HETEROCYCLIC COMPOUNDS AS INHIBITORS OF EXTRATERMINAL BROMODONIUM (BET).

Abstract

New bromodomain and extraterminal domain (BET) inhibitors and therapeutic methods for treating conditions and diseases using these new BET inhibitors are provided.

Description

HETEROCYCLIC COMPOUNDS AS EXTRATERMINAL BROMODOMAIN INHIBITORS (BET) CROSS REFERENCE WITH RELATED REQUESTS This application claims priority to US Provisional Application No. 62 / 870,020, filed on July 2, 2019 and US Provisional Application No. 62 / 017,547, filed on April 29, 2020, each one of which is incorporated herein by reference in its entirety. TECHNICAL FIELD OF THE INVENTION The present invention relates to novel bromodomain and extraterminal domain (BET) inhibitors and therapeutic methods for treating conditions and diseases using these novel BET inhibitors. BACKGROUND OF THE INVENTION Epigenetic dysregulation plays a crucial role in driving aberrant gene expressions that lead to various types of cancers. Many components involved in epigenetic regulation have been attractive targets for therapeutic interventions. Among them, the bromodomain and extraterminal (BET) family of proteins attracted much attention in recent years. BET family proteins include BRD2, BRD3, BRD4, and the testis-specific BRDT. Through their bromodomains (BRDs), they bind with high affinity to acetylation motifs, including acetylated histones in chromatin, thereby regulating gene transcription. Genes regulated by BET family proteins include many important oncogenes responsible for cell survival and cell cycle progression. BET proteins are emerging targets in cancer that directly regulate the expression of oncogenes in hematological and solid tumors. BRD4, in addition to occupying gene promoters, has a strong preference for enhancers and super-enhancers in key driver genes such as c-MYC (Loven et al, Cell 2013;153(2):320-34). BET family proteins have also been implicated in mediating acute inflammatory responses through the canonical NFKB pathway (Huang et al., Mol. Cell. Biol. 29: 1375-1387 (2009)) resulting in upregulation of genes associated with the production of atocins (Nicodeme et al., Nature 468: 1119-1123, (2010)). Additionally, bromodomain function has been linked to kidney disease (Zhang, et al., J. Biol. Chem. MA / ÓUUOO 287: 28840-28851 (2012)). BRD2 function has also been linked to a predisposition to dyslipidemia or inadequate regulation of adipogenesis, elevated inflammatory profiles, and increased susceptibility to autoimmune diseases (Denis, Discovery Medicine 10: 489-499 (2010)). The human immunodeficiency virus uses BRD4 to initiate transcription of viral RNA from stably integrated viral DNA (Jang et al., Mol. Cell, 19: 523-534 (2005)). BET bromodomain inhibitors have also been shown to reactivate HIV transcription in models of latent T cell infection and latent monocyte infection (Banerjee, et al., J. Leukocyte Biol. Doi: 10.1189 / jlb.0312165). BRDT has an important role in spermatogenesis (Matzuk, et al., Cell 150: 673-684 (2012)). Because of this potential as an epigenetic target, several small molecule compounds that inhibit the function of BET family proteins have been developed, and many of them have demonstrated promising anticancer activities with solid and hematological malignancies in preclinical studies. This has led to several early-stage clinical trials. Included among these are RO6870810 (formerly TEN-010), ZEN003694, BMS-986158, CPI-0610, IBET762, OTX015, FT-1101, INCB054329, PLX51107, GS-5829, and ABBV-075. While these efforts are promising, there is a need for better selectivity and improved durability of BET inhibitors that provide improved efficacy while reducing toxicity related to off-target effects. The present invention relates to novel BET inhibitors. BRIEF DESCRIPTION OF THE INVENTION In one aspect, a compound of formula (J) is provided: MA / t / ZUZZ / UÓUUOO a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein = , X, Gi, R1, R2, R3, Μ1, Μ2, Zi, Z2, and Z3 are defined herein. In some embodiments, the compounds provided herein are BET inhibitors that selectively target and covalently bind the protein of interest. In some embodiments, the BET inhibitors comprise a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa-11), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above. In some embodiments, provided herein is a pharmaceutical composition comprising a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), ( III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa-11) , or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, in combination with at least one pharmaceutically acceptable vehicle, diluent or excipient. In some embodiments, the use of a compound having the structure of Formula (J) or any related formula where applicable, such as Formula (I), (II), (lia-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa-11 ), or A tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, is provided for the manufacture of a medicament. In some embodiments, a method of treating a disease mediated by inhibition of the BET family of proteins in an individual is provided herein. In some embodiments, said method comprises administering to the subject an effective amount of a compound having the structure of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (Illa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va11), (VI) or (VIa-1) a (VIa-11), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, or a pharmaceutical composition comprising it, with a frequency and duration sufficient to provide a beneficial effect to the subject. In some embodiments, methods are provided herein for treating or preventing disorders that improve by inhibiting BET. In some embodiments, such methods comprise administering to the subject a therapeutically effective amount of a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (Ha -8 ), (III), (Illa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa -11), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, alone or in combination with a pharmaceutically acceptable carrier. In another aspect, the methods are directed to methods of treating or preventing an inflammatory disease or cancer or AIDS. In some embodiments, such methods comprise administering to the subject a therapeutically effective amount of a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (Ha -8 ), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa -11), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, alone or in combination with a pharmaceutically acceptable carrier. In another aspect, provided herein is the use of a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III) , (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, alone or in combination with a second active pharmaceutical agent, in the manufacture of a medicament for treating or preventing conditions and disorders described herein, with or without an acceptable pharmaceutical drug carrier. In another aspect, a synthesis method is provided for a compound having the structure of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa -8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) a (Via 11), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, as detailed herein. DETAILED DESCRIPTION OF THE INVENTION Definitions Alkyl refers to and includes saturated linear and branched univalent hydrocarbon structures and combinations thereof, having the designated number of carbon atoms (i.e., Ci-Cio means one to ten carbons). Particular alkyl groups are those with 1 to 20 carbon atoms (a C1-C20 alkyl). The most particular alkyl groups are those that have 1 to 8 carbon atoms (a Ci-Cs alkyl), 3 to 8 carbon atoms (a Cb-Cs alkyl), 1 to 6 carbon atoms (a Ci-Ce alkyl), from 1 to 5 carbon atoms (a C1-C5 alkyl), or from 1 to 4 carbon atoms (a C1-C4 alkyl). Examples of alkyl include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n- pentyl, n-hexyl, n-heptyl, n-octyl and the like. Alkenyl, as used herein, refers to an unsaturated linear or branched univalent hydrocarbon chain or a combination thereof, having at least one olefinic unsaturation site (i.e., having at least one residue of the formula C=C) and having the designated number of carbon atoms (i.e. C2-C10 means two to ten carbon atoms). The alkenyl group may be in cis or trans configurations, or alternatively in E or Z configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a C2-C20 alkenyl), which have 2 to 8 atoms. of carbon (a C2-C8 alkenyl), having 2 to 6 carbon atoms (a C2-C6 alkenyl), or having 2 to 4 carbon atoms MA / t / ZUZZ / UÓUUOO carbon (a C2-C4 alkenyl). Examples of alkenyl include, but are not limited to, groups such as ethenyl (or vinyl), prop-l-enyl, prop-2-enyl (or allyl), 2-methylprop-l-enyl, but-l-enyl , but2-enyl, but-3-enyl, buta-l,3-dienyl, 2-methylbuta-l,3-dienyl, homologs and isomers thereof and the like. Alkylene, as used herein, refers to the same residues as alkyl, but which are bivalent. Particular alkylene groups are those having 1 to 6 carbon atoms (a Ci-Ce alkylene), 1 to 5 carbon atoms (a C1-C5 alkylene), 1 to 4 carbon atoms (a C1-C4) or 1 to 3 carbon atoms (a C1-C3 alkylene). Examples of alkylene include, for example, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), and the like. Alkynyl, as used herein, refers to an unsaturated linear or branched univalent hydrocarbon chain or a combination thereof, having at least one acetylenic unsaturation site (i.e., having at least one radical of formula C =C) and having the designated number of carbon atoms (i.e. C2-C10 means two to ten carbon atoms). Particular alkynyl groups are those that have 2 to 20 carbon atoms (a C2-C20 alkynyl), that have 2 to 8 carbon atoms (a C2-C8 alkynyl), that have 2 to 6 carbon atoms. carbon (a C2-C6 alkynyl), or having 2 to 4 carbon atoms (a C2-C4 alkynyl). Examples of alkynyl include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-l-ynyl, prop-2-ynyl (or propargyl), but-l-ynyl, but-2-ynyl, but - 3-ynyl, homologs and isomers thereof and the like. Aryl refers to and includes polyunsaturated aromatic hydrocarbon groups. The aryl may contain additional fused rings (e.g., 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl and / or heterocyclyl rings. In a variation, the aryl group contains 6 to 14 ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl and the like. Carbonyl refers to the C=O group. Cycloalkyl refers to and includes cyclic univalent hydrocarbon structures, which may be fully saturated, monounsaturated or polyunsaturated, but which are not aromatic, and have the designated number of carbon atoms (for example, C1-C10 means one to ten carbons). . Cycloalkyl may consist of one ring, such as cyclohexyl, or several rings, such as adamantyl, but excludes aryl groups. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. A preferred cycloalkyl is a cyclic hydrocarbon having 3 to 13 ring carbon atoms. A more preferred cycloalkyl is a cyclic hydrocarbon having 3 to 8 ring carbon atoms (a Cs-Cs cycloalkyl). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, ΜΛ / t / ZUZZ / UÓUUOO cyclohexyl, l-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl and the like. Halo or halogen refers to group 17 series elements having an atomic number of 9 to 85. Preferred halo groups include fluorine, chlorine, bromine and iodine. When a residue is substituted with more than one halogen, it may be referred to using a prefix corresponding to the number of halogen residues attached, for example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and substituted alkyl with two (di) or three (tri) halo groups, which may be, but not necessarily, the same halo; therefore, 4-chloro-3-fluorophenyl is within the range of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is called perhaloalkyl. A preferred perhaloalkyl group is trifluoroalkyl (-CF3). Similarly, perhaloalkoxy refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon that forms the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3). Heteroaryl refers to and includes unsaturated aromatic cyclic groups having 1 to 10 ring carbon atoms and at least one ring heteroatom, including, but not limited to, heteroatoms such as nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the rest of the molecule on a ring carbon or on a ring heteroatom. The heteroaryl may contain additional fused rings (e.g., 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl and / or heterocyclyl rings. The examples of heteroly groups include, but are not limited to, pyridyl, pyrimidyl, pyridazinilo, tiofenilo, furanil xazolilo, imidazopyridine and Similar. Heterocycle or heterocyclyl refers to a saturated or unsaturated non-aromatic group having 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms, such as nitrogen, sulfur or oxygen, and the like, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. A heterocyclyl group may have a single ring or multiple fused rings, but excludes heteroaryl groups. A heterocycle comprising more than one ring may be fused, spiro, or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings may be aryl or heterocyclyl. Examples of heterocyclyl groups include, but are not limited to, tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, 2,3-dihydrobenzo[b]thiophen-2-amino-yl , 4oxopyrimidin-l(2H)-yl and the like. Oxo refers to the radical =0. Optionally substituted unless otherwise specified means that a ΜΛ / t / ZUZZ / UÓUUOO group may be unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group where the substituents may be the same or different . In one embodiment, an optionally substituted group has a substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, the 3, 1 to 4 or 1 to 5 substituents. The term BET refers to the bromodomain and the family of extraterminal domains. As used herein, BRD refers to one or more proteins of the bromodomain extraterminal domain family (BRD2, BRD3, BRD4 and BRDT). Disease specifically includes any unhealthy condition of an animal or part thereof. Optionally or optionally means that the event or circumstances described subsequently may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. Pharmaceutically acceptable means that it is useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes that it is acceptable for veterinary use, as well as for human pharmaceutical use. "Pharmaceutically acceptable salts" means salts of compounds of the present invention that are pharmaceutically acceptable, as defined above, and that possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid p-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, ptoluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis (3-hydroxy-2-ene-l-carboxylic acid) co), 3-phenylpropionic acid, trimethylacetic acid, tertiary-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like. Pharmaceutically acceptable salts also include base addition salts which can be formed when acidic protons present are capable of reacting with organic or inorganic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide, and calcium hydroxide. Acceptable organic bases ΜΛ / t / ZUZZ / UÓUUOO include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. A therapeutically effective amount means the amount of a compound that, when administered to a mammal to treat a disease, is sufficient to effect said treatment for the disease. As used herein, treatment or treating is an approach to obtaining beneficial or desired results, including clinical results. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: decreasing one or more of the symptoms resulting from the disease, decreasing the extent of the disease, stabilizing the disease ( for example, prevent or delay the worsening of the disease), prevent or delay the spread (for example, metastasis) of the disease, prevent or delay the onset or recurrence of the disease, delay or slow the progression of the disease, improve the state of the disease, providing a remission (whether partial or complete) of the disease, decreasing the dose of one or more medications necessary to treat the disease, delaying the progression of the disease, increasing the quality of life and / or prolonging the survival. Also included by treatment is a reduction in the pathological consequences of the disease or condition. The methods of the invention contemplate one or more of these aspects of treatment. Compounds that have the same molecular formula, but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called isomers. Isomers that differ in the nature or sequence of bonds of their atoms are called constitutional isomers. Isomers that differ in the arrangement of their atoms in space are called stereoisomers. Stereoisomers that are not equal images of each other are called diastereomers, and stereoisomers that are non-superimposable equal images of each other are called enantiomers or sometimes optical isomers. Stereoisomers that can be superimposed on their mirror images are called achiral and those that cannot be superimposed are called chiral. A carbon atom attached to four non-identical substituents is called a chiral center. When a compound has a chiral center, a pair of enantiomers of opposite chirality is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S- sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light and is designated as right-handed or left-handed (i.e., as (+) or (-) isomers respectively). A chiral compound can exist either as an individual enatiomer or as a mixture thereof. A mixture containing equal proportions of enantiomers is called a racemic mixture or racemate and can be described as the mixture (RS) or (±) thereof. Unless otherwise indicated, the description or appointment ΜΛ / t / ZUZZ / UÓUUOO of a particular compound in the specification and claims is intended to include both individual enantiomers and their mixtures, racemic or otherwise, thereof. Methods for the determination of stereochemistry and separation of stereoisomers are well-known in the art (see discussion in Advanced Organic Chemistry, 3rd edition J. March, John Wiley and Sons, New York, 1985). ΜΛ / t / ZUZZ / UÓUUOO Compounds In some embodiments, a compound of formula (I) is provided: a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein: each = is independently a single bond or double bond; X is O or S; R1 is hydrogen, C1-C3 alkyl, -(G-C3 alkylene)OH, C1-C3 haloalkyl, or C3-C4 cycloalkyl; Gi is CRao N, where: Raes hydrogen, halogen, or C1-C4 alkyl; Zi is C-Wi-Rc; where: each Wi is independently -O- or -NRW1-, where: RW1 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, -OH, or halogen, and Rces independently C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, Ce-Cw aryl, or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by Rcl, wherein RC1 is independently halogen, C1 alkyl -C4, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, cyano, oxo, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, -OR10, -NR10Rn, -C(O)NR10R11 , -NR10C(O)Rn, -S(O)2R10, -NR10S(O)2R11, or -S(O)2NR10R11; Z2es C-W2-Rdo N, where: W2es -O-, -NRw2-, or a link, where: Rw2 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, -OH, or halogen, and You independently release hydrogen, halogen, cyano, 3-6 membered heterocyclyl or C1-C4 alkyl; Z3 is C-Reo N, where: Reis independently hydrogen, halogen, cyano, 3-6 membered heterocyclyl or C1-C4 alkyl; M1es S or CRla; M2 is S or CR2a, provided that when M^s S, when the = adjacent to M1 is a single bond and = adjacent to M2 is a double bond, when M2 is S, when the = adjacent to M2 is a single bond and = adjacent to M1 is a double bond, and either Μ1o M2is S; Rlay R2asonindependently hydrogen, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, cyano, oxo, C1-C4 haloalkyl, C1-C4 alkoxy, haloalkoxy C1-C4, -OR10, -NR10Rn, -C(O)OR10, -C(O)NR10Rn, -NR10C(O)Rn, S(O)2R10, -NR10S(O)2R11o -S(O)2NR10Rn, each of which is independently optionally replaced by R12; R2 is hydrogen, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl -(C1-C3 alkylene), 5-10 membered heteroaryl, cyano, oxo, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR10, -NR10Rn, -C(O)OR10, QOjNR1^11, -NR10C(O)R11, -S(O)2R10, - NR10S(O)2Rn, or -S(O)2NR10R11, each of which is independently optionally substituted by R12; R3is -(CH2)mNR13S(O)2R14where m is 0, 1, 2 or 3; C3-C6 cycloalkyl optionally substituted by halogen, oxo, -CN, or -OH; C1-C4 alkyl substituted by halogen, oxo, -CN, or -OH; or Ci-Ce alkynyl; R10 and R11 are each independently hydrogen, C1-C4 alkyl, CiO alkoxy, C1-C4 alkenyl, C3-C6 cycloalkyl, Cg-Cm aryl, 3- to 6-membered heterocyclyl, -(C1-C3 alkylene )C3-C6 cycloalkyl, -(C1-C3 alkylene) 3-6 membered heterocyclyl, -(C1-C3 alkylene) C6-C14 aryl, -NR15R16, or -C(O)R12, where each one of R10 and R11 are independently optionally substituted by halogen, oxo, -CN, -CF3, -OH, -NR13R14, -C(O)NR13R14, or C1-C4 alkyl optionally substituted by halogen, oxo, -CN, - CF3, or -OH, ΜΛ / t / ZUZZ / UÓUUOO Ri°y Riisetoman together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -CF3, -OH, or C1-C4 alkyl optionally substituted by halogen, oxo, -CN, or -OH; each R12 is independently halogen, cyano, C1-C4 haloalkyl, CiC alkoxy, C1-C4 haloalkoxy, -OR15, -NR15R16, -C(O)NR15R16, -NR15C(O)R16, -S(O)2R15 , -NR15S(O)2R16, S(O)2NR15R16, C3-C6 cycloalkyl, 3- or 6-membered heterocyclyl or C1-C4 alkyl each of which is independently optionally substituted by halogen, oxo, -CF3 , -CN, -OH, NR13R14, or -NR13C(O)R14; R13 and R14 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN, or -OH, R13 and R14 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -OH, or CI-C4 alkyl optionally substituted by halogen, oxo, -CN, or -OH; and each R15 and R16 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN or -OH , rís and ^16stake together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -OH, or CI-C4 alkyl optionally substituted by halogen, oxo, - CN, or -OH. In some embodiments, a compound of formula (I) is provided: x ΜΛ / t / ZUZZ / UÓUUOO a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein: each = is independently a single bond or double bond; X is O or S; R1 is hydrogen, C1-C3 alkyl, -(Ci-Cs alkylene)OH, C1-C3 haloalkyl, or C3-C4 cycloalkyl; Gi is CRao N, where: Raes hydrogen, halogen, or C1-C4 alkyl; Zi is C-Wi-Rc; where: each Wi is independently -O- or -NRW1-, where: RW1 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, -OH, or halogen, and R is independently 4- to 6-membered heterocyclyl, Ce-Cu aryl, or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by Rcl, wherein each RC1 is independently halogen, C1-C4 alkyl, C3-C6 cyclalkyl, 3-6 membered heterocyclyl, cyano, oxo, C1-C4 alkoxy, C1-C4 halolacoxy, C1-C4 haloalkyl, -OR10, -NR10Rn, -CIONR^R11, -NR10C(O )Rn, -S(O)2R10, -NR^O^R11, or -S(O)2NR10R11; Z2es C-W2-Rdo N, where: W2es -O-, -NRw2-, or a link, where: Rw2 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, -OH, or halogen, and You independently release hydrogen, halogen, cyano, 3-6 membered heterocyclyl or C1-C4 alkyl; Z3 is C-Reo N, where: Reis independently hydrogen, halogen, cyano, 3-6 membered heterocyclyl or C1-C4 alkyl; M1es S or CRla; M2 is S or CR2a, provided that when M^s S, when the = adjacent to M1 is a single bond and = adjacent to M2 is a double bond, when M2 is S, when the = adjacent to M2 is a single bond and = adjacent to M1 is a double bond, and at least one of M1 and M2 is not S; Rlay R2ason independently hydrogen, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, cyano, oxo, C1-C4 haloalkyl, C1-C4 alkoxy, haloalkoxy of C1-C4, -OR10, -NR10Rn, -C(O)OR10, -C(O)NR10R11, -NR10C(O)Rn, S(O)2R10, -NR10S(O)2R11or -S(O)2NR10Rn , each of which is independently optionally replaced by R12; R2 is halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl (C1-C3 alkylene), 5-10 membered heteroaryl, cyano, oxo, haloalkyl. C1-C4, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR10, -NR10Rn, -C(O)OR10, -C(O)NR10Rn, -NR10C(O)R11, -S(O)2R10, -NR^ÍOhR11, or -S(O)2NR10Rn, each of which is independently optionally substituted by R12; R3 is -(CH2)m NR13S(O)2R14, C3-C6 cycloalkyl or C1-C4 alkyl substituted by halogen, oxo, -CN, or -OH, where m is 0, 1, 2 or 3; R10 and R11 are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkenyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, -(CiC3 alkylene)C3-C6 cycloalkyl, -( (C1-C3 alkylene) 3 to 6 membered heterocyclyl, -NR15R16, or -C(O)R12, wherein each of R10 and R11 are independently optionally substituted by halogen, oxo, -CN, -CF3, -OH, -NR13R14, -C(O)NR13R14, or C1-C4 alkyl optionally substituted by halogen, oxo, -CN, -CF3, or -OH, R10 and Rüse take together with the atom or atoms to which they are attached to form a 3 to 6 membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -CF3, -OH, or C1-C4 alkyl optionally substituted by halogen , oxo, -CN, or -OH; each R12is independently halogen, cyano, C1-C4 haloalkyl, CiC4 alkoxy, C1-C4 haloalkoxy, -OR15, -NR15R16, -C(O)NR15R16, -NR15C(O)R16, -S(O)2R15, -NR15S(O)2R16, S(O)2NR15R16, Cs-Cs cycloalkyl, 3- or 6-membered heterocyclyl or C1-C4 alkyl each of which is independently optionally substituted by halogen, oxo, -CF3, -CN, -OH, NR13R14, or -NR13C(O)R14; r13 and ^14 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN, or -OH, Ri3 and Ri4 take together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -OH, or CI-C4 alkyl optionally substituted by halogen, oxo, - CN, or -OH; and each R15 and R16 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN or -OH , r15y riosetoman together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -OH, or CI-C4 alkyl optionally substituted by halogen, oxo, -CN , or -OH. In some embodiments of a compound of Formula (I), M1 is S. In some embodiments, M1 is CRla. In some embodiments, Rla is hydrogen, halogen, or C1-C4 alkyl optionally substituted by R12. In some embodiments, Rla is hydrogen. In some embodiments, Rla is halogen such as fluorine or chlorine. In some embodiments, Rla is C1-C4 alkyl such as methyl or ethyl. In some embodiments, M1 is CR and Rla is hydrogen. In some embodiments of a compound of Formula (I), M2 is S. In some embodiments, M2 is CR2a. In some embodiments, R2a is hydrogen, halogen, or C1-C4 alkyl. ΜΛ / t / ZUZZ / UÓUUOO optionally replaced by R12. In some embodiments, R2a is hydrogen. In some embodiments, R2a is halogen such as fluorine or chlorine. In some embodiments, R2a is C1-C4 alkyl such as methyl or ethyl. In some embodiments, each of M2 is CR2a and R2a is hydrogen. In some embodiments of a compound of Formula (I), M1 is S and M2 is CR2a. In some embodiments, M1 is S and M2 is CR2a, where R2a is hydrogen. In some embodiments, M1 is CRla, and M2 is S. In some embodiments, M1 is CRla, where Rla is hydrogen and M2 is S. In some embodiments, a compound of formula (II) is provided: ΜΛ / t / ZUZZ / UÓUUOO a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein X, Gi, R1, R2, R3, R2a, Zi, Z2 and Z3 are defined herein for Formula (I). In some embodiments, a compound of any of the formulas (IIa-1) to (Ila8) is provided: a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein X, Gi, R1, R2, R3, R2a, Rcl, R10, R11, R12, Zi and Wi are defined herein for Formula (i)and n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, or 4; Xi is N or C; Xz, X3, X4 and X5 are each independently C, CH, CR12, S, O, N, NH, NR12; on condition that: no more than one of X2, X3, X4 and X5 is S or O, no more than three of Xi, X2, X3, X4 and and at least one of X2, X3, X4 and Xs is CR12or NR12. In some embodiments, the compound of formula (I) is of formula (IIa-1). In some embodiments, the compound of formula (I) is of formula (IIa-2). In some embodiments, the compound of formula (I) is of formula (IIa-3). In some embodiments, the compound of formula (I) is of formula (IIa-4). In some embodiments, the compound of formula (I) is of formula (IIa-5). In some embodiments, the compound of formula (I) is of formula (IIa-6). In some embodiments, the compound of formula (I) is of formula (IIa-7). In some embodiments, the compound of formula (I) is of formula (IIa-8). In some embodiments, a compound of formula (III) is provided: a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein ). In some embodiments, a compound of any of the formulas is provided ΜΛ / t / ZUZZ / UÓUUOO (IIIa-1) to (IIIa-8): or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein X, Gi, R1, R2, R3, R2a, Rcl, R10, R11, R12, Zi and Wi are defined herein for Formula (I), and n is 0, 1, 2, 3, 4, or 5; p is 0, 1, 2, 3, or 4; Xi is N or C; X2, X3, X4 and X5 are each independently C, CH, CR12, S, O, N, NH, or NR12; provided that no more than one of X 2, X 3, X 4 and X 5 is S or O; no more than three of X 1, X 2, X 3, X 4 and X 5 are N; and at least one of X 2, X 3, X 4 and X 5 is CR12or NR12 In some embodiments, the compound of formula (I) is a compound of formula (IIIa-1). In some embodiments, the compound of formula (I) is a compound of formula (IIIa-2). In some embodiments, the compound of formula (I) is a compound of formula (IIIa-3). In some embodiments, the compound of formula (I) is a compound of formula (IIIa-4). In some embodiments, the compound of embodiments, the compound of embodiments, the compound of formula (I) is a compound of formula (I) is a compound of formula (I) is a compound of formula (IIIa-5). In some of formula (IIIa-6). In some of formula (IIIa-7). In some embodiments, the compound of formula (I) is a compound of formula (IIIa-8). In some embodiments, a compound of formula (I) is provided: x a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein: each == is independently a single bond or a double bond; X is O or S; R1 is hydrogen, C1-C3 alkyl, -(Ci-C3 alkylene)OH, C1-C3 haloalkyl, or C3Q cycloalkyl; Gi is CRao N, where: R3 is (Ci-C6)alkyl, or (Ci-C6)cycloalkyl; Zi is C-Wi-Rc; where: each Wi is independently -O- or -NRW1-, where: RW1 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, -OH, or halogen, and Rces independently C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, Ce-Cw aryl, or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by Rcl, wherein RC1 is independently halogen, C1 alkyl -C4, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, cyano, oxo, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, -OR10, -NR10Rn, -C(O)NR10Rn , -NR10C(O)Rn, -S(O)2R10, -NR^OJzR11, or -S(O)2NR10R11; Z2es C-W2-Rdo N, where: W2es -O-, -NRw2-, or a link, where: Rw2 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, -OH, or halogen, and You independently release hydrogen, halogen, cyano, 3-6 membered heterocyclyl or C1-C4 alkyl; Z3 is C-Reo N, where: Reis independently hydrogen, halogen, cyano, 3-6 membered heterocyclyl or C1-C4 alkyl; M1es S or CRla; M2 is S or CR2a, provided that when M1 is S, when the == adjacent to M1 is a single bond and = adjacent to M2 is a double bond, when M2 is S, when the ----adjacent to M2 is a single bond and = adjacent to M1 is a double bond, and at least one of M1 and M2 is not S; Ria and R2a are independently hydrogen, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, cyano, oxo, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR10, -NR10Rn, -C(O)OR10, -QOjNR^R11, -NR10C(O)Rn, -S(O)2R10, -NR10S(O)2R11o -S(O)2NR10Rn , each of which is independently optionally replaced by R12; R3is -(CH2)mNR13S(O)2R14where m is 0, 1, 2 or 3; C3-C6 cycloalkyl optionally substituted by halogen, oxo, -CN, or -OH; C1-C4 alkyl substituted by halogen, oxo, -CN, or -OH; or C1-C6 alkynyl; river and R11 are cac|a independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkenyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, -(Ci-C3 alkylene)C3 cycloalkyl -C6, -(C1-C3 alkylene) 3 to 6 membered heterocyclyl, -NR15R16, or -C(O)R12, wherein each of R10 and R11 are independently optionally substituted by halogen, oxo, -CN, - CF3, -OH, NR13R14, -C(O)NR13R14, or C1-C4 alkyl optionally substituted by halogen, oxo, -CN, -CF3, or OH, R10and R11stake together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -CF3, -OH, or C1-C4 alkyl optionally substituted by halogen, oxo , -CN, or -OH; each R12is independently halogen, cyano, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR15, -NR15R16, -C(O)NR15R16, -NR15C(O)R16, -S(O) 2R15, -NR15S(O)2R16, -S(O)2NR15R16, ΜΛ / t / ZUZZ / UÓUUOO Cj-Ce cycloalkyl, 3- or 6-membered heterocyclyl or C1-C4 alkyl each of which is independently optionally substituted by halogen, oxo, -CF3, -CN, -OH, -NR13R14, or NR13C(O)R14; R13 and R14 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN, or -OH, r13 and r14 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -OH, or CI-C4 alkyl optionally substituted by halogen, oxo, -CN, or - OH; and each R15 and R16 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN or -OH, RiSy Ri6stake together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -OH, or CI-C4 alkyl optionally substituted by halogen, oxo, -CN, or -OH. In some embodiments, there is provided a compound of formula (IVc), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above M1 is S. In some embodiments, M1 is CRla. In some embodiments, Rla is hydrogen, halogen, or C1-C4 alkyl optionally substituted by R12. In some embodiments, Rla is hydrogen. In some embodiments, Rla is halogen such as fluorine or chlorine. In some embodiments, Rla is C1-C4 alkyl such as methyl or ethyl. In some embodiments, M1 is CR and Rla is hydrogen. In some embodiments, there is provided a compound of formula (IVc), or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above M2 is S. In some embodiments, M2 is CR2a. In some embodiments, R2a is hydrogen, halogen, or C1-C4 alkyl optionally substituted by R12. In some embodiments, R2a is hydrogen. In some embodiments, R2a is halogen such as fluorine or chlorine. In some embodiments, R2a is C1-C4 alkyl such as methyl or ethyl. In some embodiments, each of M2 is CR2a and R2a is hydrogen. In some embodiments, a compound of formula (IVc) is provided, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above. In some embodiments, M1 is S and M2 is CR2a, where R2a is hydrogen. In some embodiments, M1 is CRla, and M2 is S. In some embodiments, M1 is CRla, where Rla is hydrogen and M2 is S. ΜΛ / t / ZUZZ / UÓUUOO In some embodiments, a compound of formula (I) is provided: ΜΛ / t / ZUZZ / UÓUUOO a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein A, B, R3 and R2 are as detailed herein. In some embodiments, a compound of any of the formulas (Va-1) to (Va-11) is provided: a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein A, B, R3 and R2 are as detailed herein. n is 0, 1, 2, 3, 4 or 5. In some embodiments, a compound of Formula (IV) is Formula (Va-1). In some embodiments, the compound of formula (IV) is of formula (Va-2). In some embodiments, the compound of formula (IV) is of formula (Va-3). In some embodiments, the compound of formula (IV) is of formula (Va-4). In some embodiments, the compound of formula (IV) is of formula (Va-5). In some embodiments, the compound of formula (IV) is of formula (Va6). In some embodiments, the compound of formula (IV) is of formula (Va-7). In some embodiments, the compound of formula (IV) is of formula (Va-8). In some embodiments, the compound of formula (IV) is of formula (Va-9). In some embodiments, the compound of formula (IV) is of formula (Va-10). In some embodiments, the compound of formula (IV) is of formula (Valí). In some embodiments, a compound of formula (VI) is provided: MA / t / ZUZZ / UÓUUOO a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein X, Gi, R1, R3, Rla, Zi, Z2, and Z3 are as detailed herein document for formula (IV). In some embodiments, a compound of any of the formulas (VIa-1) to (VIa-11) is provided: MA / t / ZUZZ / UÓUUOO a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein X, Gi, R1, R3, Rla, Rcl, Zi and Wi are as detailed herein for formula (IV) and n is 0, 1, 2, 3, 4, or 5. In some embodiments, a compound of formula (IV) is of formula (VIa-1). In some embodiments, a compound of formula (IV) is of formula (VIa-2). In some embodiments, a compound of formula (IV) is of formula (VIa-3). In some embodiments, a compound of formula (IV) is of formula (VIa-4). In some embodiments, a compound of formula (IV) is of formula (VIa-5). In some embodiments, a compound of formula (IV) is of formula (VIa-6). In some embodiments, a compound of formula (IV) is of formula (VIa-7). In some embodiments, a compound of formula (IV) is of formula (VIa-8). In some embodiments, a compound of formula (IV) is of formula (VIa-9). In some embodiments, a compound of formula (IV) is of formula (VIa-10). In some embodiments, a compound of formula (IV) is of formula (VIa-11). The specific values ​​described herein are values ​​for a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III) , (Illa -1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa-11), or an acceptable salt or pharmaceutically acceptable tautomer thereof. It should be understood that two or more values ​​can be combined. It should be understood that any variable for a compound of Formula (J) or any related formula may be combined with any other variable in the same manner as if each and every combination of variables were specifically and individually listed. Therefore, it should be understood that any variable for a compound of Formula (I) or any related formula may be combined with any other variable for a compound of Formula (I) or any related formula just as if any and all combinations of variables were listed specifically and individually. Any modality provided for Formula (I) is equally applicable to other formulas where applicable, such as Formula (J), just as if each and every modality were specifically and individually listed. In some embodiments of a compound of Formula (I), X is O. In some embodiments of a compound of Formula (I), X is S. In some embodiments of a compound of Formula (J) or any related formula where applicable , X is as provided herein to the same extent as described for Formula (I). R1 is hydrogen, C1-C3 alkyl, -(Ci-C3 alkylene)OH, C1-C3 haloalkyl, or C3-C4 cycloalkyl; In some embodiments of a compound of Formula (I), Y is hydrogen. In some embodiments of a compound of Formula (I), R1 is C1-C3 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl. In some embodiments of a compound of Formula (I), M1 is CH. In some embodiments of a compound of Formula (I), R1 is selected from the group consisting of: In some embodiments of a compound of Formula (I), M1 is CH. In some embodiments of a compound of Formula (I), R1 is -(aiquiienoc 1-C3)OH, such as methanol, ethanol, 1-propanol or 2-propanol. In some embodiments of a compound of formula (J) or any related formulas where applicable, R1 is as presented herein to the same extent as described for Formula (I). In some embodiments of a compound of Formula (I), Ri is F. In some embodiments, Ri is Cl. In some embodiments of a compound of Formula (I), Y is hydrogen. In some embodiments, r3 is C1-C4 alkyl. In some embodiments, Ri, R40, and R41 are each hydrogen. In some embodiments of a compound of formula (J) or any related formulas where applicable, G 1 is as provided herein to the same extent as described for Formula (I). In some embodiments of a compound of formula (J) or any related formulas where applicable, R2 is as provided herein to the same extent as described for Formula (I). In some embodiments of a compound of Formula (I), R2 is selected from the group consisting of: In some embodiments of a compound of Formula (I), M2 is CH. In some embodiments of a compound of Formula (I), R2 is selected from the group that ΜΛ / t / ZUZZ / UÓUUOO consists of: In some embodiments of a compound of Formula (I), R2 is C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl , or sec-butyl. In some embodiments of a compound of Formula (I), R2 is F. In some embodiments, Ri is Cl. In some embodiments of a compound of Formula (I), M2 is CH. In some embodiments, R2 is methyl. In some embodiments of a compound of Formula (I), M2 is CH. In some embodiments, R2 is CONH3. The compound according to any of claims 1 to 11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that R2 is -C(O)NR10Rn, 5 to 10 membered heteroaryl, -(C1-C3 alkylene) 3- to 6-membered heterocyclyl, or C1-C4 alkyl, each of which is optionally independently substituted with R12. In other embodiments, R2 is -C(O)NR10S(O)nR12. In some embodiments, when R2 is -C(O)NR10R11which is optionally substituted with R12, then R3 is C3-C6 cycloalkyl or c1-C4 alkyl substituted with halogen, oxo, -CN, or -OH. The compound according to claim 12, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that R2 is -C(O)NR10Rnwhich is optionally substituted with R12, wherein R10 and R11 are each independently hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl, or R10 and R11 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen. In some ΜΛ / t / ZUZZ / UÓUUOO In some embodiments, R2 is a 5- to 10-membered heteroaryl optionally substituted with R12. In some embodiments, R2 is a 5- to 10-membered heteroaryl that is unsubstituted. In some embodiments, R2 is a 5- to 6-membered heteroaryl optionally substituted with R12. In some embodiments, R2 is a 5- to 6-membered heteroaryl that is unsubstituted. In some embodiments, R2 is a 5- to 6-membered heteroaryl optionally substituted with R12. In some embodiments, R2 is a 6-membered heteroaryl that is unsubstituted. In some embodiments, R2 is a 5- to 5-membered heteroaryl optionally substituted with R12. In some embodiments, R2 is a 5tN-m heteroaryl W J ?Nmembers who are not replaced. In some embodiments, R2 is O O O, each of which is optionally replaced independently with R12. In some modalities, of which is optionally substituted with R12- in which each R12 is independently alkyl Ci-4 haloalkyl, ci-c4 alkoxy, -NR15R16- or C1-C4 alkyl. In some embodiments, R2 is of C1-C4 optionally replaced with one or more R12. In other embodiments, B is a 5-heteroaryl. 6-membered ΜΛ / t / ZUZZ / UÓUUOO optionally replaced with R12. In some embodiments, R2 is - (C1-C3 alkylene) 3-a heterocyclyl that is unsubstituted 6-membered. In some embodiments, R2 is some modalities, R2es MA / t / ZUZZ / UÓUUOO MA / t / ZUZZ / UÓUUOO In some embodiments of a compound of Formula (J) or any related formula where applicable, the C ring is as provided herein to the same extent as described for Formula (I). R2 is halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered heterocyclyl -(C1-C3 alkylene), 5-10 membered heteroaryl, cyano, oxo, haloalkyl C1-C4, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR10, -NR10Rn, -C(O)OR10, -QOjNR1^11, -NR^OjR11, -S(O)2R10, -NR10S( O)2Rn, or -S(O)2NR10Rn, each of which is independently optionally substituted by R12; In some embodiments, R2 is -C(O) NR10R11, 5- to 10-membered heteroaryl or ci-C 4 alkyl, each of which is optionally independently substituted with R12. In some embodiments, R2 is -C(O)NR10R11, 5- to 10-membered heteroaryl optionally substituted with -NR15R16, OR15o C1-C4 alkyl optionally substituted with halogen, or C Aiquio 1 -C 4 optionally substituted with -NR13R14. In some embodiments of a compound of Formula (I), MI is CH. In some / Rlají>^r2 In modalities of a compound of Formula (I), the C ring is , where the wavy lines denote points of union with the A ring. In some embodiments of a compound of Formula (I), the C ring is selected from the group consisting of: Μ A / t / ZUZZ / UÓUUOO Μ A / t / ZUZZ / UÓUUOO In some embodiments of a compound of Formula (I), the C ring and In some embodiments of a compound of Formula (I), Wi is O and Zi is C-O-Rc. In some embodiments of a compound of Formula (I), Wi is -NRW1- and Zi is C-NRW1-RC. In some embodiments of a compound of Formula (I), RW1 is hydrogen, C3-C6 cycloalkyl or Ci32 alkyl. Q optionally substituted by oxo, OH or halogen. In some embodiments of a compound of Formula (I), RW1 is hydrogen. In some embodiments of a compound of Formula (I), Rw1 is C3-C6 cycloalkyl. In some embodiments of a compound of Formula (I), RW1 is CiC4 alkyl optionally substituted by oxo, OH or halogen. In some embodiments of a compound of Formula (I), Rwles methyl. In some embodiments of a compound of Formula (I), Wi is -NH- and Zi is C-NH-RC. In some embodiments of a compound of Formula (J) or any related formula where applicable, W 1 and Z 1 are as provided herein to the same extent as described for Formula (I). In some embodiments of a compound of Formula (I), Rc is C6-C14 aryl or 5- or 6-membered heteroaryl, wherein the C6-C14 and 5- or 6-membered aryl, Rc heteroaryl are independently optionally substituted with Rcl. In some embodiments, each RC1 is independently halogen or C1-C4 alkyl. In some embodiments of a compound of Formula (I), Rces Ce-Ci4 alryl optionally substituted by Rcl. In some embodiments of a compound of Formula (I), Rces Ce-Ci4 aryl that is unsubstituted. In some embodiments of a compound of Formula (I), Rces phenyl is optionally substituted by Rcl. In some embodiments, Rces phenyl that is unsubstituted. In some embodiments, R is phenyl optionally substituted by Rcl, where each RC1 is independently halogen or C1-C4 alkyl. In some embodiments, R is phenyl optionally substituted by Rcl, where each RC1 is independently methyl or fluorine. In some embodiments of a compound of Formula (I), Rces 5- to 6-membered heteroaryl optionally substituted by Rcl. In some embodiments, Rces 5- or heteroaryl that is unsubstituted, such as pyridinyl, pyrazinyl, pyridazinyl, primidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, thiazolyl, or furanyl, each of 6 members of which is not replaced. In some embodiments, R is 5- or 6-membered heteroaryl optionally substituted with Rcl, such as pyridinyl, pyrazinyl, pyridazinyl, primidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, thiazolyl or furazolyl., each of the which is optionally independently substituted with Rcl. In some embodiments of a compound of Formula (J) or any related formula where applicable, R1 is as provided herein to the same extent as described for Formula (I). In some embodiments, R is C3-C6 cycloalkyl optionally substituted by Rcl' where each RC1 is independently halogen or C1-C4 alkyl. In some embodiments, each RC1 is halogen. In some embodiments, Rc is C6-C14 aryl, 5-6 membered heteroaryl, or C3-C6 cycloalkyl, wherein each Rc is optionally substituted by RcL. In some embodiments of a compound of Formula (I), Rces MA / t / ZUZZ / UÓUUOO where wavy lines denote junction points and n is 0, 1, 2, 3, 4, or 5. In some embodiments, R' (Rc1)nc(Rc1)n is . In some embodiments, Rces. In some modalities, Rces (RCl)n Ny . In some embodiments, Rces (RCl)n . In some modalities, Rces (RCl)n . In some embodiments, Rces (Rc1)n . In some modalities, Rces (Rc1)n. In some embodiments, R3 is (Rc1)n (RCl)n (RCl)n NY In another embodiment, each R6 is independently (C1-C4) alkyl. In some embodiments of a compound of Formula (I), Rc is selected from the group MA / t / ZUZZ / UÓUUOO Μ Λ / t / ZUZZ / UÓUUOO F FA¿1 RcesF. In some embodiments, RcesF F. In some embodiments, Rces In some embodiments of a compound of Formula (I), Z 2 is N. In some embodiments of a compound of Formula (I), Z2 is CW2 -Rd. In some embodiments of a compound of Formula (I), W 2 is -O-. In some embodiments of a compound of Formula (I), M2 is CH. In some embodiments of a compound of Formula (I), M2 is CH. In some embodiments of a compound of Formula (I), RW2 is hydrogen or Ci-C4-achyium optionally substituted by oxo, OH or halogen. In some embodiments of a compound of Formula (I), Y is hydrogen. In some embodiments, Rw2 is C1-C4 alkyl optionally substituted with one or more -CN. In some embodiments of a compound of Formula (I), Rw2 is methyl. In some embodiments of a compound of Formula (I), Rw2 is C3-C6 cycloalkyl. In some embodiments of a compound of Formula (I), M2 is CH. In some embodiments of a compound of Formula (I), Y is hydrogen. In some embodiments of a compound of Formula (J) or any related formula where applicable, Z 2 is provided herein to the same extent as described for Formula (I). In some embodiments of a compound of Formula (I), Y is hydrogen. In some embodiments of a compound of Formula (I), R2 is C1-C4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl. In some embodiments, R2 is methyl. In some embodiments, Z 2 is CW 2 -Rd, where W2 is a bond and Rd is hydrogen. In some embodiments of a compound of Formula (I), Z3 is N. In some embodiments of a compound of Formula (I), Z3 is C-Re. In some embodiments of a compound of Formula (I), Rees hydrogen. In some embodiments of a compound of Formula (I), Reis halogen, such as fluorine, chlorine, bromine or iodine. In some embodiments of a compound of Formula (I), Rees cyano. In some embodiments, Reis 3- to 6-membered heterocyclyl, such as tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl. In some embodiments, Reis C1-C4 alkyl such as methyl, ethyl, n-propyl or isopropyl. In some embodiments, Z3 is C-King Rees hydrogen. In some embodiments of a compound of Formula (J) or any related formula where applicable, Zi is as provided herein to the same extent as described for Formula (I). In some embodiments of a compound of Formula (I), R3 is - (CHz)m NR13S (O) 2 R14o C1-C4 alkyl substituted with halogen, oxo, -CN or -OH. In other embodiments, R3 is (CH2)mNR13S(O)2R14. In some embodiments of a compound of Formula (I), m is 0. In some embodiments of a compound of Formula (I), m is 1. In some embodiments of a compound of Formula (I), m is 2. In some embodiments of a compound of Formula (I), m is 0. In some embodiments of a compound of Formula (I), m is 1. In some embodiments of a compound of Formula (I), m is 2. In some embodiments of a compound of Formula (I), m is 3. In other embodiments, R3 is -(CH2)mNR13S(O)2R14, where m is 0. In some embodiments, R3 is - (CHzjm NR13S(O)2R14, in where m is 0 and R13 and R14 are each independently hydrogen or C1-C4 alkyl. In some embodiments, R3 is - (CHzjm NR13S (0)2 R14, where m is 0, R13 is hydrogen and R14 ΜΛ / t / ZUZZ / UÓUUOO0A° A is Ci-C 4 alkyl such as methyl, ethyl, n -propyl or isopropyl. In some embodiments, R3 is h. In some embodiments of a compound of Formula (I), RW1 is C1-C4 alkyl optionally substituted by oxo, OH or halogen. In some embodiments of a compound of Formula (I), R3 is C1-C4 alkyl optionally substituted by oxo, OH or halogen. In some embodiments of a compound of Formula (I), R3es H.O. . In some embodiments of a compound of Formula (I), R3es H.O. In some embodiments, R3 is In some sheet embodiments, R3 is , where wavy lines denote joining points. In some embodiments of a compound of Formula (J) or any related formula where applicable, R3 is as provided herein to the same extent as described for Formula (I). In some embodiments of a compound of Formula (J) or any related formula where applicable, such as a compound of Formula (I), R3 is. In some embodiments R3 is C3-C6 cycloalkyl optionally substituted by halogen, oxo, -CN, or -OH. In some embodiments R3 is C3-C6 cycloalkyl optionally substituted by halogen, oxo, -CN, or 37 OH. In some embodiments, R3 is unsubstituted C3-C6 cycloalkyl. In some embodiments, R3 is H.O. ΜΛ / t / ZUZZ / UÓUUOO some modalities, R3es. In some embodiments, R3 is wavy denote joining points. In some embodiments of a compound of Formula (J) or any related formula where applicable, such as a compound of Formula (I), the compound has one or more of the following characteristics: X is O; R1 is C1-C3 alkyl such as methyl; Gi is CRa, where Ra is hydrogen; Z2is CH; Z3is CH; R2es j H° O HN—2HN—< H H -C(O)NR10Rnoptionally substituted by R12, such as 0, F F , O , -3-6 membered (Ci-C3 alkylene)heterocyclyl optionally substituted by R12, such as D / R3es A __ / N -(CH2)mNR13S(O)2R14, such as H, or sheet C1-C4 alkyl substituted by -OH, such as; and In some modalities, (I) applies. In some modalities, (II) applies. In some modalities, (III) applies. In some modalities, (IV) applies. In some modalities, (V) applies. In some modalities, (VI) applies. In some modalities, (VII) applies. In some modalities, (VIII) applies. In some embodiments, (1) applies. In some modalities, (2) applies. In some modalities, (3) applies. In some modalities, (4) applies. In some modalities, (5) applies. In some embodiments, (I), (II), (III), (IV), (V), (VI), (VII) and (VIII) apply. In some embodiments, (I), (II), (III), (IV), (V), and (1) apply. In some embodiments, (I), (II), (III), (IV), (V), and (4) apply. In some embodiments, (I), (II), (III), (IV), (V), and (5) apply. In some embodiments, (I), (II), (III), (IV), (V), and (VIII) apply. In some embodiments, (I), (II), (III), (IV), (V), and (2) apply. In some embodiments, (I), (II), (III), (IV), (V), and (3) apply. In some embodiments, (I), (II), (III), (IV), (V), (1), (VII) and (VIII) apply. In some embodiments, (I), (II), (III), (IV), (V), (2), (VII) and (VIII) apply. In some embodiments, (I), (II), (III), (IV), (V), (3), (VII) and (VIII) apply. In some embodiments, (I), (II), (III), (IV), (V), (VI), (4) and (VIII) apply. In some embodiments, (I), (II), (III), (IV), (V), (VI), (5) and (VIII) apply. In some modalities, (VIII) and (4) apply. In some embodiments, (VIII) and (5) apply. In some embodiments, (1) and (VIII) apply. In some embodiments, (2) and (VIII) apply. In some modalities, (3) and (VIII) apply. In some ΜΛ / t / ZUZZ / UÓUUOO modalities, (1) and (4) apply. In some embodiments, (1) and (5) apply. In some modalities, (2) and (4) apply. In some embodiments, (2) and (5) apply. In some modalities, (3) and (4) apply. In some embodiments, (3) and (5) apply. In some embodiments of a compound of Formula (J) or any related formula where applicable, such as a compound of Formula (I), the compound has one or more of the following characteristics: (1-1) X is O; (II-l) R1 is C1-C3 alkyl such as methyl; (III-l) Gi is CRa, where Ra is hydrogen; (IV-1) Z2es CH; (V-l) Z3es CH; (VI-1) R2es (3-1)-3- to 6-membered (Ci-C3alkylene)heterocyclyl optionally substituted by R12, such as ΜΛ / t / ZUZZ / UÓUUOO (4-1) hydrogen; (VII) R3es __ / N (5-1) - (CH2)rn NR13S (0)2 R14, as H HO. (6-l)C1-C4alkyl substituted by -OH, as NC \ (7-1) C3-C 6 cycloalkyl optionally substituted with halogen, oxo, -CN or -OH, such as , or 8) to C26 ryl, and jCX (VIII-1) Z 1 is CORc, where Rces phenyl optionally substituted with Rcl, such as F In some modalities, (1-1) applies. In some modalities, (II-l) applies. In some modalities, (III-l) applies. In some modalities, (IV-1) applies. In some modalities, (V-l) applies. In some modalities, (VI-1) applies. In some modalities, (VII-1) applies. In some modalities, (VIII-1) applies. In some modalities, (1-1) applies. In some modalities, (2-1) applies. In some modalities, (3-1) applies. In some modalities, (4-1) applies. In some modalities, (5-1) applies. In some modalities, (6-1) applies. In some modalities, (7-1) applies. In some modalities, (8-1) applies. In some embodiments, (1-1), (II-l), (III-l), (IV-1), (V-l), (VI1), (VII-1), and (VIII-1) apply. In some embodiments, (1-1), (II-l), (III-l), (IV-1), (V-l), (VII-1) and (VIII-1) apply. In some embodiments, (1-1), (II-l), (III-l), (IV-1), (V-l), and (VIII-1) apply. In some embodiments, (1-1), (II-l), (III-l), (IV-1), (V-l), and (1-1) apply. In some embodiments, (1-1), (II-l), (III-l), (IV-1), (V-l), and (5-1) apply. In some embodiments, (1-1), (II-l), (III-l), (IV-1), (V-l), and (6-1) apply. In some embodiments, (1-1), (II-l), (III-l), (IV-1), (V-l) and (VIII-1) apply. In some embodiments, (1-1), (II-l), (III-l), (IV-1), (V-l) and (2-1) apply. In some embodiments, (1-1), (II-l), (III-l), (IV-1), (V-l) and (3-1) apply. In some embodiments, (1-1), (II1), (III-l), (IV-1), (V-l), (1-1), (VII-1) and (VIII- 1) apply. In some embodiments, (1-1), (II-l), (ΙΠ1), (IV-1), (V-l), (2-1), (VII-1) and (VIII- 1) apply. In some embodiments, (1-1), (II-l), (ΙΠ-1), (IV41 1), (V-l), (3-1), (VII-1) and (VIII- 1) apply. In some modalities, (1-1), (II-l), (III-l), (IV-1), (V-l), (VI-1), (5-1) and (VIII-1) apply . In some embodiments, (1-1), (II-l), (III-l), (IV-1), (V-l), (VI-1), (61) and (VIII-1) apply. In some modalities, (VIII-1) and (5-1) apply. In some embodiments, (VIII1) and (6-1) apply. In some embodiments, (1-1) and (VIII-l) apply. In some modalities, (2-1) and (VIII-l) apply. In some modalities, (3-1) and (VIII-1) apply. In some modalities, (1-1) and (5-1) apply. In some modalities, (1-1) and (6-1) apply. In some modalities, (2-1) and (5-1) apply. In some modalities, (2-1) and (6-1) apply. In some modalities, (3-1) and (5-1) apply. In some embodiments, (3-1) and (6-1) apply. In some embodiments, (1-1), (II-l), (ΙΠ-1), (IV-1), (V-l), and (7-1) apply. In some embodiments, (1-1), (II-l), (III-l), (IV-1), (V-l) and (6-1) apply. In some embodiments, (1-1), (II-l), (ΙΠ-1), (IV-1), (V-l), (1-1) and (VIII-1) apply. In some embodiments, (1-1), (II-l), (III-l), (IV-1), (V-l), (7-1) and (VIII-1) apply. In some embodiments, (1-1), (II-l), (III-l), (IV-1), (V-l), (6-1) and (VIII-1) apply. In some embodiments, (1-1) and (VIII1) apply. In some modalities, (7-1) and (VIII-1) apply. In some modalities, (6-1) and (VIII-1) apply. In some embodiments, (1-1), (VII-1) and (8-1) apply. It should be understood that any variable for a compound of Formula (J) or any related formula, where applicable, such as a compound of formula (I) may be combined with any other variable for a compound of formula (J) or any related formula when applicable. applicable, as a compound of formula (I), the same as if each and every combination of variables were specifically and individually listed. It is understood that each description of B can be combined with each description of R1 and / or R1 in the same way as if each and every combination were listed specifically and individually. Similarly, it is understood that each description of B can be combined with each description of A (and furthermore with each description of R1 and R2) just as if each and every combination were specifically and individually listed. It is also understood that each description of each variation in ring B (R3, Z i, Z 2, Z 3) can be combined with each description of each variation in ring A (X, R \ G 1) in the same way as if each and every combination were specifically and individually listed. It is similarly understood that each description of each variation in ring B (R3, Z 1, Z 2, Z 3) can be combined with each description of each variation in ring C (Μ\M2, R2) of the same so that if each and every one of the combinations were listed specifically and individually. For example, in one aspect, it is understood that each description of each variation of ring B may be combined in one aspect with a variation of ring A in which X is O; G 1 is CH; yR1 is methyl. In one such variation, ring B is as defined in any variation herein, a ring is with variables such as X are O; G 1 is hydrogen; R1 is methyl; and ring C is substituted thiophenyl. As another example, in another aspect, there is provided a compound, or a tautomer or isomer thereof, or MA / t / ZUZZ / UÓUUOO ΗΟ a pharmaceutically acceptable salt of any of the above, wherein R3 is; Z 2 . As another example, it is provided ΜΛ / t / ZUZZ / UÓUUOO a compound, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of _ any of the above, where R3 is Η; z2 and Z3 are CH; and Zi is CWi -Rc, where - Also provided are salts of compounds referred to herein, such as pharmaceutically acceptable salts. The invention also includes any or all stereochemical forms, including any enantiomeric or diastereomeric form, and any tautomer or other forms of the described compounds. A compound as detailed herein may, in one aspect, be in purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof, such as compositions of substantially pure compounds, are provided. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. Unless otherwise indicated, substantially pure means a composition containing no more than 35% impurity, wherein the impurity indicates a compound other than the compound comprising the majority of the composition or a salt thereof. In some embodiments, a substantially pure compound composition or a salt thereof is provided wherein the composition contains no more than 25%, 20%, 15%, 10% or 5% impurity. In some embodiments, a substantially pure compound composition or a salt thereof is provided wherein the composition contains or contains no more than 3%, 2%, 1% or 0.5% impurity. Representative compounds are listed in Table 1. It is understood that the individual enantiomers and diastereomers, if not represented, and their corresponding structures can be easily determined from them. TABLE 1 MA / t / ZUZZ / UÓUUOO Representative compounds Com. No. Structure Com. No. Structure 1 LL Z ,O τ Y' —c V o ' ° \ #—\ / / o X 2 M °v^ 0 0 \ #—c # / 0 X 3 X O / \--Λ Γ-- Ζ. \ / --\ π O 4 w 0 0 Π / 4 zax° ¥¥ o ' 0 \ #—C # C / K Γ 5 X o / \--Λ / J~Z. \ / —\ ¥° -Π 0 4 ω 0 TI J ¥ 6 X 0 / A— \ / —\ ¥° -n 0 4 m P ° 0 7 A O \ ¥¥ Q N—' N |Γ~\__ / Γ ¥ ¥ Ί ho¥^ F F 8 0 \NA_S 1 Γ >—P N / ¥o\ / a 1J 12 F F ​​9 zy°_^A ω^Α o ' ' 0, ,ZI Γ 10 Λ O ÍO^ 0 ' 0 \ #—c # / 0, ,ZI ωχ Γ Μ Λ / t / ZUZZ / UÓUUOO Com. No. Structure Com. No. Structure 21 I O / “X / \r—z \ / —\ Xo -π o 4 in 4 ° o 22 1 ° / \— / 1—^· \ / —\ X° n O G in ti 23 ° \ #—4 # Z^ '- / O 1 24 LL LL GG ω G 0 u0 \ #—4 # / Z 0 °7 25 F x ÓF \ q n—' N |[ \___ / 0 ° / JO 1JL H 26 G cnC IZG y—z \ / —\ Xo -Π O 4 in 0 g 27 G en Y-Λ Λ—z \ / —\ Xo -n O 4 in cn^ JggG0 \ 0 G w 4 / 7 o^z-^G -Π 29 G4 ω G 0 ll. 0 \ #—4 # Z.—' '—¿ ' 0 r 30 / —0 i tíj \ ς N—' N |G \_ / 1° Γ J 1 J h(G[^^ f Com. No. Structure Com. No. Structure 31 F ° dF H 32 L? GO-^ TC Y--Λ z \ / —\ )=° \ O k ω Π ΊΊ 33 \=z Λ z^ o / / \ o ' ° \ #—\ / Έ.—' ^=\ ' o X 34 Co ' xo IH\ / / =\ / Γ^ \ —\ 1° \ O k ω k / / O^z - K 35 °k 36 o=<^ \ / zx Ox / 37 \ü ω o u° \ #—\ / / Z Os ,ZZ ϊω °7 38 0 i F π H Vjj Yl H 39 0 N Υτ s\__ / / N N L 1 ?—\ J1 N^\ H / k XX v ij TI F^^^F H 40 G ωζ / xo IZ\ / >=\ ¿ —(J Go -n O k ω yX λ» Μ A / t / ZUZZ / UÓUUOO Com. No. Structure Com. No. Structure 41 G -Π O G ω -Π / IZ \ 42 G ωζ / xo IZ\ / / =\ / X2 ¿ \-G \=o n O G ω p 5 o / 43 G -Π O G ω pS o / 44 0 __ / zN'N i II / —\ U s^x VJÍJ JJl H 45 G σ< -- z / gG=g -Π O G ω 0 0 o ω 46 \=z G Gz° GA ω G o \ ° \ / 7—\ / 'Z.—' \= / / ΖΞ Ox / ico G 47 0 Nóc^¿X jGoo, H 48 G^ Λ Zx ZI / / G »G> Q \ ° \ #—\ / / Z o. A 49 0 ΥΧΜχ x¿0 -- H 50 o H Μ Λ / t / ZUZZ / UÓUUOO Μ Λ / t / ZUZZ / UÓUUOO Μ Λ / t / ZUZZ / UÓUUOO Com. No. Structure Com. No. Structure 71 b T, O / ,o O5 wb 1 ( °Λ ω 72 £r XY i 1 \ o w / / / — ° \jy) 73 {Vf%o —A F 0 (^Ύ~Ρ χ> ϊ Η 75 0 χ. 77 I ο / \--Λ Γ--Ζ. \ / --\ / ^Ο \ O ¿ ω 78 λ Q ο ' ° \ #—C # / 0. ,ΖΙ ωχ Vo 79 0 ^Ν^ιΓ^\ / ΧΝ i II XX η Ο-\ XX χχ / / Ν f F ° Η 80 ο / / Ν'Ν L L / —\ 11 Γ ϊ J Ί F^^^F ΗΟ Μ Λ / t / ZUZZ / UÓUUOO Μ Λ / t / ZUZZ / UÓUUOO Com. No. Structure Com. No. Structure 101 I O / / =\ ¿ -Y \ ο / / O^Z. )----- \ / Y Z \ 102 O 'φ <k χχ°:α, H 103 0 Y^S ON Y JO XX H 104 O xArofi^ Y^s crN Y jfX Xjj H 105 0 ιΓΎ 'N' n i h yn । Y^s / L / 0. Y Xj XX N^'^ F^'^^'F H 106 O । r y^z η Y^S N'N H Y £Ύ XX H 107 0 ^n^iTA Λν i I / —\ 11 V^s N V 1 H Y jfj XX H 108 pY X tí F ω o u° \ F—\ / ^=< / ZI Οχ / ϊω Ώ 109 0 Yr^\ / ^N । 11 / —\ ii Y^s O^ YJj XX H 110 o ϊ Χτνγγ crN A / Ox V Xj XX H Μ Λ / t / ZUZZ / UÓUUOO Com. No. Structure Com. No. Structure 111 G ωζ IZC! 0^0° -π O ω G PA o / 112 0 iGG / / Nn i II >—κ 11 G^s s^x V ΓΎ YX H 113 G - CMG° -Π O ω G 0 oG o ω 114 G ωί / Ό IZ\ / >=\ ^Z ¿ )>- / 0O \ O ω 0 / — ' / m z \ 115 0 jvxa, H 116 0 -ΛΗΪ H 117 0 -- H 118 O n¿QGg ^<¿00 .. H 119 W sxM” H 120 G ωζ / xo IH\ / G=\ z^z ¿})—X \=o \ O ω G G y ω xz -Π Μ A / t / ZUZZ / UÓUUOO Com. No. Structure Com. No. Structure 121 0 ιΤΑ / / Nn l l aa íl . s^\ Α^ / Ο,^Α. Π 11 x\^\F HO 122 0 iTA / An i II 7—ii s^x ΛJ ΛΑ HO 123 0 AxMaCF3 H 124 T O / / =\ Π- ~z. ¿ Y— / \ O ω V y O^z T2 o ω 125 G IZG \ o ω G AAA -n °A O / 126 I ° / / =\ ¿ Y-'Go \ ° ω\Α Pm o / 127 O \ A _ XX JA / v Q VG N'u Λ J IjL hcA|^ F F 128 0 ιΤΆ / N'n L 1 1 í T I A ​​^>7^ F HO 129 '{ü <Λ O U- O \ #- -\ / / 2^ ^=\ / O I 130 xA uγϋ °A>h / v_ / o X Μ Λ / t / ZUZZ / UÓUUOO Μ Λ / t / ZUZZ / UÓUUOO Μ Λ / t / ZUZZ / UÓUUOO Com. No. Structure Com. No. Structure 151 9 o ' ° / o X 152 xz xz o ' ° \ #—tí # Z^ —\ / O \ / --\ )=° \ O ti ω 154 X 0 / \-A n-Z. \ / —\ )=° \ O ti θ' ti / / -Z7 zx 'Q 155 LL ωΑ O ' ° \ / 7—4 # / Z^ '—\ / 0 X 156 / / —z^z< / \ / —\ / ^° \ O ω tí ¿ Λ— _tí q / 157 0 txHO 158 otí ωχ x<° / y—λ z \ / —\ )=° -Π O tí ω tí| 159 V tí 0 \ #—€ / 7 Z^7 '—\ / O X 160 0 ΝΗ~Λ uOh a 0 tíj títí. / / N F 0 H Μ Λ / t / ZUZZ / UÓUUOO TABLE 2 MA / t / ZUZZ / UÓUUOO Representative compounds CompoundNo. Structure Composite No. Structure 2.1 o óo 1 Γ J 1 Ί HO^f F 2,330.36 (2.2) I O / / Xyy>° 2,330.36 (2.3) O / —X. / Π O ω Λ 0 2,330.36 (2.4) / O Λ at P 0 2,330.36 (2.7) I o / ~X. / τι O ω X 2,330.36 (2.8) I 0 / n 0 X ω 2,330.36 (2.9) O 2,330.36 (2.10) O NÓO χοχχχ HO | 2,330.36 (2.11) O X ^χχ XXFXXF HO | 2,330.36 (2.12) O -UCX XX HO | CompoundNo. Structure Composite No. Structure 2,330.36 (2.13) I o / A. / ¿aa >° O ω A 0 O 2,330.36 (2.14) o Ά AU LA HOT^ ^Cl 2,330.36 (2.15) I O / A. / alaa π O ω 2,330.36 (2.16) I ° / A. / π O Λ ω 2,330.36 (2.17) O / A. / AyAA y p 2,330.36 (2.18) ω / Α / Αν 2,330.36 (2.19) I O / A. / ααγ>° z \ / \ y 2,330.36 (2.20) z ° / A. / y / ” 2,330.36 (2.21) I o / yA-jA0 A 2,330.36 (2.22) o ''M'Ar-A nALL ,ΑάΆ^ r y JA F 2.23. Λ y ω o u°AA-O z-z M / A / o T 2.24. I ° / yyA>° Π O 0. ω P Μ Λ / t / ZUZZ / UÓUUoO CompoundNo. Composite Structure No. Structure 2.25. °γΧ) / / or I 2.26. or f Γ J ϊ Ί HoT^ F^F 2.27. I O / / O ω Δ .0 2.28. ΞΓ O / / O 4. ω P 2.29. or if3 VW i JX^X — F 2.30. I 0 z 2.31. ,, rf 7 ω O u° Vi) / )<1 O I 2.32. V « 7 0 u0 vXvX 7 )<| OR T 2.33. o r ° vXj / Vi o T 2.34. 0 v «70 7 V| 0 T 2.35. <^'<n o u°γΧ) 7 )0 O I 2.36. I O / n O 0 ω Μ Λ / t / ZUZZ / UÓUUOO CompoundNo. Composite Structure No. Structure 2.37. or [ II || | HO^A^N / ^Af 2.38. I 0 X. / Ο-Γ>° z \ / \ \ O 4. ω Λ 2.39. ω O ll / =< / =2 / )0 o T 2.40. or | II AND I HO. A.n AA — F F 2.41. I or Λ. / π or ω Λ 2.42. 0 O F Λ\ζ°^χΑ 1 η Y i ηο^Α^,ν fAA.n 2.43. o -n Λα 2.44. 0 Νόθ 2.45. O Λ ιΓΛ f θκ^ ρΛ 2.46. I O / νΎ^ν>° Λ / ω 2.47. or Λ\ / Zy^v° O in P 2.48. I o Λ< / O 4. ω P Μ Λ / t / ZUZZ / UÓUUOO CompoundNo. Composite Structure No. Structure 2.49. or 0 if3 2.50. or '0 nc^Cj JX^f 2.51. z o / ΓτΛο τι O in Λ 0 ΊΊ 2.52. or F—F 2.53. or 0 ° / )<| or z 2.54. z o O 0 in 0 O 2.55. or ΧϋΓΛ Y^~s F NC. J F 2.56. z o νΧ^Χ° π O ¿. in 2.57. O óo T^S 1 | II II ] NC. 2.58. 0 I 11 II 1 NC. Αχ 2.59. z o 0\ / ¿y^v° z \ z\ π O ω X 0 2.60. ,0 ω 0 u / =< / ^z O\J\J / )<] 0 z Μ A / t / ZUZZ / UÓUUOO CompoundNo. Composite Structure No. Structure 2.61. z or [G. 7 2= / Yx π O ω T 2.62. O ω y 0 □_ 7 )<] o z 2.63. or 1 G\^o._G 2.64. 7 7<] or z 2.65. LL W L ° vYO 7 )<| or z 2.66. LL· ω % O u° TYQ 7 7<] o z 2.67. G ω X o °TYO / o z 2.68. z o 7 O 4. ω .0 2.69. G. / and 2.70. Gf / R 2.71. Gf / <h {y π O ω X P 2.72. G « X O LL 0 vYO 7 Μ A / t / ZUZZ / UÓUUOO CompoundNo. Composite Structure No. Structure 2.73. o and ω O / \ 2.74. o ,, p w o / y 2.75. or y iry 1 2.76. or 2.77. z or, “X. / yyyyo 2.78. z O / / yyyy° y 2.79. or ry and ί NC | 2.80. o 'N¿0 r y y ί NC | 2.81. z O / “X. / yyyzvo O ω P P o 2.82. z O / / yyyy° O Ρω P o 2.83. z o , “X' / ^yyyo ΊΊ 2.84. z O / / y Μ Λ / t / ZUZZ / UÓUUOO CompoundNo. Composite Structure No. Structure 2.85. z O / X. / π o ω λ P 2.86. z O / / <yr>° z \ / \ π O Λ ω Ρ 2.87. ,G 'o. ,ZI G 2.88. L. ωζ I2C ζΥΥ>° \ O Λ ω P 2.89. χ ω o '}=( \=z / o. ,ZI 2.90. o 'N¿O H 2.91. G IZC QYPO n O tn J 0 2.92. G ωί I2C n O P ω P 2.93. O G / ~s <G° r Y Y η Α^,,ν A.G N F F H 2.94. o 'NÓG GP N F F H 2.98. Po -c° <qax>° ή O P ω CompoundNo. Composite Structure No. Structure 2.99. G vi' -y n O m . z; 2,100. O F XXIj H 2.101. ω o ' 7 o. 2,102. G ωζ -y \ O G. w 2.103. o ΛαΟ G^~~S o o Ότι S / 0 > L 'N ·^ ΆΓ H F 2.104. 0 'ÓO o o ΟΥ τ 1 S ,Ό J L / Of 'N ·' / ' H F ΜΛ / t / ZUZZ / UÓUUOO In some embodiments, compounds described in Table 1 are provided herein, including pharmaceutically acceptable salts thereof and uses thereof. In some embodiments, compounds 1-147 are provided herein, including either a pharmaceutically acceptable salt, hydrate, solvate, isotope, individual isomer, or mixtures of isomers thereof, and uses thereof. In some embodiments, compounds 2.12.104 are provided herein, including either a pharmaceutically acceptable salt, hydrate, solvate, isotope, individual isomer or mixtures of isomers thereof, and uses thereof. The embodiments and variations described herein are suitable for compounds of any formula detailed herein, where applicable. Representative examples of compounds detailed herein are described herein, including intermediates and final compounds according to the present description. It is understood that, in one aspect, any of the compounds may be used in the methods detailed herein, including, where applicable, intermediate compounds that may be isolated and administered to an individual. The compounds represented herein may be present as salts even if salts are not represented and the present disclosure is understood to encompass all salts and solvates of the compounds represented herein, as well as the non-salt and non-solvate form of the compound, such as the expert in the matter will understand well. In some embodiments, salts of the compounds provided herein are pharmaceutically acceptable salts. When one or more tertiary amine moieties are present in the compound, N-oxides are also provided and described. Where tautomeric forms may be present for any of the compounds described herein, it is intended that each and every tautomeric form be represented explicitly, albeit only one or some of the tautomeric forms. The tautomeric forms specifically represented may or may not be the predominant forms in solution or when used in accordance with the methods described herein. The present description also includes any or all stereochemical forms, including any enantiomeric or diastereomeric form of the described compounds. The structure or name is intended to cover all possible stereoisomers of a represented compound, and each unique stereoisomer has a compound number carrying a suffix a, b, etc. All forms of the compounds are also included in the invention, such as as crystalline or non-crystalline forms of the compounds. Also intended are compositions comprising a compound of the invention, such as a substantially pure compound composition, including a specific stereochemical form thereof, or a composition comprising mixtures of compounds of the invention in any proportion, including two or more stereochemical forms, such as in a racemic or non-racemic mixture. The invention also relates to forms of isotopically labeled and / or isotopically enriched compounds described herein. The compounds herein may contain unnatural ratios of atomic isotopes on one or more of the atoms constituting such compounds. In some embodiments, the compound is isotopically labeled, such as an isotopically labeled compound of formula (I) or variations thereof described herein, where a fraction of one or more atoms is replaced by an isotope of the same element. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, such as 2H,3H,nC,13C,14C13N,150,170,35S,18F,36CI. Certain isotope-labeled compounds (e.g., 3H and 14C) are useful in studies of the distribution of compounds or substrates in tissues. Incorporation of heavier isotopes such as deuterium (2H) may provide certain therapeutic advantages resulting from increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and may therefore be preferable in some cases. . The isotopically labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art or by procedures similar to those described in the accompanying examples, substituting the appropriate isotopically labeled reagents in place of the corresponding unlabeled reagent. MA / t / ZUZZ / UÓUUOO The invention also includes any or all metabolites of any of the described compounds. Metabolites may include any chemical species generated by a biotransformation of any of the described compounds, such as intermediates and products of the metabolism of the compound, such as would be generated in vivo after administration to a human. Articles of manufacture are provided comprising a compound described herein, or a salt or solvate thereof, in a suitable container. The container may be a vial, bottle, ampoule, prefilled syringe, i.v. bag. and the like. Preferably, the compounds detailed herein are orally bioavailable. However, the compounds can also be formulated for parenteral (eg, intravenous) administration. One or more compounds described herein can be used in the preparation of a medicament by combining the compound or compounds as an active ingredient with a pharmacologically acceptable carrier, which are known in the art. Depending on the therapeutic form of the medication, the carrier can have several forms. In a variation, the manufacture of a drug is used in any of the methods described herein, for example, for the treatment of cancer. General synthetic methods Compounds of the invention can be prepared by various procedures as described generally below and more specifically in the examples hereinafter (such as the chemical equations provided in the examples below). In the following descriptions of the procedure, it should be understood that the symbols, when used in the formulas shown, represent the groups described above in connection with the formulas herein. Where it is desired to obtain a particular enantiomer of a compound, this can be achieved from a corresponding mixture of enantiomers using any conventional procedure suitable for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives can be produced by the reaction of a mixture of enantiomers, for example, a racemate and an appropriate chiral compound. The diastereomers can then be separated by any convenient means, for example, by crystallization and recover the desired enantiomer. In another resolution procedure, a racemate can be separated using chiral high performance liquid chromatography. Alternatively, if desired, a particular enantiomer can be obtained using an appropriate chiral intermediate in one of the procedures described. Chromatography, recrystallization, and other screening procedures may also be used. MA / t / ZUZZ / UÓUUOO conventional separation with intermediates or final products when it is desired to obtain a particular isomer of a compound or to otherwise purify a product of a reaction. Also contemplated are solvates and / or polymorphs of a compound provided herein, or a pharmaceutically acceptable salt thereof. Solvates contain stoichiometric or non-stoichiometric amounts of a solvent and are often formed during the crystallization procedure. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Polymorphs include the different packing arrangements of crystals of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and / or solubility. Various factors such as recrystallization solvent, crystallization rate, and storage temperature can cause a single-crystalline form to dominate. Abbreviations used in the descriptions of chemical equations and specific examples have the following meanings: EtOH for ethyl alcohol, B 2 Pin 2 for Bis(pinacolato)diboron, KOAc for potassium acetate, DMSO for dimethyl sulfoxide, Pd (dppf ) [Ι,Γ-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Cl 2; EtOAc for ethyl acetate; Et 3 N for triethylamine; DCM for dichloromethane, DIPEA for N, N-diisopropylethylamine, THF for tetrahydrofuran, T 3 P for propylphosphonic anhydride, DMAP for 4-dimethylaminopyridine and HPLC for high performance liquid chromatography. The compounds described herein, including compounds of General Formula (I), (II), (IIa-1) to (IIa-7), (III) or (IIIa-1) to (IIIa-7), and specific examples, can be prepared, for example, through the reaction routes represented in the Chemical Equation. The variables R1, R2, R4, Rcl, Gi, G2, Z2, Z3, Wi and m used in the chemical equation have the meanings set forth in the summary and detailed description sections unless otherwise indicated. ΜΛ / t / ZUZZ / UÓUUOO CHEMICAL EQUATION 1 MA / t / ZUZZ / UÓUUOO CHEMICAL EQUATION 2 CHEMICAL EQUATION 3 MA / t / ZUZZ / UÓUUOO CHEMICAL EQUATION 4 CHEMICAL EQUATION 5 MA / t / ZUZZ / UÓUUOO General synthetic chemical equations 1 are understood to be chemical equations and present synthetic routes involving steps clearly familiar to those skilled in the art, in which the substituents described in the compounds of Formula (I), (II), (IIa- 1) to (IIa-8), (III) or (IIIa-1) to (IIIa-8) herein can be varied with a choice of starting materials and appropriate reagents used in the steps presented. It is understood that general synthetic chemical equations 1 to 6 and present synthetic routes that involve steps clearly familiar to those skilled in the art, in which the substituents described in the compounds of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (Illa-1) to (IIIa-8), (IV), (V), (Va-1 ) to (Valí), (VI) or (VIa-1) to (VIa-11) herein can be varied with a choice of starting materials and appropriate reagents used in the steps presented. The optimal reaction conditions and times for each individual step may vary depending on the particular reagents employed and the substituents present on the reagents used. Solvents, temperatures, pressures and other reaction conditions can be easily selected by a person of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. The reactions may be further processed in a conventional manner, for example, by removing the solvent from the residue and further purifying according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, starting materials and reagents are commercially available or can be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature. Experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that may not be compatible with the reaction conditions and deprotection at an appropriate point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. The synthesis of the compounds described herein may, in some embodiments, be carried out by methods analogous to those described in the chemical synthesis equations above or the specific examples below. Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the chemical equations described above or the procedures described in the synthetic examples section. Where an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step). ), or by resolution of a mixture of the stereoisomers of the compound or MA / t / ZUZZ / UÓUUOO intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution). Similarly, when a pure geometric isomer of a compound of the invention is required, it can be obtained by modality of one of the above procedures using a pure geometric isomer as a starting material, or by resolving a mixture of the isomers. geometric shapes of the compound or intermediates using a standard procedure such as chromatographic separation. Pharmaceutical compositions and formulations Pharmaceutical compositions of any of the compounds detailed herein are included in this description. Therefore, the present description includes pharmaceutical compositions comprising a compound as detailed herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an organic or inorganic acid. The pharmaceutical compositions may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation. A compound as detailed herein may, in one aspect, be in purified form and compositions comprising a compound in purified forms are detailed herein. Compositions comprising a compound as detailed herein or a salt thereof, such as compositions of substantially pure compounds, are provided. In some embodiments, a composition containing a compound as detailed herein or a salt thereof is in substantially pure form. In a variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions containing a compound in substantially pure form are provided. In another variation, the present disclosure encompasses pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier. In another variation, methods are provided for administering a compound. The purified forms, pharmaceutical compositions and methods of administration of the compounds are suitable for any compound or form thereof detailed herein. A compound detailed herein or a salt thereof can be formulated for any available route of administration, including oral, mucosal (e.g., ΜΛ / t / ZUZZ / UÓUUOO (e.g. nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g. intramuscular, subcutaneous or intravenous), topical or transdermal form. A compound or salt thereof may be formulated with suitable carriers to provide administration forms including, but not limited to, tablets, caplets, capsules (such as hard gelatin capsules or elastic soft gelatin capsules), stamps, dragees, lozenges, gums. , dispersions, suppositories, ointments, poultices, pastes, powders, dressings, creams, solutions, patches, aerosols (for example, nasal sprays or inhalers), gels, suspensions (for example, aqueous or non-aqueous liquid suspensions, emulsions oil-in-water or water-in-oil liquid emulsions), solutions and elixirs. One or more compounds described herein or a salt thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, combining the compound or compounds, or a salt thereof, as an active ingredient with a pharmaceutical carrier. acceptable, such as those mentioned above. Depending on the therapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, colorants, adjusters and salts for adjusting osmotic pressure, pH regulators, coating agents or antioxidants. Formulations comprising the compound may also contain other substances that have valuable therapeutic properties. Pharmaceutical formulations can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20aed. (2000), which is incorporated herein by reference. The compounds described herein can be administered to individuals in the form of generally accepted oral compositions, such as tablets, coated tablets and gel capsules in hard or soft shell form, emulsions or suspensions. Examples of vehicles that can be used for the preparation of such compositions are lactose, corn starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for soft shell gel capsules are, for example, semi-solid and liquid vegetable oils, waxes, fats, polyols, etc. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, colorants, adjusters and salts for adjusting osmotic pressure, pH regulators, coating agents or antioxidants. Any of the compounds described herein can be formulated into a tablet in any dosage form described, for example, a compound as described herein or a pharmaceutically acceptable salt thereof can be MA / t / ZUZZ / UÓUUOO formulate as a 10 mg tablet. Also described are compositions comprising a compound provided herein. In a variation, the composition comprises a compound or a salt thereof and a pharmaceutically acceptable carrier or excipient. In another variation, a substantially pure compound composition is provided. Methods of use The compounds and compositions detailed herein, such as a pharmaceutical composition containing a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided in this document. The compounds and compositions can also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for selection purposes and / or to perform quality control assays. In another embodiment, methods are provided for preparing a composition of a compound described herein, including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or pharmaceutical composition comprises a sugar. In some such embodiments, the methods may further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation. In one embodiment, the use of a compound having the structure of Formula (I), (II), (lia-1) to (IIa-7), (III) or (IIIa-1) to (IIIa-7) , or An isomer, racemate, hydrate, solvate, isotope or pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament. In another embodiment, methods are provided for preparing a composition of a compound described herein, including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or pharmaceutical composition comprises a sugar. In some such embodiments, the methods may further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation. In one embodiment, the use of a compound having the structure of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), ΜΛ / t / ZUZZ / UÓUUOO (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa-11), or An isomer, racemate, hydrate, solvate, isotope or salt is provided pharmaceutically acceptable thereof, for the manufacture of a medicine. Provided herein is a method of treating a disease in an individual comprising administering an effective amount of a compound of Formula (I), (II) or (III), or any embodiment, variation or aspect thereof (collectively, a compound of Formula (I), (II) or (III), or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, provided herein is a method of treating a disease mediated by a G protein-coupled receptor signaling pathway in an individual comprising administering an effective amount of a compound of formulas (I), (II) or (III). , or a pharmaceutically acceptable salt thereof, for the individual. In one embodiment, the present invention provides methods for treating or preventing disorders that improve by inhibiting BET. Provided herein is a method of treating a disease in an individual comprising administering an effective amount of a compound of Formula (I), (II) or (III), or any embodiment, variation or aspect thereof (collectively, a compound of Formula (I), (II) or (III), or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, provided herein is a method of treating a disease mediated by a G protein-coupled receptor signaling pathway in an individual comprising administering an effective amount of a compound of formulas (I), (II) or (III). , or a pharmaceutically acceptable salt thereof, for the individual. In one embodiment, the present invention provides methods for treating or preventing disorders that improve by inhibiting BET. The present compounds or their salts are believed to be effective in treating a variety of diseases and disorders. For example, in some embodiments, the present compositions can be used to treat a proliferative disease, such as cancer. In another aspect, the present invention relates to methods of treating cancer in a subject comprising administering a therapeutically effective amount of a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II) , (Ha -1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), ( VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the present invention relates to methods of treating cancer in a subject comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (IIa-1) to (IIa-8), (III) or (IIIa-1) to (IIIa-8) or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the cancer is selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, ΜΛ / t / ZUZZ / UÓUUOO adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, breast cancer cervix, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal positive breast cancer, estrogen thrombocyte tumor cancer, fibrosarcoma, follicular lymphoma, testicular germ cell cancer, glioma, glioblastoma, gliosarcoma, heavy chains, hemangioblastoma, hepatoma, hepatocellular cancer, hormone-sensitive and insensitive prostate cancer, prostate cancer resistant to enzalutamide (XTANDI) and abiraterone in the pre- and post-chemo stages, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma , lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), malignant neoplasms and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid - cell or B cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, cancer ovary, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, carcinoma of small cell lung, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom macroglobulinemia, testicular tumors, uterine cancer and Wilms tumor . In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In particular embodiments, additional therapeutic agents are selected from the group consisting of cytarabine, bortezomib and 5-azacytidine. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is any of adult and pediatric oncology, myxoid and round cell carcinoma, locally advanced tumors, metastatic cancer, human soft tissue sarcomas, including Ewing sarcoma, cancer metastases, including lymphatic metastases, carcinoma squamous cell carcinoma, particularly of the head and neck, squamous cell carcinoma of the esophagus, oral carcinoma, malignant neoplasms of blood cells, including multiple myeloma, leukemias, MA / t / ZUZZ / UÓUUOO including acute lymphocytic leukemia, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia and hairy cell leukemia, effusion lymphomas (lymphomas based on body cavities), thymic lymphoma, lung cancer, including small cell carcinoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, adrenal cortex cancer, ACTH-producing tumors, non-small cell cancers, breast cancer, including small cell carcinoma and ductal carcinoma, cancers gastrointestinal, including stomach cancer, colon cancer, colorectal cancer, polyps associated with colorectal neoplasia, pancreatic cancer, liver cancer, urologic cancers, including bladder cancer, including primary superficial bladder tumors, invasive transitional cell bladder carcinoma of the bladder, and muscle-invasive bladder cancer, prostate cancer, malignant neoplasms of the female genital tract, including ovarian carcinoma, primary periphoneal epithelial neoplasms, cervical carcinoma, uterine endometrial cancers, vaginal cancer, vulvar cancer , uterine cancer and solid tumors in the ovarian follicle, malignant neoplasms of the male genital tract, including testicular and penile cancer, kidney cancer, including renal cell carcinoma, brain cancer, including intrinsic brain tumors, neuroblastoma , astrocytic brain tumors, gliomas, metastatic tumor cell invasion into the central nervous system, bone cancers, including osteomas and osteosarcomas, skin cancers, including melanoma, tumor progression of human skin keratinocytes, squamous cell cancer, thyroid cancer , retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms tumors, gallbladder cancer, trophoblastic neoplasms, hemangiopericytoma and Kaposi sarcoma. In some embodiments, the cancer in the individual has one or more mutations or amplification or overexpression of the genes that encode the BET proteins. In some embodiments, the cancer in the individual has one or more mutations of the TP53 gene or expresses mutant BRD4. In some embodiments, the cancer in the individual has a mutation or amplification or overexpression of c-MYC. In some embodiments, the cancer in the individual has a mutation or amplification or overexpression of MYCN. In some embodiments, the cancer in the individual is characterized by the expression of the androgen receptor (AR). In some embodiments, provided herein is a method of treating a cancer in an individual, comprising (a) selecting the individual for treatment based on (i) the presence of one or more TP53 gene mutations in the cancer, or ( i) expression of mutant p53 in cancer, and administering an effective amount of a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the cancer TP53 gene is sequenced to detect one or more mutations, in some embodiments, the conjugate is selected from the following: In some embodiments, the TP53 gene is sequenced by sequencing circulating tumor DNA (cDNA). of the individual. In some embodiments, a method is provided for treating a cancer in an individual, comprising (a) selecting the individual for treatment based on (i) mutation or amplification or overexpression of BRD4 or other members of the BET family, or ( i) presence of mutation or amplification or overexpression of c-MYC in the cancer, and administering an effective amount of the compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa- 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or ( Route -1) to (VIa-11), or a pharmaceutically acceptable salt thereof, for the individual. In some embodiments, the cancer TP53 gene is sequenced to detect one or more mutations, in some embodiments, the conjugate is selected from the following: In some embodiments, the TP53 gene is sequenced by sequencing circulating tumor DNA (cDNA). of the individual. In another aspect, the present invention relates to methods of treating a disease or condition in a subject comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (IIa-1) to (IIa-8 ), (III) or (IIIa-1) to (IIIa-8), or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of: Addison's, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, blistering skin diseases, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease , Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing, cholangicitis systemic erythematosus, Takayasu arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis and Wegener's granulomatosis. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In another aspect, the present invention relates to methods of treating a disease or condition in a subject comprising administering a therapeutically effective amount of a compound of Formula (J) or any related formula where applicable, such as Formula (I), ( II). , (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), ( VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting of: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, blistering skin diseases, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing, systemic cholangitis erythematosus , Takayasu arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis and Wegener's granulomatosis. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In another aspect, the present invention relates to methods of treating a chronic kidney disease or condition in a subject that comprise administering a therapeutically effective amount of a compound of Formula (I), (II), (IIa-1) to (IIa-8), (III) or (IIIa-1) to (IIIa-8)) or a pharmaceutically acceptable salt thereof, to a subject in need thereof, where said disease or condition is selected from the group consisting of: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal and segmental glomerulosclerosis, membranous glomerulonephritis, minimal changes, polycystic kidney disease and tubular interstitial nephritis. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent.In another aspect, the present invention relates to methods of treating a chronic kidney disease or condition in a subject, comprising administering a therapeutically effective amount of a compound of Formula (J) or any related formula where applicable, such as Formula ( I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to ( Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said disease or condition is selected from the group consisting in: diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal and segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease and tubular interstitial nephritis. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In another aspect, the present invention relates to methods of treating an acute kidney injury or disease or condition in a subject comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (IIa-1) to (Ha). -8), (III) or (IIIa-1) a ΜΛ / t / ZUZZ / UÓUUOO (IIIa-8), or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said acute kidney injury or disease or condition is selected from the group consisting of: induced by ischemia -reperfusion, induced by cardiac and major surgery, induced by percutaneous coronary intervention, induced by radiocontrast agents, induced by sepsis, induced by pneumonia and induced by drug toxicity. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In another aspect, the present invention relates to methods of treating an acute kidney injury or disease or condition in a subject comprising administering a therapeutically effective amount of a compound of Formula (J) or any related formula where applicable, such as Formula (YO). , (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va- 11), (VI) or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein said acute kidney injury, disease or condition is selected from the group that It consists of: induced by ischemiareperfusion, induced by cardiac and major surgery, induced by percutaneous coronary intervention, induced by radiocontrast agents, induced by sepsis, induced by pneumonia and induced by drug toxicity. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In another aspect, the present invention relates to methods of treating AIDS in a subject comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (IIa-1) to (IIa-8), (III) or (IIIa-1) to (IIIa-8), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In another aspect, the present invention relates to methods of treating AIDS in a subject comprising administering a therapeutically effective amount of a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II) , (Ha -1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), ( VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In another aspect, the present invention relates to methods for treating obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy or diabetic neuropathy in a subject who ΜΛ / t / ZUZZ / UÓUUOO comprises administering a therapeutically effective amount of a compound of Formula (I), (II), (IIa-1) to (IIa-8), (III) or (IIIa-1) to (IIIa -8), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In another aspect, the present invention relates to methods of treating obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, hepatic steatosis, type II diabetes, insulin resistance, diabetic retinopathy or diabetic neuropathy in a subject comprising administering a therapeutically effective amount of a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1 ) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt of the same, to a subject in need of the same. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In another aspect, the present invention relates to methods of preventing conception by inhibiting spermatogenesis in a subject comprising administering a therapeutically effective amount of a compound of Formula (I), (II), (lia-1) to (IIa- 8), (III) or (IIIa-1) to (Illa8), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In another aspect, the present invention relates to methods of preventing conception by inhibiting spermatogenesis in a subject comprising administering a therapeutically effective amount of a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II). , (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), ( VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. Combination therapy As provided herein, the presently described compounds or a salt thereof may be combined with an additional therapeutic agent. In some embodiments, a method of treating a disease in an individual is provided comprising administering an effective amount of a compound of Formula (I), (II) or (III), or any embodiment, variation or aspect thereof (collectively, a compound of Formula (I), (II) or (III), or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the disease is a proliferative disease such as cancer. In another aspect, the present invention ΜΛ / t / ZUZZ / UÓUUOO refers to methods of preventing conception by inhibiting spermatogenesis in a subject comprising administering a therapeutically effective amount of a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II)., (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va- 11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In certain embodiments, the methods further comprise administering a therapeutically effective amount of at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent is a cancer immunotherapy agent. In some embodiments, the additional therapeutic agent is an immunostimulatory agent. In some embodiments, the additional therapeutic agent targets a checkpoint protein (e.g., an immune checkpoint inhibitor). In some embodiments, the additional therapeutic agent is effective to stimulate, enhance or enhance an immune response against a tumor. In some embodiments, a method of treating a disease in an individual is provided comprising administering an effective amount of a compound of Formula (I), (II) or (III), or any embodiment, variation or aspect thereof (collectively, a compound of Formula (I), (II) or (III), or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, in combination with radiation therapy. In some embodiments, a method is provided for treating a disease in an individual, the method comprising administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1 ) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or ( VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, a compound of (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa8), (IV), (V), (Va-1) to (Va-11), (VI), (VIa-1) to (VIa-11)), or the present compounds or the compounds detailed or described herein) or a pharmaceutically acceptable salt thereof, in combination with radiotherapy. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) or (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) or ( IIIa-1) to (IIIa-8)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a chemotherapeutic agent. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the additional chemotherapeutic agent. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more ΜΛ / t / ZUZZ / UÓUUOO hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the Chkl inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (IIa-1) to (IIa-8), (III ), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), (VIa-1) to (Vla11), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV) , (V), (Va-1) to (Va-11), (VI), (VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administer an effective amount of a chemotherapeutic agent. In some embodiments, Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illaθ), (IV), (V), (Va- l) a (Va-11), (VI), (VIa-1) a (VIa-11), or a pharmaceutically acceptable salt thereof, is administered before, after or simultaneously with the chemotherapeutic agent. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the additional chemotherapeutic agent. Examples of chemotherapeutic agents that can be used in combination with a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof include DNA-targeting agents, a DNA alkylating agent (such as cyclophosphamide, mechlorethamine, chlorambucil, melphalan, dacarbazine, temozolomide, or nitrosoureas), a topoisomerase inhibitor (such as a topoisomerase I inhibitor (for example, irinotecan or topotecan) or a topoisomerase II inhibitor (etoposide or teniposide)), an anthracycline (such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, or valrubicin), a histone deacetylase inhibitor (such as vorinostat or romidepsin), a bromodomain inhibitor, other paclitaxel, or docetaxel), a kinase inhibitor (such as bortezomib, erlotinib, gefitinib, imatinib , vemurafenib or vismodegib), an antiangiogenic inhibitor, a nucleotide analogue or a precursor analogue (such as azacitidine, azathioprine, capeurin, doxyflutin, 5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate or thioguanine) or a platinum-based chemotherapeutic agent (such as cisplatin, carboplatin, or oxaliplatin), pemetrexed, or a combination thereof. Examples of chemotherapeutic agents that can be used in combination with a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof include DNA-targeting agents, a DNA alkylating agent (such as cyclophosphamide, mechlorethamine, chlorambucil, melphalan, dacarbazine, temozolomide, or nitrosoureas), a topoisomerase inhibitor (such as a topoisomerase I inhibitor (for example, irinotecan or topotecan) or a topoisomerase II inhibitor (etoposide or teniposide)), an anthracycline (such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, or valrubicin), a histone deacetylase inhibitor (such as vorinostat or romidepsin), a bromodomain inhibitor, other paclitaxel, or docetaxel), a kinase inhibitor (such as bortezomib, erlotinib, gefitinib, imatinib , vemurafenib or vismodegib), an antiangiogenic inhibitor, a nucleotide analog MA / t / ZUZZ / UÓUUOO or a precursor analog (such as azacitidine, azathioprine, capeurin, doxyflutin, 5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, or thioguanine) or a platinum-based chemotherapeutic agent (such as cisplatin, carboplatin, or oxaliplatin ), pemetrexed or a combination thereof. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) or (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) or ( IIIa-1) to (IIIa-8)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a DNA damaging agent. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the DNA damaging agent. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the DNA damaging agent. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV) , (V), (Va-1) to (Va-11), (VI), (VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administer an effective amount of an agent that damages DNA. In some embodiments, Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), ( Va-1) to (Va-11), (VI), (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously with the DNA damaging agent. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the DNA damaging agent. In some embodiments, provided herein is a method of treating a disease in an individual comprising (a) administering an effective amount of a compound of Formula (I), (II) or (III), or any embodiment, variation or aspect thereof (collectively, Formula (I), (II) or (III), or pharmaceutically acceptable salt thereof, and (b) administer an effective amount of DNA alkylating agent (such as cyclophosphamide, mechlorethamine, chlorambucil, melphalan , dacarbazine, temozolomide or nitrosoureas). In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the DNA alkylating agent. In In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutical salt MA / t / ZUZZ / UÓUUOO acceptable of the same is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the DNA alkylating agent. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (IIa-1) to (IIa-8), (III ), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), ( IV), (V), (Va-1) to (Va-11), (VI), (VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administer an amount effective of a DNA alkylating agent (such as cyclophosphamide, mechlorethamine, chlorambucil, melphalan, dacarbazine or nitrosoureas). In some embodiments, Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), ( Va-1) to (Va-11), (VI), (VIa-1) to (VIa11), or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously with the DNA alkylating agent. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the DNA alkylating agent. In some embodiments, provided herein is a method of treating a disease in an individual comprising (a) administering an effective amount of a compound of Formula (I), (II) or (III), or any embodiment, variation or aspect thereof (collectively, Formula (I), (II) or (III), or pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a topoisomerase inhibitor (such as a Topoisomerase I inhibitor (e.g. e.g., irinotecan or topotecan) or a Topoisomerase II inhibitor (e.g., etoposide or teniposide). In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered. before, after or simultaneously co-administered with the topoisomerase inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours , 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the topoisomerase inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa11), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III), ( IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), (VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof and (b) administer an effective amount of a topoisomerase inhibitor (such as a topoisomerase I inhibitor (for example, irinotecan or topotecan) or a topoisomerase II inhibitor (for example, etoposide or teniposide )). In some modalities, ΜΛ / t / ZUZZ / UÓUUOO Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa- 1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutical salt acceptable thereof is administered before, after or simultaneously co-administered with the topoisomerase inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the topoisomerase inhibitor. In some embodiments, provided herein is a method of treating a disease in an individual comprising (a) administering an effective amount of a compound of Formula (I), (II) or (III), or any embodiment, variation or aspect thereof (collectively, Formula (I), (II) or (III), or pharmaceutically acceptable salt thereof, and (b) administer an effective amount of an anthracycline (such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone or valrubicin.) In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the anthracycline. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours , or 48 or more hours) before or after amtracycline. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula when appropriate applicable, as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va -1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa -1) to (Ila8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), (VIa -1) a (VIa-11)) or a pharmaceutically acceptable salt thereof and (b) administer an effective amount of an anthracycline (such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone or valrubicin). In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (Vla1) to (VIa-11), or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with anthracycline. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after amtracycline. In some embodiments, a method of treating a disease in an individual is provided comprising (a) administering an effective amount of a compound of Formula (I), (II) or (III), or any embodiment, variation or aspect thereof. (collectively, Formula (I), (II) or (III), MA / t / ZUZZ / UÓUUOO or pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a histone deacetylase inhibitor (such as vorinostat or remidepsin.) In some embodiments, a compound of Formula (I) is administered, (II) or (III) or a pharmaceutically acceptable salt thereof before, after or simultaneously co-administered with the histone deacetylase inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the histone deacetylase inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha - 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (Vla1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a histone deacetylase inhibitor (such as vorinostat or romidepsin). In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof It is administered before, after or simultaneously co-administered with the histone deacetylase inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the histone deacetylase inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) or (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) or ( IIIa-1) to (IIIa-8)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a taxane (such as paclitaxel or docetaxel). In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the taxane. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after taxane. In some embodiments, a method of treating a disease in an individual is provided, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (J) or any related formula when ΜΛ / t / ZUZZ / UÓUUOO is applicable. , such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (Illa-1) to (IIIa-8), (IV), (V), (Va 1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va- 1) to (Va-11), (VI), or (VIa-1) to (VIa11)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a taxane (such as paclitaxel or docetaxel). In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa 8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof is administered before, after, or simultaneously co-administered with the taxane. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after taxane. In some embodiments, provided herein is a method of treating a disease in an individual comprising (a) administering an effective amount of a compound of Formula (I), (II) or (III), or any embodiment, variation or aspect thereof (collectively, Formula (I), (II) or (III), or pharmaceutically acceptable salt thereof, and (b) administer an effective amount of a nucleotide analog or analog precourses (such as azacitidine, azathioprine, capecitabine , citrarabine, doxyfluridine, 5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate or thioguanine.) In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the nucleotide analog or precursor analog. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours , 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the nucleotide analog or analog precursors. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha - 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (Vla1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administer an effective amount of a nucleotide analog or a precursor analog (such as azacitidine, azathioprine, capecitabine, cytarabine, doxyfluridine, 5- fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate or thioguanine). In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va92 11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof is administered before, after, or simultaneously co-administered with the nucleotide analog or precursor analog. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the nucleotide analog or analog precursors. In some embodiments, a method of treating a disease in an individual is provided comprising (a) administering an effective amount of a compound of Formula (I), (II) or (III), or any embodiment, variation or aspect thereof. (collectively, Formula (I), (II) or (III), or pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a platinum chemotherapeutic agent (such as cisplatin, carboplatin or oxaliplatin.) In some embodiments In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the platinum chemotherapeutic agent. (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours more hours) before or after the platinum chemotherapeutic agent. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable , as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va- 1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, as Formula (I), (II), (Ha- 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va1) to (Va-11), (VI), or (VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a platinum-based chemotherapeutic agent (such as cisplatin, carboplatin or oxaliplatin). In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof It is administered before, after or simultaneously co-administered with the platinum-based chemotherapeutic agent. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the platinum chemotherapeutic agent. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8)) or a salt ΜΛ / t / ZUZZ / UÓUUOO pharmaceutically acceptable thereof, and (b) administer an effective amount of pemetrexed. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with pemetrexed. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after pemetrexed. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha - 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administer an effective amount of pemetrexed. In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof It is administered before, after or simultaneously co-administered with pemetrexed. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after pemetrexed. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a kinase inhibitor (such as bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, vismodegib or ibrutinib). In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the kinase inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the kinase inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha - 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administer an effective amount of a kinase inhibitor (such as bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, vismodegib or ibrutinib) . In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the kinase inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the kinase inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of an mTOR inhibitor (such as everolimus). In some embodiments, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or a pharmaceutically acceptable salt thereof, It is administered before, after or simultaneously co-administered with the mTOR inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha- 1 ) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or ( VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of an mTOR inhibitor (such as everolimus). In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (Vla1) to (VIa-11), or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the mTOR inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a PI3K inhibitor ΜΛ / t / ZUZZ / UÓUUOO or Akt. In some embodiments, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or a pharmaceutically acceptable salt thereof, It is administered before, after or simultaneously co-administered with the PI3K or Akt inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the PI3K or Akt inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha -1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va1) to (Va-11), (VI), or ( VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a PI3K or Akt inhibitor. In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof It is administered before, after or simultaneously co-administered with the PI3K or Akt inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the PI3K inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8),) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the PARP inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the PARP inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula when MA / t / ZUZZ / UÓUUOO is applicable, as Formula (I), (II), (Ha- 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV ), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administer an amount effective of a Bruton's tyrosine kinase (BTK) inhibitor. In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (Vla11), or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the BTK inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the PARP inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8)), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a cyclin-dependent kinase (CDK) inhibitor, such as CDK1, CDK2, CDK4, CDK5, CDK6, CDK7 or CDK9, or any combination thereof. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the PARP inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the PARP inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha - 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a cyclin-dependent kinase (CDK) inhibitor, such as an inhibitor of CDK1, CDK2 , CDK4, CDK5, CDK6, CDK7 or CDK9, or any combination thereof. In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof It is administered before, after or simultaneously co-administered with the CDK inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt of the MA / t / ZUZZ / UÓUUOO itself is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after of the PARP inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a DNA damage repair (DDR) pathway inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the DDR pathway inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the DDR pathway inhibitor. Examples of DDR pathway inhibitors include poly (ADP-ribose) polymerase (PARP) inhibitors (such as olaparib, rucaparib, niraparib, or talazoparib), ataxia telangiectasia mutated (ATM), ataxia telangiectasia, and Rad3-related (ATR) protein inhibitors. ) protein inhibitors, checkpoint kinase 1 (Chkl) inhibitors or combinations thereof. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha - 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va1) to (Va-11), (VI), or ( VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a DNA damage repair (DDR) pathway inhibitor. In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (Vla1) to (VIa-11), or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the DDR pathway inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the DDR pathway inhibitor. Examples of DDR pathway inhibitors include poly (ADP-ribose) polymerase (PARP) inhibitors (such as olaparib, rucaparib, niraparib, or talazoparib), ataxia telangiectasia mutated (ATM), ataxia telangiectasia, and Rad3-related (ATR) protein inhibitors. ) protein inhibitors, checkpoint kinase 1 (Chkl) inhibitors or combinations thereof. MA / t / ZUZZ / UÓUUOO In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8),) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a PARP inhibitor (such as olaparib, rucaparib, niraparib or talazoparib). In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the PARP inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the PARP inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha- 1 ) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or ( VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administer an effective amount of a PARP inhibitor (such as olaparib, rucaparib, niraparib or talazoparib). In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof It is administered before, after, or simultaneously co-administered with the PARP inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the PARP inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of an ATM protein inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the ATM protein inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the ΜΛ / t / ZUZZ / UÓUUOO inhibitor of the ATR protein. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha - 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of an ATM protein inhibitor. In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof It is administered before, after or simultaneously co-administered with the ATM protein inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the ATM protein inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8)), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of an ATR protein inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the ATR protein inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the ATR protein inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha - 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of an ATR protein inhibitor. In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a salt MA / t / ZUZZ / UÓUUOO 100 pharmaceutically acceptable thereof is administered before, after or simultaneously co-administered with the ATR protein inhibitor. In some embodiments, a compound of Formula (J) or any related formula if applicable, such as Formula (I), (II), (Ha-1) to (IIa-8), (III), (IIIa-1 ) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt of it is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the ATR inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a Chkl inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the Chkl inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the Chkl inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha - 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a Chkl inhibitor. In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof It is administered before, after or simultaneously co-administered with the Chkl inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the Chkl inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8)) or a salt MA / t / ZUZZ / UÓUUOO 101 pharmaceutically acceptable thereof, and (b) administer an effective amount of a Weel inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the Weel inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after Weel inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa-11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha - 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a Weel inhibitor. In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa θ), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof is administered before, after or simultaneously co-administered with the Weel inhibitor. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after Weel inhibitor. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or any modality, variation or aspect thereof (collectively, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of a therapy agent. In some modalities, the additional therapy is radiation therapy. In some embodiments, the endocrine therapy is a selective estrogen receptor degrader (SERD, such as fulvestrant). In some embodiments, the endocrine therapy is an aromatase inhibitor (such as letrozole). In some embodiments, the endocrine therapy is an anti-androgen therapy (such as enzalutamide or apalutamide). In some embodiments, the disease is a proliferative disease such as cancer. In some embodiments, Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or a pharmaceutically acceptable salt thereof, It is administered before, after or simultaneously co-administered with the endocrine therapy agent. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours ΜΛ / t / ZUZZ / UÓUUOO 102 hours) before or after the DNA alkylating agent. In some embodiments, a method is provided for treating a disease in an individual, the method comprising (a) administering an effective amount of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) , or (VIa-1) to (VIa11), or any modality, variation or aspect thereof (collectively, Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha- 1 ) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or ( VIa-1) to (VIa-11)) or a pharmaceutically acceptable salt thereof, and (b) administering an effective amount of an endocrine therapy agent. In some modalities, the additional therapy is radiation therapy. In some embodiments, the endocrine therapy is a selective estrogen receptor degrader (SERD, such as fulvestrant). In some embodiments, the endocrine therapy is an aromatase inhibitor (such as letrozole). In some embodiments, the endocrine therapy is an anti-androgen therapy (such as enzalutamide or apalutamide). In some embodiments, the disease is a proliferative disease such as cancer. In some embodiments, Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa -8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a pharmaceutically acceptable salt thereof It is administered before, after or simultaneously co-administered with the endocrine therapy agent. In some embodiments, a compound of Formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof is administered 1 or more hours (such as 2 or more hours, 4 or more hours, 8 or more hours, 12 or more hours, 24 or more hours, or 48 or more hours) before or after the DNA alkylating agent. In another aspect, provided herein is a combination therapy in which a compound of formula (I), (II) or (III) thereof is co-administered (which may be separately or simultaneously) with one or more additional agents that are effective in stimulating immune responses to enhance, stimulate or upregulate immune responses in a subject. For example, a method of stimulating an immune response in a subject is provided comprising administering to the subject a compound of formula (I), (II) or (III) or a salt thereof and one or more immunostimulatory antibodies, such as an antibody anti-PD-1, an anti-PD-Ll antibody and / or an anti-CTLA-4 antibody, so that an immune response is stimulated in the subject, for example, to inhibit tumor growth. In one embodiment, the subject is administered a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), a salt thereof and an antiPD-1 antibody. In another embodiment, the subject is administered a compound of formula (I), (II), (IIa-1) to (Ila8), (III) and (Illa-1) to (IIIa-8), a salt of same and an anti-PD-Ll antibody. In yet another embodiment, the subject is administered a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (Illa8), a salt of the same and an anti-CTLA-4 antibody. In another embodiment, the immunostimulatory antibody (for example, anti-PD-1, anti-PD-Ll and / or anti-CTLA-4 antibody) is an antibody MA / t / ZUZZ / UÓUUOO 103 human. Alternatively, the immunostimulatory antibody may be, for example, a chimeric or humanized antibody (for example, prepared from a mouse anti-PD-1, anti-PD-Ll and / or anti-CTLA-4 antibody). In another aspect, a combination therapy is provided herein in which a compound of formula (J) any of the related formulas if applicable, such as Formula (I), (II), (IIa-1) to (IIa- 8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-l)a (Va-11), (VI), or (VIa-1) to (VIa-11), thereof is co-administered (which may be separately or simultaneously) with one or more additional agents that are effective in stimulating immune responses to enhance, stimulate or upregulate immune responses in a subject. For example, a method is provided for stimulating an immune response in a subject comprising administering to the subject a compound of formula (J) or any related formula if applicable, such as formula (I), (II), (IIa-1 ) to (IIa-8), (III), (Illa1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa- 1) a (VIa-11), a salt thereof and one or more immunostimulatory antibodies, such as an anti-PD-1 antibody, an anti-PD-Ll antibody and / or an anti-CTLA-4 antibody, so that an immune response is stimulated in the subject, for example to inhibit tumor growth. In one embodiment, the subject is administered a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III) , (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa-11), or a salt thereof and an anti-PD-1 antibody. In another embodiment, the subject is administered a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III) , (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa-11), or a salt thereof and an anti-PD-Ll antibody. In yet another embodiment, the subject is administered a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ila1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa-11), or a salt thereof and an anti-CTLA-4 antibody. In another embodiment, the immunostimulatory antibody (e.g., anti-PD-1, anti-PD-Ll and / or anti-CTLA-4 antibody) is a human antibody. Alternatively, the immunostimulatory antibody may be, for example, a chimeric or humanized antibody (for example, prepared from a mouse anti-PD-1, anti-PD-Ll and / or anti-CTLA4 antibody). In one embodiment, the present disclosure provides a method of treating a proliferative disease (e.g., cancer), comprising administering a compound of formula (I), (II) or (III) or a salt thereof and an anti-antibody. PD-1 to a subject. In additional embodiments, a compound of formula (I), (II) or (III) or a salt thereof is administered in a subtherapeutic dose, the anti-PD-1 antibody is administered in a subtherapeutic dose, or both are administered in a subtherapeutic dose. In another embodiment, the present disclosure provides a method of altering an adverse event associated with the treatment of a hyperproliferative disease with an immunostimulatory agent, comprising administering a compound of 104 formula (I), (II) or (III) or a salt thereof and a subtherapeutic dose of anti-PD-1 antibody to a subject. In certain embodiments, the subject is a human. In certain embodiments, the anti-PD-1 antibody is a human sequence monoclonal antibody. In one embodiment, the present disclosure provides a method of treating a proliferative disease (e.g., cancer), comprising administering a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II ), (Ha -1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va11), (VI ), or (VIa-1) to (VIa-11), or a salt thereof and an anti-PD-1 antibody or to a subject. In additional embodiments, a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va11), (VI), or (VIa-1) to (VIa-11), or a salt thereof is administered to a subtherapeutic dose, the anti-PD-1 antibody is administered at a subtherapeutic dose, or both are administered at a subtherapeutic dose. In another embodiment, the present invention provides a method of altering an adverse event associated with the treatment of a hyperproliferative disease with an immunostimulatory agent, comprising administering a compound of formula (J) or any related formula if applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a salt thereof and a subtherapeutic dose of anti-PD-1 antibody to a subject. In certain embodiments, the subject is a human. In certain embodiments, the anti-PD-1 antibody is a human sequence monoclonal antibody. In one embodiment, the present invention provides a method of treating a hyperproliferative disease (e.g., cancer), comprising administering a compound of formula (I), (II), (IIa-1) to (IIa-8), ( III) and (IIIa-1) to (IIIa-8), or a salt thereof and an antiPD-L1 antibody to a subject. In additional embodiments, a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or a salt thereof is administered in a subtherapeutic dose, the anti-PD-Ll antibody is administered in a subtherapeutic dose, or both are administered in a subtherapeutic dose. In another embodiment, the present invention provides a method of altering an adverse event associated with the treatment of a hyperproliferative disease with an immunostimulatory agent, comprising administering a compound of formula (I), (II), (IIa-1) to ( IIa-8), (III) and (IIIa-1) to (IIIa-8), or a salt thereof and a subtherapeutic dose of anti-PD-Ll antibody to a subject. In certain embodiments, the subject is a human. In certain embodiments, the anti-PD-Ll antibody is a human sequence monoclonal antibody. In one embodiment, the present invention provides a method of treating a hyperproliferative disease (e.g., cancer), comprising administering a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha -1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a salt thereof and an anti-PD-Ll antibody against a subject. In additional embodiments, a compound of Formula (J) or any related formula ΜΛ / t / ZUZZ / UÓUUOO 105 where applicable, as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V) , (Va1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a salt thereof is administered at a subtherapeutic dose, the anti-PD-Ll antibody is administered at a subtherapeutic dose, or both are administered at a subtherapeutic dose. In another embodiment, the present invention provides a method of altering an adverse event associated with the treatment of a hyperproliferative disease with an immunostimulatory agent, comprising administering a compound of formula (J) or any related formula if applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a salt thereof and a subtherapeutic dose of anti-PD-Ll antibody to a subject. In certain embodiments, the subject is a human. In certain embodiments, the anti-PD-Ll antibody is a human sequence monoclonal antibody. In certain embodiments, the combination of therapeutic agents discussed herein may be administered simultaneously as a single composition in a pharmaceutically acceptable carrier, or simultaneously as separate compositions, each in a pharmaceutically acceptable carrier. In another embodiment, the combination of therapeutic agents can be administered sequentially. For example, an anti-CTLA-4 antibody and a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8 ), or a salt thereof may be administered sequentially, such as the anti-CTLA-4 antibody being administered first and a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8) or a salt thereof secondly, or a compound of formula (I), (II), (IIa-1) to (IIa-8), ( III) and (Illa-1) to (IIIa-8), or a salt thereof which is administered first and the anti-CTLA-4 antibody second. Additionally or alternatively, an anti-PD-1 antibody and a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa- 8), or a salt thereof may be administered sequentially, such as the anti-PD-1 antibody being administered first and a compound of formula (I), (II), (IIa-1) to (IIa-8) , (III) and (IIIa-1) to (IIIa-8) or a salt thereof secondly, or a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or a salt thereof which is administered first and the anti-PD-1 antibody second. Additionally or alternatively, an anti-PDLl antibody and a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or a salt thereof may be administered sequentially, such as the anti-PD-Ll antibody being administered first and a compound of formula (I), (II), (IIa-1) to (IIa-8), (III ) and (IIIa-1) to (IIIa-8) or a salt thereof secondly, or a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or a salt thereof which is administered first and the anti-PD-Ll antibody second. In certain embodiments, the combination of therapeutic agents discussed herein may be administered simultaneously as a single composition in a pharmaceutically acceptable carrier, or simultaneously as separate compositions, each in a carrier. MA / t / ZUZZ / UÓUUOO 106 pharmaceutically acceptable. In another embodiment, the combination of therapeutic agents can be administered sequentially. For example, an anti-CTLA-4 antibody and a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III ), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa-11), or a salt thereof may be administered sequentially, such as the anti-CTLA-4 antibody being administered first and a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (Ha- 1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI ), or (VIa-1) to (VIa-11), or a salt thereof second, or a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va1) to (Va-11), (VI) or (Via-1) to (VIa-11), or a salt thereof which is administered first and the anti-CTU\-4 antibody second. Additionally or alternatively, an anti-PD-1 antibody and a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), ( III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa-11) , or a salt thereof may be administered sequentially, such as the anti-PD-1 antibody being administered first and a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II) , (Ha -1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va11), (VI) , or (VIa-1) to (VIa-11), or a salt thereof second, or a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), ( IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (Lane -1) to (VIa-11), or a salt thereof, the anti-PD-1 antibody being administered first and secondly. Additionally or alternatively, an anti-PD-Ll antibody and a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), ( III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa-11) , or a salt thereof may be administered sequentially, such as the anti-PD-Ll antibody being administered first and a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II) , (Ha -1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), ( VI), or (VIa-1) to (VIa-11), or a salt thereof second, or a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II) , (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va11), (VI) or (Via -1) to (VIa-11), or a salt thereof, the anti-PD-Ll antibody being administered first and secondly. Additionally, if more than one dose of the combination therapy is administered sequentially, the order of sequential administration may be reversed or maintained in the same order at each administration time point, sequential administrations may be combined with concurrent administrations, or any combination from the same. Optionally, the combination of a compound of formula (I), (II), (IIa-1) to (Ha MA / t / ZUZZ / UÓUUOO 107 8), (III) and (IIIa-1) to (IIIa-8), or a salt thereof can be further combined with an immunogenic agent, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides and carbohydrate molecules ), cells and cells transfected with genes encoding immunostimulatory cytokines. Optionally, the combination of a compound of formula (J) or any related formula if applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa -1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a salt thereof can be additionally combined with an immunogenic agent, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides and carbohydrate molecules), cells and cells transfected with genes encoding immunostimulatory cytokines. A compound of formula (I), (II), (Ila1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or a salt thereof can also be additionally combined with treatments standard against cancer. A compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or a salt thereof may also be additionally combined. They can be effectively combined with chemotherapeutic regimens. In these cases, it is possible to reduce the dose of another chemotherapeutic reagent administered with the combination of the present description. Other combination therapies with a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or a salt thereof They include radiation, surgery, or hormone deprivation. Angiogenesis inhibitors can also be combined with a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or a salt thereof. Inhibition of angiogenesis leads to tumor cell death, which may be a source of tumor antigen introduced into host antigen presentation pathways. A compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (Illa- 8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa11), or a salt thereof can also be combined with standard treatments against cancer. For example, a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a salt thereof may be combined with chemotherapeutic regimens. In these cases, it is possible to reduce the dose of another chemotherapeutic reagent administered with the combination of the present description. Other combination therapies with a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a salt thereof include radiation, surgery or hormone deprivation. Angiogenesis inhibitors may also be combined with a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III) , (Illa -1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI) or (VIa-1) to (VIa-11), or a salt of it. Inhibition of angiogenesis leads to tumor cell death, which may be a source of tumor antigen introduced into antigen presentation pathways. 108 of the host. A compound of formula (I), (II), (Ila1) to (IIa-8), (III) and (Illa-1) to (IIIa-8) can also be further combined, or a salt thereof can be combined. use in conjunction with antineoplastic antibodies. By way of example and without wishing to be bound by theory, treatment with an anticancer antibody or an anticancer antibody conjugated to a toxin may lead to the death of cancer cells (e.g., tumor cells) which would enhance a CTLA-mediated immune response. 4, PD-1, PD-L1 or a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or a salt thereof. In an exemplary embodiment, a treatment of a hyperproliferative disease (e.g., a cancerous tumor) may include an anti-cancer antibody in combination with a compound of formula (I), (II), (lia-1) to (IIa-8). , (III) and (Illa-1) to (Illa8), or a salt thereof and anti-CTLA-4 and / or anti-PD-1 and / or anti-PD-Ll antibodies, simultaneously or sequentially or any combination thereof, which can enhance anti-tumor immune responses by the host. Other antibodies that can be used to activate the host immune response can also be used in combination with a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1 ) to (IIIa-8), or a salt thereof. In another example, a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a salt thereof can be used together with antineoplastic antibodies. By way of example and without wishing to be bound by theory, treatment with an anticancer antibody or an anticancer antibody conjugated to a toxin may lead to the death of cancer cells (e.g., tumor cells) which would enhance a CTLA-mediated immune response. 4, PD-1, PD-L1 or a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11), or a salt thereof. In an exemplary embodiment, a treatment of a hyperproliferative disease (e.g., a cancerous tumor) may include an anti-cancer antibody in combination with a compound of formula (I), (II), (Ha-1) to (IIa-8). , (III) and (IIIa-1) to (Illa8), (IV), (V), (Va-1) to (Va-11), (VI), or (VIa-1) to (VIa-11 ), or a salt thereof and anti-CTLA-4 and / or anti-PD-1 and / or anti-PD-Ll antibodies, simultaneously or sequentially or any combination thereof, which can enhance antitumor immune responses by of the host. Other antibodies that can be used to activate the host immune response can further be used in combination with a compound of Formula (J) or any related formula where applicable, such as Formula (I), (II), (IIa-1) to ( IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va11), (VI) or (VIa-1) to ( VIa-11), or a salt thereof. In further embodiments, a compound of formula (I), (II), (IIa-1) to (IIa-8), (III) and (IIIa-1) to (IIIa-8), or a salt thereof, It is administered in combination with another BET inhibitor. In still other embodiments, the compound of Formula (J) or any related formula where appropriate ΜΛ / t / ZUZZ / UÓUUOO 109 applicable, such as Formula (I), (II), (IIa-1) to (IIa-8), (III), (IIIa-1) to (IIIa-8), (IV), (V), (Va-1) to (Va11), (VI), or (VIa-1) to (VIa-11), or a salt thereof is administered in combination with another BET inhibitor. Dosage and method of administration The dose of a compound administered to an individual (such as a human) may vary with the particular compound or salt thereof, the method of administration, and the particular disease, such as the type and study of cancer being treated. In some embodiments, the amount of the compound or salt thereof is a therapeutically effective amount. The effective amount of the compound may be, in one aspect, a dose of between about 0.01 and about 100 mg / kg. The effective amounts or doses of the compounds of the invention can be determined by routine methods, such as modeling, dose escalation or clinical trials, taking into account routine factors, for example, the mode or route of administration or delivery of the drug, the ethical pharmacokinetics of the agent, the severity and course of the disease to be treated, the health status, condition and weight of the subject. An exemplary dose is in the range of about 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350 mg to 1.75 g daily, or about 1.75 to 7 g daily. Any of the methods provided herein may comprise in one aspect administering to an individual a pharmaceutical composition containing an effective amount of a compound provided herein or a salt thereof and a pharmaceutically acceptable excipient. A compound or composition of the invention may be administered to an individual according to an effective dosage regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least at least about 6 months, or at least about 12 months or more, which in some variations may be during the life of the individual. In a variation, the compound is administered on a daily or intermittent schedule. The compound may be administered to an individual continuously (e.g., at least once a day) over a period of time. The dosing frequency may also be less than once a day, for example, approximately once weekly dosing. The dosage frequency may be more than once a day, for example, two or three times a day. The dosing frequency may also be intermittent, including a 'drug break' (for example, once-daily dosing for 7 days followed by no dosing for 7 days, repeated over any 14-day period, such as about 2 months, approximately 4 months, approximately 6 months or more). Any of the dosage frequencies may employ any of the compounds described herein in conjunction with any of the dosages described herein. ΜΛ / t / ZUZZ / UÓUUOO 110 The compounds provided herein or a salt thereof can be administered to an individual through various routes, including, for example, intravenous, intramuscular, subcutaneous, oral and transdermal. A compound provided herein may be administered frequently at low doses, known as metronomic therapy, or as part of a maintenance therapy using the compound alone or in combination with one or more additional drugs. Metronomic therapy or maintenance therapy may comprise administration of a compound provided herein in cycles. Metronomic therapy or maintenance therapy may comprise intratumoral administration of a compound provided herein. In one aspect, the invention provides a method of treating cancer in an individual by parenterally administering to the individual (e.g., a human) an effective amount of a compound or salt thereof. In some embodiments, the route of administration is intravenous, intra-arterial, intramuscular, or subcutaneous. In some embodiments, the route of administration is oral. In still other modalities, the administration route is transdermal. The invention also provides compositions (including pharmaceutical compositions) as described herein for use in the treatment, prevention and / or delay of the onset and / or development of cancer and other methods described herein. In certain embodiments, the composition comprises a pharmaceutical formulation that is present in a unit dosage form. Also provided are articles of manufacture comprising a compound of the description or a salt thereof, the composition and the unit doses described herein in a container suitable for use in the methods described herein. Suitable containers are known in the art and include, for example, vials, containers, ampoules, bottles, jars, flexible containers and the like. A manufacturing item may also be sterilized and / or sealed kits. The present description further provides kits for carrying out the methods of the invention, comprising one or more compounds described herein or a composition comprising a compound described herein. The kits may employ any of the compounds described herein. In a variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for one or more of the uses described herein and may therefore contain instructions for the treatment of cancer. The kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged into containers ΜΛ / t / ZUZZ / UÓUUOO 111 separately or some components may be combined in one container when cross-reactivity and shelf life permit. Kits may be in unit dosage forms, bulk containers (e.g., multi-dose containers), or subunit doses. For example, kits may be provided containing sufficient doses of a compound as described herein and / or a second pharmaceutically active compound useful for a disease detailed herein (e.g., hypertension) to provide effective treatment of an individual. for an extended period, such as any one week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months or longer. Kits may also include multiple unit doses of the compounds and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies). Kits may optionally include a set of instructions, usually written instructions, although electronic storage media (e.g., a magnetic floppy disk or optical disk) containing instructions are also acceptable, related to the use of the components of the methods. the present invention. The instructions included with the kit generally include information about the components and their administration to an individual. The invention may be better understood with reference to the following examples, which are provided by way of illustration and are not intended to be limiting. General information 1H NMR spectra and 13C NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer. The spectra refer to residual chloroform (δ 7.26, Ή), DMSO (δ 2.54,ΧΗ) or methanol (δ 3.34, Ή) unless otherwise indicated. Chemical shifts are expressed in ppm (δ); Multiplicities are denoted by s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sextet (sextet), m (multiplet), and br (broad). The coupling constants were measured in Hertz. Analytical HPLC was performed on an Agilent 1200 HPLC with an Agilent G1365D diode array detector using an Agilent Eclipse XDBC18 column (4.6 x 150 mm, 5 pm). Analytical LCMS was performed on an Agilent 6410 triple quadrupole LCMS. Commercially available reagents and solvents were used as received unless otherwise indicated. MA / t / ZUZZ / UÓUUOO 112 Selected modalities Modality 1. A compound of Formula (I): ΜΛ / t / ZUZZ / UÓUUOO x a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein: each = is independently a single bond or double bond; X is O or S; R1 is hydrogen, C1-C3 alkyl, -(Ci-C3 alkylene)OH, C1-C3 haloalkyl, or C3C4 cycloalkyl; Gi is CRao N, where: Raes hydrogen, halogen, or C1-C4 alkyl; Zi is C-Wi-Rc; where: each Wi is independently -O- or -NRW1-, where: RW1 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, -OH, or halogen, and R is independently 4- to 6-membered heterocyclyl, C6-C14 aryl, or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by Rcl, wherein each RC1 is independently halogen, C1-C4 alkyl, C3-C6 cyclalkyl, 3-6 membered heterocyclyl, cyano, oxo, C1-C4 alkoxy, C1-C4 halolacoxy, C1-C4 haloalkyl, -OR10, -NR10Rn, -C(O)NR10R11, -NR ^QOjR11, -S(O)2R10, -NR10S(O)2Rn, or -S(O)2NR10Rn; Z2es C-W2-Rdo N, where: W2es -O-, -NRw2-, or a link, where: Rw2 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, -OH, or halogen, and You independently convert hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl or alkyl. C1-C4; Z3 is C-Reo N, where: Reis independently hydrogen, halogen, cyano, 3-6 membered heterocyclyl or C1-C4 alkyl; 113 M1es S or CRla; M2 is S or CR2a, provided that when M1 is S, when the = adjacent to M1 is a single bond and = adjacent to M2 is a double bond, when M2 is S, when the = adjacent to M2 is a single bond and = adjacent to M1 is a double bond , and at least one of M1 and M2 is not S; Ria and R2a are independently hydrogen, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, cyano, oxo, C1-C4 haloalkyl, C1-C4 alkoxy, haloalkoxy of C1-C4, -OR10, -NR10R11, -C(O)OR10, -qOjNR1^11, -NR10C(O)Rn, -S(O)2R10, -NR10S(O)2Rno -S(O)2NR10R11, each of which is independently optionally replaced by R12; R2 is halogen, C1-C4 alkyl, C3-Ce cycloalkyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl -(C1-C3 alkylene), 5- to 10-membered heteroaryl, cyano, oxo, haloalkyl. C1-C4, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR10, -NR10R11, -C(O)OR10, -C(O)NR10R11, -NR^OjR11, -S(O)2R10, -NR10S (O)2Rn, or -S(O)2NR10Rn, each of which is independently optionally substituted by R12; R3 is -(CH2)mNR13S(O)2R14, C3-C6O cycloalkyl C1-C4 alkyl substituted by halogen, oxo, -CN, or -OH, where m is 0, 1, 2 or 3; yRn are independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkenyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, -(Ci-C3 alkylene)C3 cycloalkyl -Cs, -(Ci-C3 alkylene) 3 to 6 membered heterocyclyl, -NR15R16, or -C(O)R12, wherein each of R10 and R11 are independently optionally substituted by halogen, oxo, -CN, - CF3, -OH, NR13R14, -C(O)NR13R14, or C1-C4 alkyl optionally substituted by halogen, oxo, -CN, -CF3, or OH, Ri° and rhsetomange together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -CF3, -OH, or C1-C4 alkyl optionally substituted by halogen , oxo, -CN, or -OH; each R12is independently halogen, cyano, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR15, -NR15R16, -C(O)NR15R16, -NR15C(O)R16, -S(O) 2R15, -NR15S(O)2R16, -S(O)2NR15R16, C3-C6 cycloalkyl, 3- or 6-membered heterocyclyl or C1-C4 alkyl each of which is independently optionally substituted by halogen, oxo, -CF3, -CN, -OH, -NR13R14, or NR13C(O)R14; R13 and R14 are independently hydrogen, C1-C4 alkyl, C3-Ce cycloalkyl or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by ΜΛ / t / ZUZZ / UÓUUOO 114 halogen, oxo, -CN, or -OH, R13 and R14 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -OH, or CI-C4 alkyl optionally substituted by halogen, oxo, -CN, or -OH; and each R15 and R16 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN or -OH , Ri5 and Ri6Se are taken together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -OH, or CI-C4 alkyl optionally substituted by halogen, oxo, -CN , or -OH. Modality 2. The compound according to modality 1, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that the compound is of Formula (II), (II). Modality 3. The compound according to modality 1, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that the compound is of Formula (III), Embodiment 4. The compound according to any of embodiments 1 to 3 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that X is O. Modality 5. The compound in accordance with any of the modalities 1 to 115 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that Gi is CH. Modality 6. The compound according to any of the embodiments 1 to 5, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that Z1es C-Wi-Rcy Rces C6-C14 aryl optionally replaced by Rcl. Modality 7. The compound according to modality 6, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that Rces phenyl optionally substituted by halogen or C1-C4 alkyl. Embodiment 8. The compound according to any of embodiments 1 to 7 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that Z2 is CH. Embodiment 9. The compound according to any of embodiments 1 to 8 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that Z3 is CH. Modality 10. The compound according to any of the embodiments 1 to 9 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that R1 is C1-C3 alkyl Modality 11. The compound according to any of the embodiments 1 to 10, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that R2 is -QOjNR^R11, 5 to 10 membered heteroaryl , (C1-C3 alkylene) 3-6 membered heterocyclyl, or C1-C4 alkyl, each of which is optionally independently substituted with R12. Modality 12. The compound according to modality 11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that R2 is -C(O)NR10Rnwhich is optionally substituted with R12, wherein rio and Ruson cac|a independently hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl, or R10 and R11 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen. Embodiment 13. The compound according to embodiment 11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that R2 is 5- to 10-membered heteroaryl optionally substituted with R12. Modality 14. The compound according to any of the embodiments 1 to 13, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that R3 is -(CH2)m NR13S(O)2R14o alkyl of Ci-C 4 substituted with MA / t / ZUZZ / UÓUUOO 116 halogen, oxo, -CN or -OH. Embodiment 15. The compound according to any of embodiments 1 to 14, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that R3 is -(CH2)mNR13S(O)2R14. Modality 16. The compound according to any of embodiments 1 to 15 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the A __ / N above, further characterized because R3is h Embodiment 17. The compound according to any of embodiments 1 to 14 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that R3 is Ci-Q alkyl substituted by -OH. Modality 18. The compound according to modality 17 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, ΜΛ / t / ZUZZ / UÓUUOO HO. A further characterized because R3es Embodiment 19. The compound according to any of embodiments 1 and 3 to 18 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that Rla is hydrogen. Modality 20. The compound in accordance with any of the modalities 1, 2, and 4 to 18, or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that R2a is hydrogen. Modality 21. The compound according to modality 1, or a pharmaceutically acceptable salt thereof, further characterized in that the compound is selected from the group consisting of the compounds of Table 1. Embodiment 22. A pharmaceutical composition comprising the compound of any of embodiments 1 to 21, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above and a pharmaceutically acceptable carrier. Modality 23. A method of treating a disease mediated by a bromodomain and extraterminal domain (BET) in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the compound of any of embodiments 1 to 21 or a tautomer or is 'mer thereof, or a pharmaceutically acceptable salt of any of the above. Modality 24. A method of treating cancer in an individual who needs it 117 comprises administering to the individual a therapeutically effective amount of the compound of any of embodiments 1 to 21 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above. Embodiment 25. A method of inhibiting the bromodomain and the extraterminal (BET) domain in a cell, comprising administering the compound of any of embodiments 1 to 21, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the previous ones, to the cells. Modality 26. Use of the compound of any of the modalities 1 to 21, or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, in the preparation of a medicament for the treatment of a bromodomain-mediated disease and extraterminal domain (BET). Mode 27. A kit comprising the compound of any of embodiments 1 to 21, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above. ΜΛ / t / ZUZZ / UÓUUOO Modality 2.1. A compound of formula (IV): a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, wherein: each = is independently a single bond or double bond; X is O or S; R1 is hydrogen, C1-C3 alkyl, -(Ci-C3 alkylene)OH, C1-C3 haloalkyl, or C3C4 cycloalkyl; Gi is CRao N, where: Raes hydrogen, halogen, Ci-Ce alkyl or Ci-Ce haloalkyl; Zi is C-Wi-Rc; where: each Wi is independently -O- or -NRW1-, where: RW1 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, 118 -OH, or halogen, and Rces independently C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, Có-Cm aryl, or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by Rcl, wherein RC1 is independently halogen, C1 alkyl -C4, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, cyano, oxo, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, -OR10, -NR10Rn, -C(O)NR10Ru , -NR10C(O)Rn, -S(O)2R10, -NR10S(O)2Rn, or -S(O)2NR10R11; Z2es C-W2-Rdo N, where: W2es -O-, -NRw2-, or a link, where: Rw2 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, -OH, or halogen, and You independently release hydrogen, halogen, cyano, 3-6 membered heterocyclyl or C1-C4 alkyl; Z3 is C-Reo N, where: Reis independently hydrogen, halogen, cyano, 3-6 membered heterocyclyl or C1-C4 alkyl; M1es S or CRla; M2 is S or CR2a, provided that when M1 is S, when the = adjacent to M1 is a single bond and == adjacent to M2 is a double bond, when M2 is S, when the = adjacent to M2 is a single bond and == adjacent to M1 is a double bond, and at least one of M1 and M2 is S; Ria and R2a are independently hydrogen, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, cyano, oxo, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR10, -NR10Rn, -C(O)OR10, -C(O)NR10R11, -NR10C(O)Rn, -S(O)2R10, -NR10S(O)2R11o -S(0 )2NR10R11, each of which is independently optionally replaced by R12; R3is -(CH2)mNR13S(O)2R14where m is 0, 1, 2 or 3; C3-C6 cycloalkyl optionally substituted by halogen, oxo, -CN, or -OH; C1-C4 alkyl substituted by halogen, oxo, -CN, or -OH; R10 and R11 are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkenyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, -(Ci-C3 alkylene)C3-cycloalkyl. C6, -(C1-C3 alkylene) 3 to 6 membered heterocyclyl, -NR15R16, or -C(O)R12, wherein each of R10 and R11 are independently optionally substituted by halogen, oxo, -CN, -CF3 , -OH, NR13R14, -C(O)NR13R14, or C1-C4 alkyl optionally substituted by halogen, oxo, -CN, -CF3, or OH, 119 R10 and R11 take together with the atom or atoms to which they are attached to form a 3 to 6 membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -CF3, -OH, or C1-C4 alkyl optionally substituted by halogen, oxo, -CN, or -OH; each R12is independently halogen, cyano, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR15, -NR15R16, -C(O)NR15R16, -NR15C(O)R16, -S(O) 2R15, -NR15S(O)2R16, -S(O)2NR15R16, C3-C6 cycloalkyl, 3- or 6-membered heterocyclyl or C1-C4 alkyl each of which is independently optionally substituted by halogen, oxo, -CF3, -CN, -OH, -NR13R14, or NR13C(O)R14; Ri3y are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN, or -OH, R13 and R14 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -OH, or CI-C4 alkyl optionally substituted by halogen, oxo, -CN, or -OH; and each R15 and R16 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3-6 membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, -CN or -OH , R15 and R16 are taken together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, -CN, -OH, or CI-C4 alkyl optionally substituted by halogen, oxo, -CN , or -OH. Modality 2.2. The compound according to embodiment 2.1 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, wherein M1 is S. Modality 2.3. The compound according to embodiment 2.1 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, wherein M2 is S. Modality 2.4. The compound according to any of embodiments 2.1 to 2.3 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that X is O. Modality 2.5. The compound according to any of embodiments 2.1 to 2.4 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that Zi is C-O-Rc. Modality 2.6. The compound according to embodiment 2.5, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that R2 is phenyl, pyridinyl or cyclohexyl, each of which is substituted MA / t / ZUZZ / UÓUUOO 120 independently optionally by Rcl. Modality 2.7. The compound according to embodiment 2.5 or 2.6 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, MA / t / ZUZZ / UÓUUOO <RC')n <R°’>n (R”')„ ΎΧ XGi ΊΓΧ where Rces , or , where n is 0, 1, 2, 3, or 4. Modality 2.8. The compound according to embodiment 2.6 or 2.7, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that RC1 is independently halogen or C1-C4 alkyl. Modality 2.9. The compound according to claim 2.8 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, Modality 2.10. The compound according to any of embodiments 2.1 to 2.9 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that Z2 is CH. Modality 2.11. The compound according to any of embodiments 2.1 to 2.9 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that Z2 is N. Modality 2.12. The compound according to any of embodiments 2.1 to 2.11 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that Z3 is CH. Modality 2.13. The compound according to any of embodiments 2.1 to 2.12 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that R1 is C1-C3 alkyl Modality 2.14. The compound according to embodiment 2.13 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that R1 is methyl. Modality 2.15. The compound according to any of embodiments 2.1 to 2.14 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that Gi is CRa, where Ra is hydrogen. 121 Modality 2.16. The compound according to any of embodiments 2.1 to 2.15 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, further characterized in that Gi is N. Modality 2.17. The compound according to embodiment 2.1, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, further characterized in that the compound is of Formula is selected from the compounds in Table 1. Modality 2.18. A pharmaceutical composition comprising the compound of any of embodiments 2.1 to 2.17, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above and a pharmaceutically acceptable carrier. Modality 2.19. A method of treating a bromodomain and extraterminal domain (BET) mediated disease in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the compound of any of embodiments 2.1 to 2.17 or a tautomer or isomer of the same, or a pharmaceutically acceptable salt of any of the above. Modality 2.20. A method of treating cancer in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the compound of any of embodiments 2.1 to 2.17 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above. Modality 2.21. A method of inhibiting the bromodomain and the extraterminal (BET) domain in a cell, comprising administering the compound of any of embodiments 2.1 to 2.17, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above, to the cells. Modality 2.22. Use of the compound of any of embodiments 2.1 to 2.17, or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the above, in the preparation of a medicament for the treatment of a disease mediated by bromodomain and extraterminal domain ( BET). Modality 2.23. A kit comprising the compound of any of embodiments 2.1 to 2.17, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the above. ΜΛ / t / ZUZZ / UÓUUOO 122 Synthetic Examples ΜΛ / t / ZUZZ / UÓUUOO EXAMPLE S-l Synthesis of N-ethH-4-(2-(4-fluoro-2,6-dimetHphenoxy)-5-(2-hydroxypropan-2-H)phenii)-6 metH-7-oxo-6,7- dihydrothiene[2,3-c]pyridine-2-carboxamide (General Procedure 1) (Compound 1) ,Step 41 p, Passóla "· Step 1. Synthesis of 4-fluoro-2,6-dimethylphenol: Step 1: Synthesis of 4-fluoro-2,6dimethylphenol: To a stirred solution of 2-bromo-5-chloropyrazin-1,3-amine (5.0 g, 24.7 mmol, leq) in dioxane: water (180 ml: 25 ml) KOH (4.15 g, 74.2 mmol, 3 eq) was added and the mixture was degassed under nitrogen for 15 min. In another configuration, t-Bu-X-phos (839 mg, 7.98 mmol 0.08 eq) and Pd 2 (dba) 3 (452 ​​mg, 0.49 mmol, 0.08 eq) in 1,4-dioxane: water (10 ml: 10 mi) was degassed under nitrogen for 15 min. The content of the first degassed mixture was transferred to the degassed solution of the second and the mixture was heated to 100 °C and monitored by TLC and LC-MS. The reaction was complete after 16 hours and the mixture was acidified with 6N HCl (pH ~ 2-3) and extracted with EtOAc (700 ml). The organic layer was washed with water (300 ml), brine (200 ml), dried over anhydrous Na2SO 4, filtered and concentrated under reduced pressure to obtain a crude residue which was purified by CombiFlash chromatography to produce 4-fluoro- 2,6-dimethylphenol (2.2 g, 64%) as a viscous brown solid. LCEM: 141 [M+l]+. Step 2. Synthesis of 1-(3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)ethanone: To a solution of 4-fluoro-2,6-dimethylphenol (0.50 g, 3.57 mmol) in DMSO (20 ml) was added to Cs2CO 3 (8.9 g, 27.2 mmol) at RT and the mixture was stirred for 15 min. Next, 1- (3 123 bromo-4-fluorophenyl)ethanone (0.93 g, 4.28 mmol, 1.2 eq) and the resulting mixture was heated at 80 °C for 16 h. The reaction was complete after 16 hours and the mixture was diluted with water (200 ml) and extracted with EtOAc (200 ml x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a crude product which was purified by CombiFlash chromatography to provide 1-(3-bromo- 4-(4-fluoro-2,6-dimethyl phenoxy)phenyl)ethanone (0.30 g, 25%) as an off-white solid. LCEM: 337 [M+H]+, 339 [M+H+2]+ Step 3. Synthesis of l-(4-(4-fluoro-2,6-dimethylphenoxy)-3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenyl)ethanone: A a solution of 1-(3-bromo-4-(4-fluoro-2,6dimethylphenoxy)phenyl)ethanone (0.55 g, 1.63 mmol, 1 eq) in dioxane (5 ml), B2Pin2 (0.50 g, 1.96 mmol) was added. ), KOAc (0.48 g, 4.89 mmol) and Pd(dppf)Cl2 (0.12 g, 0.16 mmol). The reaction mixture was degassed and purged again with N2. The mixture was then stirred overnight at 80°C. TLC analysis indicated that the reaction was complete. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-(4-(4-fluoro-2,6-dimethylphenoxy¡)-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan -2-¡l)phenyl)ethanone as a black viscous liquid (0.35 g, 56%).ΧΗ NMR (400 MHz, CDCI3): δ 8.35 (d, J = ΙΑ Hz, 1 H), 7.86 (s, 1H), 6.81 (d, J=8.8 Hz, 2H), 6.35 (d, .7=8.8 Hz, 1H), 2.57 (s, 3Η), 1.37 (s, 6H), 1.25 (d, J = 7.3Hz, 12H) Step 4a Synthesis of 4-bromo- N -ethyl-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxamide: Al 4-bromo-6-methyl-7-oxo-6 ethyl,7-dihydrotenene [2,3-c]pyridine-2-carboxylate (1.5 g, 4.3 mmol, 1 eq), ethylamine (17 ml; 70% solution in H2O) was added and the mixture was heated at 800C and controlled by TLC. The reaction was completed after 2 hours and ice water (50 ml) was added to obtain a precipitate that was filtered on a Büchner funnel; dried under vacuum to provide 4-bromo- / V-ethyl-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide (1.23 g, 95%) as a white solid. LCEM: 315 [M+H]+, 317 [M+H+2]+ Step 4. Synthesis of 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-N-ethyl-6-methyl-7oxo-6,7-dihydrothiene [2,3- c] pyridine -2-carboxamide: To a stirred solution of 4-bromo- Net¡l-6-methyl-7-oxo-6,7-di¡hydrotiene [2,3-c] pihdin -2-carboxamide (0.27 g, 0.86 mmol, 1 eq) in 1, 4-dioxane (1 ml) 1- (4- (4-fluoro-2,6-dimethylphenoxy¡) -3- (4,4 ,5,5-tetramethyl-1,3,2-dioxaboran2-yl)phenyl)ethanone (0.49 g, 1.28 mmol, 1.5 eq) and Na2CO3 (0.27 g, 2.57 mmol, 3 eq) dissolved in water (0.3 mi ) followed by the addition of Pd(dppf)Cb (63 mg, 0.085 mmol, 0.1 eq) at RT. The reaction mixture was heated by microwave radiation to 100°C and monitored by TLC. The reaction was complete after 45 min and the mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 300 mL). The organic layer was washed with water (100 mL), brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to produce a crude material which was purified by CombiFlash chromatography to provide 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy¡)phenyl)-N-ethyl ΜΛ / t / ZUZZ / UÓUUOO 124 6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide (0.16 g, 38%) as a brown viscous liquid. LCEM: 493 [M+H]+ Step 5. Synthesis of N -ethyl-4-(2-(4-fluoro-2,6-dimethylphenoxy¡)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo-6 ,7-dihydrothieno[2,3-c]pyridine-2-carboxamide: To a stirred solution of 4- (5-acetyl-2- (4-fluoro-2,6-dimethylphenoxy¡) phenyl) - N - Ethyl-6-methyl-7-oxo-6,7-dihydrothyene[2,3-c]pyridine-2-carboxamide (0.050 g, 0.10 mmol) in anhydrous THF (3 ml) was added methyl lithium (0.2 ml, 0.33 mmol, 6 eq) at 0°C dropwise and the mixture was stirred at the same temperature for 10 min. The reaction was complete after 10 min and the mixture was slowly quenched with NH4Cl solution (10 ml). The aqueous layer was extracted with EtOAc (100 ml x 2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a crude product which was purified by reverse phase HPLC to yield / V -ethyl-4-(2-(4-fluoro-2,6-dimet¡lfenoxy¡)-5-(2-hydroxypropan-2-¡l)phenyl)-6-methyl-7-oxo- 6,7dihydrotiene[2,3-c]pindin-2-carboxamide (3.5 mg, 7%) as an off-white solid. LCEM: 509 [M+l]+.XH NMR (400 MHz, DMSO-ofe): δ 8.86 (t, 7 = 5.6 Hz, 1H), 7.85 (s , 1H), 7.69 (s , 1H), 7.51 ( d, J = 2.4 Hz, 1H), 7.40 (dd, J = 8.4, 2.5 Hz, 1H), 6.97 (d, 7 = 9.0 Hz, 2H), 6.35 (d, 7 = 8.6 Hz, 1H), 5.02 ( s , 1H), 3.63 (s , 3H), 3.24 (q, 7= 7.2Hz, 2H), 2.00 (s , 6H), 1.45 (s , 6H), 1.09 (t, 7= 7.2 Hz, 3H). ΜΛ / t / ZUZZ / UÓUUOO EXAMPLE S-2 Synthesis of 4-(2-(2,4-didorophenoxy)-5-(2-hydroxypropan-2-H)phenyl)-N-ethii-6-methyl-7oxo-6,7-dihydrothiene [2,3-c]pyridine-2-carboxamide (Compound 2) Step 1| B;Pirv Pd dppfiCk Na-CO· I 4-S :x3: MW ird ICC:C. 1 hour Cl ] Step -2. I Step 3. Step 4] 125 Step 1. Synthesis of l-(3-bromo-4-(2,4-dichlorophenoxy)phenyl)ethanone: 1-(3-bromo4-(2,4-dichlorophenoxy)phenyl)ethanone (1.56 g, 71%) was prepared , white solid) following General Procedure 1, Step 2 using 2,4-dichlorophenol (1 g, 6.1 mmol, leq). LCEM: 359 [M+H]+, 361 [M+H+2]+ Step 2: Synthesis of 1-(4-(2,4-dichlorophenoxy¡-3-(4,4,5,5-tetramethi-l,3,2-dioxaborolan-2yl)phenyl)ethanone: 1- (4- (2,4-dichlorophenoxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-l)phenyl)ethanone (0.19 g, 17%, white solid ) was prepared following General Procedure 1, Step 3 using 1-(3-bromo-4-(2,4-dichlorophenoxy)phenyl)ethanone (1 g, 2.77 mmol, 1 eq). LCEM: 407 [M+H] + Step 3a Synthesis of 4-Bromo-N-ethyl-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxamide: 4-bromo-N-ethyl-6-methyl- was prepared 7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide (1.23 g, 95%, white solid) following General Procedure 1, Step 4a using 4-bromo6-methyl-7-oxo Ethyl -6,7-dihydrothyene [2,3-c]pyridine-2-carboxylate (1.5 g, 4.3 mmol, 1 eq). LCEM: 315 [M+H]+, 317[M+H+2]+. Step 3: Synthesis of 4-(5-acetyl-2-(2,4-dichlorophenoxy)phenyl)-N-ethyl-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridin-2- carboxamide: 4-(5-acetyl-2-(2,4-dichlorophenoxy)phenyl)-N-ethyl-6methyl-7-oxo-6,7-dihydrotenene[2,3-c]pyridine-2-carboxamide (0.10 g, 61%, black viscous liquid) following General Procedure 1, Step 4 using 1- (4- (2,4-dichlorophenoxy) -3- (4,4,5,5-tetramethyl1,3,2 - dioxaborolan-2-yl)phenyl)ethanone (0.1 g, 0.31 mmol, 1.0 eq). LCEM: 515 [M+H]+ Step 4: Synthesis of 4-(2-(2,4-dichlorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-N-ethyl-6methyl-7-oxo-6,7-dihydrothiene [2, 3-c]pyridine-2-carboxamide: 4-(2-(2,4-dichlorophenoxy)-5(2-hydroxypropan-2-yl)phenyl)-N-ethyl-6-methyl-7-oxo- 6,7-Dihydrothyene[2,3-c]pyridine-2-carboxamide (0.012 mg, 11.5%, off-white solid) was prepared following General Procedure 1, Step 5 using 4-(5-acetyl- 2-(2,4-dichlorophenoxy)phenyl)-N-ethyl-6-methyl-7-oxo-6,7-dihydrotiene[2,3-c]pyridine2-carboxamide ( 1.0 g, 0.19 mmol, 1.0 eq). LCEM: 531 [M+H]+,XH NMR (400 MHz, MeOH-ώ): δ 7.68 (s , 1H), 7.65-7.57 (m, 2H), 7.50 (s , 1H), 7.33 (d, J = 2.6 Hz, 1H), 7.13-7.06 (m, 2H), 6.74 (d, J = 8.8 Hz, 1H), 3.65 (s, 3H), 3.40-3.35 (m, 2H), 1.59 (s, 6H) , 1.20 (t, J = 7.3 Hz, 3H). ΜΛ / t / ZUZZ / UÓUUOO EXAMPLE S-3 Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-H)fenü)-N-ethii-6-metH-7oxo-6,7-dihydrothiene [2 ,3-c]pyridine-2-carboxamide (Compound 3) 126 B;Pind-, KOAc 4 2-:x3: : SG ’C |Step 2| MA / t / ZUZZ / UÓUUOO Pddppl Úl; fhrCC; t C:x3-: ΗΌ | Passed Step 1: Synthesis of l-(3-bromo-4-(2,4-difluorophenoxy)phenyl)ethan-l-one: 1-(3bromo-4-(2,4-difluorophenoxy)phenyl)ethan-l was prepared -one (1.0 g, 40%, white solid) following General Procedure 1, Step 2 using 2,4-difluorophenol (0.98 g, 8.46 mmol, 1.1 eq). LCEM: 327[M+H]+, 329 [M+H+2]+ Step 2: Synthesis of 1-(4-(2,4-dichlorophenoxy-3-(4,4,5,5-tetramethi-l,3,2-dioxaborolan-2yl)phenyl)ethanone: 1- (4- ( 2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-l)phenyl)ethanone (1.0 g, 87%, white solid) was prepared following General Procedure 1, Step 3 using 1-(3-bromo-4-(2,4-difluorophenoxy) phenyl) ethan-l-one (1.0 g, 3.06 mmol, 1.0 eq.) LCEM: 375 [M+H ]+Step 3: Synthesis of 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-N-ethyl-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridin- 2-carboxamide: 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-N-ethyl-6methyl-7-oxo-6,7-dihydrothyene [2,3-c ]pyridine-2-carboxamide (0.2 g, 65%, white solid) following General Procedure 1, Step 4 using 1-(4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl -l,3,2dioxaborolan-2-yl)phenyl)ethanone (0.28 g, 0.76 mmol, 1.2 eq). LCEM: 483 [M+H]+ Step 4: Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-N-ethyl-6methyl-7-oxo-6,7-dihydrothiene [2, 3-c]pyridine-2-carboxamide: 4-(2-(2,4-difluorophenoxy)-5(2-hydroxypropan-2-yl)phenyl)-N-ethyl-6-methyl-7-oxo-6 ,7-dihydrothieno[2,3-c]pyridine-2-carboxamide (0.006 g, 7%, off-white solid)) was prepared following General Procedure 1, Step 5 using 4-(5-acetyl-2-( 2,4-dichlorophenoxy)phenyl)-N-ethyl-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxamide (0.08 g, 0.16 mmol, 1 eq) . LCEM: 499 [M+l]+,JH NMR (400 MHz, ΜεΟΗ-Λ): δ 7.69 (s, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 9.2 Hz, 2H), 7.04-6.91 (m, 3H), 6.88-6.78 (m, 1H), 3.68 (s, 3H), 3.38 (q, J = 7.2 Hz, 2H), 1.58 (s, 6H). 127 MA / t / ZUZZ / UÓUUOO EXAMPLE S-4 Synthesis of N- (4- (2,6-dimethyphenoxy) -3- (6-metii-2- (5-metH-l,3,4-oxadiazoi-2-H) -7oxo-6, 7-dihydrothieno[2,3-c]pyridin-4-H)phenii)ethanesifonamide (General Procedure 2) (Compound 4) |Step- / ¡ Step 1: Synthesis of 2-(2-bromo-4-nitrophenoxy¡)-1,3-dimethylbenzene: To a stirred solution of 2,6-dimethylphenol (2.0 g, 16.03 mmol, 1.0 eq) in DMF (10 ml) NaH (0.721 g, 18.00 mmol, 1.1 eq) was added at 0 °C followed by an addition of 2-bromo-l-fluoro-4-nitrobenzene (3.49 g, 18.0 mmol, 1.1 eq) and controlled by TLC and LC- MS. The reaction was completed after 10 min and ice water (50 ml) was added to the mixture to obtain a precipitate that was filtered on a Büchner funnel; dried under vacuum to yield 2-(2-bromo-4-nitrophenoxy¡)-1,3-dimethylbenzene (4.5 g, 68%) as a yellow solid. LCEM: 322 [M+H]+, 324 [M+H+2]+ Step 2: Synthesis of 3-bromo-4-(2,6-dimethylphenoxy)aniline: To a solution of 2-(2-bromo-4nitrophenoxy)-1,3-dimethylbenzene (4.0 g, 12.42 mmol, 1.0 eq) in ethanol (20 mL), a solution of NH 4 Cl (6.6 g, 124.16 mmol) in water (22 mi) followed by the addition of iron powder (5.5 g, 99.3 mmol). The reaction mixture was stirred at 90°C for 1 h. TLC analysis indicated that the reaction was complete. The reaction mixture was filtered through a fine pad of celite. The filtrate was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 3-bromo-4-(2,6dimethylphenoxy)anline (3.5 g, 97%) as a black viscous liquid. LCEM: 292 [M+H]+, 294 [M+H+2]+Step 3: Synthesis of 4-(2,6-dimethylphenoxy)-3-(4,4,5,5-tetramethyl-l,3 ,2-dioxaborolan-2yl)aniline: 4- (2,6-dimethylphenoxy) -3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline was prepared 128 (0.700 g, 66%, black viscous liquid) below General Procedure 1, Step 3 using aniline 3-bromo-4- (2,6-dimethylphenoxy) (1.0 g, 45.6 mmol, 1.0 eq) and Pd(dppf) Cb (0.16 g, 0.228 mmol, 0.05 eq). Ή NMR: (400 MHz, CDCh) δ 6.97 - 7.11 (m, 3H), 6.58 (d, J= 3.95 Hz, 1H), 6.14 (d, J= 8.77 Hz, 1H), 2.05 - 2.18 (m, 6H ), 1.23 - 1.28 (m, 12H). Step 4: Synthesis of 4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxylic acid: To a stirred solution of 4-bromo-6-methyl-7-oxo Methyl-6,7-dihydrothieno[2,3-c]pyridine-2carboxylate (0.50 g, 1.66 mmol, 1 eq) in THF:MeOH:H2O (6:3:1) (10 mi) was IJOH.H2O (0.7 g, 16.6 mmol, 10 eq) was added and the mixture was stirred at RT for 1 h. The reaction was complete after 1 hour and the mixture was concentrated under reduced pressure. The obtained residue was then diluted with ice water (20 mL) and acidified using 2N HCl (pH ~ 2) to obtain a precipitate that was filtered over a Büchner funnel to produce 4-bromo-6-methyl-7-oxo-acid. 6,7-Dihydrothieno[2,3-c]pyridine-2-carboxylic acid (430 mg, 90%) as an off-white solid. LCEM: 288 [M-H]-, 290 [M-H]-. Step 5: Synthesis of N'-acetyl-4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carbohydrazide: To a stirred solution of 4-bromo-6-acid methyl-7-oxo-6,7-dihydrothyene [2,3-c]pyridine-2-carboxylic acid (0.3 g, 1.9 mmol) in DMF (7 ml) was added to HATU (1.10 g, 3. mmol, 2.0 eq) and DIPEA (1.6 ml, 8.84 mmol, 6 eq) at 0°C and the mixture was stirred at the same temperature for 10 min. Acetohydrazide (0.33 g, 4.47 mmol, 3.0 eq) was then added to the mixture and the resulting mixture was stirred at RT for 1 h. The reaction was complete after 1 h, the mixture was diluted with water (20 ml) and extracted with EtOAc (30 ml x 2). The combined organic layers were washed with water (25 ml), brine (25 ml), dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure to obtain a crude product which was purified by CombiFlash chromatography to yield N' acetyl-4. -bromo-6-methyl-7-oxo-6,7-dihydrotiene [2,3-c]pyridine-2-carbohydrazide (350 mg, 68%) as a yellow solid. LCEM: 344 [M-H]', 346 [M-H]'. Step 6: Synthesis of 4-bromo-6-methyl-2-(5-methyl-l,3,4-oxadiazol-2-¡l)thieno[2,3-c]pyridin7(6H)-one: At a stirred solution of N'-acetyl-4-bromo-6-methyl-7-oxo-6,7-dihydrotiene[2,3-c]pyridine-2-carbohydrazide (0.2 g, 0.58 mmol) in acetonitrile (10 ml), POCl 3 (0.35 g, 2.38 mmol, 5.0 eq) was added at 00C and the mixture was heated to 50°C for 1 h. The reaction was completed after 1 hour and the mixture was slowly quenched with saturated NaHCO3 solution under ice condition and then extracted with EtOAc (100 ml x 3). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure to obtain a crude oil which was purified by CombiFlash chromatography to produce 4-bromo6. -methyl-2-(5-methyl-1,3,4-oxad¡azol-2-¡l)thieno[2,3-c]pyridin-7(6H)-one (110 mg, 58%) as a yellow sticky solid. LCEM: 326 [M-H]', 328 [M-H]'. Step 7: Synthesis of 4-(5-amino-2-(2,6-dimethylphenoxy)phenyl)-6-methyl-2-(5-methyl-l,3,4oxadiazol-2-yl)thieno[2,3 - c]pyridin-7(6H)-one: 4-(5-amino-2-(2,6-dimethylphenoxy)phenyl)-6 MA / t / ZUZZ / UÓUUOO 129 methyl-2-(5-methyl-l,3,4-oxadiazol-2-¡l)thieno[2,3-c] Pyridin-7(6H)-one (0.085 g, 56%, off-white solid) was prepared ) following General Procedure 1, Step 3 using 4-bromo-6-methyl-2-(5methyl-1,3,4-oxadiazol-2-yl)thieno[2,3-c]pyridin-7(6H)- one (0.11 g, 0.33 mmol, 1 eq). LCEM: 459 [M+l] Step 8: Synthesis of N-(4-(2,6-dimethylphenoxy)-3-(6-methyl-2-(5-methyl-l,3,4-oxadiazol-2yl)-7-oxo-6,7 -dihydrothieno[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide: To a stirred solution of 4-(5-amino-2-(2,6-dimethylphenoxy)phenyl)-6-methyl-2-( 5-methyl-l,3,4-oxadilazo-2-yl)thieno[2,3-c]pyridin-7(6H)-one (0.085 g, 0.185 mmol) in THF (8 mL) triethylamine was added (0.056 g, 0.55 mmol, 3 eq) followed by the addition of ethanesulfonyl chloride (0.095 g, 0.74 mmol, 4.0 eq.) at 0°C and the resulting mixture was stirred at RT for 16 h. The reaction was complete after 16 h and water (30 ml) was added to the mixture and extracted with EtOAc (30 ml x 2). The combined organic layers were washed with saturated NaHCO 3 solution (30 ml), brine (30 ml), dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure to obtain a crude product which was purified by Reversed phase HPLC to produce N-(4-(2,6-dimethylphenoxy)-3-(6-methyl-2-(5-methyl-l,3,4oxadiazol-2-yl)-7-oxo-6, 7-Dihydrothieno[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (4.2 mg, 4.1%) as an off-white solid. LCEM: 551 [M+l]+, *Η NMR (400 MHz, MeOH-íÁ): δ 7.88 (s, 1H), 7.74 (s, 1H), 7.38 (d, J = 2.7 Hz, 1H), 7.18 (dd, .7=8.8, 2.7 Hz, 1H), 7.12-6.99 (m, 3H), 6.45 (d, J= 8.8 Hz, 1H), 3.77 (s, 3H), 3.21-315 (m, 2H) , 2.62 (s, 3H), 2.07 (s, 6H), 1.34 (t, J = 7.4 Hz, 3H). MA / t / ZUZZ / UÓUUOO EXAMPLE S-5 Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-H)phenyl)-6-metii-7-oxoN-(2,2,2-trifluoroethii) -6,7-dihydrothieno[2,3-c]pyridine-2-carboxa (Compound 5) [Step'j |Step4 ] Step 1: Synthesis of 4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2 carboxylic acid: 4-bromo-6-methyl-7-oxo- 6,7-dihydrothyene[2,3-c]pyridine-2-carboxylic acid (0.43 g, 90%, off-white solid) following General Procedure 2, Step 4 using methyl-4-bromo 130 6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylate (0.50 g, 1.66 mmol, 1 eq). LCEM: 288 [ΜΗ]; 290 [M-Η]'. Step 2: Synthesis of 4-bromo-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydrothieno[2,3c]pyridine-2-carboxamide: 4-bromo-6 -methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide (0.2 g, 78%, off-white solid) following General Procedure 2, Step 5 using 4-bromo-6-methyl-7-oxo-6,7-dihydrotiene[2,3-c]pyridine-2-carboxylic acid (0.2 g, 0.69 mmol , 1 eq) and 2,2,2-trifluoroethanamine (0.04 g, 0.26 mmol, 2.0 eq). LCEM: 369 [M-H]; 371 [M-H]'. Step 3: Synthesis of 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-N-(2,2,2trifluoroethyl)-6,7-dihydrothiene [2, 3-c]pyridine-2-carboxamide: 4-(5-acetyl-2-(2,4difluorophenoxy)phenyl)-6-methyl-7-oxo-N-(2,2,2-trifluoroethyl)-6,7 -dihydrothiene [2,3- c] Pyridine2-carboxamide (70 mg, 24%, white solid) was prepared following General Procedure 1, Step 4 using 4-bromo-6-methyl-7-oxo-N- (2, 2,2-trifluoroethyl)-6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide (0.2 g, 0.54 mmol, 1.0 eq). LCEM: 537 [M+l]+. Step 4: Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7oxo-N-(2,2,2-trifluoroethyl)- 6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide: 4-(2-(2,4difluorophenoxy)-5-(2-hydroxypropan-2-¡l)phenyl)-6-methyl-7- oxo-N-(2,2,2-trifluoroethyl)-6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide (0.006 g, 12.5%, off-white solid) was prepared following General Procedure 1, Step 5 using 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-N(2,2,2-trifluoroethyl)-6,7-dihydrothiene [2,3- c] pyridine-2-carboxamide (0.095 g, 0.18 mmol, 1.0 eq). LCEM: 553 [M+l]+,4H NMR (400 MHz, MeOD-ώ): δ 7.79 (s, 1H), 7.62-7.50 (m, 3H), 7.03-6.90 (m, 3H), 6.82 (ddd , J = 12.8, 6.9, 2.3 Hz, 1H), 4.05 (q, J = 9.3 Hz, 2H), 3.69 (s, 3H), 1.58 (s, 6H). ΜΛ / t / ZUZZ / UÓUUOO EXAMPLE S-6 Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-i)phenyl)-6-meth-2(piperidin-l-carbonii) thieno[2,3-c]pyridin-7(6H)-one (Compound 6) 131 MA / t / ZUZZ / UÓUUOO Step 1: Synthesis of 4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxylic acid: To a stirred solution of 4-bromo-6-methyl-7-oxo Methyl -6,7-dihydrotiene[2,3-c]pyridine-2carboxylate (1.0 g, 3.3 mmol) in THF:MeOH:H2O [6:3:1; (10 ml)] was LÍOH.H2O (1.39 mg, 33.3 mmol, 10 eq) and the mixture was stirred at RT for 1 h. The reaction was complete after 1 h and the mixture was concentrated under reduced pressure. The residue obtained was diluted with water (30 mL) and acidified using 1N-HCI (pH ~ 2) to obtain a solid precipitate that was filtered through a Büchner funnel to produce 4-bromo-6-methyl-7-oxo acid. -6,7-hydrothieno[2,3-c]pyridin-2-carboxylic acid (380 mg, 39%) as an off-white solid. LCEM: 287 [M-H]', 290 [M-H]'. Step 2: Synthesis of 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridine-2-carboxylic acid: 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl7-oxo-6,7-dihydrotenene[2,3-c]pyridine-2-carboxylic acid (0.1 g, 79% , white solid) following General Procedure 1, Step 4 using 4-bromo-6-methyl-7-oxo-6,7-dihydrotiene[2,3-c]pyridine-2-carboxylic acid ( 0.08 g, 0.28 mmol, 1 eq). LCEM: 456 [M+l]+. Step 3: Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7oxo-6,7-dihydrothiene[2,3-c] pyridine -2-carboxylic acid: 4- (2- (2,4-difluorophenoxy) -5- (2hydroxypropan-2-yl) phenyl) -6-methyl-7-oxo-6,7-dihydrothieno [2,3- c]pyridine-2-carboxylic acid (0.10 g, 97%, off-white solid) following General Procedure 1, Step 5 using 4-(5-acetyl-2-(2,4difluorophenoxy)phenyl)-6-methyl-7- oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (0.10 g, 0.22 mmol, 1 eq). LCEM: 472 [M+l]+. 132 Step 4: Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-2(piperidin-l-carbonyl)thieno[2,3- c]pyridin-7(6H)-one: To a stirred solution of 4-(2-(2,4difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo-6 ,7-dihydrotiene[2,3-c]pyridine-2carboxylic acid (0.1 g, 0.22 mmol, 1 eq)) in DMF (4 ml) were successively added to HATU (0.13 g, 0.33 mmol, 1.5 eq) and DIPEA (0.153 ml, 0.88 mmol, 4 eq) at 0°C and the mixture was stirred at the same temperature for 10 min. Piperidine was then added to the mixture (37 mg, 0.44 mmol, 2.0 eq) and the resulting mixture was stirred at RT for 2 h. The reaction was complete after 2 h and the mixture was diluted with water (100 ml) and extracted with EtOAc (100 ml x 2). The combined organic layers were washed with water (100 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to produce a crude oil that was purified by reverse phase HPLC to yield 4-(2 -(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-2-(piperidin-l-carbonyl)thieno[2,3-c]pyridin-7(6H) - one (0.004 g, 4%) as an off-white solid. LCEM: 539 [M+l]+,XH NMR (400 MHz, DMSO-rf;): δ 7.69 (s , 1H), 7.54 (d, J= 2.3 Hz, 1H), 7.49 (dd, J= 8.5, 2.4 Hz, 1H), 7.38 (ddd, 7 = 11.3, 8.7, 3.0 Hz, 1H), 7.20 (s , 1H), 7.11 (td, 7 = 9.3, 5.6 Hz, 1H), 7.02 (t, 7= 8.6 Hz, 1H), 6.85 (d, 7 = 8.5 Hz, 1H), 5.08 (s, 1H), 3.60 (s, 3H), 3.52 (m, 4H), 2.08 (m, 4H), 1.60 (m, 2H ), 1.46 (s, 6H). ΜΛ / t / ZUZZ / UÓUUOO EXAMPLE S-7 Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-H)phenyl)-6-metii-2(piperidin-l-iimetU)thieno[2,3 -c]pyridin-7 (6H) -one (Compound 7) Step 1: Synthesis of 4-bromo-2-(hydroxymethyl)-6-methylthieno[2,3-c]pyridin-7(6H)-one: Towards LiAIH 4 (113 mg, 2.9 mmol, 1.8 eq) in THF ( 10 ml) methyl 4-bromo-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridine-2-carboxylate (500 mg, 1.60 mmol in THF) was added at -10°C slowly and The mixture was stirred at the same temperature for 10 min. The reaction was complete after 10 min and the mixture was slowly quenched with saturated sodium sulfate solution (30 ml). The 133 mixture was then filtered through Celite® and washed with EtOAc (500 mL). The organic layer was then washed with water (200 mL), brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to yield a crude material which was purified by CombiFlash chromatography to yield 4-bromo-2. -(hydroxymethyl)-6-methylthieno[2,3-c]pyridin-7(6H)-one (305 mg, 67%) as a sticky solid. LCEM: 274 [M-H]', 276 [M-H]'. Step 2: Synthesis of (4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridin-2-yl)methyl methanesulfonate: To a stirred solution of 4-bromo-2 -(hydroxymethyl)-6-methylthieno[2,3-c]pyridin7(6H)-one (300 mg, 1.1 mmol, 1 eq) in DCM (10 ml) triethylamine (0.75 ml, 5.5 mmol, 5 eq) was added successively. ) and methanesulfonyl chloride (0.18 ml, 2.2 mmol, 3 eq) at 0°C slowly and the mixture was stirred at RT for 1 h. The reaction was completed after 1 hour and ice water (100 ml) was added to the mixture and extracted with DCM (100 ml x 2). The combined organic layers were washed with water (100 mL x 2), brine (150 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to yield (4-bromo-6-methyl-7- Methyl oxo-6 methanesulfonate, 7-dihydrothieno[2,3-c]pyridin-2-yl) (300 mg, 77%) as a brown sticky liquid which was taken to the next step without further purification. NMR (400 MHz, DMSO-οί): δ 8.02 (s, 1H), 7.49 (s, 1H), 5.61 (s, 2H), 3.50-3.56 (m, 3 H). Step 3: Synthesis of 4-bromo-6-methyl-2-(piperidin-l-ylmethyl)thieno[2,3-c]pyridin-7(6H)one: To a stirred solution of piperidine (0.114 mg, 1.7 mmol , 2 eq) in ethanol (8 ml), DIPEA (0.5 ml, 3.4 mmol, 4 eq) was added and the mixture was stirred at RT for 15 min. Then (4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridin-2-yl)methyl methanesulfonate (300 mg, 0.85 mmol) dissolved in EtOH was added ( 2 ml) to the mixture and the mixture was heated at 100°C for 1 h. The reaction was complete after 1 h and the mixture was concentrated under reduced pressure to obtain a crude product which was purified by CombiFlash chromatograph to yield 4-bromo-6-methyl-2-(piperidin-lylmethyl)thieno[2,3- c]pyridin-7(6H)-one (120 mg, 41%) as an off-white solid. LCEM: 341 [ΜΗ]-, 343 [M-H]-. Step 4: Synthesis of 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-2-(piperidin-lylmethyl)thieno[2,3-c]pyridin-7(6H)- one: 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-2(piperidin-l-ylmethyl)thieno[2,3-c]pyridin-7(6H)-one ( 140 mg, 78%, off-white solid) following General Procedure 1, Step 4 using 4-bromo-6-methyl-2-(piperidin-l-ylmethyl)thieno[2,3-c]pyridin7(6H)-one ( 120 mg, 0.35 mmol, 1 eq). LCEM: 509 [M+l]+. Step 5: Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-2(piperidin-l-ylmethyl)thieno[2,3- c]pyridin-7(6H)-one: 4-(2-(2,4-difluorophenoxy)-5-(2hydroxypropan-2-yl)phenyl)-6-methyl-2-(piperidin-l-ylmethyl)thiene [2,3-c]pyridin- 7(6H)-one (28 mg, 40%, off-white solid) was prepared following General Procedure 1, Step 5 using 4-(5-acetyl-2(2,4-difluorophenoxy )phenyl)-6-methyl -2-(piperidin-l-ylmethyl)thieno[2,3-c]pyridin-7(6H)-one (0.070 g, ΜΛ / t / ZUZZ / UÓUUOO 134 0.13 mmol, 1 eq). LCEM: 525 [M+l]+, íH NMR (400 MHz, MeOH-cA): δ 7.56 (d, 7 = 2.4 Hz, 1H), 7.52 (dd, J= 8.5, 2.4 Hz, 1H), 7.48 ( s,lH), 7.04-6.88 (m, 4H), 6.87-6.77 (m, 1H), 3.75 (s, 2H), 3.68 (s, 3H), 2.46 (s, 4H), 1.93 (d, J = 2.5 Hz, 2H), 1.58 (d, 7 = 6.2 Hz, 10H). EXAMPLE S-8 Synthesis of 4- (2- (2,4-difluorophenoxy) -5- (2-hydroxy¡propan-2-¡i) phenii) -6-metH-2- (3methi / -l / 2, 4-oxadiazoi-5- ¡i) has[2,3-c]pyridin-7(6H) -one (Compounds) ΜΛ / t / ZUZZ / UÓUUOO Step 1: Synthesis of 4-bromo-6-methyl-2-(3-methyl-l,2,4-oxadiazol-5-yl)thieno[2,3-c]pyridin7(6H)-one: To a solution Stirred mixture of methyl 4-bromo-6-methyl-7-oxo-6,7-dihydrotiene [2,3-c]pyridine-2carboxylate (0.4 g, 1.32 mmol) in toluene (6 ml) and K2CO3 was added. (0.27 g, 1.99 mmol, 3 eq) and (E)-N'-hydroxyacetimidamide (0.15 g, 1.99 mmol, 1.5 eq) at RT and the mixture was heated to 120°C for 16 h. The reaction was complete after 16 hours and water (20 ml) was added to the mixture. The aqueous layer was extracted with EtOAc (30x 2). The combined organic layers were washed with water (10 mL), brine (15 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a crude product which was purified by CombiFlash chromatograph to yield 4-bromo-6. methyl-2-(3-methyl-l,2,4-oxad¡azol-5-yl)thieno[2,3-c]pyridin-7(6H)-one (0.4 g, 92%) an off-white solid. LCEM: 326 [M-H]-, 328 [M-H]-. Step 2: Synthesis of 4-(5-acetyl-2-(2,4-difluorophenoxy)phenii)-6-methyl-2-(3-methyl-l,2,4oxadiazol-5-yl)thieno[2,3 - c]pyridin-7(6H)-one: 4-(5-acetyl-2-(2,4-difluorophenoxy)phenii)-6methyl-2-(3-methyl-l,2,4-oxadiazol-5- il)thieno[2,3-c] Pyridin-7(6H)-one (0.15 g, 33%, off-white solid) was prepared following General Procedure 1, Step 4 using 4-bromo-6-methyl-2- ( 3-methyl-l,2,4-oxadiazol-5-yl)thieno[2,3-c]pyridin-7(6H)-one (0.3 g, 0.92 mmol, 1 eq). LCEM: 494 [M+l]+. Step 3: Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenii)-6-methyl-2(3-methyl-l,2,4-oxadiazol- 5- I) thieno[2,3-c]pyridin-7(6H)-one: 4-(2-(2,4-difluorophenoxy) 135 5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-2-(3-methyl-l,2,4-oxad¡azol-5-yl) Thiene [2,3-c] was prepared pyridin-7(6H)-one (2 mg, 2.7%, off-white solid) following General Procedure 1, Step 5 using 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl- 2-(3-methyl-l,2,4-oxad¡azol-5-l)thieno[2,3c]pyridin-7(6H)-one (0.070 g, 0.14 mmol, 1 eq). LCEM: 510 [M+l]+,XH NMR (400 MHz, MeOH-úQ: δ 7.89 (s, 1H), 7.65-7.59 (m, 2H), 7.56 (dd, J = 8.6, 2.4 Hz, 1H) , 7.07-6.96 (m, 2H), 6.92 (d, J= 8.5 Hz, 1H), 6.85 (t, J = 8.7 Hz, 1H), 3.72 (s, 3H), 2.44 (s, 3H), 1.59 ( s, 6H). MA / t / ZUZZ / UÓUUOO EXAMPLE S-9 Synthesis of 4- (2- (2,4-difluorophenoxy) -5- (2-hydroxypropan-2-ii) phenyl) -6-metii-7-oxoN- (1- (tnfiuoromethii) ciciopropii) - 6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide (Compound 14) l |()H 11.0 THP MeOH H, G Step 1 HATU DI PEA DMF [Z Step| C u í T Yo Pd:dppf:CI; I Step 3 | MeLi THF | Step 4] Step 1: Synthesis of 4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxylic acid: 4-bromo-6-methyl-7-oxo-6 acid was prepared ,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (430 mg, 90%, off-white solid) following General Procedure 2, Step 4 using 4-bromo-6methyl-7-oxo-6,7-dihydrothiene Methyl [2,3-c]pyridine-2-carboxylate (0.50 g, 1.66 mmol, 1 eq). LCEM: 288 [M+l]+, 290 [M+H+2]+ Step 2: Synthesis of 4-bromo-6-methyl-7-oxo-N-(1-(trifluoromethyl)cyciopropii)-6,7dihydrothieno[2,3-c]pyridine-2-carboxamide: 4-bromo-6- methyl-7-oxo-N-(1-(trifluoromethyl)cyciopropii)-6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide (0.14 g, 59%, off-white solid) following the General Procedure 2, Step 5 using 4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (0.18 g, 0.63 mmol, 1 eq) and 1-(trifluoromethyl ) cyclopropanamine (0.30 g, 1.8 mmol, 3.0 eq). LCEM: 395 [M+l]+, 397 [M+H+2]+ Step 3: Synthesis of 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-N-(1(trifluoromethyl)cyciopropii)-6,7-dihydrothiene [2, 3- c] pyridine-2-carboxamide: 4- (5-acetyl2- (2,4-difluorophenoxy) phenyl) -6-methyl-7-oxo-N- (1- (trifluoromethyl) ciciopropii) -6,7- dihydrothiene [2,3-c] 136 Pyridine-2-carboxamide (0.16 g, 80%, off-white solid) was prepared following General Procedure 1, Step 4 using 4-bromo-6-methyl-7-oxo-N-(1-(trifluoromethyl)cyclopropyl)-6 ,7-dihydrothieno[2,3-c]pyridine-2-carboxamide (0.14 g, 0.36 mmol, 1 eq) and 1-(4-(2,4-difluorophenoxy)-3-(4,4,5,5tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethanone (0.19 g, 0.55 mmol, 1.5 eq). LCEM: 563 [M+l]+. Step 4: Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7oxo-N-(1-(trifluoromethyl)cyclopropyl)-6 , 7-dihydrothieno[2,3-c]pyridine-2-carboxamide: 4(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo -N- (1,2trifluoromethyl)cyclopropyl)-6,7-dihydrotheno[2,3-c]pyridin-2-carboxamide (5 mg, 6%, off-white solid) was prepared following General Procedure 20, Step 5 using 4-(5-acetyl-2-(2,410 difluorophenoxy¡)phen¡l)-6-methyl-7-oxo-N- (l-trifluoromethyl)cyclopropyl)-6,7-dihydrotiene[2,3-c]pindin-2carboxamide (0.080 g, 0.14 mmol, leq) . LCEM: 579 [M+l]+,JH NMR (400 MHz, MeOH-ώ): δ 7.77 (s, 1H), 7.61-7.50 (m, 3H), 6.97 (dt, J = 15.5, 9.4 Hz, 3H ), 6.83 (t, J= 8.2 Hz, 1H), 3.68 (s, 3H), 1.57 (s, 6H), 1.43-1.31 (m, 2H), 1.18 (s, 2H). ΜΛ / t / ZUZZ / UÓUUOO EXAMPLE S-1O Synthesis of N-ddopropii-4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-ii)phenyl)6-metii-7-oxo-6,7-dihydrothiene [ 2,3-c]pyridine-2-carboxamide (Compound 145) .o ,A L -------------- l, L tic o ii --γ···- ~3=: 3a Br Step 1: Synthesis of l-(3-bromo-4-(2,4-(fluorophenoxyl)phenyl)ethanone: 1-(3-bromo4-(2,4-difluorophenoxy)phenyl)ethanone (1.0 g, 40 %, white solid) following the general procedure 137 1, Step 2 using 1-(3-bromo-4-fluorophenyl)ethanone (0.98 g, 8.46 mmol, 1.1 eq). LCEM: 327[M+H]+, 329 [M+H+2]+ Step 2: Synthesis of 1-(4-(2,4-dichlorophenoxy¡-3-(4,4,5,5-tetramethi-l,3,2-dioxaborolan-2yl)phenyl)ethanone: 1- (4- (2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl·l,3,2-dioxaborolan-2-¡l)phenyl)ethanone (1.0 g, 87%, white solid) was prepared following General Procedure 1, Step 3 using 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-N-ethyl-6-methyl-7-oxo-6 ,7dihydrothieno[2,3-c]pyridine-2-carboxamide (1.0 g, 3.06 mmol, 1.0 eq) LCEM: 375[M+H]+ Step 3a: Synthesis of 4-bromo-N-cyclopropyl-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine2-carboxamide: 4-bromo-N-cyclopropyl-6-methyl was prepared -7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxamide (0.20 g, 93%, white solid) following General Procedure 1, Step 4a using 4bromo-6-methyl-7-oxo Ethyl -6,7-dihydrothyene [2,3-c]pyridine-2-carboxylate (0.2 g, 0.664 mmol, 1 eq). LCEM: 327 [M+H]+, 329 [M+H+2]+ Step 3: Synthesis of 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-N-cyclopropyl-6-methyl-7-oxo6,7-dihydrothieno[2,3-c]pyridin-2- carboxamide: 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-Ncyclopropyl-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide e ( 0.07 g, 41%, brown solid) following General Procedure 1, Step 4 using 1-(4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan- 2-yl)phenyl)ethanone (0.13 g, 0.97 mmol, 1.2 eq). LCEM: 495 [M+H]+ Step 4: Synthesis N-cyclopropyl-4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo-6,7-dihydrothiene[2 ,3- c]pyridine-2-carboxamide: N-cyclopropyl-4-(2-(2,4difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo-6, 7-Dihydrothiene[2,3-c]pyridine-2carboxamide (0.009 g, 12%, off-white solid) was prepared following General Procedure 1, Step 5 using 4-(5-acetyl-2-(2, 4-difluorophenoxy)phenyl)-N-cyclopropyl-6-methyl-7-oxo-6,7-dihydrotiene[2,3-c]pyridine-2-carboxamide (0.070 g, 0.141 mmol, 1.0 eq). LCEM: 511[M+H]+,XH NMR (400 MHz, MeOH-ίΛ): δ 7.68 (s, 1H), 7.60-7.49 (m, 3H), 7.04-6.90 (m, 3H), 6.83 (t , J = 8.5 Hz, 1H), 3.68 (s, 3H), 2.83 (tt, J = 7.4, 3.8 Hz, 1H), 1.57 (s, 6H), 0.79 (td, J = 7.1, 5.0 Hz, 2H) , 0.62 (p, J= 4.7 Hz, 2H). ΜΛ / t / ZUZZ / UÓUUOO 138 ΜΛ / t / ZUZZ / UÓUUOO EXAMPLE S-ll Synthesis of N-ethH-7- (2- (4-fluoro-2,6-dimethiphenoxy) -5- (2-hydroxypropan-2-ii) phenii) 5-metü-4-oxo- 4,5-Dihydrothieno[3,2-c]pyridine-2-carboxamide (Compound 146) Step 1: Synthesis of 4-fluoro-2,6-dimethylphenol: 4-fluoro-2,6-dimethylphenol (2.2 g, 64%) following General Procedure 1, Step 1 using 2-bromo-5-fluoro-l, 3-dimethylbenzene (5.0 g, 24.7 mmol 1 eq). LCEM: 141 [M+l]+. Step 2: Synthesis of 1- (3-bromo-4- (4-fluoro-2,6-dimethylphenoxy¡) phenii) ethanone: 1- (3-bromo-4- (4-fluoro-2,6- dimethylphenoxy)phenii)ethanone (0.30 g, 25%, off-white solid) following General Procedure 1, Step 2 using 1-(3-bromo-4-fluorophenyl)ethanone (0.93 g, 4.28 mmol, 1.2 eq). LCEM: 337 [M+H]+, 339 [M+H+2]+ Step 3: Synthesis of l-(4-(4-fluoro-2,6-dimethylphenoxy)-3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenyl)ethanone: 1 - (4-(4-fluoro-2,6-dimethylphenoxy¡)-3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenii)ethanone (0.35 g, 56 %, black viscous liquid) following General Procedure 1, Step 3 using 1-(3-bromo-4-(4-fluoro-2,6-dimethylphenoxy¡)phenii)ethanone (0.55 g, 1.63 mmol, 1 eq ). XH NMR (400 MHz, CDCh) 8.8 Hz, 1H), 2.57 (s, 3H), 1.37 (s, 6H), 1.25 (d, J= 7.3 Hz, 12H). Step 4a: Synthesis of 7-bromo-N-ethyl-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2carboxamide: 7-bromo-N-ethyl-5 was prepared -methyl-4-oxo-4,5-dihydrotiene [3,2-c]pyridine-2carboxamide (1.23 g, 95%, white solid) following General Procedure 1, Step 4a using 7bromo Ethyl -5-methyl-4-oxo-4,5-dihydrothyene [3,2-c]pyridine-2-carboxylate (1.5 g, 4.3 mmol, 1 eq). 139 LCEM: 315 [M+H]+, 317 [M+H+2]+. Step 4: Synthesis of 7-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy¡)phenyl)-N-ethyl-5-methyl-4oxo-4,5-dihydrothiene[3,2 -c] pyridine -2-carboxamide: 7- (5-acetyl-2- (4-fluoro-2,6dimethylphenoxy) phenyl) -N-ethyl-5-methyl-4-oxo-4,5- dihydrothiene[3,2-c]pyridine-2-carboxamide (0.13 g, 52%, brown solid) was prepared following General Procedure 1, Step 4 using 1-(4-(4-fluoro2,6-dimethylphenoxy)-3 - (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-l)phenyl)ethanone (0.25 g, 0.66 mmol, 1.3 eq) and 7-bromo-N-ethyl-5 -methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxamide (0.16 g, 0.80 mmol, 1 eq). LCEM: 493 [M+H]+ Step 5: Synthesis of N -ethyl-7-(2-(4-fluoro-2,6-dimethylphenoxy¡)-5-(2-hydroxypropan-2-yl)phenyl)-5-methyl-4-oxo-4 ,5-dihydrothieno[3,2-c]pyridine-2-carboxamide: N-ethyl-7-(2-(4-fluoro2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)- 5-methyl-4-oxo-4,5-dihydrothiene [3, 2-c]pyridine-2-carboxamide (35 mg, 25%, off-white solid) was prepared following General Procedure 1, Step 5 using 7-(5 -acetyl-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-N-ethyl-5-methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxamide (0.13 g, 0.263 mmol, 1.0 eq). LCEM: 509 [M+l]+,XH NMR (400 MHz, MeOHd)\ δ 8.14 (s, 1H), 7.67 (s, 1H), 7.62 (d, 7 = 2.5 Hz, 1H), 7.43 (dd, 7 = 8.7, 2.5 Hz, 1H), 6.85 (d, 7 = 8.9 Hz, 2H), 6.42 (d, 7= 8.7 Hz, 1H), 3.72 (s, 3H), 3.45-3.32 (m, 2H), 2.07 (s, 6H), 1.55 (s, 6H), 1.23 (t, 7= 7.2 Hz, 3H). ΜΛ / t / ZUZZ / UÓUUOO EXAMPLE S-12 Synthesis of 4- (2- (4-f / uoro-2,6-dimetHphenoxy) -5- (2-hydroxypropan-2-H) phenyl) -6metH-2- (5-met / -l,3,4-oxadiazol-2-yl)thieno[2,3-c]pyridin-7(6H)-one (Compound 13) 140 Step 1: Synthesis of 4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxylic acid: 4-bromo-6-methyl-7-oxo-6 acid was prepared ,7-dihydrotiene[2,3-c]pyridine-2-carboxylic acid (0.43 g, 90%, off-white solid) following General Procedure 2, Step 4 using 4-bromo-6methyl·7-oxo Methyl -6,7-dihydrotiene [2,3-c]pyridine-2-carboxylate (0.50 g, 1.66 mmol, 1 eq). LCEM: 288 [Μ-H]', 290 [M-H]'. Step 2: Synthesis of N,-acetyl-4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carbohydrazide: N'-acetyl-4-bromo was prepared -6-methyl-7-oxo-6,7-dihydrotiene [2,3-c]pyridine-2carbohydrazide (350 mg, 68%, yellow solid) following General Procedure 2, Step 5 using 4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (0.43 g, 1.49 mmol, 1 eq). LCEM: 344 [M-H]', 346 [M-H]'. Step 3: Synthesis of 4-bromo-6-methyl-2-(5-methyl-l,3,4-oxadiazol-2-yl)thieno[2,3-c]pyridin7(6H)-one: 4-bromo -6-methyl-2-(5-methyl-l,3,4-oxadiazol-2-yl)thieno[2,3-c]pyridin-7(6H)-one (110 mg, 58%, yellow solid) was prepared following General Procedure 2, Step 6 using N'-acetyl4-bromo-6-methyl-7-oxo-6,7-dihydrotene[2,3-c]pyridine-2-carbohydrazide (0.20 g, 0.58 mmol, 1 eq). LCEM: 326 [M-H]', 328 [M-H]'. Step 4: Synthesis of 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-6-methyl-2-(5-methyll,3,4-oxadiazol-2-yl)thiene [2,3-c]pyridin-7(6H)-one: 4-(5-acetyl-2-(4-fluoro-2,6dimethylphenoxy)phenyl)-6-methyl-2-(5-methyl-l, 3,4-oxadiazol-2-yl)thieno[2, 3-c]pyridin-7(6H)one (0.1 g, 32%, off-white solid) was prepared following General Procedure 2, Step 7 using 4-bromo6- methyl-2-(5-methyl-l, 3,4-oxadiazol-2-yl)thieno[2,3-c]pyridin-7(6H)-one (0.2 g, 0.306 mmol, 1 eq) and 1· (4'(4-fluoro-2,6-dimethylphenoxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethanone (0.306 g, 0.797 mmol, 1.3 eq). LCEM: 504 [M+l]+. Step 5: Synthesis of 4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6methyl-2-(5-methyl-l,3,4 -oxadiazol-2-yl)thieno[2,3-c]pyridin-7(6H)-one: 4-(2-(4-fluoro-2,6dimethylphenoxy)-5-(2-hydroxypropan-2-yl) phenyl)-6-methyl-2-(5-methyl-1,3,4-oxadiazol- 2-¡l)thieno[2,3-c]pyridin-7(6H)-one (13 mg, 25 %, off-white solid) following General Procedure 1, Step 5 using 4- (5-acetyl-2 - (4-fluoro-2,6-dimethylphenoxy) phenyl) -6-methyl-2- (5-methyl-l, 3,4-oxadiazol2-¡l)thieno[2,3-c]pyridin-7(6H)-one (0.05 g, 0.099 mmol, 1 eq). LCEM: 520 [M+l]+, NMR (400 MHz, DMSO-¿¿): δ 7.82 (s, 1H), 7.66 (s, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.41 ( dd, J= 8.6, 2.4 Hz, 1H), 6.99 (d, J= 9.1 Hz, 2H), 6.37 (d, J = 8.6 Hz, 1H), 5.04 (s, 1H), 3.67 (s, 3H), 2.57 (s, 3H), 2.02 (s, 6H), 1.45 (s, 6H) EXAMPLE S-13 Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-H)phenyl)-2-(3,3difluoropiperidin-l-carbonyl)-6-methHthiene [2 , 3-c]pyridin-7(6H)-one (Compound 23) ΜΛ / t / ZUZZ / UÓUUOO 141 ΜΛ / t / ZUZZ / UÓUUOO Step 1: Synthesis of methyl 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-6,7 dihydrothieno[2,3-c]pyridine-2-carboxylate : Methyl 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)6-methyl-7-oxo-6,7-dihydrotiene[2,3-c]pyridine-2-carboxylate (0.85 mg, 65%, white solid) following General Procedure 1, Step 4, using 4-bromo-6-methyl-7-oxo-6,7-dihydrothyene[2,3c]pyridin-2- methyl carboxylate (0.9 g, 3.3 mmol, 1 eq). LCEM: 470 [M+l]+. Step 2: Synthesis of 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridine-2-carboxylic acid: 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (450 mg, 92%, solid off-white) following General Procedure 2, Step 4 using 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridin- 2-carboxylate (0.50 g, 1.06 mmol, 1 eq). LCEM: 456 [M+l]+. Step 3: Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7oxo-6,7-dihydrothiene[2,3-c] pyridine -2-carboxylic acid: 4- (2- (2,4-difluorophenoxy) -5- (2hydroxypropan-2-yl) phenyl) -6-methyl-7-oxo-6,7-dihydrothieno [2,3- c]pyridine-2-carboxylic acid (200 mg, 72%, off-white solid) following General Procedure 1, Step 5 using 4-(5-acetyl-2-(2,4difluorophenoxy)phenyl)-6-methyl-7- oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (0.20 g, 0.44 mmol, 1 eq). LCEM: 472 [M+l]+. Step 4: Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(3,3difluoropiperidin-l-carbonyl)-6-methylthiene[2, 3-c]pyridin-7(6H)-one: 4-(2-(2,4difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(3,3-difluoropiperidin-l-carbonyl )-6-methylthiene[2,3c] Pyridin-7(6H)-one (0.018 g, 10%, off-white solid) was prepared following General Procedure 2, Step 5 using 4-(2-(2,4-difluorophenoxy )-5-(2-hydroxypropan-2-yl acid)phenyl)-6-methyl-7 142 oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (0.15 g, 0.33 mmol, 1 eq) and 3,3-difluoropiperidine (0.150 g, 0.95 mmol, 3.0 eq). LCEM: 575 [M+l] VHRMN (400 MHz, DMSO-rá): δ 7.70 (s, 1H), 7.54 (d, J= 2.4 Hz, 1H), 7.50 (dd, J= 8.7, 2.5 Hz, 1H ), 7.35 (ddd, J = 11.4, 8.7, 3.0 Hz, 1H), 7.27 (s, 1H), 7.09 (td, J = 9.1, 5.4 Hz, 1H), 7.04-6.95 (m, 1H), 6.86 ( d, J = 8.5 Hz, 1H), 5.09 (s, 1H), 3.91 (t, J = 11.8 Hz, 2H), 3.60 (s, 5H), 2.10 (ddt, J = 14.5, 10.4, 6.3 Hz, 2H ), 1.67 (s, 2H), 1.46 (s, 6H). MA / t / ZUZZ / UÓUUOO EXAMPLE S-14 Synthesis of N-(4-(4-fiuoro-2,6-dimethiphenoxy)-3-(6-metii-2-(5-metH-1,3,4oxadiazoi-2-H ) -7-oxo- 6,7-dihydrothieno[2,3-c]pyridin-4-Ü)phenyl)ethanesifonamide (Compound 10) POCI, MeCN RT Ϊ Br |Step 4 Step 3. Step 1: Synthesis of 4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2 carboxylic acid: 4-bromo-6-methyl-7-oxo-6 acid, 7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (0.43 mg, 90%, off-white solid) following General Procedure 2, Step 4 using methyl 4-bromo-6 methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylate (0.5 g, 1.66 mmol , 1 eq). LCEM: 288 [ΜΗ]', 290 [M-H]'. Step 2: Synthesis of N'-acetyl-4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carbohydrazide: N'-acetyl-4-bromo was prepared -6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carbohydrazide (450 mg, 87%, yellow solid) following General Procedure 2, Step 5 using 4-bromo-6-acid methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (0.43 g, 1.5 mmol, 1 eq). LCEM: 344 [M-H], 346 [M-H] . 143 Step 3: Synthesis of 4-bromo-6-methyl-2-(5-methyl-l,3,4-oxadiazol-2-yl)thieno[2,3-c]pyridin7(6H)-one: 4-bromo -6-methyl-2-(5-methyl-l,3,4-oxad¡azol-2-yl)thieno[2,3-c]pyridin-7(6H)-one (240 mg, 50%, solid yellow) was prepared following General Procedure 2, Step 6 using N'-acetyl4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carbohydrazide (0.45 g, 1.35 mmol, 1 eq). LCEM: 326 [M-H]-, 328 [M-H]\ Step 4: Synthesis of 4-(5-amino-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-6-methyl-2-(5methyl-l,3,4-oxadiazol-2-yl)thiene [2,3-c]pyridin-7(6H)-one: 4-(5-amino-2-(4-fluoro-2,6dimethylphenoxy)phenyl)-6-methyl-2-(5-methyl-l, 3,4-oxad¡azol-2-yl)thiene was prepared [2,3-c]pyridin-7(6H)one (0.018 g, 10%, off-white solid) following General Procedure 2, Step 7 using 4bromo- 6-methyl-2-(5-methyl-l,3,4-oxadiazol-2-yl)thieno[2,3-c]pyridin-7(6H)-one (0.24 g, 0.73 mmol, 1 eq). LCEM: 477 [M+l]+. Step 5: Synthesis of N-(4-(4-fluoro-2,6-dimethylphenoxy)-3-(6-methyl-2-(5-methyl-l,3,4oxadiazol-2-yl)-7-oxo - 6,7-dihydrothieno[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide: N-(4(4-fluoro-2,6-dimethylphenoxy¡)-3-(6-methyl-2-( 5-methyl-l,3,4-oxadiazol-2-yl)-7-oxo-6, 7-dihydrothieno[2,3-c]pyridin-4-yl)phenyl)ethanesulfonamide (0.018 g, 16%, solid) was prepared off-white) following General Procedure 2, Step 8 using 4-(5-amino-2-(4-fluoro-2,6-dimethylphenoxy¡)phenyl)-6-methyl2-(5-methyl-1,3,4- oxadiazol-2-yl)thieno[2,3-c]pyridin-7(6H)-one (0.11 g, 0.23 mmol, 1 eq). LCEM: 569 [M+l]+,!H NMR (400 MHz, DMSO-cQ: δ 7.85 (s, 1H), 7.71 (s, 1H), 7.26 (d, J= 2.6 Hz, 1H), 7.14 ( d, J= 8.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.40 (d, J = 8.8 Hz, 1H), 3.66 (s, 3H), 3.06 (d, 7= 7.5 Hz, 2H), 2.57 (s, 3H), 2.02 (s, 6H), 1.21 (t, J = 7.5 Hz, 3H). EXAMPLE S-15 Synthesis of 4-(2-(2,6-dimethyphenoxy)-5-(ethylisuifonamido)phenyl)-N-ethH-6-methyl-7-oxo6,7-dihydrothiene [2,3-c ]pyridine-2-carboxamide (compound 147) MA / t / ZUZZ / UÓUUOO 144 ΜΛ / t / ZUZZ / UÓUUOO Faith.' NH4Cl I.oY B;Pin;. KC+c aggtA I J ] | AAcATA ñGC.Ih H-N' c A. q Q h>n- · h r - y —------► l I. an'C 2h | - go.- Step 4η I bi Step 1: Synthesis of 2-(2-bromo-4-nitrophenoxy)-l,3-dimethylbenzene: 2-(2-bromo4-nitrophenoxy)-1,3-dimethylbenzene (4.5 g, 68%, yellow solid) was prepared. following General Procedure 2, Step 1 using 2,6-dimethylphenol (2.0 g, 16.03 mmol, 1.0 eq). LCEM: 322 [M+H]+, 324 [M+H+2]+Step 2: Synthesis of 3-bromo-4-(2,6-dimethylphenoxy)aniline: 3-bromo-4 was prepared - (2,6dimethylphenoxy)aniline (3.5 g, 97%, black viscous liquid) following General Procedure 2, Step 2 using 2-(2-bromo-4-nitrophenoxy¡)-1,3-dimethylbenzene (4.0 g, 12.46 mmol, 1.0 eq). LCEM: 292 5 [M+H]+, 294 [M+H+2]+ Step 3: Synthesis of 4-(2,6-dimethylphenoxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)aniline: 4-(2,6-dimethylphenoxy) was prepared ) -3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-¡l)aniline (0.700 g, 66%, black viscous liquid) below General Procedure 2, step 3 using 3 -bromo4- (2,6-dimethylphenoxy)aniline (1.0 g, 45.6 mmol, 1.0 eq).JH NMR: (400 MHz, CDCh) δ 6.97-7.11 (m, 10 3H), 6.58 (d, J= 3.95 Hz , 1H), 6.14 (d, J = 8.77 Hz, 1H), 2.05-2.18 (m, 6H), 1.23-1.28 (m, 12H). Step 4a: Synthesis of 7-bromo- N -ethyl-5-methyl-4-oxo-4,5-dihydrotiene [3,2-c]pyridine-2carboxamide: 7-bromo- N was prepared -ethyl-5-methyl-4-oxo-4,5-dihydrothyene [3,2-c]pyridine-2-carboxamide (100 mg, 67%, brown solid)) following the General Procedure 1, Step 4a using ethyl 7-bromo5-methyl-4-oxo-4,5-dihydrotenene[3,2-c]pyridine-2-carboxylate (1.0 g, 45.6 mmol, 1.0 eq). LCEM: 15,315 [M+H]+, 317 [M+H+2]+ Step 4: Synthesis of 7-(5-amino-2-(2,6-dimethylphenoxy)phenyl)-N-ethyl-5-methyl-4-oxo-4,5dihydrothieno[3,2-c]pyridin-2- carboxamide: 7-(5-amino-2-(2,6-dimethylphenoxy)phenyl)-N-ethyl-5 145 methyl-4-oxo-4,5-dihydrotiene [3,2-c]pyridine-2-carboxamide (0.23 g, 30%, brown viscous liquid) following General Procedure 2, Step 7 using 4- (2 ,6-dimethylphenoxy)-3-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)aniline (0.807 g, 2.37 mmol, 1.5 eq) and 7-bromo-N-ethyl-5 -methyl-4-oxo-4,5dihydrothieno[3,2-c]pyridine-2-carboxamide (0.50 g, 1.58 mmol, 1 eq). LCEM: 448[M+H]+ Step 5: Synthesis of 4-(2-(2,6-dimethylphenoxy)-5-(ethylsulfonamido)phenyl)-N-ethyl-6-methyl7-oxo-6,7-dihydrothieno[2,3-c]pyridine- 2-carboxamide: 4-(2-(2,6-dimethylphenoxy)-5(ethylsulfonamido)phenyl)-N-ethyl-6-methyl-7-oxo-6,7-dihydrothiene [2, 3-c]pyridine-2-carboxamide (30 mg, 16.5%) was prepared following General Procedure 2, Step 8 using 7-(5-amino-2-(2,6dimethylphenoxy)phenyl)-N-ethyl-5- methyl-4-oxo-4,5-dihydrothieno[3,2-c]pyridine-2-carboxamide (0.15 g, 0.335 mmol, 1.0 eq). LCEM: 540 [M+H] VH NMR: (400 MHz, MeOH-ώ) δ 7.81 (s, 1H), 7.68 (s, 1H), 7.35 (d, J = 2.6 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.12-6.98 (m, 3H), 6.43 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H), 3.40-3.20 (m, 2H), 3.09 (d, J = 7.5 Hz, 2H), 2.05 (s, 6H), 1.34 (t, J = 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H). MA / t / ZUZZ / UÓUUOO EXAMPLE S-16 Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-H)phenyl)-2-(4,4difluoropiperidin-l-carbonii)-6-methithiene [2 ,3-c]pyridin-7(6H)-one (Compound 22) Step 1: Synthesis of methyl 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridine-2-carboxylate: Methyl 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)6-methyl-7-oxo-6,7-dihydrotenene[2,3-c]pyridine-2-carboxylate ( 0.85 mg, 65%, white solid) following General Procedure 1, Step 4, using 4-bromo-6-methyl-7-oxo-6,7-dihydrothyene [2,3 146 c] methyl pyridine-2-carboxylate (0.9 g, 3.3mmol, 1 eq). LCEM: 470 [M+l]+. Step 2: Synthesis of 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridine-2-carboxylic acid: 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (450 mg, 92%, solid off-white) following General Procedure 2, Step 4 using 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridin- 2-carboxylate (0.50 g, 06 mmol, 1 eq). LCEM: 456 [M+l]+. Step 3: Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7oxo-6,7-dihydrothiene[2,3-c] pyridine -2-carboxylic acid: 4- (2- (2,4-difluorophenoxy) -5- (2hydroxypropan-2-yl) phenyl) -6-methyl-7-oxo-6,7-dihydrothieno [2,3- c]pyridine-2-carboxylic acid (200 mg, 72%, off-white solid) following General Procedure 1, Step 5 using 4-(5-acetyl-2-(2,4difluorophenoxy)phenyl)-6-methyl-7- oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (0.20 g, 0.44 mmol, 1 eq). LCEM: 472 [M+l]+. Step 4: Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(4,4difluoropiperidin-l-carbonyl)-6-methylthiene[2, 3-c]pyridin-7(6H)-one: 4-(2-(2,4difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(4,4-difluoropiperidin-l-carbonyl ) -6-methylthieno [2,3-c]pyridín-7(6H)-one (0.018 g, 10%, off-white solid) following General Procedure 2, Step 5 using 4- (2- (2 ,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridine-2-carboxylic acid (0.09 g, 0.19 mmol , 1 eq) and 4,4-difluoropiperidine (0.90 g, 0.57 mmol, 3.0 eq). LCEM: 575 [M+l] VH NMR (400 MHz, MeOH-ώ): δ 7.64-7.49 (m, 3H), 7.36 (s, 1H), 7.02 (br. s., 1H), 6.99-6.88 ( m, 2H), 6.86-6.8 (m, 1H), 3.8 (br. s., 4H), 3.69 (s, 3H), 2.04 (br. s., 4H), 1.58 (s, 6H). EXAMPLE S-17 Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-H)phenyl)-2-(3,3difluoropyrrolidin-l-carbonyl)-6-metHthiene [2,3-c]pyridin-7(6H)-one (Compound 76) MA / t / ZUZZ / UÓUUOO 147 MA / t / ZUZZ / UÓUUOO Step 1: Synthesis of methyl 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridine-2-carboxylate: Methyl 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)6-methyl-7-oxo-6,7-dihydrotenene[2,3-c]pyridine-2-carboxylate (0.85 mg , 65%, white solid) following General Procedure 1, Step 4, using methyl 4-bromo-6-methyl-7-oxo-6,7-dihydrotenene[2,3c]pyridine-2-carboxylate (0.9 g, 3.3mmol, 1 eq). LCEM: 470 [M+l]+. Step 2: Synthesis of 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridine-2-carboxylic acid: 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (450 mg, 92%, solid off-white) following General Procedure 2, Step 4 using 4-(5-acetyl-2-(2,4-difluorophenoxy)phenyl)-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridin- 2-carboxylate (0.50 g, 06 mmol, 1 eq). LCEM: 456 [M+l]+. Step 3: Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7oxo-6,7-dihydrothiene[2,3-c] pyridine -2-carboxylic acid: 4- (2- (2,4-difluorophenoxy) -5- (2hydroxypropan-2-yl) phenyl) -6-methyl-7-oxo-6,7-dihydrothieno [2,3- c]pyridine-2-carboxylic acid (200 mg, 72%, off-white solid) following General Procedure 1, Step 5 using 4-(5-acetyl-2-(2,4difluorophenoxy)phenyl)-6-methyl-7- oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (0.20 g, 0.44 mmol, 1 eq). LCEM: 472 [M+l]+. Step 4: Synthesis of 4-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(3,3difluoropyrrolidin-l-carbonyl)-6-methylthiene [2, 3-c]pyridin-7(6H)-one: 4-(2-(2,4difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(3,3-difluoropyrrolidin-l-carbonyl )-6-methylthieno[2,3c]pyridin-7(6H)-one (0.006 g, 2.2%, off-white solid) was prepared following General Procedure 2, Step 5 using 4-(2-(2,4- difluorophenoxy)-5-(2-hydroxylpropane-2-l)phenyl)-6-methyl-7148 oxo-6,7-dihydrothene[2,3-c]pyridin -2-carboxylic acid (0.15 g, 0.3 mmol, 1 eq) and 3,3-difluoropyrrolidine (0.15 g, 0.95 mmol, 3.0 eq). LCEM: 561 [M+l]+,1HRMN (400 MHz, MeOH-ώ): δ 7.61 (s, 1H), 7.60-7.48 (m, 3H), 7.05-6.91 (m, 3H), 6.85 (d, J = 6.6 Hz, 1H), 4.17 (br. s., 1H), 4.01 (br. s., 2H), 3.86 (br. s., 1H), 3.70 (s, 3H), 2.49 (br. s. ., 2H), 1.58 (s, 6H). MA / t / ZUZZ / UÓUUOO EXAMPLE S-18 Synthesis of N-ethH-4-(2-(4-fiuoro-2,6-dimethylphenoxy!)-5-(prop-l-en-2-ii)phenyl)-6-metii7- oxo-6,7-dihydrodene[2,3-c]pyridine-2-carboxamide (Compound 148) Step 1: Synthesis of 4-fluoro-2,6-dimethylphenol: 4-fluoro-2,6-dimethylphenol (2.2 g, 64%) was prepared following General Procedure 1, Step 1 using 2-bromo-5-fluoro- l,3-dimethylbenzene (5.0 g, 24.7 mmol, 1 eq). LCEM: 141 [M+l]+. Step 2: Synthesis of 1-(3-bromo-4-(4-fluoro-2,6-dimethylphenoxy¡)phenyl)ethanone: 1-(3bromo-4-(4-fluoro-2,6-dimethylphenoxy¡) phenyl)ethanone (0.30 g, 25%) following General Procedure 1, Step 2 using 4-fluoro-2,6-dimethylphenol (0.50 g, 3.57 mmol) and 1-(3-bromo-4-fluorophenyl)ethanone (0.93 g, 4.28 mmol, 1.2 eq). LCEM: 337 [M+H]+, 339 [M+H+2]+ Step 3: Synthesis of l-(4-(4-fluoro-2,6-dimethylphenoxy)-3-(4,4,5,5-tetramethyl-l,3,2dioxaborolan-2-yl)phenyl)ethanone : 1-(4-(4-fluoro-2,6-dimethylphenoxy¡)-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)ethanone (0.35 g, 56%) was prepared following General Procedure 1, Step 3 using 1-(3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)ethanone (0.55 g, 1.63 mmol, 1 eq). Ή NMR (400 MHz, CDCb): δ 8.35 (d, J= 2.4 Hz, 1 H), 7.86 (s, 1H), 6.81 (d, 7=8.8 Hz, 2H), 6.35 (d, 7=8.8 Hz , 149 1Η), 2.57 (s, 3H), 1.37 (s, 6H), 1.25 (d, 7 = 7.3 Hz, 12H) Step 4a: Synthesis of 4-bromo- N -ethyl-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxamide: 4-bromo-N-ethyl-6 was prepared -methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxamide (1.23 g, 95%, white solid) following General Procedure 1, Step 4a using 4bromo-6-methyl-7-oxo Ethyl -6,7-dihydrothieno[2,3-c]pyridine-2-carboxylate (1.5 g, 4.3 mmol, 1 eq). LCEM: 315 [M+H]+, 317 [M+H+2]+ Step 4: Synthesis of 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy¡)phenyl)-N-ethyl-6-methyl-7oxo-6,7-dihydrothiene[2,3-c ] pyridine -2-carboxamide: 4- (5-acetyl-2- (4-fluoro-2,6dimethylphenoxy) phenyl) - N -ethyl-6-methyl-7-oxo-6,7-dihydrothieno [2,3- c]pyridine-2-carboxamide (0.16 g, 38%, off-white solid) was prepared following General Procedure 1, Step 4 using 1-(4-(4fluoro-2,6-dimethylphenoxy¡)-3-(4,4 ,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethanone (0.46 g, 1.2 mmol, 1.5 eq) and 4-Bromo- N -ethyl-6-methyl-7-oxo- 6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide (0.27 g, 0.80 mmol, 1 eq). LCEM: 493 [M+H]+ Step 5: Synthesis of N-ethyl-4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(prop-l-en-2-yl)phenyl)-6methyl-7-oxo-6, 7-dihydrothieno[2,3-c]pyridine-2-carboxamide: To a stirred solution of 4-(5acetyl-2-(4-fluoro-2,6-dimethylphenoxy¡)phenyl)-N-ethyl-6 -methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxamide (0.60 g, 1.21 mmol) in anhydrous THF (3 ml) methyl lithium (0.2 ml, 4.86 mmol, 4 eq) was added at 0°C dropwise and the mixture was stirred at the same temperature for 10 min. The reaction was complete after 10 min and the mixture was slowly quenched with NH4Cl solution (10 ml). The aqueous layer was extracted with EtOAc (lOOx 2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain a crude product which was purified by CombiFlash chromatography to yield / V-ethyl-4. - (2-(4-fluoro-2,6-dimethylphenoxy¡)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridine -2-carboxamide as main product and N-ethyl-4-(2-(4-fluoro-2,6dimethylphenoxy)-5-(prop-l-en-2-yl)phenyl)-6-methyl-7-oxo -6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide as a by-product (46 mg, 7%). LCMS: 491 [M+l]+; NMR (400 MHz, DMSO-gG): δ 8.82 (s, 1H), 7.86 (s, 1H), 7.77 (s, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.48 (dd, 7 = 2.4, 8.6 Hz, 1H), 6.99 (d, 7 = 9.2 Hz, 2H), 6.55 (s, 1H), 6.40 (d, 7= 8.8 Hz, 1H), 3.62 (s, 3H), 3.29-3.19 ( m, 2H), 2.11 (s, 3H), 2.00 (br. s„ 6H), 1.08 (t, 7= 7.2 Hz, 3H) EXAMPLE S-19 Synthesis of N-bencu-4-(2-(4-fluoro-2,6-dimetHphenoxy)-5-(2-hydroxypropan-2-i)phenyl)-6-metH-7-oxo- 6,7-Dihydrothieno[2,3-c]pyridine-2-carboxamide (General Procedure 3) (Compound 149) ΜΛ / t / ZUZZ / UÓUUOO Step 1: Synthesis of methyl 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy)phenii)-6-methyl-7oxo-6,7-dihydrothieno[2,3-c]pyridine-2 - carboxylate: To a stirred solution of methyl 4-bromo-6methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylate (5 g, 16.55 mmol, 1 eq) in ethanol ( 90 ml) 1- (4- (4-fluoro-2,6-dimethylphenoxy¡) -3- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2¡I) phenii was added to them ) ethanone (7.62 g, 19.86 mmol, 1.2 eq) and NazCOs (3.50 g, 33.11 mmol, 2 eq) dissolved in water (10 mi). Silia DPP-Pd was then added to the mixture (0.30 mmol / g loading; 1.65 g, 0.496 mmol, 0.03 eq) and the resulting mixture was then heated at 100 °C for 2 h. The reaction was complete after 2 h and the mixture was filtered through the celite pad, washed with 5% MeOH in DCM (200 ml). The filtrate was concentrated under reduced pressure to give a residue. The residue obtained (7.0 g) was stirred in MeOH (50 mL) for 30 min, filtered through a Büchner funnel and concentrated under reduced pressure to obtain a solid compound. Then, the solid obtained (6.0 g) was further stirred in diethyl ether (50 ml) for 30 min, filtered over a Büchner funnel; dried in vacuo to yield the title compound (5.0 g, 63%). LCEM: 480 [M+l]+ Step 2: Synthesis of 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy)phenii)-N-benzyl-6-methyl-7oxo-6,7-dihydrothiene[2,3-c] pyridine -2-carboxamide: A 4-(5-acetyl-2-(4-fluoro-2,6dimethylphenoxy)phenii)-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine- Methyl 2-carboxylate (0.1 g, 0.208 mmol) was added to benzylamine (2 ml) and the mixture was heated to 80 °C. The reaction was complete after 6 h and the mixture was concentrated under reduced pressure to obtain a crude residue that purified by CombiFlash-chromatography to yield the title compound (0.1 g, 86%). LCEM: 555 [M+l]+. Step 3: Synthesis of N-benzyl-4-(2-(4-fluoro-2,6-dimethylphenoxy¡)-5-(2-hydroxypropan-2-yl)phenii)-6-methyl7-oxo-6,7 -dihydrothieno[2,3-c]pyridine-2-carboxamide: N-benzyl-4-(2-(4-fluoro-2,6-dimethylphenoxy¡)-5(2-hydroxypropan-2-yl)phenyl) - 6-methyl-7-oxo-6,7-dihydrotiene [2, 3-c]pyridine-2-carboxamide (0.016 g, 15.6%) was prepared following General Procedure 1, Step 5 using 4 - (5-acetyl-2- (4-fluoro-2,6dimethylphenoxy) phenyl) - N-benzyl-6-methyl-7-oxo-6,7-dihydrothene [2,3- c] pyridine-2-carboxamide (0.10 g, 0.18 mmol). LCEM: 571 [M+l]+;JH NMR (400 MHz, DMSO-ufe): δ 9.42 (s, 1H), 7.91 (s, 1H), 7.69 (s, 1H), 7.50 (d, 7= 2.2 Hz, 1H), 7.43-7.21 (m, 6H), 6.96 (d, 7= 8.8 Hz, 2H), 6.34 (d, 7= 8.3 Hz, 1H), .00 (s, 1H), 4.43 (d, 7= 5.3 Hz, 2H), 3.63 (s, 3H), 1.96 (br. s., 6H), 1.44 (s, 6H). EXAMPLE S-20 Synthesis of 4-(2-(4-fiuoro-2,6-dimetHphenoxy)-5-(2-hydroxypropan-2-H)phenyl)-N,6dimetH-7-oxo-6,7 -dihydrothiene[2,3-c]pyridine-2-carboxamide (Compound 150) ΜΛ / t / ZUZZ / UÓUUOO Siha OPP Pd ΕΌΗ H-U [ Step 1. I Step'-2| HN— AND THF. 9 X-PT 152 Step 1: Synthesis of methyl 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-6-methyl-7oxo-6,7-dihydrothieno[2,3-c]pyridine-2 - carboxylate: 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy¡)phenyl)-6-methyl-7-oxo-6,7-di¡hydrotiene [2,3 -c] methyl pyridine-2-carboxylate (5.0 g, 63%) following General Procedure 3, Step 1, using 4-bromo-6-methyl·7-oxo-6,7-dihydrotene Methyl [2,3-c]pyridine-2carboxylate (5 g, 16.55 mmol, 1 eq) and 1-(4-(4-fluoro-2,6-dimethylphenoxy¡)-3-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-ilo)phenyl)ethanone (7.62 g, 19.86 mmol, 1.2 eq). LCEM: 480 [M+l]+ Step 2: Synthesis of 4- (5-acetyl-2- (4-fluoro-2,6-dimethylphenoxy) phenyl) -N, 6-dimethyl-7-oxo6,7-dihydrothiene [2,3-c]pyridine-2-carboxamide: 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy¡)phenyl)-N,6-dimethyl-7-oxo-6,7 -dihydrothieno[2,3-c]pyridine-2- Carboxamide (0.14 g, 73%) was prepared following General Procedure 3, Step 2 using methyl 4-(5-acetyl-2-(4-fluoro-2,6 -dimethylphenoxy¡)phenyl)-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2-carboxylate (0.2 g, 0.42 mmol, 1 eq). LCEM: 479 [M+l]+. Step 3: Synthesis of 4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-N,6-dimethyl-7-oxo-6,7- dihydrothiene[2,3-c]pyridine-2-carboxamide: 4-(2-(4-fluoro-2,6dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-N,6-dimethyl-7 -oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxamide (0.009 g, 9%) was prepared following General Procedure 1, Step 5 using 4-(5acetyl-2-(4-fluoro-2, 6-dimethylphenoxy)phenyl)-N,6-dimethyl-7-oxo-6,7-dihydrotiene[2,3-c]pyridine-2carboxamide (0.10 g, 0.209 mmol). LCEM: 495 [M+l]+; d, 7 = 2.2 Hz, 1H), 7.40 (dd, J = 2.2, 8.8 Hz, 1H), 6.97 (d, 7 = 9.2 Hz, 2H), 6.35 (d, 7= 8.3 Hz, 1H), 5.01 ( s, 1H), 3.63 (s, 3H), 2.74 (d, 7= 4.8 Hz, 3H), 1.99 (s, 6H), 1.45 (s, 6H). ΜΛ / t / ZUZZ / UÓUUOO 153 EXAMPLE S-21 Synthesis of 4- (2- (4-fiuoro-2,6-dimetHfenox¡) -5- (2-hydroxypropan-2-ii) phenyl) -6-metH7-oxo-N-phenü- 6,7-dihydrothieno[2,3-c]pyridine-2-carboxamide (Compound 151) HATU.D PEA. DMF RT 2h | Step 3| Silia CPP Pd Na^CCFTCH h:C 1UU ’C Jli ' Step 1| xitii THF. 3 T-RT | Step 41 Step 1: Synthesis of methyl 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy¡)phenyl)-6-methyl-7oxo-6,7-dihydrothieno[2,3-c]pyridine- 2- carboxylate: 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy¡)phenyl)-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridin- methyl 2-carboxylate (5.0 g, 63%) following General Procedure 3, Step 1, using 4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxylate methyl (5 g, 16.55 mmol, 1 eq) and 1- (4- (4-fluoro-2,6-dimethylphenoxy¡) -3- (4,4,5,5-tetra methyl-1,3,2- dioxaborolan-2-lo)phenyl)ethanone (7.62 g, 19.86 mmol, 1.2 eq). LCEM: 480 [M+l]+ Step 2: Synthesis of 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-6-methyl-7-oxo-6,7dihydrothieno[2,3-c]pyridin-2- Carboxylic acid: 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy¡)phenyl)-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridin- 2-carboxylic (0.35 g, 86%) following General Procedure 2, Step 4 using methyl 4- (5-acetyl-2- (4-fluoro-2,6-dimethylphenoxy¡)phenyl) -6methyl-7-oxo- 6,7-dihydrothieno[2,3-c]pyridine-2-carboxylate (0.30 g, 0.626 mmol). LCEM: 466 [M+l]+. Step 3: Synthesis of 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy¡)phenyl)-6-methyl-7-oxo-Nphenyl-6,7-dihydrothiene[2,3-c ] pyridine -2-carboxamide: To a stirred solution of 4- (5-acetyl2- (4-fluoro-2,6-dimethylphenoxy¡)phenyl) -6-methyl-7-oxo-6,7-dihydrothiene [2, 3-c]pyridine-2-carboxylic acid (0.1 g, 0.215 mmol) in DMF (5 ml) HATU (0.16 g, 0.43 mmol, 2.0 eq) was added at 0 °C and the mixture was stirred for 10 min. DIPEA (0.19 ml, 1.07 mmol, 4 eq) and aniline (0.3 g, 0.332 mmol, 1.5 eq) were then added to the mixture and the resulting mixture was stirred at RT for 16 h. The reaction was complete after 16 h and water (200 mL) was added to the mixture and extracted with EtOAc (300 mL). The layers 154 combined organics were washed with water (40 ml), brine (40 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a crude residue which was purified by reverse phase column chromatography to yield the product desired as an off-white solid (0.1 g, 86%). LCEM: 541 [M+l]+. Step 4: Synthesis of 4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6methyl-7-oxo-N-phenyl-6,7- dihydrothiene[2,3-c]pyridine-2-carboxamide: 4-(2-(4-fluoro-2,6dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6-methyl-7 -oxo-N-phenyl-6,7-dihydrothene [2, 3-c]pyridine-2-carboxamide (0.007 g, 14%) was prepared following General Procedure 1, Step 5 using 4- (5acetyl-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-6-methyl-7-oxo-N-phenyl-6,7-dihydrothieno[2,3-c]pyridine-2carboxamide (0.050 g, 0.090 mmol). LCMS:557 [M+l]+;4H NMR (400 MHz, DMSO-rá): δ 10.59 (s, 1H), 8.20 (s, 1H), 7.77-7.66 (m, 2H), 7.56 (d, J = 2.2 Hz, 1H), 7.45-7.39 (m, 1 H), 7.38-7.32 (m, 1 H), 7.13 (s, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.38 (d, J= 8.3 Hz, 1H), 5.03 (s, 1H), 3.66 (s, 3H), 2.02 (br. s., 6H), 1.47 (s, 6H). MA / t / ZUZZ / UÓUUOO EXAMPLE S-22 Synthesis of 4-(2-(4-fiuoro-2,6-dimetHphenoxy)-5-(2-hydroxypropan-2-H)phenyl)-6-methi 2-(5-metii-4H-l,2,4-triazol-3-yl) has [2,3-c]pyridin-7(6H)-one (Generic Procedure 4) (Compound 152) Step 1 ] NILNIl· II / ) O J. o hiijic:i ';NHNH;NaOMe BOH I Step 2. Xylene .Step 3 | Br 'Step 4 | \1eLi. THF | Step Λ Step 1: Synthesis of 4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carbohydrazide: To a stirred solution of 4-bromo-6-methyl-7-oxo- Methyl 6,7-dihydrothieno[2,3-c]pyridine-2carboxylate (0.50 g, 1.66 mmol) in MeOH (10 ml) was added with hydrazine hydrate (5.3 ml, 16.61 mmol, 10 eq) and the mixture was refluxed at 800C for 3 h. The reaction was complete after 3 h; Water (100 ml) was added to obtain a precipitate which was filtered on a Büchner funnel, washed with EtOAc (100 ml) to produce the title compound (400 mg, 80%). LCEM: 302 155 [Μ+Η]+, 304 [Μ+Η+2]+ Step 2: Synthesis of N'-acetyl-4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carbohydrazide: To a stirred hydrochloride solution of acetamide (0.22 g, 2.31 mmol) in ethanol (5 ml), sodium methoxide (0.125 g, 2.13 mmol, 2.0 eq) was added and the mixture was heated at 700 C for 3 h. After 3 h, the mixture was filtered over a Büchner funnel. To the filtrate obtained, 4-bromo-6-methyl-7-oxo-6,7-dihydrothyene [2,3-c]pyridine-2-carbohydrazide (0.35 mg, 1,115 mmol) was added and the mixture was further heated at 70 °C for 16 h. The reaction was complete after 16 h and the mixture was poured into water (50 ml) to obtain a precipitate which was filtered over a Büchner funnel to yield the title compound (300 mg, 75%). LCEM: 343 [M]+, 344 [M+2H]+, 346 [M+H+2]+ Step 3: Synthesis of 4-bromo-6-methyl-2-(5-methyl-4H-l,2,4-triazol-3-yl)thieno[2,3-c]pyridin-7(6H)-one : N'-acetyl-4-bromo-6-methyl-7-oxo-6,7-dihydrotiene [2,3-c]pyridine-2carbohydrazide (0.30 g, 0.87 mmol) in a mixture of xylene (5 ml) and EtOH (2 mL) was heated at 1200C for 48 h. Once complete, the mixture was filtered through a Büchner funnel and the filtrate was collected, concentrated under reduced pressure to obtain a crude oil that was purified by CombiFlash chromatography to yield the title compound (100 mg, 35%). LCEM: 325 [M+H]+, 327 [M+H+2]+ Step 4: Synthesis of 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-6-methyl-2-(5-methyl4H-l,2,4-triazol-3-yl ) thieno[2,3-c]pyridin-7(6H)-one: To a stirred solution of 4-bromo-6methyl-2-(5-methyl-4H-l,2,4-triazol-3-yl) thieno[2,3-c]pyridin-7(6H)-one (0.1 g, 0.307 mmol, 1 eq) in DMF (3 ml) 1-(4-(4-fluoro-2,6-dimethylphenoxy) was added -3- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan2-¡l)phenyl)ethanone (0.15 g, 0.04 mmol, 1.3 eq) and Na 2 CO 3 (0.08 g, 0.77 mmol, 2.5 eq) were dissolved in water (0.5 mL) and the mixture was degassed, under nitrogen for 40 min. Then, Pd(PPh 3)4 (0.017 g, 0.01 mmol, 0.03 eq) was added to the mixture and the mixture was further degassed under nitrogen for 20 min. The resulting mixture was then heated at 120°C for 16 h. Once complete, the mixture was diluted with water (50 ml) and extracted with EtOAc (100 ml x 2). The combined organic layers were washed with water (40 mL), brine (40 mL), dried over NazSO, filtered and concentrated under reduced pressure to produce a crude residue that was purified by reverse phase column chromatography to yield the desired product as a whitish solid (0.075 g, 50%). LCEM: 503 [M+l]+ Step 5: Synthesis of 4-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-6methyl-2-(5-methyl-4H-l,2 , 4-triazol-3-yl)thieno[2,3-c]pyridin-7(6H)-one: 4-(2-(4-fluoro2,6-dimethylphenoxy)-5-(2-hydroxypropan-2- il) phenyl) -6-methyl-2- (5-methyl-4H-l,2,4- Triazol-3¡I) thieno [2,3-c] pyridin-7 (6H) -on e ( 0.009 g, 17.6%) following General Procedure 1, Step 5 using 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-6-methyl-2-(5-methyl -4H-l,2,4-triazol-3-¡l) ΜΛ / t / ZUZZ / UÓUUOO 156 thieno[2,3-c]pyridin-7(6H)-one (0.050 g, 0.099 mmol). LCEM: 519 [M+l]+; NMR (400 MHz, DMSO-cfe): δ 13.93 (br. s., 1H), 7.71 (br. s., 1H), 7.51 (br. s., 2H), 7.39 (br. s., 1H) , 6.97 (d, J = 8.8 Hz, 2H), 6.33 (br. s., 1H), 5.02 (br. s., 1H), 3.64 (br. s., 3H), 2.39 (br. s., 3H), 2.01 (br. s., 6H), 1.45 (br. s., 6H) ΜΛ / t / ZUZZ / UÓUUOO EXAMPLE S-23 Synthesis of 2-(benzo[d]oxazoi-2-H)-4-(2-(4-fiuoro-2,6-dimethifenox¡)-5-(2hydroxypropan-2-ii)phenyl ) -6-meththiene[2,3-c]pyridin-7(6H)-one (Generic Procedure 5) (Compound 153) Step 1: Synthesis of 4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxylic acid: 4-bromo-6-methyl-7-oxo-6 acid was prepared ,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (4 g, 84%) following General Procedure 2, Step 4 using methyl 4-bromo-6-methyl-7-oxo-6,7dihydrothieno[2 ,3-c]pyridine-2-carboxylate (5.0 g, 16.6 mmol). LCEM: 288 [M+H]+, 290 [M+H+2]+Step 2: Synthesis of 2-(benzo[d]oxazol-2-yl)-4-bromo-6-methylthiene [2,3- c]pyridin-7(6H)-one: To a stirred solution of 4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxylic acid (1.0 g, 3.47 mmol ) in polyphosphoric acid (10 ml), 2-aminophenol (0.45 g, 4.10 mmol, 1.2 eq) was added and the mixture was heated to 1800C. The reaction was complete after 2 h and the mixture was quenched with 2N NaOH (200 ml) to obtain a precipitate which was filtered over a Büchner funnel to yield the title compound (0.5 g, 41%). LCEM: 361 [M+H]+, 363 [M+H+2]+ Step 3: Synthesis of 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy¡)phenyl)-2-(IH-benzo[d]imidazol-2-yl)-6-methylthiene[2 ,3-c]pyridin-7(6H)-one: 4-(5-acetyl-2-(4-fluoro-2,6dimethylphenoxy)phenyl)-2-(IH-benzo[d]imidazol-2-yl) -6-methylthieno[2,3-c]pyridine-7(6H)-one (0.15 g, 20%) was prepared following General Procedure 4, Step 4 using 2-(IH-benzo[d]imidazole-2- il)-4-bromo-6-methylthieno[2,3-c]pyridin-7(6H)-one (0.5 g, 1.392 mmol, 1 eq). LCMS: 539 [M+l]+ 157 Step 4: Synthesis of 2-(IH-benzo[d]imidazol-2-yl)-4-(2-(4-fluoro-2,6-dimethylphenoxy)-5(2-hydroxypropan-2-yl)phenyl) -6-methylthieno[2,3-c]pyridin-7(6H)-one: 2-(IH-benzo[d]imidazol-2-yl)-4-(2-(4-fluoro-2,6- [2,3-c]pyridin-7(6H)-one (0.022 g, 21%) was prepared following General Procedure 1. , Step 5 using 4-(5-amino-2-(4-dimethylphenoxy)phenyl)-6-methyl-2-(5-methyl-l,3,4-oxad¡azol-2-yl)thiene [2, 3-c]pyridin-7(6H)-one (0.10 g, 0.185 mmol, 1 eq). LCMS: 555 [M+l]+; Ή NMR (400 MHz, DMSO-ofe): δ 7.84 (d, J= 8.3 Hz, 3H), 7.78 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.52- 7.37 (m, 3H), 6.98 (d, J = 9.2 Hz, 2H), 6.40 (d, J= 8.8 Hz, 1H), 5.06 (s, 1H), 3.68 (s, 3H), 2.05 (s, 6H ), 1.46 (s, 6H). ΜΛ / t / ZUZZ / UÓUUOO EXAMPLE S-24 Synthesis of 2-(IH-benzo[d]imidazol-2-yl)-4-(2-(4-fluoro-2,6-dimethylphenoxy¡)-5-(2hydroxypropan-2-H)phenyl )-6-methylthieno[2,3-c]pyridin-7(6H)-one (General Procedure 6) (Compound 154) Step 1: Synthesis of 4-bromo-6-methyl-7-oxo-6,7-dihydrothieno[2,3-c]pyridine-2carboxylic acid: 4-bromo-6-methyl-7-oxo-6 acid was prepared ,7-dihydrothieno[2,3-c]pyridine-2-carboxylic acid (4 g, 84%) following General Procedure 2, Step 4 using methyl 4-bromo-6-methyl-7-oxo-6 ,7dihydrothieno[2,3-c]pyridine-2-carboxylate (5.0 g, 16.6 mmol). LCEM: 288 [M+H]+, 290 [M+H+2]+Step 2: Synthesis of 2-(IH-benzo[d]imidazol-2-yl)-4-bromo-6-methylthiene [2, 3-c]pyridin7(6H)-one: To a stirred solution of 4-bromo-6-methyl-7-oxo-6,7-di¡hydrotiene[2,3-c]pyridine2-carboxylic acid (1.0 g, 3.47 mmol) in polyphosphoric acid (10 ml) 2-aminophenol (449 mg, 4.10 mmol, 1.2 eq) was added and the mixture was heated to 180 °C. The reaction was complete after 2 h and the mixture was quenched with 2N NaOH (200 ml) to obtain a precipitate which was filtered over a Büchner funnel to yield the title compound (0.5 g, 41%). LCEM: 360 [M+H]+, 362 [M+H+2]+ Step 3: Synthesis of 4-(5-acetyl-2-(4-fluoro-2,6-dimethylphenoxy)phenyl)-2-(IH-benzo[d] 158 imidazol-2-yl)-6-methylthieno[2,3-c]pyridin-7(6H)-one: 4-(5-acetyl-2-(4-fluoro-2,6dimethylphenoxy)phenyl)-2- (IH-benzo[d]imidazol-2-yl)-6-methylthieno[2,3-c]pyridine-7(6H)-one (0.2 g, 26%) was prepared following General Procedure 4, Step 4 using 2-(IH-benzo[d]imidazol-2-yl)-4-bromo-6-methylthieno[2,3-c]pyridin-7(6H)-one (0.5 g, 1.39 mmol, 1 eq). LCEM: 538 [M+l]+. Step 4: Synthesis of 2-(IH-benzo[d]imidazol-2-yl)-4-(2-(4-fluoro-2,6-dimethylphenoxy)-5(2-hydroxypropan-2-yl)phenyl) -6-methylthieno[2,3-c]pyridin-7(6H)-one: 2-(IH-benzo[d]imidazol-2-yl)-4-(2-(4-fluoro-2,6- dimethylphenoxy¡)-5-(2-hydroxypropan-2-yl)phenyl)-6-methylthiene [2,3-c]pyridin-7(6H)-one (0.007 g, 7%) was prepared following General Procedure 1 , Step 5 using 4-(5-amino-2-(2,6-dimethylphenoxy)phenyl)-6-methyl-2-(5-methyl-l,3,4-oxadiazol-2-yl)thiene [2, 3-c]pyridin7(6H)-one (0.20 g, 0.186 mmol, 1 eq). LCEM: 554 [M+l]+; Ή NMR (400 MHz, ...

Claims

1. A compound of Formula (J): MA / t / ZUZZ / UÓUUOO, a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: each = is independently a single or double bond; X is O or S; R1 is hydrogen, C1-C3 alkyl, -(C3-alkylene)OH, C1-C3 haloalkyl, or C3C4 cycloalkyl; Gi is CRa or N, wherein: Ra is hydrogen, halogen, or C1-C4 alkyl; Zi is C-Wi-Rc;where: each Wi is independently -O- or -NRW1-, where: RW1 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, -OH, or halogen, and Rc is independently C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, Cs-Ci4 aryl, or 5- or 6-membered heteroaryl, each of which is independently substituted optionally by Rcl, where RC1 is independently halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, cyano, oxo, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, -OR10, -NR10Rn, -C(O)NR10Rn, -NR10C(O)Rn, -S(O)2R10, -NR10S(O)2R11, or -S(O)2NR10Rn; Z2 is C-W2-Rd or N, wherein: W2 is -O-, NRw2-, or a bond, wherein: Rw2 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, -OH, or halogen, and Rd is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C1-C4 alkyl;Z3 is C-Re or N, wherein: Re is independently hydrogen, halogen, cyano, 3- to 6-membered heterocycle or C1-C4 alkyl; M1 is S or CR1a; M2 is S or CR2a, provided that when M1 is S, the bond adjacent to M1 is a single bond and the bond adjacent to M2 is a double bond, when M2 is S, the bond adjacent to M2 is a single bond and the bond adjacent to M1 is a double bond, and either M1 or M2 is S; Rla and R2a are independently hydrogen, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, cyano, oxo, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR10, NR10Rn, -C(O)OR10, -C(O)NR10R11, -NR10C(O)Rn, -S(O)2R10, -NR10S(O)2Rn or -S(O)2NR10Rn, each of which is independently and optionally substituted by R12;R2 is hydrogen, 184 halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl -(C1-C3 alkylene), 5- to 10-membered heteroaryl, cyano, oxo, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR10, -NR10R11, -C(O)OR10, -C(O)NR10R11, -NR10C(O)Rn, -S(O)2R10, -NR10S(O)2Rn, or -S(O)2NR10Rn, each of which is independently and optionally substituted by R12; R3 is -(CH2)mNR13S(O)2R14 where m is 0, 1, 2 or 3; C3-C6 cycloalkyl optionally substituted with halogen, oxo, -CN, or -OH; C1-C4 alkyl substituted with halogen, oxo, -CN, or -OH; or Ci-Ce alkynyl;R10 and R11 are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkenyl, C3C6 cycloalkyl, C6-C14 aryl, 3- to 6-membered heterocyclyl, -(C1-C3 alkylene)C3-C6 cycloalkyl, -(C1-C3 alkylene)3- to 6-membered heterocyclyl, -(C1-C3 alkylene)Ce-Ci4 aryl, -NR15R16, or -C(O)R12, wherein each of R10 and R11 is independently optionally substituted with halogen, oxo, -CN, -CF3, -OH, -NR13R14, -C(O)NR13R14, or C1-C4 alkyl optionally substituted with halogen, oxo, -CN, -CF3, or -OH, R10 and R11 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted with halogen, oxo, CN, -CF3, -OH, or C1-C4 alkyl optionally substituted with halogen, oxo, -CN, or -OH;each R12 is independently halogen, cyano, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR15, -NR15R16, -C(O)NR15R16, -NR15C(O)R16, -S(O)2R15, -NR15S(O)2R16, -S(O)2NR15R16, C3-C6 cycloalkyl, 3- or 6-membered heterocyclyl, or C1-C4 alkyl, each of which is independently substituted optionally with halogen, oxo, -CF3, -CN, -OH, -NR13R14, or -NR13C(O)R14; R13 and R14 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted with halogen, oxo, -CN, or -OH; R13 and R14 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted with halogen, oxo, -CN, OH, or a C1-C4 alkyl optionally substituted with halogen, oxo, -CN, or -OH;and each R15 and R16 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently substituted optionally with halogen, oxo, -CN, or -OH, R15 and R16 are taken together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted with halogen, oxo, -CN, -OH, or a C4-C4 alkyl optionally substituted with halogen, oxo, -CN, or -OH.

2. The compound according to claim 1, further characterized in that the compound of formula (I): ML / t / ZUZZ / UÓUUOO 185 X ML / t / ZUZZ / UÓUUOO is a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein: each = is independently a single or double bond; X is O or S; R1 is hydrogen, C1-C3 alkyl, -(C1-C3 alkylene)OH, C1-C3 haloalkyl, or C3Q cycloalkyl; Gi is CRa or N, wherein: Ra is hydrogen, halogen, or C1-C4 alkyl; Zi is C-Wi-Rc;where: each Wi is independently -O- or -NRW1-, where: RW1 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, -OH, or halogen, and Rc is independently 4- to 6-membered heterocyclyl, C6-C14 aryl, or 5- or 6-membered heteroaryl, each of which is independently substituted optionally by Rcl, where each RC1 is independently halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, cyano, oxo, C1-C4 alkoxy, C1-C4 haloakoxy, C1-C4 haloalkyl, -OR10, -NR10Rn, -C(O)NR10Rn, NR10C(O)Rn, -S(O)2R10, -NR10S(O)2Rn, or -S(O)2NR10R11; Z2 is C-W2-Rd or N, wherein: W2 is -O-, NR”2-, or a bond, wherein: Rw2 is hydrogen, C3-C6 cycloalkyl, or C1-C4 alkyl optionally substituted with oxo, -OH, or halogen, and Rd is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or Ci-Q alkyl;Z3 is C-Re or N, wherein: Re is independently hydrogen, halogen, cyano, 3- to 6-membered heterocycle or C1-C4 alkyl; M1 is S or CR1a; M2 is S or CR2a, provided that when M1 is S, the bond adjacent to M1 is a single bond and the bond adjacent to M2 is a double bond, when M2 is S, the bond adjacent to M2 is a single bond and the bond adjacent to M1 is a double bond, and at least one of M1 and M2 is not S; Rla and R2a are independently hydrogen, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, cyano, oxo, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, OR10, -NR10R11, -C(O)OR10, -C(O)NR10Rn, -NR10C(O)Rn, -S(O)2R10, -NR10S(O)2Rn or S(O)2NR10Rn, each of which is independently and optionally substituted by R12;R2 is halogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, 3- to 6-membered heterocyclyl -(C1-C3 alkylene), 5- to 10-membered heteroaryl, cyano, oxo, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR10, -NR10Rn, -C(O)OR10, -CÍOJNR^R11, -NR10C(O)Rn, S(O)2R10, -NR10S(O)2Rn, or -S(O)2NR10R11, each of which is independently and optionally substituted by R12; R3 is -(CH2)mNR13S(O)2R14, C3-C6 cycloalkyl or C1-C4 alkyl substituted by halogen, oxo, -CN, or -OH, where m is 0, 1, 2 or 3;R10 and R11 are each independently hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkenyl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, -(C1-C3 alkylene)C3-C6 cycloalkyl, -(C1-C3 alkylene)3- to 6-membered heterocyclyl, -NR15R16, or -C(O)R12, wherein each of R10 and R11 is independently substituted optionally with halogen, oxo, -CN, -CF3, -OH, -NR13R14, C(O)NR13R14, or C1-C4 alkyl optionally substituted with halogen, oxo, -CN, -CF3, or -OH, R10 and R11 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclic ring optionally substituted with halogen, oxo, -CN, -CF3, -OH, or C1-C4 alkyl optionally substituted with halogen, oxo, -CN, or -OH;each R12 is independently halogen, cyano, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, -OR15, -NR15R16, -C(O)NR15R16, NR15C(O)R16, -S(O)2R15, -NR15S(O)2R16, -S(O)2NR15R16, C3-C6 cycloalkyl, 3- or 6-membered heterocyclyl, or C1-C4 alkyl, each of which is independently substituted optionally with halogen, oxo, -CF3, -CN, -OH, -NR13R14, or -NR13C(O)R14; R13 and R14 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted with halogen, oxo, CN, or -OH; R13 and R14 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted with halogen, oxo, -CN, -OH, or a C1-C4 alkyl optionally substituted with halogen, oxo, -CN, or -OH;and each R15 and R16 are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently substituted optionally with halogen, oxo, -CN, or -OH, R15 and R16 are taken together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted with halogen, oxo, -CN, -OH, or a C4-C4 alkyl optionally substituted with halogen, oxo, -CN, or -OH.

3. The compound according to claim 1 or 2, or a tautomer or ML / OOU ÓUOO isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that the compound is of Formula (II), 4. The compound according to claim 1 or 2, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that the compound is of Formula (III), 187 ML / t / ZUZZ / UÓUUOO 5. The compound according to any of claims 1 to 4 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that X is O.

6. The compound according to any of claims 1 to 5 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that Gi is CH.

7. The compound according to any of claims 1 to 6, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that Z1 is C-Wi-Rc and Rc is a C6-C14 aryl optionally substituted by Rcl.

8. The compound according to claim 7, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that Rc is optionally halogen or C1-C4 alkyl substituted phenyl.

9. The compound according to any of claims 1 to 8 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that Z2 is CH.

10. The compound according to any of claims 1 to 9 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that Z3 is CH.

11. The compound according to any of claims 1 to 10 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that R1 is a C1-C3 alkyl 12. The compound according to any one of claims 1 to 11, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing, further characterized in that R2 is -C(O)NR10Rn, a 5- to 10-membered heteroaryl, a C1-C3 (alkylene) 3- to 6-membered heterocyclyl, or a C1-C4 alkyl, each of which is optionally independently substituted with R12.

13. The compound according to claim 12, or a tautomer or isomer 188 thereof, or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that R2 is -C(O)NR10Rn optionally substituted with R12, wherein R10 and R11 are each independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl, or R10 and R11 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted with halogen. ML / ÓUUOO 14. The compound according to claim 12, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that R2 is a 5- to 10-membered heteroaryl optionally substituted with R12.

15. The compound according to any of claims 1 to 14, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that R3 is -(CH2)mNR13S(O)2R14 or a halogen, oxo, -CN or -OH substituted Ci-C 4 alkyl.

16. The compound according to any of claims 1 to 15, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that R3 is -(CH2)mNR13S(O)2R14.

17. The compound according to any of claims 1 to 16 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that R3 is h.

18. The compound according to any of claims 1 to 15 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that R3 is a C1-C4 alkyl substituted by -OH.

19. The compound according to claim 18 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that R3 is 20. The compound according to any of claims 1 and 4 to 19 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that Rla is hydrogen.

21. The compound according to any of claims 1, 2, 3 and 5 to 19, or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the foregoing, further characterized in that R2a is hydrogen.

22. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, further characterized in that the compound is selected from the group consisting of the compounds in Table 1. 189 23. A pharmaceutical composition comprising the compound of any one of claims 1 to 22, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any one of the foregoing, and a pharmaceutically acceptable carrier.

24. A method for treating a bromodomain and extraterminal domain (BET) mediated disease in an individual in need thereof comprising administering to the individual a therapeutically effective amount of the compound of any of claims 1 to 22 or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

25. A method for treating cancer in an individual in need comprising administering to the individual a therapeutically effective amount of the compound of any of claims 1 to 22 or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the foregoing.

26. A method for inhibiting the bromodomain and extraterminal domain (BET) in a cell, comprising administering the compound of any of claims 1 to 22, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to the cells.

27. The use of the compound of any of claims 1 to 22, or a tautomer or isomer thereof or a pharmaceutically acceptable salt of any of the foregoing, in the preparation of a medicament for the treatment of a bromodomain and extraterminal domain (BET)-mediated disease.

28. A kit comprising the compound of any of claims 1 to 22, or a tautomer or isomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.