018.tif40170

[0611] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0612] a is between 0 and 2;

[0613] R 1 and R 2 The following is selected from (i) or (ii):

[0614] (i)R 1 R is alkyl, cycloalkyl, or haloalkyl; 2 is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo; or

[0615] (ii)R1 and R 2 They combine to form alkylenes;

[0616] R 3 is -O-(CH2) b -R 8 and;

[0617] b is 1 to 4;

[0618] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0619] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0620] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0621] R 12 is alkyl or NR 14 R 15 and;

[0622] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0623] R 4 is H or alkoxy;

[0624] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0625] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0626] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0627] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0628] Z 4 CR 16 and;

[0629] R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0630] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[0631] Het and R 6 The following is selected from (i) or (ii):

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

[0633] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0634] R 7 is -C(O)R 17 or -SO2R 18 and;

[0635] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0636] R 18Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0637] In another embodiment, the compound for use in the compositions and methods provided herein has formula II or IIa, wherein:

[0638] R 1 and R 2 The following is selected from (i) or (ii):

[0639] (i)R 1 R is alkyl, cycloalkyl or haloalkyl, 2 is H or alkoxy, or

[0640] (ii)R 1 and R 2 They combine to form alkylenes;

[0641] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[0642] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[0643] R 11 is alkyl or alkoxy;

[0644] R 5and R 16 They combine to form alkylenes;

[0645] X is either O or CH2;

[0646] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0647] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0648] In another embodiment, the compound for use in the compositions and methods provided herein has formula II or IIa, wherein:

[0649] R 1 and R 2 The following is selected from (i) or (ii):

[0650] (i)R 1 is alkyl or haloalkyl, and R 2 is H or alkoxy, or

[0651] (ii)R 1 and R 2 They combine to form alkylenes;

[0652] R 8 H, CN, OH, aryl, NR 9 R 10 or C(O)R 11 and;

[0653] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl;

[0654] R 11 It is an alkoxy;

[0655] R 5 and R 16 They combine to form alkylenes;

[0656] X is either O or CH2;

[0657] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0658] R 18 These are 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 R 5 and R 16 They are together C 3-5 Forms alkylenes.

[0660] In another embodiment, the compounds for use in the compositions and methods provided herein have formula II or IIa, wherein R 5 and R 16 They combine to form propylene.

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

[0662] In another embodiment, the compound for use in the compositions and methods provided herein is Formula II: TIFF2026534467000019.tif45170

[0663] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0664] a is between 0 and 2;

[0665] R 1 and R 2 The following is selected from (i) or (ii):

[0666] (i)R 1 R is alkyl, cycloalkyl or haloalkyl, 2 is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo,

[0667] (ii)R 1 and R 2 They combine to form alkylenes;

[0668] R 3 is -O-(CH2) b -R 8 and;

[0669] b is 1 to 4;

[0670] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0671] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0672] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0673] R 12 is alkyl or NR 14 R 15 and;

[0674] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0675] R 4 is H or alkoxy;

[0676] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0677] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0678] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0679] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0680] Z 4 , Z 5 and Z 6 The following is selected from (i), (ii), (iii), or (iv):

[0681] (i)Z 4 is N, Z 5 CR 5 Z 6 CH is

[0682] (ii)Z 4 CR 16 Z 5 is N, Z 6 CH is

[0683] (iii)Z 4 CR 16 Z 5 CR 5 Z 6 is N, or

[0684] (iv)Z 4 CR 16 Z 5 CR 5 Z 6 is CH;

[0685] R 5 and R 16 The following is selected from (i) or (ii):

[0686] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl,

[0687] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0688] X is O or S(O) x And in the equation x is between 0 and 2;

[0689] Het and R 6 The following is selected from (i) or (ii):

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

[0691] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0692] R 7 is -C(O)R 17 ,-S(O)R 18 or -SO2R 18 and;

[0693] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0694] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0695] In another embodiment, the compound for use in the compositions and methods provided herein is of formula IIa: TIFF2026534467000020.tif45170

[0696] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0697] a is between 0 and 2;

[0698] R 1 and R 2 The following is selected from (i) or (ii):

[0699] (i)R 1 R is alkyl, cycloalkyl or haloalkyl, 2 is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo,

[0700] (ii)R 1 and R 2 They combine to form alkylenes;

[0701] R 3 is -O-(CH2) b-R 8 and;

[0702] b is 1 to 4;

[0703] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0704] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0705] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0706] R 12 is alkyl or NR 14 R 15 and;

[0707] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0708] R 4 is H or alkoxy;

[0709] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0710] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0711] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0712] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0713] Z 4 is N or CR 16 and;

[0714] R 5 and R 16 The following is selected from (i) or (ii):

[0715] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl, or haloalkyl,

[0716] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0717] X is O or S(O) x And in the equation x is between 0 and 2;

[0718] Het and R 6 The following is selected from (i) or (ii):

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

[0720] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0721] R 7 is -C(O)R 17 or -SO2R 18 and;

[0722] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0723] R 18Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0724] In another embodiment, the compound for use in the compositions and methods provided herein has formula II or IIa, wherein:

[0725] R 1 and R 2 The following is selected from (i) or (ii):

[0726] (i)R 1 R is alkyl, cycloalkyl or haloalkyl, 2 is H or alkoxy, or

[0727] (ii)R 1 and R 2 They combine to form alkylenes;

[0728] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[0729] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[0730] R 11 is alkyl or alkoxy;

[0731] R 5and R 16 The following is selected from (i) or (ii):

[0732] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, or alkynyl,

[0733] (ii)R 5 and R 16 They combine to form alkylenes;

[0734] X is O,

[0735] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0736] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0737] In another embodiment, the compound for use in the compositions and methods provided herein has formula II or IIa, wherein:

[0738] R 1 and R 2 The following is selected from (i) or (ii):

[0739] (i)R 1 is alkyl or haloalkyl, and R 2 is H or alkoxy, or

[0740] (ii)R 1 and R 2 They combine to form alkylenes;

[0741] R 8H, CN, OH, aryl, NR 9 R 10 or C(O)R 11 and;

[0742] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl;

[0743] R 11 It is an alkoxy;

[0744] R 5 and R 16 The following is selected from (i) or (ii):

[0745] (i)R 5 is H, cyano, alkoxy, or alkyl, and R 16 is H, alkyl, alkoxy, halo or alkynyl, or

[0746] (ii)R 5 and R 16 They combine to form alkylenes;

[0747] X is O,

[0748] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0749] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0750] In another embodiment, the compound for use in the compositions and methods provided herein is of formula IIa: TIFF2026534467000021.tif43170

[0751] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0752] a is between 0 and 2;

[0753] R 1 and R 2 The following is selected from (i) or (ii):

[0754] (i)R 1 R is alkyl, cycloalkyl or haloalkyl, 2 is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo,

[0755] (ii)R 1 and R 2 They combine to form alkylenes;

[0756] R 3 is -O-(CH2) b -R 8 and;

[0757] b is 1 to 4;

[0758] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0759] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R15 and;

[0760] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0761] R 12 is alkyl or NR 14 R 15 and;

[0762] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0763] R 4 is H or alkoxy;

[0764] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0765] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0766] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0767] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0768] Z 4 is N or CR16 And in the formula R 16 is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl;

[0769] R 5 is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl;

[0770] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[0771] Het and R 6 The following is selected from (i) or (ii):

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

[0773] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0774] R 7 is -C(O)R 17 or -SO2R 18 and;

[0775] R 17Alkyl, 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0776] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0777] In another embodiment, the compound for use in the compositions and methods provided herein has formula II or IIa, wherein:

[0778] R 1 and R 2 The following is selected from (i) or (ii):

[0779] (i)R1 R is alkyl, cycloalkyl or haloalkyl, 2 is H or alkoxy, or

[0780] (ii)R 1 and R 2 They combine to form alkylenes;

[0781] R 5 is alkenyl or alkinyl;

[0782] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[0783] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[0784] R 11 is alkyl or alkoxy;

[0785] X is either O or CH2;

[0786] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0787] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0788] In another embodiment, the compound for use in the compositions and methods provided herein has formula II or IIa, wherein:

[0789] R 1 and R 2 The following is selected from (i) or (ii):

[0790] (i)R 1 is alkyl or haloalkyl, and R 2 is H or alkoxy, or

[0791] (ii)R 1 and R 2 They combine to form alkylenes;

[0792] R 5 is Alkinnil;

[0793] R 8 H, CN, OH, aryl, NR 9 R 10 or C(O)R 11 and;

[0794] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl;

[0795] R 11 It is an alkoxy;

[0796] X is either O or CH2;

[0797] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0798] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0799] In another embodiment, the compound for use in the compositions and methods provided herein is of formula I: TIFF2026534467000022.tif43170

[0800] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0801] a is between 0 and 2;

[0802] R 1 is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo;

[0803] R 2 and R 4 They form heteroalkylenes together;

[0804] R 3 is -O-(CH2) b -R 8 and;

[0805] b is 1 to 4;

[0806] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0807] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0808] R 11 is hydroxy, alkyl, alkoxy or NR14 R 15 and;

[0809] R 12 is alkyl or NR 14 R 15 and;

[0810] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0811] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0812] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0813] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0814] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0815] Z 4 , Z 5 and Z 6 The following is selected from (i), (ii), (iii), or (iv):

[0816] (i)Z 4 is N, Z 5 CR 5 Z 6CH is

[0817] (ii)Z 4 CR 16 Z 5 is N, Z 6 CH is

[0818] (iii)Z 4 CR 16 Z 5 CR 5 Z 6 is N, or

[0819] (iv)Z 4 CR 16 Z 5 CR 5 Z 6 is CH;

[0820] R 5 and R 16 The following is selected from (i) or (ii):

[0821] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl,

[0822] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0823] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[0824] Het and R 6 The following is selected from (i) or (ii):

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

[0826] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0827] R 7 is -C(O)R 17 ,-S(O)R 18 or -SO2R 18 and;

[0828] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0829] R 18Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0830] In another embodiment, the compound for use in the compositions and methods provided herein is of formula Ia: TIFF2026534467000023.tif44170

[0831] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0832] a is between 0 and 2;

[0833] R 1 is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo;

[0834] R 2 and R 4 They form heteroalkylenes together;

[0835] R 3 is -O-(CH2) b -R 8 and;

[0836] b is 1 to 4;

[0837] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0838] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0839] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0840] R 12 is alkyl or NR 14 R 15 and;

[0841] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0842] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0843] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0844] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0845] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2and Z 3 The other side is N;

[0846] Z 4 is N or CR 16 and;

[0847] R 5 and R 16 The following is selected from (i) or (ii):

[0848] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl, or haloalkyl,

[0849] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0850] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[0851] Het and R 6 The following is selected from (i) or (ii):

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

[0853] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0854] R 7 is -C(O)R 17 or -SO2R 18 and;

[0855] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0856] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[0857] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, wherein:

[0858] R 1 is H or alkoxy;

[0859] R 2 and R 4 Together, -O-(CH2) r -or -O-(CH2) 1-3 -O-(CH2) 1-3 - forms the R of equation I, where r is an integer between 2 and 5, and terminal O is R of equation I. 4 It is linked to the position;

[0860] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[0861] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[0862] R 11 is alkyl or alkoxy;

[0863] R 5 and R 16 The following is selected from (i) or (ii):

[0864] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, or alkynyl,

[0865] (ii)R 5 and R 16 They combine to form alkylenes;

[0866] X is either O or CH2;

[0867] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0868] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0869] In another embodiment, the compound for use in the compositions and methods provided herein has formula I or Ia, wherein:

[0870] R 1 is H or alkoxy;

[0871] R 2 and R 4 Together, -O-(CH2) r -or -O-(CH2) 1-3 -O-(CH2) 1-3 - forms the R of equation I, where r is an integer between 2 and 5, and terminal O is R of equation I. 4 It is linked to the position;

[0872] R 8 H, CN, OH, aryl, NR 9 R 10 or C(O)R 11 and;

[0873] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl;

[0874] R 11 It is an alkoxy;

[0875] R 5 and R 16 The following is selected from (i) or (ii):

[0876] (i)R 5 is H, cyano, alkoxy, or alkyl, and R 16is H, alkyl, alkoxy, halo or alkynyl, or

[0877] (ii)R 5 and R 16 They combine to form alkylenes;

[0878] X is either O or CH2;

[0879] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[0880] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[0881] In another embodiment, the compound for use in the compositions and methods provided herein is Formula II: TIFF2026534467000024.tif41170

[0882] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0883] a is between 0 and 2;

[0884] R 1 These are alkyl, cycloalkyl, or haloalkyl;

[0885] R 2 is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo;

[0886] R 3 is -O-(CH2) b -R 8 and;

[0887] b is 1 to 4;

[0888] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0889] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0890] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0891] R 12 is alkyl or NR 14 R 15 and;

[0892] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0893] R 4 is H or alkoxy;

[0894] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0895] (i)Z 1 is N, Z 2 and Z3 One of them is C, and Z 2 and Z 3 The other side is N.

[0896] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0897] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0898] Z 4 , Z 5 and Z 6 The following is selected from (i), (ii), (iii), or (iv):

[0899] (i)Z 4 is N, Z 5 CR 5 Z 6 CH is

[0900] (ii)Z 4 CR 16 Z 5 is N, Z 6 CH is

[0901] (iii)Z 4 CR 16 Z 5 CR 5 Z 6 is N, or

[0902] (iv)Z 4 CR 16 Z 5 CR 5 Z 6 is CH;

[0903] R 5 and R16 The following is selected from (i) or (ii):

[0904] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl,

[0905] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0906] X is CR 22 R 23 And in the formula R 22 and R 23 Each of these is independently either H or alkyl;

[0907] Het and R 6 The following is selected from (i) or (ii):

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

[0909] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0910] R 7 -C(O)R 17 and;

[0911] R 17 These are alkoxy, alkenyloxy, alkynyloxy or -O-(CH2)2-R 19 And; in the formula, R 19is -OR 9 or -NR 9 R 10 That is the case.

[0912] In another embodiment, the compound for use in the compositions and methods provided herein is of formula IIa: TIFF2026534467000025.tif43170

[0913] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[0914] a is between 0 and 2;

[0915] R 1 These are alkyl, cycloalkyl, or haloalkyl;

[0916] R 2 is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo;

[0917] R 3 is -O-(CH2) b -R 8 and;

[0918] b is 1 to 4;

[0919] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0920] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R15 and;

[0921] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0922] R 12 is alkyl or NR 14 R 15 and;

[0923] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0924] R 4 is H or alkoxy;

[0925] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0926] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[0927] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0928] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0929] Z 4 is N or CR16 and;

[0930] R 5 and R 16 The following is selected from (i) or (ii):

[0931] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl, or haloalkyl,

[0932] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0933] X is CR 22 R 23 And in the formula R 22 and R 23 Each of these is independently either H or alkyl;

[0934] Het and R 6 The following is selected from (i) or (ii):

[0935] (i) Het is a 5-membered or 6-membered heteroaryl, R 6 is H, alkyl or haloalkyl, or

[0936] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0937] R 7 -C(O)R 17 and;

[0938] R 17These are alkoxy, alkenyloxy, alkynyloxy or -O-(CH2)2-R 19 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 That is the case.

[0939] In another embodiment, the compound for use in the compositions and methods provided herein has formula II or IIa, wherein:

[0940] R 1 These are alkyl, cycloalkyl, or haloalkyl;

[0941] R 2 is H or alkoxy;

[0942] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[0943] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[0944] R 11 is alkyl or alkoxy;

[0945] X is CH2;

[0946] R 17 It is an alkoxy.

[0947] In another embodiment, the compound for use in the compositions and methods provided herein has formula II or IIa, wherein:

[0948] R 1 is alkyl or haloalkyl;

[0949] R 2 is H or alkoxy;

[0950] R 8 H, CN, OH, aryl, NR 9 R 10 or C(O)R 11 and;

[0951] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl;

[0952] R 11 It is an alkoxy;

[0953] X is CH2;

[0954] R 17 It is an alkoxy.

[0955] In one embodiment, Formula III for use in compositions and methods provided herein: TIFF2026534467000026.tif43170

[0956] A compound of or a pharmaceutically acceptable derivative thereof, wherein the formula is:

[0957] a is between 0 and 2;

[0958] R 1 and R 2 They combine to form alkylenes;

[0959] R 3 is -O-(CH2) b -R 8 and;

[0960] b is 1 to 4;

[0961] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0962] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0963] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0964] R 12 is alkyl or NR 14 R 15 and;

[0965] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0966] R 4 is H or alkoxy;

[0967] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0968] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2and Z 3 The other side is N.

[0969] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[0970] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[0971] Z 4 , Z 5 and Z 6 The following is selected from (i), (ii), (iii), or (iv):

[0972] (i)Z 4 is N, Z 5 CR 5 Z 6 CH is

[0973] (ii)Z 4 CR 16 Z 5 is N, Z 6 CH is

[0974] (iii)Z 4 CR 16 Z 5 CR 5 Z 6 is N, or

[0975] (iv)Z 4 CR 16 Z 5 CR 5 Z 6 is CH;

[0976] R 5 and R 16 The following is selected from (i) or (ii):

[0977] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl,

[0978] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[0979] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[0980] Het and R 6 The following is selected from (i) or (ii):

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

[0982] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[0983] R 7 is -C(O)R 17 ,-S(O)R 18 or -SO2R 18 and;

[0984] R 17Alkyl, 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[0985] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 20 R 21 That is the case.

[0986] In one embodiment, Formula IIIa for use in compositions and methods provided herein: TIFF2026534467000027.tif46170

[0987] A compound of or a pharmaceutically acceptable derivative thereof, wherein the formula is:

[0988] a is between 0 and 2;

[0989] R 1 and R 2 They combine to form alkylenes;

[0990] R 3 is -O-(CH2) b -R 8 and;

[0991] b is 1 to 4;

[0992] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[0993] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[0994] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[0995] R 12 is alkyl or NR 14 R 15 and;

[0996] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[0997] R 4 is H or alkoxy;

[0998] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[0999] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[1000] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[1001] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[1002] Z 4 is N or CR 16 and;

[1003] R 5 and R 16 The following is selected from (i) or (ii):

[1004] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl, or haloalkyl,

[1005] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[1006] X is O, S(O)x Alternatively, it is CH2, where x is between 0 and 2;

[1007] Het and R 6 The following is selected from (i) or (ii):

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

[1009] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[1010] R 7 is -C(O)R 17 or -SO2R 18 and;

[1011] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[1012] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 20 R 21 That is the case.

[1013] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, wherein:

[1014] R 8 H, CN, OH, alkoxy, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[1015] R 9 H is R 10 is H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[1016] R 11 is alkyl or alkoxy;

[1017] R 5 and R 16 The following is selected from (i) or (ii):

[1018] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, or alkynyl,

[1019] (ii)R 5 and R 16 They combine to form alkylenes;

[1020] X is either O or CH2;

[1021] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[1022] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[1023] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, wherein:

[1024] R 8 H, CN, OH, alkoxy, aryl, NR 9 R 10 or C(O)R 11 and;

[1025] R 9 H is R 10 is C(O)R 13 And; in the formula, R 13 is alkyl;

[1026] R 11 It is an alkoxy;

[1027] R 5 and R 16 The following is selected from (i) or (ii):

[1028] (i)R 5 is H, cyano, alkoxy, or alkyl, and R 16is H, alkyl, alkoxy, halo or alkynyl, or

[1029] (ii)R 5 and R 16 They combine to form alkylenes;

[1030] X is either O or CH2;

[1031] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[1032] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[1033] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, wherein R 1 and R 2 Together, C may be substituted with one or more halos or methyl groups. 1-4 Forms alkylenes.

[1034] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, wherein R 1 and R 2 These combine to form methylene or ethylene, each which may be substituted with one or two halos or methyl groups. In another embodiment, the compounds for use in the compositions and methods provided herein have formula III or IIIa, where R 1 and R 2 They combine to form unsubstituted methylene or ethylene.

[1035] In another embodiment, the compound for use in the compositions and methods provided herein is Formula III: TIFF2026534467000028.tif46170

[1036] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[1037] a is between 0 and 2;

[1038] R 1 and R 2 The following is selected from (i) or (ii):

[1039] (i)R 1 and R 2 Each of these is independently alkyl, cycloalkyl, or haloalkyl, or

[1040] (ii)R 1 and R 2 They combine to form alkylenes;

[1041] R 3 is -O-(CH2) b -R 8 and;

[1042] b is 1 to 4;

[1043] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[1044] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[1045] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[1046] R 12 is alkyl or NR 14 R 15 and;

[1047] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[1048] R 4 is H or alkoxy;

[1049] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[1050] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[1051] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[1052] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[1053] Z 4 CR 16 and;

[1054] Z 5 CR 5 and;

[1055] Z 6 is N or CH;

[1056] R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[1057] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[1058] Het and R 6 The following is selected from (i) or (ii):

[1059] (i) Het is a 5-membered or 6-membered heteroaryl, R 6 is H, alkyl or haloalkyl, or

[1060] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[1061] R 7 is -C(O)R 17 ,-S(O)R 18 or -SO2R 18 and;

[1062] R 17Alkyl, 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[1063] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[1064] In another embodiment, the compound for use in the compositions and methods provided herein is of formula IIIa: TIFF2026534467000029.tif45170

[1065] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[1066] a is between 0 and 2;

[1067] R 1 and R 2 The following is selected from (i) or (ii):

[1068] (i)R 1 and R 2 Each of these is independently alkyl, cycloalkyl, or haloalkyl, or

[1069] (ii)R 1 and R 2 They combine to form alkylenes;

[1070] R 3 is -O-(CH2) b -R 8 and;

[1071] b is 1 to 4;

[1072] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[1073] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[1074] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[1075] R 12is alkyl or NR 14 R 15 and;

[1076] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[1077] R 4 is H or alkoxy;

[1078] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[1079] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[1080] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[1081] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[1082] Z 4 CR 16 and;

[1083] R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[1084] X is O, S(O) xAlternatively, it is CH2, where x is between 0 and 2;

[1085] Het and R 6 The following is selected from (i) or (ii):

[1086] (i) Het is a 5-membered or 6-membered heteroaryl, R 6 is H, alkyl or haloalkyl, or

[1087] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[1088] R 7 is -C(O)R 17 or -SO2R 18 and;

[1089] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[1090] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[1091] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, wherein:

[1092] R 1 and R 2 The following is selected from (i) or (ii):

[1093] (i)R 1 and R 2 These are alkyl groups, or

[1094] (ii)R 1 and R 2 These combine to form an alkylene which may be substituted with one or more halos or methyl groups;

[1095] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[1096] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[1097] R 11 is alkyl or alkoxy;

[1098] R 5 and R 16 They combine to form alkylenes;

[1099] X is either O or CH2;

[1100] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[1101] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[1102] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, wherein R 5 and R 16 They are together C 3-5 Forms alkylenes.

[1103] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, wherein R 5 and R 16 They combine to form propylene.

[1104] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, where X is O or S(O) x In another embodiment, the compounds for use in the compositions and methods provided herein have formula III or IIIa, where X is O or S.

[1105] In another embodiment, the compound for use in the compositions and methods provided herein is Formula III: TIFF2026534467000030.tif43170

[1106] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[1107] a is between 0 and 2;

[1108] R 1 and R 2 The following is selected from (i) or (ii):

[1109] (i)R 1 and R 2 Each of these is independently alkyl, cycloalkyl, or haloalkyl, or

[1110] (ii)R 1 and R 2 They combine to form alkylenes;

[1111] R 3 is -O-(CH2) b -R 8 and;

[1112] b is 1 to 4;

[1113] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[1114] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13is alkyl, alkoxy or NR 14 R 15 and;

[1115] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[1116] R 12 is alkyl or NR 14 R 15 and;

[1117] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[1118] R 4 is H or alkoxy;

[1119] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[1120] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[1121] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[1122] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[1123] Z 4 , Z 5 and Z 6 The following is selected from (i), (ii), (iii), or (iv):

[1124] (i)Z 4 is N, Z 5 CR 5 Z 6 CH is

[1125] (ii)Z 4 CR 16 Z 5 is N, Z 6 CH is

[1126] (iii)Z 4 CR 16 Z 5 CR 5 Z 6 is N, or

[1127] (iv)Z 4 CR 16 Z 5 CR 5 Z 6 is CH;

[1128] R 5 and R 16 The following is selected from (i) or (ii):

[1129] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl,

[1130] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[1131] X is O or S(O)x And in the equation x is between 0 and 2;

[1132] Het and R 6 The following is selected from (i) or (ii):

[1133] (i) Het is a 5-membered or 6-membered heteroaryl, R 6 is H, alkyl or haloalkyl, or

[1134] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[1135] R 7 is -C(O)R 17 ,-S(O)R 18 or -SO2R 18 and;

[1136] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[1137] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[1138] In another embodiment, the compound for use in the compositions and methods provided herein is of formula IIIa: TIFF2026534467000031.tif45170

[1139] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[1140] a is between 0 and 2;

[1141] R 1 and R 2 The following is selected from (i) or (ii):

[1142] (i)R 1 and R 2 Each of these is independently alkyl, cycloalkyl, or haloalkyl, or

[1143] (ii)R 1 and R 2 They combine to form alkylenes;

[1144] R 3 is -O-(CH2) b -R 8 and;

[1145] b is 1 to 4;

[1146] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[1147] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[1148] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[1149] R 12 is alkyl or NR 14 R 15 and;

[1150] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[1151] R 4 is H or alkoxy;

[1152] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[1153] (i)Z 1 is N, Z2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[1154] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[1155] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[1156] Z 4 is N or CR 16 and;

[1157] R 5 and R 16 The following is selected from (i) or (ii):

[1158] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl, or haloalkyl,

[1159] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[1160] X is O or S(O) x And in the equation x is between 0 and 2;

[1161] Het and R 6 The following is selected from (i) or (ii):

[1162] (i) Het is a 5-membered or 6-membered heteroaryl, R 6 is H, alkyl or haloalkyl, or

[1163] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[1164] R 7 is -C(O)R 17 or -SO2R 18 and;

[1165] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[1166] R 18Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[1167] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, wherein:

[1168] R 1 and R 2 The following is selected from (i) or (ii):

[1169] (i)R 1 and R 2 These are alkyl groups, or

[1170] (ii)R 1 and R 2 These combine to form an alkylene which may be substituted with one or more halos or methyl groups;

[1171] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[1172] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[1173] R 11 is alkyl or alkoxy;

[1174] R5 and R 16 The following is selected from (i) or (ii):

[1175] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, or alkynyl,

[1176] (ii)R 5 and R 16 They combine to form alkylenes;

[1177] X is O,

[1178] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[1179] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[1180] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, wherein:

[1181] R 1 and R 2 The following is selected from (i) or (ii):

[1182] (i)R 1 and R 2 These are alkyl groups, or

[1183] (ii)R 1 and R 2 These combine to form an alkylene which may be substituted with one or more halos or methyl groups;

[1184] R 8 H, CN, OH, aryl, NR 9 R 10 or C(O)R 11 and;

[1185] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl;

[1186] R 11 It is an alkoxy;

[1187] R 5 and R 16 The following is selected from (i) or (ii):

[1188] (i)R 5 is H, cyano, alkoxy, or alkyl, and R 16 is H, alkyl, alkoxy, halo or alkynyl, or

[1189] (ii)R 5 and R 16 They combine to form alkylenes;

[1190] X is O,

[1191] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[1192] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[1193] In another embodiment, the compound for use in the compositions and methods provided herein is of formula IIIa: TIFF2026534467000032.tif43170

[1194] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[1195] a is between 0 and 2;

[1196] R 1 and R 2 The following is selected from (i) or (ii):

[1197] (i)R 1 and R 2 Each of these is independently alkyl, cycloalkyl, or haloalkyl, or

[1198] (ii)R 1 and R 2 They combine to form alkylenes;

[1199] R 3 is -O-(CH2) b -R 8 and;

[1200] b is 1 to 4;

[1201] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[1202] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[1203] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[1204] R 12 is alkyl or NR 14 R 15 and;

[1205] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[1206] R 4 is H or alkoxy;

[1207] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[1208] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[1209] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[1210] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[1211] Z 4 is N or CR 16 And in the formula R 16is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl;

[1212] R 5 is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl;

[1213] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[1214] Het and R 6 The following is selected from (i) or (ii):

[1215] (i) Het is a 5-membered or 6-membered heteroaryl, R 6 is H, alkyl or haloalkyl, or

[1216] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[1217] R 7 is -C(O)R 17 or -SO2R 18 and;

[1218] R 17Alkyl, 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[1219] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[1220] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, wherein:

[1221] R 1 and R 2 The following is selected from (i) or (ii):

[1222] (i)R1 and R 2 Each of these is independently alkyl, cycloalkyl, or haloalkyl, or

[1223] (ii)R 1 and R 2 These combine to form an alkylene which may be substituted with one or more halos or methyl groups;

[1224] R 5 is alkenyl or alkinyl;

[1225] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[1226] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[1227] R 11 is alkyl or alkoxy;

[1228] X is either O or CH2;

[1229] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[1230] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[1231] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, wherein:

[1232] R 1 and R 2 The following is selected from (i) or (ii):

[1233] (i)R 1 and R 2 Each of these is independently alkyl or haloalkyl, or

[1234] (ii)R 1 and R 2 These combine to form an alkylene which may be substituted with one or more halos or methyl groups;

[1235] R 5 is Alkinnil;

[1236] R 8 H, CN, OH, aryl, NR 9 R 10 or C(O)R 11 and;

[1237] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl;

[1238] R 11 It is an alkoxy;

[1239] X is either O or CH2;

[1240] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[1241] R 18These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[1242] In another embodiment, the compound for use in the compositions and methods provided herein is Formula III: TIFF2026534467000033.tif42170

[1243] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[1244] a is between 0 and 2;

[1245] R 1 is alkyl or haloalkyl;

[1246] R 2 and R 4 They form heteroalkylenes together;

[1247] R 3 is -O-(CH2) b -R 8 and;

[1248] b is 1 to 4;

[1249] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[1250] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R15 and;

[1251] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[1252] R 12 is alkyl or NR 14 R 15 and;

[1253] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[1254] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[1255] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[1256] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[1257] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N;

[1258] Z 4 , Z 5 and Z 6 The following is selected from (i), (ii), (iii), or (iv):

[1259] (i)Z 4 is N, Z 5 CR 5 Z 6 CH is

[1260] (ii)Z 4 CR 16 Z 5 is N, Z 6 CH is

[1261] (iii)Z 4 CR 16 Z 5 CR 5 Z 6 is N, or

[1262] (iv)Z 4 CR 16 Z 5 CR 5 Z 6 is CH;

[1263] R 5 and R 16 The following is selected from (i) or (ii):

[1264] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl,

[1265] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[1266] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[1267] Het and R 6 The following is selected from (i) or (ii):

[1268] (i) Het is a 5-membered or 6-membered heteroaryl, R 6 is H, alkyl or haloalkyl, or

[1269] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[1270] R 7 is -C(O)R 17 ,-S(O)R 18 or -SO2R 18 and;

[1271] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[1272] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[1273] In another embodiment, the compound for use in the compositions and methods provided herein is of formula IIIa: TIFF2026534467000034.tif43170

[1274] A derivative having or pharmaceutically acceptable thereof, wherein the formula is:

[1275] a is between 0 and 2;

[1276] R 1 is alkyl or haloalkyl;

[1277] R 2 and R 4 They form heteroalkylenes together;

[1278] R 3 is -O-(CH2) b -R 8 and;

[1279] b is 1 to 4;

[1280] R 8 H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 9 R 10 , C(O)R 11 , C(=NH)(R 12 ) or C(=NOR 9 )(R 12 ) and;

[1281] R 9 and R 10 These are, independently, H, alkyl, or C(O)R 13 And; in the formula, R 13 is alkyl, alkoxy or NR 14 R 15 and;

[1282] R 11 is hydroxy, alkyl, alkoxy or NR 14 R 15 and;

[1283] R 12 is alkyl or NR 14 R 15 and;

[1284] R 14 and R 15 Each of these elements, independently, is either H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded, to form a heterocycline;

[1285] Z 1 , Z 2 and Z 3 The following is selected from (i), (ii), or (iii):

[1286] (i)Z 1 is N, Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The other side is N.

[1287] (ii)Z 1 is NH or O, Z 2 and Z 3 is C, or

[1288] (iii)Z 1 CH is, Z 2 and Z 3 One of them is C, and Z 2and Z 3 The other side is N;

[1289] Z 4 is N or CR 16 and;

[1290] R 5 and R 16 The following is selected from (i) or (ii):

[1291] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, alkynyl, or haloalkyl,

[1292] (ii)R 5 and R 16 They combine to form alkylenes or heteroalkylenes;

[1293] X is O, S(O) x Alternatively, it is CH2, where x is between 0 and 2;

[1294] Het and R 6 The following is selected from (i) or (ii):

[1295] (i) Het is a 5-membered or 6-membered heteroaryl, R 6 is H, alkyl or haloalkyl, or

[1296] (ii) Het is a 5-membered or 6-membered heteroaryl, R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems;

[1297] R 7 is -C(O)R 17 or -SO2R 18 and;

[1298] R 17 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-R 19 -O-(CH2)2-R 19 or -NR 20 R 21 And; in the formula, R 19 is -OR 9 or -NR 9 R 10 And R 20 and R 21 Each of these is independently H, alkyl, cycloalkyl, or haloalkyl;

[1299] R 18 Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl, or -NR 9 R 10 That is the case.

[1300] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, wherein:

[1301] R 1 It is an alkyl,

[1302] R 2 and R 4 Together, -O-(CH2) r -or -O-(CH2) 1-3 -O-(CH2) 1-3 - forms the formula where r is an integer between 2 and 5, and terminal O is R of formula III or IIIa. 4 It is linked to the position;

[1303] R 8 H, CN, OH, aryl, heteroaryl, NR 9 R 10 or C(O)R 11 and;

[1304] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl or alkoxy;

[1305] R 11 is alkyl or alkoxy;

[1306] R 5 and R 16 The following is selected from (i) or (ii):

[1307] (i)R 5 and R 16 Each of these is independently H, cyano, halo, alkoxy, alkyl, alkenyl, or alkynyl,

[1308] (ii)R 5 and R 16 They combine to form alkylenes;

[1309] X is either O or CH2;

[1310] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[1311] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[1312] In another embodiment, the compound for use in the compositions and methods provided herein has formula III or IIIa, wherein:

[1313] R 1 It is an alkyl,

[1314] R 2 and R 4 Together, -O-(CH2) r -or -O-(CH2) 1-3 -O-(CH2) 1-3 - forms the formula where r is an integer between 2 and 5, and terminal O is R of formula III or IIIa. 4 It is linked to the position;

[1315] R 8 H, CN, OH, aryl, NR 9 R 10 or C(O)R 11 and;

[1316] R 9 and R 10 These are, independently, H or C(O)R 13 And; in the formula, R 13 is alkyl;

[1317] R 11 It is an alkoxy;

[1318] R 5 and R 16 The following is selected from (i) or (ii):

[1319] (i)R 5 is H, cyano, alkoxy, or alkyl, and R 16is H, alkyl, alkoxy, halo or alkynyl, or

[1320] (ii)R 5 and R 16 They combine to form alkylenes;

[1321] X is either O or CH2;

[1322] R 17 These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl;

[1323] R 18 These are alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

[1324] In another embodiment, the compound for use in the compositions and methods provided herein has formula I, Ia, II, IIa, III, or IIIa, where X is O. In another embodiment, the compound for use in the compositions and methods provided herein has formula I, Ia, II, IIa, III, or IIIa, where 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 compound for use in the compositions and methods provided herein has formula I or Ia, where R 2 is alkyl. In another embodiment, the compounds for use in the compositions and methods provided herein have formula I or Ia, where R 2 is methyl. In another embodiment, the compounds for use in the compositions and methods provided herein have formula I or Ia, where R 2is a haloalkyl. In another embodiment, the compounds for use in the compositions and methods provided herein have formula I or Ia, where R 2 is fluoromethyl, difluoromethyl, or trifluoromethyl. In another embodiment, the compounds for use in the compositions and methods provided herein have formula I or Ia, where R 2 It is difluoromethyl.

[1327] In another embodiment, the compound for use in the compositions and methods provided herein has formula II or IIa, wherein R 2 is H. In another embodiment, the compounds for use in the compositions and methods provided herein have formula II or IIa, where R 2 is an alkoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have formula II or IIa, where R 2 is methoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have formula II or IIa, where R 2 is a haloalkoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have formula II or IIa, where R 2 is fluoromethoxy, difluoromethoxy, or trifluoromethoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have formula II or IIa, where R 2 It is 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, where R 8is 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, where R 8 is 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, where R 8 is hydrogen. In another embodiment, the compounds for use in the compositions and methods provided herein have formula I, Ia, II, IIa, III or IIIa, where b is 1 and R 8 It is 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, where R 4 is an alkoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have formula I, Ia, II, IIa, III or IIIa, where R 4 is methoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have formula I, Ia, II, IIa, III or IIIa, where R 4 H is 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 Z 1 is NH or O, Z 2 and Z 3is C. In another embodiment, the compounds for use in the compositions and methods provided herein have formula I, Ia, II, IIa, III or IIIa, where Z 1 is O, Z 2 and Z 3 C is C.

[1332] In another embodiment, Z 4 In another embodiment, Z 4 CR 16 That is the case.

[1333] In another embodiment, the compounds for use in the compositions and methods provided herein have formula I, Ia, II, IIa, III, or IIIa, where R 5 is H, cyano, alkoxy, or alkyl, and R 16 is 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, where R 5 is H, cyano, methoxy, or methyl, and R 16 is 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, where R 5 is H, cyano, methoxy, or methyl, and R 16 is H, methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, ethinyl, 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, where R 5 H is R 16 The elements are 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, where Het is a 5-membered or 6-membered heteroaryl, and R 6 is 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, where Het is a 5-membered heteroaryl and R 6 R is 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, where Het is pyrazolyl, oxazolyl, thiazolyl or pyridyl, and R 6 is 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, where Het is pyrazolyl and R 6 is 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, where Het is a 5-membered or 6-membered heteroaryl, and R 6 ha-(CH2) 1-2 - and R 6 And Het, together with the atoms to which they are bonded, 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, where Het is a 5-membered heteroaryl and R 6 is -(CH2)-, and R 6 And Het, together with the atoms to which they are bonded, 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, where Het is pyrazolyl and R 6 is -(CH2)-, and R 6And Het, together with the atoms to which they are bonded, 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, where R 7 -C(O)R 17 In another embodiment, the compounds for use in the compositions and methods provided herein have formula I, Ia, II, IIa, III or IIIa, where R 7 -S(O)R 18 In another embodiment, the compounds for use in the compositions and methods provided herein have formula I, Ia, II, IIa, III or IIIa, where R 7 ha-SO2R 18 In another embodiment, the compounds for use in the compositions and methods provided herein have formula I, Ia, II, IIa, III or IIIa, where R 17 Alkyl, alkoxy, alkenyl, haloalkenyl, alkynyl, NR 20 R 21 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, where R 17 is 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, where R 17 is methyl, methoxy, NHMe, ethenyl, 1-fluoro-1-ethenyl, ethinyl, or 1-propyne-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, where R 17is methyl, methoxy, ethenyl, 1-fluoro-1-ethenyl, ethinyl, or 1-propyne-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, where R 17 is 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, where R 17 is methoxy. In another embodiment, the compounds for use in the compositions and methods provided herein have formula I, Ia, II, IIa, III or IIIa, where R 17 is ethenyl, 1-fluoro-1-ethenyl, ethinyl, or 1-propyne-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, where R 18 It is methyl or tert-butyl.

[1336] In another embodiment, the compounds for use in the compositions and methods provided herein are selected from the following: TIFF2026534467000035.tif100170

[1337] In another embodiment, the compounds for use in the compositions and methods provided herein are selected from the following: TIFF2026534467000036.tif135170

[1338] In another embodiment, the compounds for use in the compositions and methods provided herein are selected from the following: TIFF2026534467000037.tif137170

[1339] In another embodiment, the compounds for use in the compositions and methods provided herein are selected from the following: TIFF2026534467000038.tif81170

[1340] In another embodiment, the compounds for use in the compositions and methods provided herein are selected from the following: TIFF2026534467000039.tif228170TIFF2026534467000040.tif219170TIFF2026534467000041.tif225170TIFF2026534467000042.tif104170

[1341] In another embodiment, the compounds for use in the compositions and methods provided herein are as follows: TIFF2026534467000043.tif84170

[1342] In another embodiment, the compounds for use in the compositions and methods provided herein are as follows: TIFF2026534467000044.tif88170

[1343] In another embodiment, the compounds for use in the compositions and methods provided herein are as follows: TIFF2026534467000045.tif63170

[1344] In another embodiment, the compounds for use in the compositions and methods provided herein are as follows: TIFF2026534467000046.tif162170

[1345] In another embodiment, the compounds for use in the compositions and methods provided herein are as follows: TIFF2026534467000047.tif37170

[1346] Synthesis of III compounds The compounds provided herein can be prepared, isolated, or obtained by any method obvious to those skilled in the art. The compounds provided herein can also be prepared according to the exemplary preparation schemes provided below. Reaction conditions, steps, and reactants not provided in the exemplary preparation schemes are obvious to and known to those skilled in the art.

[1347] Additional steps and reagents not provided in the exemplary preparation scheme will be known to those skilled in the art. The exemplary preparation method is described in detail in the examples herein.

[1348] General scheme 1 is Z 1 O is Z 2 and Z 3 The preparation of a compound of formula I is described, wherein the group is C; and all other groups are as defined in the abstract or any embodiment described herein. TIFF2026534467000048.tif76170

[1349] General Scheme 1 outlines a method for preparing a appropriately substituted benzo[d]isoxazole compound provided herein, in which, in step 1, a appropriately substituted 2-fluorobenzonitrile is converted to a benzo[d]isoxazole-3-amine skeleton by reacting it with an N-hydroxyacetamide in the presence of a base such as potassium t-butoxide. In step 2, the free amine is reacted with an aryl or heteroarylsulfonyl chloride in the presence of a base such as sodium tert-pentoxide, triethylamine, pyridine, or sodium hydride. This can be achieved at 0°C, but may need to be carried out at room temperature or at a high temperature such as 60°C. The final step involves deprotection of the amine (step 3), followed by amide formation in step 4 (by reaction with an appropriately substituted acid chloride, or by 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 triethylamine. To prepare carbamates or urea derivatives, appropriately substituted carbonochlorides or isocyanates can be reacted with free amines in the presence of a base such as triethylamine.

[1350] General scheme 2 is Z 1 and Z 3 N is Z 2 The preparation of a compound of formula I is described, wherein the group is C; and all other groups are as defined in the abstract or any embodiment described herein. TIFF2026534467000049.tif66170

[1351] As shown herein, the [1,2,4]triazolo[4,3-a]pyridine compounds provided herein can be prepared by starting from appropriately substituted 2-chloropyridine, which can be converted to the corresponding 2-hydrazinopyridine by heating in the presence of hydrazine hydrate (Step 1). In Step 2, the reaction with cyanide bromide results in the construction of the [1,2,4]triazolo[4,3-a]pyridine-3-amine skeleton. Steps 3, 4 and 5 are carried out according to the protocol detailed above for General Scheme 1 (Steps 2, 3, and 4), Z 1 and Z 3 N is Z 2 This leads to the synthesis of the compound of formula I, where C is present.

[1352] General scheme 3 is Z 1 and Z 2 N is Z 3 The preparation of a compound of formula I is described, wherein the group is C; and all other groups are as defined in the abstract or any embodiment described herein. TIFF2026534467000050.tif72170

[1353] The appropriately substituted 2-cyanopyridine is converted to 1-amino2-cyanopyridine by reacting it with a sulfonylated hydroxylamine or (aminooxy)sulfonic acid (Step 1, conditions A or B), followed by cyclization in the presence of hydroxylamine and acetic anhydride (Step 2). Steps 3, 4 and 5 are carried out according to the protocol detailed above for General Scheme 1 (Steps 2, 3, 4), Z 1 and Z 2 N is Z 3 This leads to the synthesis of the compound of formula I, where C is present.

[1354] General scheme 4 is Z 1 NH is Z 2 and Z 3 The preparation of a compound of formula I is described, wherein the group is C; and all other groups are as defined in the abstract or any embodiment described herein. TIFF2026534467000051.tif71170

[1355] The appropriately substituted 2-fluorobenzonitrile starting material is converted to 3-aminobenzopyrazole using hydrazine in the presence of a base such as potassium carbonate, as shown above (Step 1). Steps 2, 3, and 4 are carried out according to the protocol detailed above for General Scheme 1 (Steps 2, 3, and 4), Z 1 NH is Z 2 and Z 3 This leads to the synthesis of the compound of formula I, where C is present.

[1356] General scheme 5 is Z 1 N is Z 2 and Z 3 One of them is C, and Z 2 and Z 3 The preparation of the compound of formula I is described, wherein the other of the two groups is N; and all other groups are as defined in the abstract or any embodiment described herein. TIFF2026534467000052.tif105170

[1357] General scheme 5(A) shows that a appropriately substituted picolinonitrile is reduced by LAH in a solvent such as THF in step 1. The resulting 2-aminomethylpyridine intermediate is treated with cyanogen bromide in toluene (step 2) to obtain imidazo[1,5-a]pyridine-3-amine intermediate A. In general scheme 5(B), a appropriately substituted 2-cyanopyridine is reduced to the corresponding 2-aminomethylpyridine (step 1 as in scheme 5A above), and then subjected to steps 2 and 3, which include reflux in phosphorus oxychloride followed by N-formylation, to construct an imidazo[1,5-a]pyridine ring. Nitration and reduction with reagents in step 4 yield a substituted imidazo[1,5-a]pyridine-1-amine (intermediate B). In the final step, intermediates A and B are subjected to Z according to the protocol detailed above for general scheme 1 (steps 2, 3, and 4). 1 N is Z 2 and Z 3One of them is C, and Z 2 and Z 3 This leads to the synthesis of the compound of formula I, where the other element is N.

[1358] General scheme 6 is R 2 and R 4 The preparation of the compound of formula I is described, wherein the groups together form a heteroalkylene; and all other groups are as defined in the abstract or any embodiment described herein. TIFF2026534467000053.tif113170

[1359] The synthesis of macrocyclic compounds is achieved by assembling the starting materials using the general method described above. In general scheme 6(A), R 4 R is produced in the presence of a base such as NaH or K2CO3. 2 It is a phenoxy or heteroaryloxy group having a terminal leaving group that reacts with the hydroxyl group. Alternatively, in general scheme 6(B), R 4 In the ring-closing metathesis (RCM) reaction in the presence of a Grubb catalyst, R 2 A phenoxy or heteroaryloxy group having a terminal alkene that reacts with the terminal alkene. The resulting alkene is either a feature of the final molecule or is reduced to a saturated heterocycle. Steps 2 and 3 are carried out according to the protocol detailed above for general scheme 1 (steps 2, 3, and 4), R 2 and R 4 This leads to the synthesis of compounds of formula I that form heteroalkylenes.

[1360] IV. Pharmaceutical Compositions The pharmaceutical compositions provided herein contain one or more of the compounds provided herein in a therapeutically effective amount, along with a pharmaceutically acceptable carrier, diluent, or excipient.

[1361] The compounds can be formulated into appropriate pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained-release formulations, or elixirs for oral administration, or into sterile solutions or suspensions for ophthalmic or parenteral administration, as well as into transdermal patch preparations and dry powder inhalations. Typically, the above compounds are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999).

[1362] In the composition, an effective concentration of one or more compounds or pharmaceutically acceptable salts is mixed with a suitable pharmaceutical carrier or vehicle. In certain embodiments, the concentration of the compound in the composition is effective in delivering an amount that, at the time of administration, treats, prevents, or improves one or more of the symptoms and / or progressions of the diseases or disorders disclosed herein.

[1363] Typically, compositions are formulated for single-dose administration. To formulate a composition, the weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed in a selected vehicle at an effective concentration so as to alleviate or improve the treated symptom. Suitable pharmaceutical carriers or vehicles for administering the compounds provided herein include any carrier known to those skilled in the art to be suitable for a particular mode of administration.

[1364] Furthermore, the compounds may be formulated as the sole pharmaceutically active ingredient in a composition, or in combination with other active ingredients. Liposome suspensions containing tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as known in the art. Briefly, liposomes such as multilayer vesicles (MLVs) can be formed by drying egg phosphatidylcholine and brain phosphatidylserine (molar ratio 7:3) inside a flask. A solution of the compound provided herein in phosphate-buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compounds, pelletized by centrifugation, and then resuspended in PBS.

[1365] The active compound is contained in a pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the subject being treated. The therapeutically effective concentration is empirically determined by testing the compound in the in vitro and in vivo systems described herein and can then be extrapolated therefrom to human doses. In some embodiments, the active compound is administered in a manner that achieves a therapeutically effective concentration of the drug. In some embodiments, companion diagnostics (see, e.g., Olsen D and Jorgensen JT, Front. Oncol., 2014 May 16, 4:105, doi:10.3389 / fonC.2014.00105) are used to determine the therapeutic concentration and safety profile of the active compound in a specific subject or population.

[1366] The concentration of the active compound in the pharmaceutical composition depends on the absorption, tissue distribution, inactivation and excretion rates of the active compound, the physicochemical properties of the compound, the administration schedule and dosage, and other factors known to those skilled in the art. For example, the amount delivered is sufficient to improve one or more symptoms of the diseases or disorders disclosed herein.

[1367] In certain embodiments, the therapeutically effective dose should produce serum concentrations of the active ingredient ranging from about 0.1 ng / mL to about 50-100 μg / mL. In one embodiment, the pharmaceutical composition provides a dosage of the compound from about 0.001 mg to about 2000 mg per kilogram of body weight per day. The pharmaceutical unit dosage forms are prepared to provide about 1 mg to about 1000 mg per unit dosage form, and in certain embodiments, about 10 to about 500 mg of the essential active ingredient or combination of essential ingredients.

[1368] The active ingredient may be administered as a single dose or divided into several smaller doses administered at time intervals. It is understood that the exact dosage and duration of treatment depend on the disease being treated and may be determined empirically using known test protocols or by extrapolation from in vivo or in vitro test data. It should be noted that the concentration and dosage values ​​may also vary depending on the severity of the symptoms being relieved. For any particular subject, a specific dosing regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering or monitoring the composition, and it should be further understood that the concentration ranges described herein are merely illustrative and are not intended to limit the scope or implementation of the claimed composition.

[1369] Accordingly, an effective concentration or amount of one or more compounds described herein or a pharmaceutically acceptable salt thereof is mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical, or local administration to form a pharmaceutical composition. The compounds are included in an effective amount for improving, treating, delaying, or preventing one or more symptoms. The concentration of the active compound in the composition depends on the absorption, tissue distribution, inactivation, excretion rate, administration schedule, dosage, specific formulation, and other factors known to those skilled in the art.

[1370] The composition is intended to be administered by appropriate routes, including but not limited to oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, mucosal, cutaneous, transdermal, buccal, rectal, topical, nasal, or inhalation. For oral administration, capsules and tablets may be formulated. The composition may be in liquid, semi-liquid, or solid form and may be formulated in a manner suitable for each route of administration.

[1371] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application may contain any of the following components: sterile diluents, e.g., water for injection, saline, fixative oil, polyethylene glycol, glycerin, propylene glycol, dimethylacetamide, or other synthetic solvents; antimicrobial agents, e.g., benzyl alcohol and methylparaben; antioxidants, e.g., ascorbic acid and sodium bisulfite; chelating agents, e.g., ethylenediaminetetraacetic acid (EDTA); buffers, e.g., acetic acid, citric acid, and phosphoric acid; and agents for adjusting isotonicity, e.g., sodium chloride or dextrose. Parenteral preparations may be sealed in ampoules, pens, disposable syringes, or single-dose or multi-dose vials made of glass, plastic, or other suitable material.

[1372] If a compound exhibits insufficient solubility, methods for solubilizing the compound may be used. Such methods are known to those skilled in the art and include, but are not limited to, the use of a cosolvent such as dimethyl sulfoxide (DMSO), the use of a surfactant such as TWEEN®, or dissolution in an aqueous solution of sodium bicarbonate.

[1373] When compounds are mixed or added, the resulting mixture may be a solution, suspension, emulsion, or the like. The form of the resulting mixture depends on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration, which is sufficient to improve the symptoms of the disease, disorder, or condition being treated, can be determined empirically.

[1374] 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 appropriate amounts of the compound or pharmaceutically acceptable salt thereof. pharmaceutically therapeutically active compounds and their salts are formulated and administered in unit or multiple dosage forms. As used herein, unit dose forms refer to physically distinct units suitable for human and animal subjects, individually packaged as known in the art. Each unit dose contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect when combined with the necessary pharmaceutical carrier, vehicle, or diluent. Examples of unit dose forms include ampoules and syringes, as well as individually packaged tablets or capsules. Unit dose forms may be administered in part or in multiples. Multiple dose forms are multiple identical unit dosage forms packaged in a single container, administered in separate unit dose forms. Examples of multiple dose forms include vials, bottles of tablets or capsules, or pint or gallon bottles. Therefore, the multiple-dose form consists of multiple unit doses that are not separated in the packaging.

[1375] Sustained-release preparations can also be prepared. A suitable example of a sustained-release preparation involves a semipermeable matrix of a solid hydrophobic polymer containing the compounds provided herein, the matrix being in the form of a molded article, e.g., a film or microcapsules. Examples of sustained-release matrices include iontophoresis patches, polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid, copolymers of L-glutamic acid and ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT® (injectable microspheres consisting of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. Polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid can release molecules for more than 100 days, although certain hydrogels have a shorter period of protein release. When encapsulated compounds remain in the body for extended periods, they may denature or aggregate as a result of exposure to moisture at 37°C, potentially leading to loss of biological activity and changes in their structure. Depending on the mechanism of action involved, reasonable strategies for stabilization can be devised. For example, if the aggregation mechanism is found to be intermolecular SS bond formation via thio-disulfide interexchange, stabilization can be achieved by modifying sulfhydryl residues, freeze-drying from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

[1376] Dosage forms or compositions can be prepared containing active ingredients in the range of 0.005% to 100%, with the remainder consisting of a non-toxic carrier. For oral administration, pharmaceutically acceptable non-toxic compositions are formed by incorporating any of the commonly used excipients, e.g., pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, croscarmellose sodium, glucose, sucrose, magnesium carbonate, or saccharin sodium. Such compositions include solutions, suspensions, tablets, capsules, powders, and sustained-release formulations, e.g., implants and microencapsulated delivery systems, as well as biodegradable and biocompatible polymers, e.g., collagen, ethylene vinyl acetate, polyanhydride, polyglycolic acid, polyorthoesters, polylactic acid, etc. Methods for preparing these compositions are known to those skilled in the art. The compositions under consideration may contain about 0.001% to 100% active ingredients, in certain embodiments about 0.1% to 85% active ingredients, or in other embodiments about 75% to 95% active ingredients.

[1377] The active compound or pharmaceutically acceptable salt may be prepared using a carrier, such as a time-release formulation or coating, that protects the compound from rapid elimination from the body.

[1378] The composition may contain other active compounds to obtain a desired combination of properties. The compounds provided herein or their pharmaceutically acceptable salts described herein may also be advantageously administered for therapeutic or preventive purposes in conjunction with other pharmacological agents known in the general art to be valuable in treating one or more of the diseases or medical conditions mentioned above herein, such as diseases related to oxidative stress. It should be understood that such combination therapies constitute further embodiments of the compositions and treatment methods provided herein.

[1379] The lactose-free compositions provided herein are well known in the art and may contain, for example, excipients listed in the United States Pharmacopeia (USP) SP(XXI) / NF(XVI). Generally, lactose-free compositions contain pharmaceutically acceptable amounts of active ingredients, binders / fillers, and lubricants. An exemplary lactose-free dosage form contains an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[1380] This specification further encompasses anhydrous pharmaceutical compositions and dosage forms containing the compounds provided herein. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical field as a means of simulating long-term storage to determine properties such as shelf life or stability of formulations over time. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2nd Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In practice, water and heat accelerate the decomposition of several compounds. Therefore, since moisture and / or humidity are commonly encountered during the manufacture, handling, packaging, storage, transport, and use of formulations, the effect of water on formulations can be very important.

[1381] The anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low-moisture-containing components and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms comprising lactose and at least one active ingredient comprising a primary or secondary amine are anhydrous if substantial contact with moisture and / or humidity is expected during manufacturing, packaging, and / or storage.

[1382] Anhydrous pharmaceutical compositions should be prepared and stored in such a way that their anhydrous nature is maintained. Therefore, anhydrous compositions are packaged using materials known to prevent exposure to water so that they can be included in appropriate formulation kits. Examples of appropriate packaging include, but are not limited to, sealed foil, plastic, unit dose containers (e.g., vials), blister packs, and strip packs.

[1383] A. Oral dosage form Oral pharmaceutical dosage forms are solid, gel, or liquid. Solid dosage forms include tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed chewable lozenges and tablets that may be enterically coated, sugar-coated, or film-coated. Capsules may be rigid or soft gelatin capsules, while granules and powders may be supplied in non-foaming or effervescent forms in combination with other components known to those skilled in the art.

[1384] In certain embodiments, the formulation is a solid dosage form such as a capsule or tablet. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds of similar properties: binders; diluents; disintegrants; lubricants; sweeteners; and flavoring agents.

[1385] Examples of binders include microcrystalline cellulose, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, sucrose, and starch paste. Lubricants include talc, starch, magnesium stearate or calcium stearate, lycopodium, and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol, and dicalcium phosphate. Colloidal silicon dioxide is an example of a lubricant, but is not limited to it. Disintegrants include croscarmellose sodium, sodium starch glycolate, crospovidone, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Colorants include, for example, any of the approved and certified water-soluble FD and C dyes, or mixtures thereof; and water-insoluble FD and C dyes suspended in alumina hydrate. Sweeteners include artificial sweeteners such as sucrose, lactose, mannitol, and saccharin, as well as any number of spray-dried flavorings. Flavorings include natural flavorings extracted from plants such as fruits, as well as, but not limited to, blends of synthetic compounds that produce pleasant sensations, such as peppermint and methyl salicylate. Humectants include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammonia-modified shellac, and cellulose phthalate acetate. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose phthalate acetate.

[1386] If oral administration is desired, the compound may be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition may be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestines. The composition may also be formulated in combination with antacids or other such components.

[1387] If the unit dosage form is a capsule, it may contain a liquid carrier such as fatty oil in addition to the materials of the types described above. Furthermore, the unit dosage form may include coatings of various other materials that modify the physical form of the unit dosage form, such as sugars and other enteric coatings. The compound can also be administered as a component of elixirs, suspensions, syrups, wafers, sprinkles, chewing gum, etc. In addition to the active compound, the syrup may contain sucrose as a sweetener, as well as certain preservatives, dyes and colorants, and flavorings.

[1388] The active material may also be mixed with other active materials that do not impair the desired effect, or with materials that complement the desired effect, such as antacids, H2 blockers, and diuretics. The active ingredient is the compound described herein or a pharmaceutically acceptable salt thereof. Higher concentrations, up to approximately 98% (by weight), of the active ingredient may be present.

[1389] Pharmaceutically acceptable carriers contained in tablets include binders, lubricants, diluents, disintegrants, colorants, flavorings, and wetting agents. Enteric-coated tablets resist the action of stomach acid due to the enteric coating and dissolve or disintegrate in a neutral or alkaline enteric environment. Sugar-coated tablets are compressible tablets to which different layers of pharmaceutically acceptable substances are applied. Film-coated tablets are compressible tablets coated with a polymer or other suitable coating. Multi-compressible tablets are compressible tablets produced by two or more compression cycles using the aforementioned pharmaceutically acceptable substances. Colorants may also be used in the above dosage forms. Flavorings and sweeteners are used in compressible tablets, sugar-coated tablets, multi-compressible tablets, and chewable tablets. Flavorings and sweeteners are particularly 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-foaming granules, as well as 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, suspensions are suspensions of microparticles or nanoparticles. In some embodiments, emulsions are emulsions of microparticles or nanoparticles.

[1391] Elixirs are clear, sweet-tasting aqueous alcohol preparations. A pharmaceutically acceptable carrier used in elixirs is a solvent. A syrup is a concentrated aqueous solution of sugar, such as sucrose, and may contain preservatives. An emulsion is a two-phase system in which one liquid is dispersed in the form of spheres throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifiers, and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non-effervescent granules reconstituted into liquid oral dosage forms include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable substances used in effervescent granules reconstituted into liquid oral dosage forms include organic acids and carbon dioxide sources. Colorants and flavorings 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 propylparabens, benzoic acid, sodium benzoate, and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifiers include surfactants such as gelatin, acacia, tragacanth, bentonite, and polyoxyethylene sorbitan monooleate. Suspensioning agents include sodium carboxymethylcellulose, pectin, tragacanth, veegum, and acacia. Diluents include lactose and sucrose. Sweeteners include sucrose, syrup, glycerin, and artificial sweeteners such as saccharin. Humectants include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic additives include citric acid and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Colorants include any approved and certified water-soluble FD and C dyes, as well as mixtures thereof. Flavorings include natural flavors extracted from fruits and other plants, as well as blends of synthetic compounds that create pleasant tastes.

[1393] In the case of solid dosage forms, solutions or suspensions in, for example, propylene carbonate, vegetable oil, or triglycerides are encapsulated in gelatin capsules. Such solutions, as well as their preparation and encapsulation, are disclosed in U.S. Patents 4,328,245; 4,409,239; and 4,410,545. In the case of liquid dosage forms, solutions in, for example, polyethylene glycol, can be diluted with a pharmaceutically acceptable liquid carrier, such as water, in an amount sufficient 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 oil, glycol, triglycerides, propylene glycol esters (e.g., propylene carbonate), and other such carriers, and encapsulating these solutions or suspensions in rigid or soft gelatin capsule shells. Other useful formulations include, but are not limited to, the compounds provided herein, dialkylated mono- or polyalkylene glycols, including: 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (where 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol), and those containing one or more antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, 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 alcohol solutions containing pharmaceutically acceptable acetals. The alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvent having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. The acetals include, but are not limited to, di(lower alkyl) acetals of lower alkylaldehydes, such as acetaldehyde diethyl acetal.

[1396] In all embodiments, tablet and capsule formulations may be coated as known to those skilled in the art to modify or maintain the dissolution of the active ingredient. For example, they may be coated with conventional enterally digestible coatings such as phenyl salicylate, wax, and cellulose phthalate acetate.

[1397] B. Injectable preparations, solutions, and emulsions Parenteral administration, generally characterized by subcutaneous, intramuscular, or intravenous injection, is also contemplated herein. Injectable preparations can be prepared conventionally as liquid solutions or suspensions, as solid forms suitable for solutions or suspensions in liquids prior to injection, or as emulsions. In some embodiments, the suspension is a suspension of microparticles or nanoparticles. In some embodiments, the emulsion is an emulsion of microparticles or nanoparticles. Suitable excipients include, for example, water, saline, dextrose, glycerol, or ethanol. Furthermore, if desired, the administered pharmaceutical composition may also contain small amounts of non-toxic adjuncts, such as wetting or emulsifying agents, pH buffers, stabilizers, solubility enhancers, and other such agents, such as sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrin. Embedding of sustained-release or sustained-release systems, such as maintaining a constant dose level, is also contemplated herein. In short, the compounds provided herein are dispersed in a solid internal matrix, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrogels of acrylic and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate, and are insoluble in body fluids. It is surrounded by an outer polymer film, such as polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyl oxyethanol copolymer.The compounds diffuse through the outer polymer film during the release rate control step. The percentage of active compounds contained in such parenteral compositions depends largely on their specific properties, as well as the compound's activity and the needs of the target.

[1398] Parenteral administration of the composition includes intravenous, subcutaneous, and intramuscular administration. Preparations for parenteral administration include sterile solutions ready for injection, sterile dried soluble products ready for combination with a solvent immediately before use, such as lyophilized powders (including subcutaneous tablets), sterile suspensions ready for injection, sterile dried insoluble products ready for combination with a vehicle immediately before use, and sterile emulsions. The solutions may be aqueous or non-aqueous.

[1399] When administered intravenously, suitable carriers include physiological saline or phosphate-buffered saline (PBS), as well as solutions containing thickeners and solubilizers such as glucose, polyethylene glycol, and polypropylene glycol, and mixtures thereof.

[1400] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, topical anesthetics, suspending and dispersing agents, emulsifiers, sequestering or chelating agents, and other pharmaceutically acceptable substances.

[1401] Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose, and lactated Ringer's injection. Non-aqueous parenteral vehicles include plant-derived fixative oils, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents at bacteriostatic or fungiostatic concentrations must be added to parenteral preparations packaged in multi-dose containers containing phenol or cresol, mercury, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphoric acid and citric acid. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspensions and dispersants include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. The emulsifier includes polysorbate 80 (TWEEN® 80). The metal ion scavenger or chelating agent includes EDTA. The pharmaceutical carrier also includes ethyl alcohol, polyethylene glycol, and propylene glycol for water-miscible vehicles, as well as sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[1402] The concentration of the pharmaceutically active compound is adjusted so that the injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight, and symptoms of the subject or animal, as is known in the art.

[1403] Parenteral preparations for a unit dose are packaged in ampoules, vials, or syringes with needles. All preparations for parenteral administration must be sterile, as is known and practiced in the art.

[1404] Exemplary, an effective mode of administration is intravenous or intra-arterial infusion of a sterile aqueous solution containing the active compound. Another embodiment is a sterile aqueous or oily solution or suspension containing the active material, which is injected as needed to produce the desired pharmacological effect.

[1405] Injectable formulations are designed for topical and systemic administration. Typically, therapeutically effective doses are formulated to contain concentrations of the active compound ranging from at least about 0.1% w / w to at least about 90% w / w, e.g., above 1% w / w, relative to the treated tissue. The active ingredient may be administered in a single dose or divided into several smaller doses administered at time intervals. It is understood that the exact dose and duration of treatment depend on the treated tissue and may be determined empirically using known test protocols or by extrapolation from in vivo or in vitro test data. It should also be noted that concentration and dose values ​​may also vary with the age of the treated individual. For any particular subject, specific dosing regimens should be adjusted over time according to individual needs and the professional judgment of the person administering or monitoring the formulation, and it should be further understood that the concentration ranges described herein are merely illustrative and not intended to limit the scope or practice of the claimed formulation.

[1406] The compound may be suspended in micronized or other suitable forms, or derivatized to produce a more soluble active product or a prodrug. The form of the resulting mixture depends on many factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration, sufficient to improve the symptoms of the condition, can be determined empirically.

[1407] C. Freeze-dried powder Of particular interest herein are lyophilized powders that can be reconstituted for administration as solutions, emulsions, and other mixtures. They can also be reconstituted and formulated as solids or gels.

[1408] Sterile lyophilized powders are prepared by dissolving the compounds provided herein or pharmaceutically acceptable salts thereof in a suitable solvent. The solvent may contain excipients that improve the stability of the powder or the reconstituted solution prepared from the powder or other pharmacological components. Excipients that may be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agents. The solvent may also contain buffers such as citrate, sodium phosphate or potassium phosphate, or other such buffers known to those skilled in the art, and in one embodiment is approximately neutral pH. Subsequent sterile filtration of the solution, followed by lyophilization under standard conditions known to those skilled in the art, provides the desired formulation. Generally, the resulting solution is dispensed into vials for lyophilization. Each vial contains a single dose (containing, but not limited to, 10 to 1000 mg or 100 to 500 mg) or multiple doses of the compound. The lyophilized powders can be stored under suitable conditions, for example, about 4°C to room temperature.

[1409] By reconstituting this lyophilized powder with sterile water for injection, a formulation for parenteral administration is provided. For reconstitution, approximately 1–50 mg, 5–35 mg, or 9–30 mg of the lyophilized powder is added per 1 mL of sterile water or other suitable carrier. The exact amount depends on the compound selected. Such an amount can be determined empirically.

[1410] D. Local administration Topical mixtures are prepared as described for topical and systemic administration. The resulting mixture may be a solution, suspension, emulsion, etc., and may be formulated as a cream, gel, ointment, emulsion, solution, elixir, lotion, suspension, tincture, paste, foam, aerosol, irrigation, spray, suppository, bandage, skin patch, or any other formulation suitable for topical administration.

[1411] Compounds or pharmaceutically acceptable salts thereof may be formulated as aerosols for topical application, such as by inhalation (see, for example, U.S. Patents 4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivering steroids useful in the treatment of inflammatory diseases, particularly asthma). These formulations for administration to the airways may be alone or in combination with an inert carrier such as lactose, in the form of aerosols or solutions for nebulizers, or as fine powders for air insufflation. In such cases, the particles of the formulation have a diameter of less than 50 microns or less than 10 microns.

[1412] The compound may be formulated in the form of gels, creams, and lotions for topical or intratopic application, for example, to the skin and mucous membranes, for example, to the eyes, as well as for application to the eyes, or for intracisional or intraspinal application. Topical administration is intended for transdermal delivery, for administration to the eyes or mucous membranes, or for inhalation therapy. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients may also be administered.

[1413] These solutions, especially those intended for ophthalmic use, can be formulated as 0.01% to 10% isotonic solutions with a pH of approximately 5 to 7, containing the appropriate salt.

[1414] E. Compositions for other routes of administration Other routes of administration, such as topical application, transdermal patch, and rectal administration, are also intended herein.

[1415] For example, pharmaceutical dosage forms for rectal administration include rectal suppositories, capsules, and tablets for systemic effects. Rectal suppositories, as used herein, mean solid objects for insertion into the rectum that melt or soften at body temperature and release one or more pharmacological or therapeutic active ingredients. Pharmaceutically acceptable substances used in rectal suppositories are bases or vehicles and agents for raising the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol), and suitable mixtures of mono, di, and triglycerides of fatty acids. Various combinations of bases may be used. Agents for raising the melting point of suppositories include whale wax and other waxes. Rectal suppositories can be prepared by either compression or molding. An example weight of a rectal suppository is about 2-3 grams.

[1416] Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substances and methods as formulations for oral administration.

[1417] F. Sustained-release composition The active ingredients provided herein can be administered by controlled release means or delivery devices well known to those skilled in the art. Examples include, but are not limited to, U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and U.S. Patents 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, and 5,922,356. Examples include those described in Nos. 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 incorporated herein by reference. Using such dosage forms, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof, it is possible to provide sustained or controlled release of one or more active ingredients, and to provide desired release profiles in various proportions. Suitable controlled-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[1418] All controlled-release pharmaceuticals share the common goal of improving drug therapy beyond what can be achieved by their uncontrolled counterparts. In one embodiment, the use of an optimally designed controlled-release preparation in a medical procedure is characterized by a minimal amount of active pharmaceutical ingredient used to cure or control symptoms in the shortest possible time. In certain embodiments, the advantages of controlled-release formulations include extended drug activity, reduced administration frequency, and increased compliance with the target. Furthermore, controlled-release formulations can be used to influence other properties such as the time of action onset or the blood level of the drug, and thus influence the occurrence of side effects (e.g., adverse effects).

[1419] Most controlled-release formulations are designed to initially release a rapid amount of the drug (active ingredient) to produce the desired therapeutic effect, and then gradually and continuously release other amounts of the drug to maintain this level of therapeutic or preventive effect over a longer period. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug metabolized and excreted from the body. The controlled release of the active ingredient can be stimulated by a variety of conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[1420] In certain embodiments, the drug may be administered by intravenous infusion, implantable osmotic pump, transdermal patch, liposome, or other mode 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, polymer materials may be used. In yet another embodiment, a controlled release system may be placed near the therapeutic target, i.e., requiring only a portion of the systemic dose (see, for example, Goodson, Medical Applications of Controlled Release, vol.2, pp.115-138(1984)).

[1421] In some embodiments, controlled-release devices are introduced to targets near sites of inappropriate immune activation or tumors. Other controlled-release systems are described in a review by Langer (Science 249:1527-1533 (1990)). The active ingredient can be dispersed in a solid internal matrix, such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrogels of acrylic and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate, and insoluble in body fluids in an external polymer membrane, such as polyethylene, polypropylene, ethylene / propylene copolymer. The composition is surrounded by polymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyl oxyethanol copolymers. The active ingredient is then diffused through the outer polymer membrane in a release rate control step. The percentage of active ingredient contained in such parenteral compositions depends largely on their specific properties and the needs of the target.

[1422] G. Targeted Therapies The compounds provided herein or pharmaceutically acceptable salts thereof may also be formulated to target specific tissues, receptors, or other areas of the body being treated, and include liposomes, resealed red blood cells, and antibody-based delivery systems. Many such targeting methods are well known to those skilled in the art. All such targeting methods are contemplated herein for use in the compositions of the present invention. For non-limiting examples of targeting methods, see, for example, U.S. Patents 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"), for example, as described in Hamilton GS, Biologicals, 2015 September, 43(5):318-32; Kim EG and Kim KM, 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 incorporated herein by reference.

[1424] In one embodiment, liposome suspensions containing tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. For example, liposome formulations can be prepared as described in U.S. Patent No. 4,522,811. Briefly, liposomes such as multilayer vesicles (MLVs) can be formed by drying egg phosphatidylcholine and brain phosphatidylserine (molar ratio 7:3) inside a flask. A solution of the compound provided herein in phosphate-buffered saline (PBS) lacking divalent cations is added, and the flask is shaken until the lipid membrane is dispersed. The resulting vesicles are washed to remove unencapsulated compounds, pelletized by centrifugation, and then resuspended in PBS.

[1425] H. Manufactured articles A compound or a pharmaceutically acceptable salt may be packaged as a manufactured article containing packaging material, the compound or a pharmaceutically acceptable salt provided herein, used for the treatment, prevention, or improvement of one or more symptoms or progressions of a disease or disorder disclosed herein, and a label indicating that the compound or a pharmaceutically acceptable salt is used for the treatment, prevention, or improvement of one or more symptoms or progressions of a disease or disorder disclosed herein.

[1426] The manufactured articles provided herein include packaging materials. Packaging materials for use in packaging pharmaceuticals are well known to those skilled in the art. See, for example, U.S. Patents 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 materials suitable for the selected formulation and the intended mode of administration and treatment. A wide range of formulations of the compounds and compositions provided herein are intended.

[1427] In certain embodiments, kits are also provided herein that, when used by healthcare professionals, can simplify the administration of an appropriate amount of the active ingredient to a subject. In certain embodiments, the kit provided herein comprises a container and a dosage form of the compound provided herein, comprising a mixture of a single enantiomer or its diastereomers; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[1428] In certain embodiments, the kit includes a container containing a dosage form of the compound provided herein, comprising a single enantiomer or a mixture of its diastereomers; or a container containing a pharmaceutically acceptable salt, solvate, or prodrug thereof, comprising one or more other therapeutic agents described herein.

[1429] The kits provided herein may further include devices used for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, needleless injector drip bags, patches, and inhalers. The kits provided herein may also include condoms for administering the active ingredient.

[1430] The kits provided herein may further comprise pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may comprise a sealed container of a suitable vehicle from which the active ingredient can be dissolved to form a particulate-free sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to, aqueous vehicles (water for injection USP, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, 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).

[1431] V. Medication The compounds and pharmaceutical compositions provided herein may be administered in specific therapeutic or prophylactic doses, at specific time intervals, in specific dosage forms, and in specific methods of administration, as described below.

[1432] In certain embodiments, therapeutic or prophylactic effective doses of the compound are approximately 0.005 to approximately 1,000 mg / day, approximately 0.01 to approximately 500 mg / day, approximately 0.01 to approximately 250 mg / day, approximately 0.01 to approximately 100 mg / day, approximately 0.1 to approximately 100 mg / day, approximately 0.5 to approximately 100 mg / day, approximately 1 to approximately 100 mg / day, approximately 0.01 to approximately 50 mg / day, approximately 0.1 to approximately 50 mg / day, approximately 0.5 to approximately 50 mg / day, approximately 1 to approximately 50 mg / day, approximately 0.02 to approximately 25 mg / day, approximately 0.05 to approximately 10 mg / day, approximately 0.05 to approximately 5 mg / day, approximately 0.1 to approximately 5 mg / day, or approximately 0.5 to approximately 5 mg / day.

[1433] In certain embodiments, therapeutic or prophylactic effective doses are 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 / day.

[1434] In one embodiment, the recommended daily dose range of the compounds or derivatives provided herein for the symptoms described herein is in the range of about 0.5 mg to about 50 mg / day, and in one embodiment, it is given as a single once-daily dose or in divided doses throughout the day. In some embodiments, the dose is in the range of about 1 mg to about 50 mg / day. In other embodiments, the dose is in the range of about 0.5 to about 5 mg / day. Specific daily doses 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 / day.

[1435] In specific embodiments, the recommended starting dose may be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, or 50 mg / day. In other embodiments, the recommended starting dose may be 0.5, 1, 2, 3, 4, or 5 mg / day. Doses may be increased to 15, 20, 25, 30, 35, 40, 45, and 50 mg / day. In specific embodiments, the compound may be administered in amounts of about 25 mg / day. In specific embodiments, the compound may be administered in amounts of about 10 mg / day. In specific embodiments, the compound may be administered in amounts of about 5 mg / day. In specific embodiments, the compound may be administered in amounts of about 4 mg / day. In specific embodiments, the compound may be administered in amounts of about 3 mg / day.

[1436] In certain embodiments, therapeutic or prophylactic effective doses are approximately 0.001 to 100 mg / kg / day, approximately 0.01 to 50 mg / kg / day, approximately 0.01 to 25 mg / kg / day, approximately 0.01 to 10 mg / kg / day, approximately 0.01 to 9 mg / kg / day, 0.01 to 8 mg / kg / day, approximately 0.01 to 7 mg / kg / day, approximately 0.01 to 6 mg / kg / day, approximately 0.01 to 5 mg / kg / day, approximately 0.01 to 4 mg / kg / day, approximately 0.01 to 3 mg / kg / day, approximately 0.01 to 2 mg / kg / day, approximately 0.01 to 1 mg / kg / day, or approximately 0.01 to 0.05 mg / kg / day.

[1437] The dose administered can also be expressed in units other than mg / kg / day. For example, the dose for parenteral administration can be expressed in mg / m 2 It can be expressed as / day. A person skilled in the art can change the dose from mg / kg / day to mg / m 2 You will likely know how to convert this to a daily dose and give the subject's height, weight, or both (see www.fda.gov / cder / cancer / animalframe.htm). For example, a dose of 1 mg / kg / day for a 65 kg person is 38 mg / m². 2 / day is roughly equivalent to

[1438] In certain embodiments, the amount of compound administered is sufficient to provide plasma concentrations of the compound in the range of 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, about 1 to about 50 μM, about 0.02 to about 25 μM, about 0.05 to about 20 μM, about 0.1 to about 20 μM, about 0.5 to about 20 μM, or about 1 to about 20 μM at a steady state.

[1439] In other embodiments, the amount of compound administered is sufficient to provide plasma concentrations of the compound in the range of 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 about 50 to about 100 nM at a steady state.

[1440] As used herein, the term “steady-state plasma concentration” refers to the concentration reached after a period of administration of the compound or its derivatives provided herein. Upon reaching a steady state, small peaks and troughs are present on the time-dependent curve of the plasma concentration of the compound.

[1441] In certain embodiments, the amount of compound administered is sufficient to provide a maximum plasma concentration (peak concentration) of the compound in the range of 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, about 1 to about 50 μM, about 0.02 to about 25 μM, about 0.05 to about 20 μM, about 0.1 to about 20 μM, about 0.5 to about 20 μM, or about 1 to about 20 μM.

[1442] In certain embodiments, the amount of compound administered is sufficient to provide minimum plasma concentrations (trough concentrations) of the compound in the range of approximately 0.001 to 500 μM, approximately 0.002 to 200 μM, approximately 0.005 to 100 μM, approximately 0.01 to 50 μM, approximately 1 to 50 μM, approximately 0.01 to 25 μM, approximately 0.01 to 20 μM, approximately 0.02 to 20 μM, approximately 0.02 to 20 μM, or approximately 0.01 to 20 μM.

[1443] In certain embodiments, the amount of compound administered is sufficient to provide area under the curve (AUC) of compounds in the ranges of about 100 to about 100,000 ng*hr / mL, about 1,000 to about 50,000 ng*hr / mL, about 5,000 to about 25,000 ng*hr / mL, or about 5,000 to about 10,000 ng*hr / mL.

[1444] The methods provided herein encompass treating patients regardless of their age, although some diseases or disorders are more common in specific age groups.

[1445] Depending on the disease being treated and the symptoms of the target, the compounds or derivatives provided herein may be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous injection, or implant), by inhalation, nasal, vaginal, rectal, sublingual, or topically (e.g., percutaneous or topical) routes of administration. The compounds or derivatives provided herein may be formulated alone or in appropriate dosage units with pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles suitable for each route of administration.

[1446] In one embodiment, the compounds or derivatives provided herein are administered orally. In another embodiment, the compounds or derivatives provided herein are administered parenterally. In yet another embodiment, the compounds or derivatives provided herein are administered intravenously.

[1447] The compounds or derivatives provided herein can be delivered, for example, as a single bolus injection or as a single dose such as an oral tablet or pill; or over time, for example, by continuous infusion over time or by divided bolus administration over time. The compounds can be administered repeatedly as needed, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity. For example, stable disease in solid tumors generally means that the orthogonal diameter of the measurable lesion has not increased by more than 25% since the last measurement. Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3):205 216(2000). Stable disease or its absence is determined by methods known in the art, such as evaluation of the patient's symptoms, physical examination, visualization of the tumor imaged using X-ray, CAT, PET, or MRI scans, and other generally accepted forms of evaluation.

[1448] The compounds or derivatives provided herein may 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). Furthermore, administration may be continuous (i.e., daily or consecutive days), intermittent, or cyclical (i.e., including drug-free periods of several days, weeks, or months). As used herein, the term “daily” is intended to mean that the therapeutic compound, e.g., the compounds or derivatives provided herein, is administered once or multiple times each day, for example, over a period of time. The term “continuous” is intended to mean that the therapeutic compound, e.g., the compounds or derivatives provided herein, is administered daily over an uninterrupted period of at least 10 days to 52 weeks. As used herein, the terms “intermittent” or “intermittently” are intended to mean stopping and starting at regular or irregular intervals. For example, intermittent administration of the compounds or derivatives provided herein may be administration 1 to 6 days per week, cyclical administration (e.g., daily administration for 2 to 8 consecutive weeks, followed by a rest period of up to 1 week), or every other day. The term “cycling” as used herein is intended to mean that the therapeutic compound, e.g., the compounds or derivatives provided herein, is administered daily or continuously, but with rest periods. In some such embodiments, administration is once daily for 2 to 6 days, followed by a rest period of 5 to 7 days without administration.

[1449] In some embodiments, the frequency of administration is in the range of approximately daily to approximately monthly doses. In specific embodiments, administration is once daily, twice daily, three times daily, four times daily, once every other day, twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the compound or derivative provided herein is administered once daily. In another embodiment, the compound or derivative provided herein is administered twice daily. In yet another embodiment, the compound or derivative provided herein is administered three times daily. In yet another embodiment, the compound or derivative provided herein is administered four times daily.

[1450] In certain embodiments, the compounds or derivatives provided herein are administered once daily for 1 day to 6 months, 1 week to 3 months, 1 week to 4 weeks, 1 week to 3 weeks, or 1 week to 2 weeks. In certain embodiments, the compounds or derivatives provided herein are administered once daily over 1 week, 2 weeks, 3 weeks, or 4 weeks. In one embodiment, the compounds or derivatives provided herein are administered once daily over 4 days. In one embodiment, the compounds or derivatives provided herein are administered once daily over 5 days. In one embodiment, the compounds or derivatives provided herein are administered once daily over 6 days. In one embodiment, the compounds or derivatives provided herein are administered once daily over 1 week. In another embodiment, the compounds or derivatives provided herein are administered once daily over 2 weeks. In yet another embodiment, the compounds or derivatives provided herein are administered once daily over 3 weeks. In yet another embodiment, the compounds or derivatives provided herein are administered once daily over 4 weeks.

[1451] VI. Treatment Methods Inhibitors of KAT-mediated post-translational lysine acetylation of the MYST family are promising antineoplastic agents and therefore useful therapeutic agents for use in the treatment of cancer, for example. Such agents are also useful as therapeutic agents for treating cancers that exhibit overexpression of MYST proteins.

[1452] In another embodiment, a method is provided for treating a subject having cancer by administering a compound or composition provided herein. In yet another embodiment, a method is provided herein for treating a symptom, disease or disorder by inhibiting the MYST family of lysine acetyltransferases, including KAT6A and KAT6B, comprising administering a therapeutically effective amount of a compound or composition provided herein.

[1453] In another embodiment, a method is provided for treating a symptom, disease, or disorder in which the symptom, disease, or disorder is an overproliferative disorder 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, chondrosarcoma, osteosarcoma). In some embodiments, the cancer is a MYST-overexpressing cancer. In another embodiment, the cancer overexpresses the MYST protein compared to non-cancerous tissue. In some embodiments, the cancer overproduces MYST mRNA compared to non-cancerous tissue. In another embodiment, the cancer is a MYST-overexpressing cancer in which the overexpressed MYST protein or MYST mRNA is one of the KATs of the MYST family, e.g., KAT6A. In some embodiments, cancers include leukemia, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), non-Hodgkin lymphoma, Hodgkin's disease, prostate cancer, lung cancer, melanoma, breast cancer, ductal carcinoma, colorectal cancer, colon cancer, squamous cell carcinoma, gastric cancer, adrenocortical carcinoma, anal cancer, bladder cancer, hematological cancer, bone cancer, brain tumor, cancers of the female reproductive system, cancers of the male reproductive system (including testicular and penile cancer), central nervous system lymphoma, cervical cancer, pediatric rhabdomyosarcoma, pediatric sarcoma, endometrial cancer, endometrial sarcoma, esophageal cancer, eye cancer, gallbladder cancer, gastrointestinal cancer, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, hypopharyngeal cancer, Kaposi's sarcoma, and kidney cancer. These include laryngeal cancer, liver cancer, malignant fibrous histiocytoma, malignant thymoma, mesothelioma, multiple myeloma, myeloma, nasal and paranasal sinus cancer, nasopharyngeal cancer, nervous system cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pituitary tumor, plasma cell neoplasm, primary CNS lymphoma, rectal cancer, respiratory system cancer, retinoblastoma, salivary gland cancer, skin cancer, small intestine cancer, soft tissue sarcoma, gastric cancer, testicular cancer, thyroid cancer, urinary tract cancer, uterine cancer, uterine sarcoma, vaginal cancer, endocrine cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumor, glioblastoma, brainstem glioma, pituitary adenoma, vascular cancer, Waldenström 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 hematological cancer (including 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, a method is provided for inhibiting the activity of MYST KAT by contacting MYST KAT or a composition containing MYST KAT with a compound or composition provided herein. In one embodiment, MYST KAT is KAT6 lysine acetyltransferase. In another embodiment, MYST KAT is KAT6A.

[1455] While we do not wish 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 an acetyl group from acetyl coenzyme A (Ac-CoA) to transiently form an acetyl-enzyme intermediate. This acetyl-enzyme intermediate then serves as a source of acetyl groups to be transferred to a substrate, typically lysine on a histone (Wapenaar et al., 2016, cited above). The MYST family of KATs contains conserved cysteines that are transiently acylated as part of the catalytic cycle, as indicated by the bolded C in the following sequence. Amino acid sequence alignment near the Ac-CoA binding site of the MYST family of KAT [Table 1]

[1456] Accordingly, one embodiment provides a method for inhibiting MYST KAT by covalent modification of the conserved cysteine ​​residue using a compound or composition provided herein. Another embodiment provides a method for covalent modification of the conserved MYST KAT cysteine ​​residue by contacting MYST KAT or a composition containing 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, play a crucial role in promoting myc-driven transcriptional regulation. Myc is a transcriptional regulator known to mobilize HATs to target chromatin to promote chromatin rearrangement, resulting in transcription, proliferation, and tumor growth. Myc is a transcriptional regulator with many protein interacting factors in a complex that mediates this transcriptional activity. One such interacting protein, known as a transformation / transcription domain-associated protein or TRRAP, is a member of several HAT-containing protein complexes, and it acts as a crosslinking protein between transcription factors like myc and HATs. It has been demonstrated that Myc mobilizes histone acetylation via the TRRAP complex, which promotes nucleosome acetylation at histone H4 via HATs (including, but not limited to, KAT2A, KAT5, and Tip60 / p400). This myc-associated HAT activity enables chromatin opening that structurally promotes transcription (see, e.g., Laurenco, et al. Nature Reviews Cancer 2021, 21, 579-591). Myc recruits HAT to target chromatin, locally promoting the acetylation of multiple specific lysines in both H3 and H4, some of which are known targets of KAT6A acetylation, leading to 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 certain cancers and cell types and may be an important mediator of HAT activity recruited to myc-driven transcriptional activation sites in some tumors.

[1458] Furthermore, prominent targets of myc-induced transcriptional regulation (myc pathway targets) are reduced by the use of KAT6A inhibitors. This includes the myc pathway in KAT6A-amplified breast cancer cell lines after administration of KAT6 inhibitors (see, for example, Sharma et al. Cell Chemical Biology 2023, doi.org / 10.1016 / j.chembiol.2023.07.005).

[1459] In fact, KAT6 may be a HAT that plays a crucial role in myc-driven transcriptional regulation, and there is direct evidence that loss of KAT6 activity can disrupt myc-driven transcriptional programming. Myc-driven growth in lymphoma cell lines in vivo is inhibited by systemic administration of KAT6 inhibitors. Specifically, two small molecule inhibitors, KAT6A and KAT6B, evoke antitumor 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, esophageal, breast, gastric, pancreatic, and liver cancers. Several overlapping solid tumor types exist that exhibit characteristic myc activity and also include KAT6 genome amplification. Therefore, inhibition of KAT6A activity is expected to reduce transcriptional activity and tumorigenicity in solid tumors where myc is a key transcriptional regulator.

[1461] Accordingly, in another embodiment, a method is provided for treating a myc-driven cancer in a subject by administering the subject to a compound or composition provided herein. In another embodiment, the myc-driven cancer is lung cancer, ovarian cancer, esophageal cancer, breast cancer, gastric cancer, pancreatic cancer, or liver cancer. In another embodiment, the myc-driven cancer is a cancer in which myc is amplified. In another embodiment, a method is provided for treating a cancer in which myc is amplified in a subject by administering the subject to a compound or composition provided herein.

[1462] KAT6A is an acetyltransferase of p53 at K120 and K382 and colocalizes with p53 in the nucleus of promyelocytic leukemia (PML) after cellular stress (Rokudai, et al. PNAS 2013, 110(10), 3895-3900). This ternary complex enhances p53-dependent p21 expression. Therefore, KAT6A acetylation of p53, which affects the formation or stability of the complex and alters its downstream activity, is involved in the pathogenesis of tumors and leukemia. Thus, KAT6A inhibitors can be used to treat hematological malignancies. In another embodiment, a method is provided for treating hematological malignancies in a subject by administering the compound or composition provided herein to the subject.

[1463] KAT6A acetylation of SMAD3 modulates the recruitment, metastasis, and immunotherapy of bone marrow-derived suppressor cells in triple-negative breast cancer (TNBC) (Yu, et al. Adv. Sci. 2021, 8, 2100014). Therefore, KAT6A inhibitors can be used to treat TNBC. In another embodiment, a method is provided for treating TNBC in a subject by administering the subject a compound or composition provided herein.

[1464] VII. Combination therapy with other active agents The compounds or derivatives provided herein may also be combined with, or used in combination with, other therapeutic agents useful for treating and / or preventing hyperproliferative diseases, including cancer.

[1465] In one embodiment, a method for treating, preventing or managing hyperproliferative diseases, including cancer, is provided herein, comprising administering a compound or derivative thereof provided herein to a subject in combination with one or more second active agents.

[1466] As used herein, the term “combined” includes the use of two or more treatments (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term “combined” does not limit the order in which treatments (e.g., prophylactic and / or therapeutic agents) are administered to a subject with a disease or disorder. The first treatment (e.g., a prophylactic or therapeutic agent such as a compound or derivative thereof provided herein) may be administered to the subject before (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 prior to), simultaneously with, or subsequently 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 prior to), simultaneously with, or subsequently 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 prior to), or after. Triple treatment is also intended herein.

[1467] The compounds or derivatives thereof provided herein, and one or more other active agents, may be administered to a target simultaneously or sequentially via the same or different routes of administration. The suitability of a particular route of administration used for a particular active agent depends on the active agent itself (e.g., whether it can be administered orally without being broken down before entering the bloodstream) and the disease or disorder being treated.

[1468] The route of administration of the compounds or derivatives provided herein is independent of the route of administration of the second treatment. In one embodiment, the compounds or derivatives provided herein are administered orally. In another embodiment, the compounds or derivatives provided herein are administered intravenously. Accordingly, according to these embodiments, the compounds or derivatives provided herein are administered orally or intravenously, and the second treatment can be administered orally, parenterally, intraperitoneally, intravenously, intra-arterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, via liposomes, inhalation, vaginally, intraocularly, locally by catheter or stent, subcutaneously, intrafatally, intra-articularly, intrathecally, or in sustained-release form. In one embodiment, the compounds or derivatives provided herein and the second treatment are administered orally or IV by the same mode of administration. In another embodiment, the compounds or derivatives provided herein are administered by one mode of administration, for example IV, and the second drug is administered by another mode of administration, for example orally.

[1469] In one embodiment, the second active agent is administered intravenously or subcutaneously once or twice daily in amounts of about 1 to about 1000 mg, about 5 to about 500 mg, about 10 to about 350 mg, or about 50 to about 200 mg. The specific amount of the second active agent depends on the specific drug used, the type of disease being treated or managed, the severity and stage of the disease, as well as the compound or its derivatives provided herein, and the amount of any additional active agents administered concurrently to the subject.

[1470] In the methods and compositions provided herein, one or more other active ingredients or agents may be used together with the compounds or derivatives thereof provided herein. The other agents may be high molecular weight (e.g., proteins) or low molecular weight (e.g., synthetic inorganic molecules, organometallic molecules, or organic molecules).

[1471] Examples of macromolecular-weight active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies, as well as immune-based therapeutics in the known classification of immuno-oncology, particularly therapeutic antibodies against cancer antigens, which improve the immune-mediated recognition of tumors. Typical macromolecular-weight active agents are biological molecules such as natural, synthetic, or recombinant proteins.

[1472] In one embodiment, the compounds or derivatives provided herein are administered orally daily in amounts ranging from about 0.1 to about 150 mg, about 1 to about 25 mg, or about 2 to about 10 mg, either alone or in combination with a second active agent before, during, or after use of conventional treatment.

[1473] In another embodiment, the selection of other active agents depends on the disease being treated. Examples of second active agents for specific cancers are well known to those skilled in the art. For example, if the disease is breast cancer, 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 KAT6 inhibitors for the 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 in PIK3CA is very common in breast cancer and other solid tumors. KAT6 inhibitors can be combined with mutation-selective PI3Kα inhibitors for the treatment of breast cancer and other cancers.

[1474] Another example of a solid tumor type with KAT6A genome and mRNA amplification is ovarian cancer. Ovarian cancer is often treated with platinum-based chemotherapy agents such as cisplatin, which have high levels of toxicity that limit dosage and the achievement of maximum effective exposure. In some cases, PARP inhibitors or CDK2 inhibitors are used to treat ovarian cancer. KAT6 inhibitors can be used in combination with these agents to treat ovarian cancer, but are not limited to these agents.

[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 and AML. KAT6 inhibitors can be applied alone, or in combination with menin and menin pathway inhibitors, to treat hematological malignancies such as AML and tumors in which the menin-MLL / KMT2 complex drives tumor growth.

[1476] VIII. Examples The following examples are for illustrative purposes only and are not intended to limit the scope of the disclosure.

[1477] Where used herein, the symbols and conventions used in these processes, schemes, and examples are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry, whether or not specific abbreviations are specifically defined.Specifically, though not limited to, the following abbreviations may be used throughout the examples and specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimole); μM (micromoles); Hz (hertz); MHz (megahertz); mmol (millimole); h, hr or hrs (hours); min (minutes); MS (mass spectrometry); ESI (electrospray ionization); rt (room temperature); Rf (retention coefficient); TLC (thin-layer chromatography); LCMS (liquid chromatography-mass spectrometry); HPLC (high-performance liquid chromatography); AcOH (acetic acid); n-BuLi (n-butyllithium); tBuOK (potassium tert butoxide); CDCl3 (chloroform-d); CH3CN (acetonitrile); Cs2CO3 (cesium carbonate); DMF (N,N-dimethylformamide); DCM (dichloromethane); DEA (diethylamine); DIPEA (diisopropylethylamine); DMSO (dimethyl sulfoxide); DMSO-d6 Dimethyl sulfoxide-d6); Â or EA (ethyl acetate); Et3N (triethylamine); EtOH (ethanol); HCl (hydrochloric acid); H2SO4 (sulfuric acid); K2CO3 (potassium carbonate); LiOH (lithium hydroxide); MsCl (methanesulfonyl 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 sulfate); K3FeCN6 (potassium ferricyanide); Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium(0)); SO2 (sulfur dioxide); SO2Cl2 (sulfuryl chloride); T3P (propanephosphonic anhydride); THF (tetrahydrofuran); TMEDA (1,2-bis(dimethylamino)ethane); Zn (zinc); ZnCN2 (zinc cyanide).

[1478] For all the following examples, standard post-treatment and purification methods known to those skilled in the art can be used. Unless otherwise specified, all temperatures are expressed in °C (Celsius). Unless otherwise specified, all reactions are carried out at room temperature. The synthetic methodologies described herein are intended to illustrate the chemistry applicable by the use of the specific examples and do not represent the scope of this disclosure.

[1479] Examples 1-2 Scheme 1: Synthesis of 5-chloro-2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.1) and 5-chloro-2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.2) TIFF2026534467000055.tif72170

[1480] Synthesis of 4-bromo-2-fluoro-6-methoxybenzonitrile (2)

[1481] To a stirred solution of compound 1 (50 g, 229.35 mmol) in MeOH (500 mL), NaOMe (14.86 g, 275.22 mmol) was added, and the reaction mixture was stirred at 0°C for 2 hours. 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 to obtain title compound 2 (55 g) as a yellow solid. LC-MS calculated value of C8H5BrFNO: 228.95; measured value: 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 a steel cylinder, triethylamine (1.58 mL, 11.303 mmol) was added and the mixture was purged with nitrogen for 5 minutes. Palladium(II) acetate (634 mg, 2.823 mmol) and DPPP (1,3-bis(diphenylphosphino)propane) (2.33 g, 5.59 mmol) were added, and the reaction mixture was heated at 80°C for 16 hours in the presence of CO gas (110 psi). After completion (monitored by TLC), the mixture was cooled to room temperature and filtered through a Celite bed. The filtrate was concentrated under vacuum and purified by combiflash chromatography using 14% HCl / hexane to obtain methyl 4-cyano-3-fluoro-5-methoxy-benzoate 3 (10 g, 47.81%) as a white solid. TLC: 20% HCl / heptane (R f :0.5).LCMS calculated value of C10H8FNO3: 209.05; measured value: 210.0 (M+1).

[1484] Synthesis of 2-fluoro-4-(hydroxymethyl)-6-methoxybenzonitrile (4)

[1485] Compound 3 (10 g, 47.80 mmol) from THF (600 mL) was added dropwise to a stirred solution of LiBH4 (2.08 g, 95.611 mmol) in THF (100 mL) at 0°C. The reaction mixture was stirred at 80°C for 4 hours. After completion (monitored by TLC), the mixture was cooled to room temperature, quenched with ice water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the title compound 4 (6 g, 69.27%) as a white solid. TLC: 50% siRNA / heptane(R f :0.25). LCMS calculated value of C9H8FNO2: 181.05; measured value: 182.0 (M+1).

[1486] Synthesis of 4-(bromomethyl)-2-fluoro-6-methoxybenzonitrile (5)

[1487] Compound 4 (7 g, 38.637 mmol) was added to a stirred solution in ACN (70 mL) with PPh3 (16.82 g, 64.138 mmol), followed by Br2 (3.08 mL, 64.137 mmol) at 0°C. The reaction mixture was stirred at 60°C for 2 hours. After completion (monitored by TLC), the mixture was quenched with sodium thiosulfate (110 mL) and extracted with HCl (3 × 60 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by combiflash chromatography (15% HCl in heptane) to obtain the title compound 5 (4 g, 16.389 mmol, 42.46%) as a white solid. TLC: 30% HCl / heptane (R f :0.6). LCMS calculated value of C9H7BrFNO: 242.97; measured value: 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), DIPEA (2.146 mL, 12.292 mmol) was added, 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 hours. 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 Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography using a gradient method of 0-50% siRNA / heptane to obtain the title compound 6 (1.0 g, 48.65%, isolated as an inseparable mixture positional isomer) as a yellow solid. TLC: 80% siRNA / heptane (Rf :0.45).C 19 H 21 LCMS calculated value for FN4O3: 372.16; measured value: 373.40 (M+1).

[1490] Synthesis of tert-butyl 1-((3-amino-4-methoxybenzo[d]isoxazole-6-yl)methyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate and tert-butyl 2-((3-amino-4-methoxybenzo[d]isoxazole-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (7)

[1491] To a stirred solution of compound 6 (a mixture of positional isomers) (0.50 g, 1.34 mmol) in DMF (7 mL), acetohydroxamic acid (0.31 g, 4.02 mmol) was added, followed by K2CO3 (0.56 g, 4.02 mmol). The reaction mixture was stirred at 65°C for 16 hours. 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 was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel (100-200 mesh) column chromatography using a gradient method of 0-50% HCl / heptane to obtain the title compound 7 (a mixture of isomers) (0.20 g, 38.64%, isolated as an inseparable mixture of positional isomers) as a grayish-white solid. TLC: 70% HCl / heptane (R f :0.40).C 19 H 23 LCMS calculated value for N5O4: 385.42; measured value: 386.00 (M+1). 1 The 1H NMR spectrum is complex and shows a mixture of positional isomers.

[1492] Synthesis of tert-butyl 1-((3-((5-chloro-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate and tert-butyl 2-((3-((5-chloro-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (8)

[1493] Compound 7 (0.75 g, 1.945 mmol) was added to a stirred solution in THF (20 mL) with a 1 M solution of KOtBu in THF (5.8 mL, 5.838 mmol) at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, 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 16 hours. After completion (monitored by TLC), the mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography using 50-60% EA in heptane to obtain the title compound 8 (mixture of positional isomers) (0.50 g, 43.55%) as a grayish-white solid. TLC: 50% ethyl acetate / heptane (R f :0.5). Calculated value of C26H28ClN5O7S in LCMS: 589.14; Measured value: 590.20 (M+1).

[1494] Synthesis of 5-chloro-N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-2-methoxybenzenesulfonamide hydrochloride and 5-chloro-N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-2-methoxybenzenesulfonamide hydrochloride (9)

[1495] To a stirred solution of compound 8 (0.50 g, 0.8475 mmol) in DCM (10 mL), 4 M HCl in 1,4-dioxane (5 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 4 hours. After completion (monitored by TLC), the mixture was concentrated under reduced pressure. The residue was washed with Et2O and dried under reduced pressure to obtain the title compound 9 (a mixture of positional isomers) (0.42 g, 94.17%) as a grayish-white solid. TLC: 10% MeOH / DCM(R f :0.3). LCMS value of C21H20ClN5O5S: Calculated value: 489.09; Measured value: 490.10 (M+1).

[1496] Synthesis of 5-chloro-2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.1) and 5-chloro-2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.2)

[1497] To a stirred solution of compound 9 (0.20 g, 0.379 mmol) in DMF (5 mL), propiolic acid (0.032 g, 0.455 mmol), DIPEA (0.198 mL, 1.137 mmol), and a 50% solution of T3P in ethyl acetate (0.36 g, 1.139 mmol) were added at 0°C under an N2 atmosphere. The reaction mixture was stirred at room temperature for 2 hours. 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, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash column chromatography using 5% MeOH in DCM to obtain a mixture of positional isomers, which was further purified by chiral HPLC to obtain 5-chloro-2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.1; 35 mg, 16.15%) as a grayish-white solid, and 5-chloro-2-methoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.2; 15 mg, 7.28%) as a grayish-white solid. TLC: 10% MeOH / DCM(R f :0.3), (See Table 1 for analysis data).

[1498] Example 3 Scheme 2: Synthesis of 2-methoxy-N-(4-methoxy-6-((5-propionyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.3) TIFF2026534467000056.tif71170

[1499] Synthesis of tert-butyl 1-((4-methoxy-3-((2-methoxyphenyl)sulfonamide)benzo[d]isoxazole-6-yl)methyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate and tert-butyl 2-((4-methoxy-3-((2-methoxyphenyl)sulfonamide)benzo[d]isoxazole-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), add 2-methoxybenzenesulfonyl chloride (0.320 g, 1.55 mmol) and NaO t Pn (0.428 g, 3.89 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. 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 combiflush using a gradient of 70-80% ethyl acetate to obtain title compound 10 (mixture of positional isomers) (310 mg, 71.75%) as a brown solid. TLC: 5% MeOH / DCM(R f :0.6).C 26 H 29 LCMS calculated value for N5O7S: 555.18; measured value: 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]pyrazole-1(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide and 2-methoxy-N-(4-methoxy-6-((5-(2,2,2-trifluoroacetyl)-5,6-dihydro-5l4-pyrrolo[3,4-c]pyrazole-2(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (11)

[1502] To a stirred solution of compound 10 (mixture of positional isomers) (0.4 g, 0.68 mmol) in DCM (4 mL), TFA (0.52 mL, 6.83 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure, polished with ether, and dried under vacuum to obtain the title compound 11 (mixture of positional isomers) (410 mg, crude) as a brown solid. TLC: 10% MeOH / DCM(R f :0.5).LCMS calculated value of C21H21N5O5S:455.13:Measured value:454.3(M-1).

[1503] Synthesis of 2-Methoxy-N-(4-Methoxy-6-((5-propionyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.3)

[1504] To a stirred solution of compound 11 (260 mg, 0.570 mmol) in DMF (3 mL), propionic acid (63 mg, 0.856 mmol), DIPEA (0.398 mL, 2.28 mmol), and a 50% solution of T3P in ethyl acetate (0.867 mL, 1.141 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC), the mixture was quenched with ice-cold water and extracted with ethyl acetate (2 x 50 mL). The organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure. The crude product was polished with Et2O and purified by chiral HPLC, yielding 2-methoxy-N-(4-methoxy-6-((5-propionyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.3; 50 mg, 17.18%) as a grayish-white solid. Other positional isomers were not isolated from the mixture in their pure form. TLC: 5% MeOH / DCM(R f :0.4). (See Table 1 for analysis data)

[1505] Examples 4-5 Scheme 3: Synthesis of 2,5-dimethoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.4) and 2,5-dimethoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.5) TIFF2026534467000057.tif68170

[1506] Synthesis of tert-butyl 1-((3-((2,5-dimethoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate and tert-butyl 2-((3-((2,5-dimethoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (12)

[1507] A stirred solution of compound 7 (a mixture of positional isomers) (750 mg, 1.945 mmol) in THF (20 mL) was mixed with KO in THF. t A 1M solution of Bu (5.8 mL, 5.837 mmol) was added at 0°C. The reaction mixture was stirred for 10 minutes, after which 2,5-dimethoxybenzenesulfonyl chloride (0.69 g, 2.917 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. 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 product was purified by combiflash column chromatography using 80-90% EA / heptane to obtain the title compound 12 (mixture of positional isomers) (450 mg, 39.50%) as a grayish-white solid. TLC: 50% EA / heptane (R f:0.5). LCMS calculated value of C27H31N5O8S: 585.19; measured value: 586.2 (M+H).

[1508] Synthesis of N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-2,5-dimethoxybenzenesulfonamide hydrochloride and N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-2,5-dimethoxybenzenesulfonamide hydrochloride (13)

[1509] To a stirred solution of compound 12 (450 mg, 0.768 mmol) in DCM (5 mL), 4 M HCl (4 mL) in 1,4-dioxane was added at 0°C. The reaction mixture was stirred at room temperature for 4 hours. After completion (monitored by TLC), the mixture was concentrated under vacuum. The residue was washed with diethyl ether and dried under vacuum to obtain the title compound 13 (a mixture of positional isomers) (350 mg, 87.28%) as a grayish-white solid (HCl salt). TLC: 10% MeOH / DCM(R f :0.2).LCMS calculated value of C22H23N5O6S: 485.14; measured value: 486.30 (M+1).

[1510] Synthesis of 2,5-dimethoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.4) and 2,5-dimethoxy-N-(4-methoxy-6-((5-propioloyl-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.5)

[1511] To a stirred solution of compound 13 (200 mg, 0.383 mmol) in DMF (5 mL), DIPEA (0.2 mL, 1.149 mmol), propiolic acid (32 mg, 0.459 mmol), and a 50% solution of T3P in toluene (0.87 mL, 1.149 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. 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 product was washed with diethyl ether to obtain a mixture of positional isomers, which was further purified by chiral HPLC to obtain 2,5-dimethoxy-N-(4-methoxy-6((5-propioloyl5,6dihydropyrrolo[3,4c]pyrazole-1(4H)yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.4; 35 mg, 15.02%) as a grayish-white solid, and 2,5-dimethoxy-N-(4-methoxy-6-((5-propioloyl5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.5; 15 mg) as a grayish-white solid. TLC: 10% MeOH / DCM(R f :0.4). (See Table 1 for analysis data).

[1512] Examples 6-7 Scheme 4: Synthesis of 2-methoxy-N-(4-methoxy-6-((4-(methylsulfonamidemethyl)-1H-pyrazole-1-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.6) and synthesis of methyl((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamide)benzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)carbamate (Syn.Ex.7) TIFF2026534467000058.tif144170

[1513] Synthesis of tert-butyl((1H-pyrazole-4-yl)methyl)carbamate (19)

[1514] To a stirred solution of compound 18 (5 g, 53.711 mmol) in methanol (400 mL), NiCl2.6H2O (5.01 g, 38.671 mmol) was added, followed by sodium borohydride (21.00 g, 549.5 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours, after which di-tert-butyl dicarbonate (24 mL, 107.422 mmol) was added. The mixture was stirred at room temperature for 48 hours. After completion (monitored by TLC), the mixture was quenched with H2O (50 mL) and evaporated under reduced pressure. The aqueous layer was extracted with ELISA (5 × 30 mL). The combined organic layers were filtered through a Celite pad, dried over anhydrous Na2SO4, and concentrated under vacuum to obtain the title compound 19 (2.5 g, 24%) as a blue solid. TLC: 5% MeOH / DCM(R f :0.30). LC-MS calculated value of C9H15N3O2: 197.12; measured value: 198.20 (M+1).

[1515] Synthesis of tert-butyl((1-(4-cyano-3-fluoro-5-methoxybenzyl)-1H-pyrazole-4-yl)methyl)carbamate (14)

[1516] To a stirred solution of compound 5 (15 g, 61.460 mmol) in DMF (15 mL), DIPEA (21.46 mL, 122.92 mmol) and compound 19 (14.54 g, 73.752 mmol) were added at room temperature. The resulting reaction mixture was heated at 70 °C for 12 hours. After completion (monitored by TLC), the mixture was cooled to room temperature, quenched with ice 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 combiflash chromatography using a gradient method of 40–70% HCl / heptane to obtain the title compound 14 (12 g, 33.30%) as a colorless semi-solid. TLC: 60% HCl / heptane (R f :0.45).C 18 H 21 LCMS calculated value for FN4O3: 360.39; measured value: 361.00 (M+1).

[1517] Synthesis of tert-butyl((1-((3-amino-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)carbamate (15)

[1518] To a stirred solution of compound 14 (0.2 g, 0.55 mmol) (6:1 mixture DMF:H2O (7 mL)), acetohydroxamic acid (0.112 g, 1.50 mmol) and K2CO3 (0.414 g, 3.0 mmol) were added at room temperature. The reaction mixture was stirred at 60 °C for 16 hours. After completion (monitored by TLC), the mixture was cooled to room temperature, quenched with ice 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 combiflash chromatography using a gradient method of 40-60% siRNA / heptane to obtain the title compound 15 (0.1 g, 48.25%) as a brown semi-solid. TLC: 80% siRNA / heptane (R f :0.40).C 18 H 23 LCMS calculated value for N5O4: 373.41; measured value: 374.05 (M+1).

[1519] Synthetic tert-butyl((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamide)benzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)carbamate(16)

[1520] To a stirred solution of compound 15 (0.45 g, 1.20 mmol) in THF (5 mL), add 2-methoxybenzenesulfonyl chloride (0.49 g, 2.41 mmol), followed by NaO tPn (0.396 g, 3.60 mmol) was added. The resulting reaction mixture was stirred at 60°C for 16 hours. 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 combiflash chromatography using a gradient method of 60-80% ethyl acetate / heptane to obtain the title compound 16 (0.130 g, 19.9%) as a brown, rubbery solid. TLC: 5% MeOH / DCM(R f :0.6).C 25 H 29 LCMS calculated value for N5O7S: 543.60; measured value: 542.1 (M-1).

[1521] Synthesis of N-(6-((4-(aminomethyl)-1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-2-methoxybenzenesulfonamide hydrochloride (17)

[1522] Compound 16 (0.13 g, 0.239 mmol) was stirred in DCM (3 mL), to which 4 M HCl (0.5 mL, 2.39 mmol) in 1,4-dioxane was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After completion (monitoring by TLC), the reaction mixture was concentrated under reduced pressure to obtain the title compound 17 (0.1 g, 94.3% HCl salt) as a brown semi-solid. TLC: 10% MeOH / DCM(R f :0.5). LCMS calculated value of C20H22ClN5O5S: 479.10: Measured value: 442.4 (M-1).

[1523] Synthesis of 2-Methoxy-N-(4-Methoxy-6-((4-(methylsulfonamidemethyl)-1H-pyrazole-1-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.6)

[1524] To a stirred solution of compound 17 (0.13 g, 0.270 mmol) in DCM (5 mL), Et3N (0.11 mL, 0.812 mmol) was added at 0°C, followed by MsCl (0.037 g, 0.324 mmol) in DCM (1 mL). The reaction mixture was stirred at 0°C for 1 hour. 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. Purification of the crude product by preparative HPLC yielded the title compound 2-methoxy-N-(4-methoxy-6-((4-(methylsulfonamidemethyl)-1H-pyrazole-1-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.6; 30 mg, 21.24%) as a grayish-white solid. TLC: 40% Â / heptane(R f :0.5). (See Table 1 for analysis data).

[1525] Synthesis of methyl((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamide)benzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)carbamate (Syn.Ex.7)

[1526] To a solution of compound 17 (0.12 g, 0.250 mmol) in DCM (10 mL), Et3N (0.1 mL, 0.750 mmol) was added, 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 minutes. 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. Purification of the crude product by preparative HPLC yielded the title compound methyl((1-((4-methoxy-3-((2-methoxyphenyl)sulfonamide)benzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)carbamate (Syn.Ex.7; 25 mg, 20%) as a grayish-white solid. TLC: 50% Â / heptane(R f :0.5). (See Table 1 for analysis data).

[1527] Example 8 Scheme 5: Synthesis of N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)acetamide (Syn.Ex.8) TIFF2026534467000059.tif68170

[1528] Synthesis of tert-butyl((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)carbamate (20)

[1529] To a stirred solution of compound 15 (0.150 g, 0.401 mmol) in THF (3 mL), a 1 M solution of tBuOK in THF (1.2 mL, 1.20 mmol), followed by 5-ethyl-2-methoxybenzenesulfonyl chloride (185 mg, 0.898 mmol), was added at 0°C. The reaction mixture was stirred at 0°C for 3 hours. 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 product was purified by combiflash column chromatography using a gradient method of 40-60% Â / heptane to obtain the title compound 20 (130 mg, 56.76%) as a grayish-white solid. TLC: 80% ₹ / heptane (Rf: 0.35). LC-MS calculated value of C27H33N5O7S: 571.21; measured value: 572.03 (M+1).

[1530] Synthesis of N-(6-((4-(aminomethyl)-1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-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), 4 M HCl in 1,4-dioxane (2 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC), the mixture was evaporated under reduced pressure. The crude product was polished with DCM / heptane to obtain the title compound 21 (100 mg, salt) as a grayish-white solid. TLC: 5% MeOH / DCM (Rf: 0.3). LC-MS calculated value of C22H25N5O5S: 471.16; measured value: 472.30.

[1532] Synthesis of N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)acetamide (Syn.Ex.8)

[1533] To a stirred solution of compound 21 (100 mg, 0.196 mmol) in DCM (3 mL), triethylamine (0.082 mL, 0.590 mmol) was added at 0°C. The reaction mixture was stirred for 10 minutes, after which Ac2O (0.022 mL, 0.235 mmol) in DCM (1 mL) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. 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 obtain the crude product. The crude product was purified by preparative HPLC to obtain N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)acetamide (Syn.Ex.8; 45 mg, 44.55%) as a grayish-white solid. TLC: 10% MeOH / DCM(R) f :0.5). (See Table 1 for analysis data).

[1534] Example 9 Scheme 6: Synthesis of 5-ethyl-2-methoxy-N-(4-methoxy-6-((6-propioloyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepine-1(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.9) TIFF2026534467000060.tif64170

[1535] Synthesis of tert-butyl 1-(4-cyano-3-fluoro-5-methoxybenzyl)-4,5,7,8-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), DIPEA (1.6 mL, 9.219 mmol) was added, 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 hours. After completion (monitored by TLC), the mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound 22 (1.2 g, crude) as a brown liquid. TLC: 40% siRNA / heptane(R) f :0.4).LCMS calculated value of C21H25FN4O3: 400.19; measured value: 400.30

[1537] Synthesis of tert-butyl 1-((3-amino-4-methoxybenzo[d]isoxazole-6-yl)methyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(1H)-carboxylate and tert-butyl 2-((3-amino-4-methoxybenzo[d]isoxazole-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 DMF:H2O mixture (48 mL, 6:1 ratio), K2CO3 (2.48 g, 17.979 mmol) and N-hydroxyacetamide (0.674 g, 8.988 mmol) were added. The reaction mixture was stirred at 70°C for 16 hours. 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 obtain the title compound 23 (750 mg, 60.53%) as a yellow solid. TLC: 40% siRNA / heptane(R) f :0.4). LCMS calculated value of C21H27N5O4: 413.21; measured value: 414.5 (M+1).

[1539] Synthesis of tert-butyl 1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(1H)-carboxylate and tert-butyl 2-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (24)

[1540] Mixing solution of compound 23 (750 mg, 1.813 mmol) in THF (8 mL) with NaO t Bu (0.87 g, 9.069 mmol), followed by 5-ethyl-2-methoxybenzenesulfonyl chloride (0.510 g, 2.175 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. 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 obtain the title compound 24 (1.1 g, 99.18%) as a brown, rubbery oil. The crude product was not further purified before proceeding to the next step. TLC: 40% toluene / heptane(R f:0.4). LCMS calculated value of C30H37N5O7S: 611.24; measured value: 612.5 (M+1).

[1541] Synthesis of 5-ethyl-2-methoxy-N-(4-methoxy-6-((5,6,7,8-tetrahydropyrazolo[3,4-d]azepine-1(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide hydrochloride and 5-ethyl-2-methoxy-N-(4-methoxy-6-((5,6,7,8-tetrahydropyrazolo[3,4-d]azepine-2(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide hydrochloride (25)

[1542] To a solution of compound 24 (1.0 g, 1.63 mmol) in DCM (10 mL), 4 M HCl (5 mL) in 1,4-dioxane was added at 0°C, and the reaction mixture was stirred at room temperature for 4 hours. After completion (the reaction was monitored by TLC), the mixture was concentrated under reduced pressure. The residue was washed three times with diethyl ether and dried under vacuum to obtain the title compound 25 (750 mg, HCl salt) as a grayish-white solid. The crude product was carried to the next reaction. This was not further purified before proceeding to the next step. TLC: 40% HCl / heptane (R f :0.4). LCMS calculated value of C25H29N5O5S: 511.19; measured value: 512.30.

[1543] Synthesis of 5-ethyl-2-methoxy-N-(4-methoxy-6-((6-propioloyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepine-1(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.9)

[1544] Compound 25 (0.750 g, 1.368 mmol) and propa-2-ic acid (0.143 g, 2.052 mmol) were stirred in DMF (7.5 mL), to which DIPEA (0.716 mL, 4.104 mmol) and a 50% solution of T3P in toluene (5.22 mL, 8.208 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. 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 product was purified by combiflash chromatography (5% MeOH in DCM) followed by preparative HPLC to obtain the desired compound as a mixture of positional isomers. By subjecting this mixture to preparative SFC, the desired positional isomer (Syn.Ex.9) was obtained, yielding 5-ethyl-2-methoxy-N-(4-methoxy-6-((6-propioloyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepine-1(4H)-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.9; 55 mg, 7.13%) as a grayish-white solid. No other positional isomers were isolated. TLC: 10% MeOH / DCM(R f :0.5). (See the analysis data in Table 1).

[1545] Example 10 Scheme 7: Synthesis of 2,4-dimethoxy-N-(4-methoxy-6-((4-(methylsulfonamidemethyl)-1H-pyrazole-1-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.10) TIFF2026534467000061.tif60170

[1546] Synthesis of tert-butyl((1-((3-((2,4-dimethoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)carbamate (26)

[1547] Mixed solution of compound 15 (500 mg, 1.339 mmol) in THF (15 mL)t A 1M solution of Bu (4 mL, 4.017 mmol) was added at 0°C. The reaction mixture was stirred at 0°C for 10 minutes, followed by the addition of 2,4-dimethoxybenzenesulfonyl chloride (0.475 g, 2.008 mmol) in THF (1 mL). The reaction mixture was stirred at room temperature for 16 hours. 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 product was purified by combiflash chromatography using a (neutral alumina) gradient of 30-50% EA / heptane to obtain the title compound 26 (140 mg, 18.22%) as a pale yellow solid. TLC: 10% MeOH / DCM(R f :0.6).C 26 H 31 LCMS calculated value for N5O8S: 573.62; measured value: 574.06 (M+1).

[1548] Synthesis of N-(6-((4-(aminomethyl)-1H-pyrazole-1-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-2,4-dimethoxybenzenesulfonamide hydrochloride (27)

[1549] To a stirred solution of compound 26 (140 mg, 0.274 mmol) in DCM (3 mL), 4 M HCl (2 mL) in 1,4-dioxane was added at 0°C. The reaction mixture was stirred at room temperature for 4 hours. After completion (monitoring by TLC), the mixture was concentrated under reduced pressure. Washing the residue with diethyl ether yielded title compound 27 (110 mg, 74.24%) as a grayish-white solid (HCl salt). TLC: 10% MeOH / DCM(R f :0.6). LCMS calculated value of C21H23N5O6S: 473.14; measured value: 474.20.

[1550] Synthesis of 2,4-dimethoxy-N-(4-methoxy-6-((4-(methylsulfonamidemethyl)-1H-pyrazole-1-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.10)

[1551] To a stirred solution of compound 27 (110 mg, 0.2157 mmol) in DCM (3 mL), triethylamine (0.09 mL, 0.647 mmol) was added, followed by methanesulfonyl chloride (0.029 g, 0.2588 mmol) in DCM (1 mL) at 0°C. The reaction mixture was stirred at room temperature for 15 minutes. 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. Purification of the crude product by preparative HPLC yielded 2,4-dimethoxy-N-(4-methoxy-6-((4-(methylsulfonamidemethyl)-1H-pyrazole-1-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.10; 29 mg, 24.57%) as a grayish-white solid. TLC: 10% MeOH / DCM(R f :0.5). (See Table 1 for analysis data).

[1552] Examples 11-13 Scheme 8: N-(6-((5-(buta-2-inoyl)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide (Syn.Ex.11), N-(6-((5-(buta-2-inoyl)-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)methyl)-4- Synthesis of methoxybenzo[d]isoxazole-3-yl)-5-ethyl-2-methoxybenzenesulfonamide (Syn.Ex.12) and 5-ethyl-N-(6-((5-(2-fluoroacryloyl)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-2-methoxybenzenesulfonamide (Syn.Ex.13) TIFF2026534467000062.tif98170

[1553] Synthesis of tert-butyl 1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate and tert-butyl 2-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (28)

[1554] Mixing solution of compound 15 (mixture of isomers) (1.3 g, 3.372 mmol) in THF (20 mL) with NaO t Pn (2.22 g, 20.237 mmol), followed by 5-ethyl-2-methoxybenzenesulfonyl chloride (1.58 g, 6.744 mmol), was added at 0°C. The reaction mixture was stirred at 60°C for 16 hours. 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 product was purified by combiflush using a gradient method of 20-60% ethyl acetate / heptane to obtain the title compound 28 (mixture of isomers) (1.0 g, 51.02%) as a pale yellow solid. TLC: 100% ethyl acetate (R f :0.5). LCMS calculated value of C28H33N5O7S: 583.21; measured value: 584.5 (M+1).

[1555] Synthesis of N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide hydrochloride and N-(6-((5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide hydrochloride (29)

[1556] Compound 28 (mixture of isomers) (1 g, 1.713 mmol) was stirred in DCM (5 mL) and 4 M HCl in 1,4-dioxane (4.28 mL, 17.133 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC), the mixture was concentrated under reduced pressure and polished with Et2O to obtain the title compound 29 (mixture of isomers) (750 mg, HCl salt) as a rubbery grayish-white solid. TLC: 5% MeOH / DCM(R f :0.2). LCMS calculated value of C23H25N5O5S: 483.16; measured value: 484.20.

[1557] Synthesis of N-(6-((5-(buta-2-inoyl)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazol-3-yl)-5-ethyl-2-methoxybenzenesulfonamide (Syn.Ex.11) and N-(6-((5-(buta-2-inoyl)-5,6-dihydropyrrolo[3,4-c]pyrazole-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 (a mixture of isomers) (350 mg, 0.673 mmol) in DMF (3 mL), DIPEA (0.352 mL, 2.019 mmol), buta-2-ic acid (67 mg, 0.807 mmol), and subsequently a 50% solution of T3P in  (1.28 mL, 2.019 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by TLC), the mixture was concentrated under reduced pressure. Purification of the crude product by chiral HPLC yielded two isomers: N-(6-((5-(buta-2-inoyl)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-5-ethyl-2-methoxybenzenesulfonamide (Syn.Ex.11; 45 mg, 11.31%) as a grayish-white solid, and N-(6-((5-(buta-2-inoyl)-5,6-dihydropyrrolo[3,4-c]pyrazole-2(4H)-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-5-ethyl-2-methoxybenzenesulfonamide (Syn.Ex.12; 14 mg, yield 5.31%) as a grayish-white solid. TLC: 5% MeOH / DCM(R f :0.5). (See Table 1 for analysis data).

[1559] Synthesis of 5-ethyl-N-(6-((5-(2-fluoroacryloyl)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-2-methoxybenzenesulfonamide (Syn.Ex.13)

[1560] To a stirred solution of compound 29 (a mixture of isomers) (200 mg, 0.384 mmol) in DMF (3 mL), DIPEA (0.2 mL, 1.153 mmol), 2-fluoroacrylic acid (41 mg, 0.460 mmol), and subsequently a 50% solution of T3P in ¼ (0.733 mL, 1.153 mmol) were added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After completion (monitored by TLC), the reaction mixture was concentrated under reduced pressure. Purification of the crude product by chiral HPLC yielded the title compound N-(6-((5-(buta-2-inoyl)-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-yl)methyl)-4-methoxybenzo[d]isoxazole-3-yl)-5-ethyl-2-methoxybenzenesulfonamide (Syn.Ex.13; 15 mg, yield 6.52%) as a grayish-white solid. TLC: 5% MeOH / DCM(R f :0.5) (See Table 1 for analytical data). No other isomers were isolated.

[1561] Examples 14-18 Scheme 9: N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)-2-fluoroacrylamide (Syn.Ex.14), N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)buta-2-inamide (Syn.Ex.15), ethyl((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d ]Isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)carbamate (Syn.Ex.16), methyl((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)carbamate (Syn.Ex.17) and 5-ethyl-2-methoxy-N-(4-methoxy-6-((4-(((2-methoxyethyl)sulfonamide)methyl)-1H-pyrazole-1-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.18) TIFF2026534467000063.tif141170

[1562] Synthesis of N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)-2-fluoroacrylamide (Syn.Ex.14)

[1563] 2-fluoroacrylic acid (0.042 g, 0.472 mmol) and DIPEA (0.20 mL, 1.181 mmol) were added at 0°C to a stirred solution of compound 21 (0.12 g, 0.236 mmol) in DMF (2 mL). The reaction mixture was stirred at 0°C for 10 minutes, after which a 50% solution of T3P in ethyl acetate (0.375 mL, 0.590 mmol) was added at 0°C. The mixture was stirred at room temperature for 3 hours. 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. Purification of the crude product by preparative HPLC yielded the title compound N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)-2-fluoroacrylamide (Syn.Ex.14; 3.8 mg, 2.96%) as a grayish-white solid. (See Table 1 for analytical data).

[1564] Synthesis of N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)buta-2-inamide (Syn.Ex.15)

[1565] To a stirred solution of compound 21 (0.12 g, 0.236 mmol) in DMF (2 mL), buta-2-ic acid (0.039 g, 0.472 mmol) and DIPEA (0.20 g, 1.181 mmol) were added at 0°C. After stirring the reaction mixture for 10 minutes, a 50% solution of T3P in ethyl acetate (0.36 mL, 0.590 mmol) was added at 0°C. The mixture was stirred at room temperature for 3 hours. 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. Purification of the crude product by preparative HPLC yielded the title compound N-((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)buta-2-inamide (Syn.Ex.15; 5.4 mg, 4.28%) as a grayish-white solid. (See Table 1 for analytical data.)

[1566] Synthesis of ethyl((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)carbamate (Syn.Ex.16)

[1567] To a stirred solution of compound 21 (150 mg, 0.295 mmol) in DCM (2 mL), TEA (0.12 mL, 0.885 mmol) was added, followed by ethyl chloroformate (48 mg, 0.442 mmol) in DCM (1 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After completion (monitored by TLC and LCMS), the mixture was quenched with ice water (20 mL) and extracted with DCM (30 mL x 3). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC to obtain ethyl ((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)carbamate (Syn.Ex.16; 14 mg, 8.75%) as a grayish-white solid. (See Table 1 for analysis data).

[1568] Synthesis of methyl((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)carbamate (Syn.Ex.17)

[1569] To a stirred solution of compound 21 (120 mg, 0.236 mmol) in DCM (2 mL), TEA (0.09 mL, 0.708 mmol) was added, followed by methyl chloroformate (26 mg, 0.283 mmol) in DCM (1 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After completion (monitored by TLC and LCMS), the reaction mixture was quenched with ice-cold water (30 mL) and extracted with ethyl acetate (100 mL x 2). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC to obtain methyl ((1-((3-((5-ethyl-2-methoxyphenyl)sulfonamide)-4-methoxybenzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)carbamate (Syn.Ex.17; 9 mg, 6.834%) as a grayish-white solid. (See Table 1 for analysis data).

[1570] Synthesis of 5-ethyl-2-methoxy-N-(4-methoxy-6-((4-(((2-methoxyethyl)sulfonamide)methyl)-1H-pyrazole-1-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.18)

[1571] To a stirred solution of compound 21 (120 mg, 0.236 mmol) in DCM (2 mL), TEA (0.09 mL, 0.708 mmol), followed by 2-methoxyethane-1-sulfonyl chloride (44 mg, 0.283 mmol) in DCM (1 mL), was added at 0°C. The reaction mixture was stirred at 0°C to room temperature for 16 hours. After completion (monitored by TLC and LCMS), the mixture was quenched with 1N HCl (10 mL) and extracted with  (2 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. Purification of the crude product by preparative HPLC yielded 5-ethyl-2-methoxy-N-(4-methoxy-6-((4-(((2-methoxyethyl)sulfonamide)methyl)-1H-pyrazole-1-yl)methyl)benzo[d]isoxazole-3-yl)benzenesulfonamide (Syn.Ex.18; 4.5 mg, 3.04%) as a grayish-white solid. (See Table 1 for analytical data).

[1572] Examples 19-20 Scheme 10: Synthesis of N-((1-((4-methoxy-3-((2-methoxy-4,5-dimethylphenyl)sulfonamide)benzo[d]isoxazole-6-yl)methyl)-1H-pyrazole-4-yl)methyl)propioluamide (Syn.Ex.19)...

Claims

1. Formula I: A compound or a pharmaceutically acceptable derivative thereof, wherein the formula is: a is between 0 and 2; R １ and R ２ They combine to form alkylenes; R ３ is -O-(CH ２ ) ｂ -R ８ And; b is 1 to 4; R ８ is H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ９ R １０ , C(O)R １１ , C(=NH)(R １２ ) or C(=N-O-R ９ )(R １２ ); R ９ and R １０ These are, independently, H, alkyl, or C(O)R. １３ And; in the formula, R １３ is alkyl, alkoxy or NR １４ R １５ And; R １１ is hydroxy, alkyl, alkoxy or NR １４ R １５ And; R １２ is alkyl or NR １４ R １５ And; R １４ and R １５ Each of these elements independently forms a heterocycline, either as H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded; R ４ is H or alkoxy; Z １ Z ２ and Z ３ The following options are selected: (i), (ii), or (iii): (i) Z １ is N, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N. (ii) Z １ is NH or O, Z ２ and Z ３ is C, or (iii) Z １ CH is, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N; Z ４ Z ５ and Z ６ The following options are selected: (i), (ii), (iii), or (iv): (i) Z ４ is N, Z ５ CR ５ Z ６ CH is (ii) Z ４ CR １６ Z ５ is N, Z ６ CH is (iii) Z ４ CR １６ Z ５ CR ５ Z ６ is N, or (iv) Z ４ CR １６ Z ５ CR ５ Z ６ is CH; R ５ and R １６ The following is selected from (i) or (ii): (i) R ５ and R １６ Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl, (ii) R ５ and R １６ They combine to form alkylenes or heteroalkylenes; X is O, S(O) ｘ or CH ２ And in the formula, x is between 0 and 2; Het and R ６ The following is selected from (i) or (ii): (i) Het is a 5-membered or 6-membered heteroaryl, R ６ is H, alkyl or haloalkyl, or (ii) Het is a 5-membered or 6-membered heteroaryl, R ６ ha- (CH ２ ) １－２ - and R ６ And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems; R ７ is -C(O)R １７ , -S(O)R １８ or -SO ２ R １８ And; R １７ is 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-(CH ２ ) ２ -R １９ , -O-(CH ２ ) ２ -R １９ or -NR ２０ R ２１ ; wherein R １９ is -OR ９ or -NR ９ R １０ , and R ２０ and R ２１ are each independently H, alkyl, cycloalkyl or haloalkyl; R １８ Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl or -NR ２０ R ２１ A compound or a pharmaceutically acceptable derivative thereof.

2. Formula I: A compound or a pharmaceutically acceptable derivative thereof, wherein the formula is: a is between 0 and 2; R １ and R ２ The following is selected from (i) or (ii): (i) R １ is H, alkyl, haloalkyl or halo; and R ２ is alkyl, cycloalkyl or haloalkyl, or (ii) R １ and R ２ They combine to form alkylenes; R ３ is -O-(CH ２ ) ｂ -R ８ And; b is 1 to 4; R ８ H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ９ R １０ , C(O)R １１ , C (=NH) (R １２ ) or C (= N-O-R ９ ) (Caution １２ ) and; R ９ and R １０ These are, independently, H, alkyl, or C(O)R. １３ And; in the formula, R １３ is alkyl, alkoxy or NR １４ R １５ And; R １１ is hydroxy, alkyl, alkoxy or NR １４ R １５ And; R １２ is alkyl or NR １４ R １５ And; R １４ and R １５ Each of these elements independently forms a heterocycline, either as H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded; R ４ is H or alkoxy; Z １ Z ２ and Z ３ The following options are selected: (i), (ii), or (iii): (i) Z １ is N, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N. (ii) Z １ is NH or O, Z ２ and Z ３ is C, or (iii) Z １ CH is, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N; Z ４ CR １６ And; Z ５ CR ５ And; Z ６ is N or CH; R ５ and R １６ They combine to form alkylenes or heteroalkylenes; X is O, S(O) ｘ or CH ２ And in the formula, x is between 0 and 2; Het and R ６ The following is selected from (i) or (ii): (i) Het is a 5-membered or 6-membered heteroaryl, R ６ is H, alkyl or haloalkyl, or (ii) Het is a 5-membered or 6-membered heteroaryl, R ６ ha- (CH ２ ) １－２ - and R ６ And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems; R ７ is -C(O)R １７ , -S(O)R １８ or -SO ２ R １８ And; R １７ 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-(CH ２ ) ２ -R １９ , -O-(CH ２ ) ２ -R １９ or -NR ２０ R ２１ And; in the formula, R １９ is, -OR ９ or -NR ９ R １０ And R ２０ and R ２１ Each of these is independently H, alkyl, cycloalkyl, or haloalkyl; R １８ Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl or -NR ９ R １０ A compound or a pharmaceutically acceptable derivative thereof.

3. Formula I: A compound or a pharmaceutically acceptable derivative thereof, wherein the formula is: a is between 0 and 2; R １ and R ２ The following is selected from (i) or (ii): (i) R １ is H, alkyl, haloalkyl or halo; and R ２ is alkyl, cycloalkyl or haloalkyl, or (ii) R １ and R ２ They combine to form alkylenes; R ３ is -O-(CH ２ ) ｂ -R ８ And; b is 1 to 4; R ８ H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ９ R １０ , C(O)R １１ , C (=NH) (R １２ ) or C (= N-O-R ９ ) (Caution １２ ) and; R ９ and R １０ These are, independently, H, alkyl, or C(O)R. １３ And; in the formula, R １３ is alkyl, alkoxy or NR １４ R １５ And; R １１ is hydroxy, alkyl, alkoxy or NR １４ R １５ And; R １２ is alkyl or NR １４ R １５ And; R １４ and R １５ Each of these elements independently forms a heterocycline, either as H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded; R ４ is H or alkoxy; Z １ Z ２ and Z ３ The following options are selected: (i), (ii), or (iii): (i) Z １ is N, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N. (ii) Z １ is NH or O, Z ２ and Z ３ is C, or (iii) Z １ CH is, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N; Z ４ Z ５ and Z ６ The following options are selected: (i), (ii), (iii), or (iv): (i) Z ４ is N, Z ５ CR ５ Z ６ CH is (ii) Z ４ CR １６ Z ５ is N, Z ６ CH is (iii) Z ４ CR １６ Z ５ CR ５ Z ６ is N, or (iv) Z ４ CR １６ Z ５ CR ５ Z ６ is CH; R ５ and R １６ The following is selected from (i) or (ii): (i) R ５ and R １６ Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl, (ii) R ５ and R １６ They combine to form alkylenes or heteroalkylenes; X is O or S(O) ｘ And in the formula, x is between 0 and 2; Het and R ６ The following is selected from (i) or (ii): (i) Het is a 5-membered or 6-membered heteroaryl, R ６ is H, alkyl or haloalkyl, or (ii) Het is a 5-membered or 6-membered heteroaryl, R ６ ha- (CH ２ ) １－２ - and R ６ And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems; R ７ is -C(O)R １７ , -S(O)R １８ or -SO ２ R １８ And; R １７ 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-(CH ２ ) ２ -R １９ , -O-(CH ２ ) ２ -R １９ or -NR ２０ R ２１ And; in the formula, R １９ is, -OR ９ or -NR ９ R １０ And R ２０ and R ２１ Each of these is independently H, alkyl, cycloalkyl, or haloalkyl; R １８ Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl or -NR ９ R １０ A compound or a pharmaceutically acceptable derivative thereof.

4. Formula I: A compound or a pharmaceutically acceptable derivative thereof, wherein the formula is: a is between 0 and 2; R １ is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo; R ２ and R ４ They form heteroalkylenes together; R ３ is -O-(CH ２ ) ｂ -R ８ And; b is 1 to 4; R ８ H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ９ R １０ , C(O)R １１ , C (=NH) (R １２ ) or C (= N-O-R ９ ) (Caution １２ ) and; R ９ and R １０ These are, independently, H, alkyl, or C(O)R. １３ And; in the formula, R １３ is alkyl, alkoxy or NR １４ R １５ And; R １１ is hydroxy, alkyl, alkoxy or NR １４ R １５ And; R １２ is alkyl or NR １４ R １５ And; R １４ and R １５ Each of these elements independently forms a heterocycline, either as H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded; Z １ Z ２ and Z ３ The following options are selected: (i), (ii), or (iii): (i) Z １ is N, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N. (ii) Z １ is NH or O, Z ２ and Z ３ is C, or (iii) Z １ CH is, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N; Z ４ Z ５ and Z ６ The following options are selected: (i), (ii), (iii), or (iv): (i) Z ４ is N, Z ５ CR ５ Z ６ CH is (ii) Z ４ CR １６ Z ５ is N, Z ６ CH is (iii) Z ４ CR １６ Z ５ CR ５ Z ６ is N, or (iv) Z ４ CR １６ Z ５ CR ５ Z ６ is CH; R ５ and R １６ The following is selected from (i) or (ii): (i) R ５ and R １６ Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl, (ii) R ５ and R １６ They combine to form alkylenes or heteroalkylenes; X is O, S(O) ｘ or CH ２ And in the formula, x is between 0 and 2; Het and R ６ The following is selected from (i) or (ii): (i) Het is a 5-membered or 6-membered heteroaryl, R ６ is H, alkyl or haloalkyl, or (ii) Het is a 5-membered or 6-membered heteroaryl, R ６ ha- (CH ２ ) １－２ - and R ６ And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems; R ７ is -C(O)R １７ , -S(O)R １８ or -SO ２ R １８ And; R １７ 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-(CH ２ ) ２ -R １９ , -O-(CH ２ ) ２ -R １９ or -NR ２０ R ２１ And; in the formula, R １９ is, -OR ９ or -NR ９ R １０ And R ２０ and R ２１ Each of these is independently H, alkyl, cycloalkyl, or haloalkyl; R １８ Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl or -NR ９ R １０ A compound or a pharmaceutically acceptable derivative thereof.

5. Formula I: A compound or a pharmaceutically acceptable derivative thereof, wherein the formula is: a is between 0 and 2; R １ is H, alkyl, haloalkyl or halo; R ２ These are alkyl, cycloalkyl, or haloalkyl; R ３ is -O-(CH ２ ) ｂ -R ８ And; b is 1 to 4; R ８ H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ９ R １０ , C(O)R １１ , C (=NH) (R １２ ) or C (= N-O-R ９ ) (Caution １２ ) and; R ９ and R １０ These are, independently, H, alkyl, or C(O)R. １３ And; in the formula, R １３ is alkyl, alkoxy or NR １４ R １５ And; R １１ is hydroxy, alkyl, alkoxy or NR １４ R １５ And; R １２ is alkyl or NR １４ R １５ And; R １４ and R １５ Each of these elements independently forms a heterocycline, either as H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded; R ４ is H or alkoxy; Z １ Z ２ and Z ３ The following options are selected: (i), (ii), or (iii): (i) Z １ is N, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N. (ii) Z １ is NH or O, Z ２ and Z ３ is C, or (iii) Z １ CH is, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N; Z ４ Z ５ and Z ６ The following options are selected: (i), (ii), (iii), or (iv): (i) Z ４ is N, Z ５ CR ５ Z ６ CH is (ii) Z ４ CR １６ Z ５ is N, Z ６ CH is (iii) Z ４ CR １６ Z ５ CR ５ Z ６ is N, or (iv) Z ４ CR １６ Z ５ CR ５ Z ６ is CH; R ５ and R １６ The following is selected from (i) or (ii): (i) R ５ and R １６ Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl, (ii) R ５ and R １６ They combine to form alkylenes or heteroalkylenes; X is CR ２２ R ２３ And in the formula R ２２ and R ２３ Each of these is independently either H or alkyl; Het and R ６ The following is selected from (i) or (ii): (i) Het is a 5-membered or 6-membered heteroaryl, R ６ is H, alkyl or haloalkyl, or (ii) Het is a 5-membered or 6-membered heteroaryl, R ６ ha- (CH ２ ) １－２ - and R ６ And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems; R ７ Ha-C(O)R １７ And; R １７ These are alkoxy, alkenyloxy, alkynyloxy or -O-(CH ２ ) ２ -R １９ And; in the formula, R １９ is, -OR ９ or -NR ９ R １０ A compound or a pharmaceutically acceptable derivative thereof.

6. Equation Ia: A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable derivative thereof, having the above.

7. A compound according to any one of claims 1 to 6, wherein the formula: R １ H is; R ２ These are alkyl, cycloalkyl, or haloalkyl; R ８ H, CN, OH, aryl, heteroaryl, NR ９ R １０ or C(O)R １１ And; R ９ and R １０ These are, independently, H or C(O)R １３ And; in the formula, R １３ is alkyl or alkoxy; R １１ is alkyl or alkoxy; X is CH ２ And; R １７ It is an alkoxy compound.

8. A compound according to any one of claims 1 to 7, wherein the formula: R １ H is; R ２ is alkyl or haloalkyl; R ８ H, CN, OH, aryl, NR ９ R １０ or C(O)R １１ And; R ９ and R １０ These are, independently, H or C(O)R １３ And; in the formula, R １３ is alkyl; R １１ is an alkoxy; X is CH ２ And; R １７ It is an alkoxy compound.

9. Formula II: A compound or a pharmaceutically acceptable derivative thereof, wherein the formula is: a is between 0 and 2; R １ and R ２ They combine to form alkylenes; R ３ is -O-(CH ２ ) ｂ -R ８ And; b is 1 to 4; R ８ H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ９ R １０ , C(O)R １１ , C (=NH) (R １２ ) or C (= N-O-R ９ ) (Caution １２ ) and; R ９ and R １０ These are, independently, H, alkyl, or C(O)R. １３ And; in the formula, R １３ is alkyl, alkoxy or NR １４ R １５ And; R １１ is hydroxy, alkyl, alkoxy or NR １４ R １５ And; R １２ is alkyl or NR １４ R １５ And; R １４ and R １５ Each of these elements independently forms a heterocycline, either as H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded; R ４ is H or alkoxy; Z １ Z ２ and Z ３ The following options are selected: (i), (ii), or (iii): (i) Z １ is N, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N. (ii) Z １ is NH or O, Z ２ and Z ３ is C, or (iii) Z １ CH is, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N; Z ４ Z ５ and Z ６ The following options are selected: (i), (ii), (iii), or (iv): (i) Z ４ is N, Z ５ CR ５ Z ６ CH is (ii) Z ４ CR １６ Z ５ is N, Z ６ CH is (iii) Z ４ CR １６ Z ５ CR ５ Z ６ is N, or (iv) Z ４ CR １６ Z ５ CR ５ Z ６ is CH; R ５ and R １６ The following is selected from (i) or (ii): (i) R ５ and R １６ Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl, (ii) R ５ and R １６ They combine to form alkylenes or heteroalkylenes; X is O, S(O) ｘ or CH ２ And in the formula, x is between 0 and 2; Het and R ６ The following is selected from (i) or (ii): (i) Het is a 5-membered or 6-membered heteroaryl, R ６ is H, alkyl or haloalkyl, or (ii) Het is a 5-membered or 6-membered heteroaryl, R ６ ha- (CH ２ ) １－２ - and R ６ And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems; R ７ is -C(O)R １７ , -S(O)R １８ or -SO ２ R １８ And; R １７ 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-(CH ２ ) ２ -R １９ , -O-(CH ２ ) ２ -R １９ or -NR ２０ R ２１ And; in the formula, R １９ is, -OR ９ or -NR ９ R １０ And R ２０ and R ２１ Each of these is independently H, alkyl, cycloalkyl, or haloalkyl; R １８ Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl or -NR ２０ R ２１ A compound or a pharmaceutically acceptable derivative thereof.

10. Formula II: A compound or a pharmaceutically acceptable derivative thereof, wherein the formula is: a is between 0 and 2; R １ and R ２ The following is selected from (i) or (ii): (i) R １ is alkyl, cycloalkyl or haloalkyl; R ２ is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo, (ii) R １ and R ２ They combine to form alkylenes; R ３ is -O-(CH ２ ) ｂ -R ８ And; b is 1 to 4; R ８ H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ９ R １０ , C(O)R １１ , C (=NH) (R １２ ) or C (= N-O-R ９ ) (Caution １２ ) and; R ９ and R １０ These are, independently, H, alkyl, or C(O)R. １３ And; in the formula, R １３ is alkyl, alkoxy or NR １４ R １５ And; R １１ is hydroxy, alkyl, alkoxy or NR １４ R １５ And; R １２ is alkyl or NR １４ R １５ And; R １４ and R １５ Each of these elements independently forms a heterocycline, either as H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded; R ４ is H or alkoxy; Z １ Z ２ and Z ３ The following options are selected: (i), (ii), or (iii): (i) Z １ is N, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N. (ii) Z １ is NH or O, Z ２ and Z ３ is C, or (iii) Z １ CH is, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N; Z ４ CR １６ And; Z ５ CR ５ And; Z ６ is N or CH; R ５ and R １６ They combine to form alkylenes or heteroalkylenes; X is O, S(O) ｘ or CH ２ And in the formula, x is between 0 and 2; Het and R ６ The following is selected from (i) or (ii): (i) Het is a 5-membered or 6-membered heteroaryl, R ６ is H, alkyl or haloalkyl, or (ii) Het is a 5-membered or 6-membered heteroaryl, R ６ ha- (CH ２ ) １－２ - and R ６ And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems; R ７ is -C(O)R １７ , -S(O)R １８ or -SO ２ R １８ And; R １７ 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-(CH ２ ) ２ -R １９ , -O-(CH ２ ) ２ -R １９ or -NR ２０ R ２１ And; in the formula, R １９ is, -OR ９ or -NR ９ R １０ And R ２０ and R ２１ Each of these is independently H, alkyl, cycloalkyl, or haloalkyl; R １８ Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl or -NR ９ R １０ A compound or a pharmaceutically acceptable derivative thereof.

11. Formula II: A compound or a pharmaceutically acceptable derivative thereof, wherein the formula is: a is between 0 and 2; R １ and R ２ The following is selected from (i) or (ii): (i) R １ R is alkyl, cycloalkyl or haloalkyl, ２ is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo, (ii) R １ and R ２ They combine to form alkylenes; R ３ is -O-(CH ２ ) ｂ -R ８ And; b is 1 to 4; R ８ H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ９ R １０ , C(O)R １１ , C (=NH) (R １２ ) or C (= N-O-R ９ ) (Caution １２ ) and; R ９ and R １０ These are, independently, H, alkyl, or C(O)R. １３ And; in the formula, R １３ is alkyl, alkoxy or NR １４ R １５ And; R １１ is hydroxy, alkyl, alkoxy or NR １４ R １５ And; R １２ is alkyl or NR １４ R １５ And; R １４ and R １５ Each of these elements independently forms a heterocycline, either as H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded; R ４ is H or alkoxy; Z １ Z ２ and Z ３ The following options are selected: (i), (ii), or (iii): (i) Z １ is N, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N. (ii) Z １ is NH or O, Z ２ and Z ３ is C, or (iii) Z １ CH is, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N; Z ４ Z ５ and Z ６ The following options are selected: (i), (ii), (iii), or (iv): (i) Z ４ is N, Z ５ CR ５ Z ６ CH is (ii) Z ４ CR １６ Z ５ is N, Z ６ CH is (iii) Z ４ CR １６ Z ５ CR ５ Z ６ is N, or (iv) Z ４ CR １６ Z ５ CR ５ Z ６ is CH; R ５ and R １６ The following is selected from (i) or (ii): (i) R ５ and R １６ Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl, (ii) R ５ and R １６ They combine to form alkylenes or heteroalkylenes; X is O or S(O) ｘ And in the formula, x is between 0 and 2; Het and R ６ The following is selected from (i) or (ii): (i) Het is a 5-membered or 6-membered heteroaryl, R ６ is H, alkyl or haloalkyl, or (ii) Het is a 5-membered or 6-membered heteroaryl, R ６ ha- (CH ２ ) １－２ - and R ６ And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems; R ７ is -C(O)R １７ , -S(O)R １８ or -SO ２ R １８ And; R １７ 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-(CH ２ ) ２ -R １９ , -O-(CH ２ ) ２ -R １９ or -NR ２０ R ２１ And; in the formula, R １９ is, -OR ９ or -NR ９ R １０ And R ２０ and R ２１ Each of these is independently H, alkyl, cycloalkyl, or haloalkyl; R １８ Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl or -NR ９ R １０ A compound or a pharmaceutically acceptable derivative thereof.

12. Formula II: A compound or a pharmaceutically acceptable derivative thereof, wherein the formula is: a is between 0 and 2; R １ These are alkyl, cycloalkyl, or haloalkyl; R ２ is H, alkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy or halo; R ３ is -O-(CH ２ ) ｂ -R ８ And; b is 1 to 4; R ８ H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ９ R １０ , C(O)R １１ , C (=NH) (R １２ ) or C (= N-O-R ９ ) (Caution １２ ) and; R ９ and R １０ These are, independently, H, alkyl, or C(O)R. １３ And; in the formula, R １３ is alkyl, alkoxy or NR １４ R １５ And; R １１ is hydroxy, alkyl, alkoxy or NR １４ R １５ And; R １２ is alkyl or NR １４ R １５ And; R １４ and R １５ Each of these elements independently forms a heterocycline, either as H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded; R ４ is H or alkoxy; Z １ Z ２ and Z ３ The following options are selected: (i), (ii), or (iii): (i) Z １ is N, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N. (ii) Z １ is NH or O, Z ２ and Z ３ is C, or (iii) Z １ CH is, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N; Z ４ Z ５ and Z ６ The following options are selected: (i), (ii), (iii), or (iv): (i) Z ４ is N, Z ５ CR ５ Z ６ CH is (ii) Z ４ CR １６ Z ５ is N, Z ６ CH is (iii) Z ４ CR １６ Z ５ CR ５ Z ６ is N, or (iv) Z ４ CR １６ Z ５ CR ５ Z ６ is CH; R ５ and R １６ The following is selected from (i) or (ii): (i) R ５ and R １６ Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl, (ii) R ５ and R １６ They combine to form alkylenes or heteroalkylenes; X is CR ２２ R ２３ And in the formula R ２２ and R ２３ Each of these is independently either H or alkyl; Het and R ６ The following is selected from (i) or (ii): (i) Het is a 5-membered or 6-membered heteroaryl, R ６ is H, alkyl or haloalkyl, or (ii) Het is a 5-membered or 6-membered heteroaryl, R ６ ha- (CH ２ ) １－２ - and R ６ And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems; R ７ Ha-C(O)R １７ And; R １７ These are alkoxy, alkenyloxy, alkynyloxy or -O-(CH ２ ) ２ -R １９ And; in the formula, R １９ is, -OR ９ or -NR ９ R １０ A compound or a pharmaceutically acceptable derivative thereof.

13. Formula IIa: A compound according to any one of claims 9 to 12 or a pharmaceutically acceptable derivative thereof, having the above.

14. A compound according to any one of claims 9 to 13, wherein the formula: R １ These are alkyl, cycloalkyl, or haloalkyl; R ２ H is; R ８ is H, CN, OH, aryl, heteroaryl, NR ９ R １０ or C(O)R １１ and is; R ９ and R １０ These are, independently, H or C(O)R １３ And; in the formula, R １３ is alkyl or alkoxy; R １１ is alkyl or alkoxy; X is CH ２ And; R １７ It is an alkoxy compound.

15. A compound according to any one of claims 9 to 13, wherein the formula: R １ is alkyl or haloalkyl; R ２ H is; R ８ H, CN, OH, aryl, NR ９ R １０ or C(O)R １１ And; R ９ and R １０ These are, independently, H or C(O)R １３ And; in the formula, R １３ is alkyl; R １１ is an alkoxy; X is CH ２ And; R １７ It is an alkoxy compound.

16. Formula III: A compound or a pharmaceutically acceptable derivative thereof, wherein the formula is: a is between 0 and 2; R １ and R ２ They combine to form alkylenes; R ３ is -O-(CH ２ ) ｂ -R ８ And; b is 1 to 4; R ８ H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ９ R １０ , C(O)R １１ , C (=NH) (R １２ ) or C (= N-O-R ９ ) (Caution １２ ) and; R ９ and R １０ These are, independently, H, alkyl, or C(O)R. １３ And; in the formula, R １３ is alkyl, alkoxy or NR １４ R １５ And; R １１ is hydroxy, alkyl, alkoxy or NR １４ R １５ And; R １２ is alkyl or NR １４ R １５ And; R １４ and R １５ Each of these elements independently forms a heterocycline, either as H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded; R ４ is H or alkoxy; Z １ Z ２ and Z ３ The following options are selected: (i), (ii), or (iii): (i) Z １ is N, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N. (ii) Z １ is NH or O, Z ２ and Z ３ is C, or (iii) Z １ CH is, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N; Z ４ Z ５ and Z ６ The following options are selected: (i), (ii), (iii), or (iv): (i) Z ４ is N, and Z ５ is CR ５ , and Z ６ is CH (ii) Z ４ CR １６ Z ５ is N, Z ６ CH is (iii) Z ４ CR １６ Z ５ CR ５ Z ６ is N, or (iv) Z ４ CR １６ Z ５ CR ５ Z ６ is CH; R ５ and R １６ The following is selected from (i) or (ii): (i) R ５ and R １６ Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl, (ii) R ５ and R １６ They combine to form alkylenes or heteroalkylenes; X is O, S(O) ｘ or CH ２ And in the formula, x is between 0 and 2; Het and R ６ The following is selected from (i) or (ii): (i) Het is a 5-membered or 6-membered heteroaryl, R ６ is H, alkyl or haloalkyl, or (ii) Het is a 5-membered or 6-membered heteroaryl, R ６ ha- (CH ２ ) １－２ - and R ６ And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems; R ７ is -C(O)R １７ , -S(O)R １８ or -SO ２ R １８ And; R １７ 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-(CH ２ ) ２ -R １９ , -O-(CH ２ ) ２ -R １９ or -NR ２０ R ２１ And; in the formula, R １９ is, -OR ９ or -NR ９ R １０ And R ２０ and R ２１ Each of these is independently H, alkyl, cycloalkyl, or haloalkyl; R １８ Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl or -NR ２０ R ２１ A compound or a pharmaceutically acceptable derivative thereof.

17. Formula III: A compound or a pharmaceutically acceptable derivative thereof, wherein the formula is: a is between 0 and 2; R １ and R ２ The following is selected from (i) or (ii): (i) R １ and R ２ Each of these is independently alkyl, cycloalkyl, or haloalkyl, or (ii) R １ and R ２ They combine to form alkylenes; R ３ is -O-(CH ２ ) ｂ -R ８ And; b is 1 to 4; R ８ H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ９ R １０ , C(O)R １１ , C (=NH) (R １２ ) or C (= N-O-R ９ ) (Caution １２ ) and; R ９ and R １０ These are, independently, H, alkyl, or C(O)R. １３ And; in the formula, R １３ is alkyl, alkoxy or NR １４ R １５ And; R １１ is hydroxy, alkyl, alkoxy or NR １４ R １５ And; R １２ is alkyl or NR １４ R １５ And; R １４ and R １５ Each of these elements independently forms a heterocycline, either as H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded; R ４ is H or alkoxy; Z １ Z ２ and Z ３ The following options are selected: (i), (ii), or (iii): (i) Z １ is N, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N. (ii) Z １ is NH or O, Z ２ and Z ３ is C, or (iii) Z １ CH is, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N; Z ４ CR １６ And; Z ５ CR ５ And; Z ６ is N or CH; R ５ and R １６ They combine to form alkylenes or heteroalkylenes; X is O, S(O) ｘ or CH ２ And in the formula, x is between 0 and 2; Het and R ６ The following is selected from (i) or (ii): (i) Het is a 5-membered or 6-membered heteroaryl, R ６ is H, alkyl or haloalkyl, or (ii) Het is a 5-membered or 6-membered heteroaryl, R ６ ha- (CH ２ ) １－２ - and R ６ And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems; R ７ is -C(O)R １７ , -S(O)R １８ or -SO ２ R １８ And; R １７ 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-(CH ２ ) ２ -R １９ , -O-(CH ２ ) ２ -R １９ or -NR ２０ R ２１ And; in the formula, R １９ is, -OR ９ or -NR ９ R １０ And R ２０ and R ２１ Each of these is independently H, alkyl, cycloalkyl, or haloalkyl; R １８ Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl or -NR ９ R １０ A compound or a pharmaceutically acceptable derivative thereof.

18. Formula III: A compound or a pharmaceutically acceptable derivative thereof, wherein the formula is: a is between 0 and 2; R １ and R ２ The following is selected from (i) or (ii): (i) R １ and R ２ Each of these is independently alkyl, cycloalkyl, or haloalkyl, or (ii) R １ and R ２ They combine to form alkylenes; R ３ is -O-(CH ２ ) ｂ -R ８ And; b is 1 to 4; R ８ H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ９ R １０ , C(O)R １１ , C (=NH) (R １２ ) or C (= N-O-R ９ ) (Caution １２ ) and; R ９ and R １０ These are, independently, H, alkyl, or C(O)R. １３ And; in the formula, R １３ is alkyl, alkoxy or NR １４ R １５ And; R １１ is hydroxy, alkyl, alkoxy or NR １４ R １５ And; R １２ is alkyl or NR １４ R １５ And; R １４ and R １５ Each of these elements independently forms a heterocycline, either as H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded; R ４ is H or alkoxy; Z １ Z ２ and Z ３ The following options are selected: (i), (ii), or (iii): (i) Z １ is N, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N. (ii) Z １ is NH or O, Z ２ and Z ３ is C, or (iii) Z １ CH is, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N; Z ４ Z ５ and Z ６ The following options are selected: (i), (ii), (iii), or (iv): (i) Z ４ is N, Z ５ CR ５ Z ６ CH is (ii) Z ４ CR １６ Z ５ is N, Z ６ CH is (iii) Z ４ CR １６ Z ５ CR ５ Z ６ is N, or (iv) Z ４ CR １６ Z ５ CR ５ Z ６ is CH; R ５ and R １６ The following is selected from (i) or (ii): (i) R ５ and R １６ Each of these is independently H, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, alkyl, alkenyl, alkynyl, or haloalkyl, (ii) R ５ and R １６ They combine to form alkylenes or heteroalkylenes; X is O or S(O) ｘ And in the formula, x is between 0 and 2; Het and R ６ The following is selected from (i) or (ii): (i) Het is a 5-membered or 6-membered heteroaryl, R ６ is H, alkyl or haloalkyl, or (ii) Het is a 5-membered or 6-membered heteroaryl, R ６ ha- (CH ２ ) １－２ - and R ６ And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems; R ７ is -C(O)R １７ , -S(O)R １８ or -SO ２ R １８ And; R １７ 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-(CH ２ ) ２ -R １９ , -O-(CH ２ ) ２ -R １９ or -NR ２０ R ２１ And; in the formula, R １９ is, -OR ９ or -NR ９ R １０ And R ２０ and R ２１ Each of these is independently H, alkyl, cycloalkyl, or haloalkyl; R １８ Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl or -NR ９ R １０ A compound or a pharmaceutically acceptable derivative thereof.

19. Formula IIIa: A compound according to any one of claims 16 to 18, having the following characteristics.

20. Formula IIIa: A compound or a pharmaceutically acceptable derivative thereof, wherein the formula is: a is between 0 and 2; R １ and R ２ The following is selected from (i) or (ii): (i) R １ and R ２ Each of these is independently alkyl, cycloalkyl, or haloalkyl, or (ii) R １ and R ２ They combine to form alkylenes; R ３ is -O-(CH ２ ) ｂ -R ８ And; b is 1 to 4; R ８ H, CN, OH, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR ９ R １０ , C(O)R １１ , C (=NH) (R １２ ) or C (= N-O-R ９ ) (Caution １２ ) and; R ９ and R １０ These are, independently, H, alkyl, or C(O)R. １３ And; in the formula, R １３ is alkyl, alkoxy or NR １４ R １５ And; R １１ is hydroxy, alkyl, alkoxy or NR １４ R １５ And; R １２ is alkyl or NR １４ R １５ And; R １４ and R １５ Each of these elements independently forms a heterocycline, either as H, OH, alkoxy, or alkyl, or together with the nitrogen atom to which they are bonded; R ４ is H or alkoxy; Z １ Z ２ and Z ３ The following options are selected: (i), (ii), or (iii): (i) Z １ is N, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N. (ii) Z １ is NH or O, Z ２ and Z ３ is C, or (iii) Z １ CH is, Z ２ and Z ３ One of them is C, and Z ２ and Z ３ The other side is N; Z ４ is N or CR １６ And in the formula R １６ is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl; R ５ is H, alkyl, haloalkyl, alkoxy, halo, alkenyl or alkynyl; X is O, S(O) ｘ or CH ２ And in the formula, x is between 0 and 2; Het and R ６ The following is selected from (i) or (ii): (i) Het is a 5-membered or 6-membered heteroaryl, R ６ is H, alkyl or haloalkyl, or (ii) Het is a 5-membered or 6-membered heteroaryl, R ６ ha- (CH ２ ) １－２ - and R ６ And Het, together with the atoms to which they are bonded, form 5,5-, 5,6-, 5,7-, 6,5-, 6,6- or 6,7-bicyclic ring systems; R ７ is -C(O)R １７ or -SO ２ R １８ And; R １７ 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-(CH ２ ) ２ -R １９ , -O-(CH ２ ) ２ -R １９ or -NR ２０ R ２１ And; in the formula, R １９ is, -OR ９ or -NR ９ R １０ And R ２０ and R ２１ Each of these is independently H, alkyl, cycloalkyl, or haloalkyl; R １８ Alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, cyanoalkenyl, hydroxymethylalkenyl, alkoxymethylalkenyl, aminomethylalkenyl, alkynyl, haloalkynyl, cyanoalkynyl, hydroxymethylalkynyl, alkoxymethylalkynyl, aminomethylalkynyl or -NR ９ R １０ A compound or a pharmaceutically acceptable derivative thereof.

21. A compound according to any one of claims 16 to 20, wherein the formula: R １ and R ２ The following is selected from (i) or (ii): (i) R １ and R ２ These are alkyl groups, or (ii) R １ and R ２ They combine to form alkylenes; R ８ H, CN, OH, aryl, heteroaryl, NR ９ R １０ or C(O)R １１ And; R ９ and R １０ These are, independently, H or C(O)R １３ And; in the formula, R １３ is alkyl or alkoxy; R １１ is alkyl or alkoxy; R ５ and R １６ They combine to form alkylenes; X is O or CH ２ And; R １７ These are alkyl, haloalkyl, alkoxy, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl; R １８ A compound that is alkyl, haloalkyl, alkoxyalkyl, aminoalkyl, alkenyl, haloalkenyl, alkynyl, or hydroxymethylalkynyl.

22. A compound according to any one of claims 1 to 4, 6, 9 to 11, 13 and 16 to 21, wherein X is O.

23. X is CH ２ The compound according to any one of claims 1, 2, 4 to 10 and 11 to 21.

24. The compound according to any one of claims 1 to 23, wherein a is 0 or 1.

25. R ２ The compound according to any one of claims 1 to 8, wherein the parent is alkyl.

26. R ２ The compound according to any one of claims 1 to 8, wherein is a haloalkyl.

27. R ２ The compound according to any one of claims 1 to 8, wherein is difluoromethyl.

28. R １ The compound according to any one of claims 9 to 15, wherein the parent is alkyl.

29. R １ The compound according to any one of claims 9 to 15, wherein is a haloalkyl.

30. R １ The compound according to any one of claims 9 to 15, wherein is difluoromethyl.

31. R １ A compound according to any one of claims 1 to 6, wherein is H.

32. R ２ The compound according to any one of claims 9 to 15, wherein is H.

33. R １ and R ２ Together, C may be substituted with one or more halos or methyl groups. １－４ A compound according to any one of claims 16 to 21, which forms an alkylene.

34. The compound according to any one of claims 1 to 33, wherein b is 1 or 2.

35. R ８ The compound according to any one of claims 1 to 6, 9 to 13 and 16 to 21, wherein is H, phenyl, 4-fluorophenyl, mofolinyl, COOH, COOMe, C(=NH)NHOH, tetrazolyl, oxadiazolyl, triazolyl, pyridyl, imidazolyl, oxazolidinyl, NHC(O)OMe, cyano, hydroxy, amino, or acetylamino.

36. R ８ The compound according to any one of claims 1 to 35, wherein is hydrogen.

37. R ４ A compound according to any one of claims 1 to 36, wherein is H.

38. R ４ The compound according to any one of claims 1 to 37, wherein is methoxy.

39. Z １ is NH or O, Z ２ and Z ３ A compound according to any one of claims 1 to 38, wherein C is present.

40. Z １ O is Z ２ and Z ３ A compound according to any one of claims 1 to 39, wherein C is present.

41. Z ４ A compound according to any one of claims 1 to 40, wherein is N.

42. Z ４ CR １６ The compound according to any one of claims 1 to 40.

43. R ５ is H, cyano, alkoxy or alkyl, and R １６ The compound according to any one of claims 1 to 42, wherein is H, alkyl, alkoxy, halo, or alkynyl.

44. R ５ is H, cyano, methoxy, or methyl, and R １６ The compound according to any one of claims 1 to 43, wherein is H, methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, fluoro, ethynyl, or propynyl.

45. Het is a 5-membered or 6-membered heteroaryl, R ６ The compound according to any one of claims 1 to 44, wherein is H or alkyl.

46. Het is a 5-membered heteroaryl, and R ６ The compound according to any one of claims 1 to 45, wherein is H or methyl.

47. Het is pyrazolyl, oxazolyl, thiazolyl, or pyridyl, and R ６ The compound according to any one of claims 1 to 46, wherein is H or methyl.

48. Het is pyrazolyl, and R ６ The compound according to any one of claims 1 to 47, wherein is H or methyl.

49. R ７ ga-C(O)R １７ The compound according to any one of claims 1 to 48.

50. R ７ ga-S(O)R １８ The compound according to any one of claims 1 to 48.

51. R ７ ga-SO ２ R １８ The compound according to any one of claims 1 to 48.

52. R １７ However, alkyl, alkoxy, alkenyl, haloalkenyl, alkynyl, NR ２０ R ２１ The compound according to any one of claims 1 to 6, 9 to 13, and 16 to 21, which is a hydroxyalkynyl compound.

53. R １７ The compound according to any one of claims 1 to 6, 9 to 13, and 16 to 21, wherein the compound is methyl, methoxy, NHMe, ethenyl, 1-fluoro-1-ethenyl, ethinyl, or 1-propyne-1-yl.

54. R １８ The compound according to any one of claims 1 to 53, wherein is methyl or tert-butyl.

55. The compound according to any one of claims 1 to 54, wherein the compound is one of the compounds disclosed herein.

56. A pharmaceutical composition comprising a compound according to any one of claims 1 to 55 and a pharmaceutically acceptable carrier.

57. A method for treating a subject having cancer, comprising administering to the subject a compound according to any one of claims 1 to 55 or a pharmaceutical composition according to claim 56.

58. A method for treating a subject having myc-driven cancer, comprising administering to the subject a compound according to any one of claims 1 to 55 or a pharmaceutical composition according to claim 56.

Images