Compounds for the targeted degradation of smarca2

Abstract

The present invention provides compounds that degrade SMARC A2 via the targeted ubiquitination of SMARCA2 and subsequent proteasomal degradation. These compounds are useful for the treatment of SMARCA2- or SMARCA4-mediated disorders, for example a SMARCA2- or SMARCA4-mediated abnormal cellular proliferation, including tumors and cancer.

Description

[0001] COMPOUNDS FOR THE TARGETED DEGRADATION OF SMARCA2 CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. provisional application 63 / 610,378 filed December 14, 2023, and 63 / 691,284 filed September 5, 2024. The entirety of each of these applications is hereby incorporated by reference for all purposes. FIELD OF THE INVENTION The present invention provides compounds that degrade SMARCA2 via the targeted ubiquitination of SMARCA2 and subsequent proteasomal degradation. These compounds are useful for the treatment of SMARCA2- or SMARCA4-mediated disorders, for example a SMARCA2- or SMARCA4-mediated abnormal cellular proliferation, including tumors and cancer. BACKGROUND OF THE INVENTION Most small molecule drugs bind enzymes or receptors in tight and well-defined pockets. However, protein-protein interactions are notoriously difficult to target using small molecules due to their large contact surfaces and the shallow grooves or flat interfaces. E3 Ubiquitin ligases (of which hundreds are known in humans) confer substrate specificity for ubiquitination, and therefore, are attractive therapeutic targets due to their specificity for certain protein substrates. The development of compounds that bind to E3 ligases and disrupt protein interactions has proven challenging. However, recently, some progress has been made. One E3 ligase with therapeutic potential is cereblon (CRBN). CRBN is known as a primary target for thalidomide analogs with anti-cancer activity. The discovery that thalidomide binds to the cereblon E3 ubiquitin ligase led to research to investigate incorporating thalidomide and certain derivatives into selected compounds for the targeted destruction of proteins. Celgene has disclosed imides for uses, including those in U.S. Patents 6,045,501; 6,315,720; 6,395,754; 6,561,976; 6,561,977; 6,755,784; 6,869,399; 6,908,432; 7,141,018; 7,230,012; 7,820,697; 7,874,984; 7,959,566; 8,204,763; 8,315,886; 8,589,188; 8,626,531; 8,673,939; 8,735,428; 8,741,929; 8,828,427; 9,056,120; 9,101,621; 9,101,622; 9,587,281; 9,857,359; and 10,092,555. Patent applications filed by C4 Therapeutics, Inc., that describe compounds capable of binding to an E3 ubiquitin ligase and a target protein for degradation include: WO / 2024 / 119111, titled “Morphic Forms Of A Mutant Braf Degrader And Methods Of Manufacture Thereof”; WO / 2023 / 244764, titled “Compounds for the Targeted Degradation of SMARCA2”; WO / 2023 / 239750, titled “Bicyclic-Substituted Glutarimide Cereblon Binders”; WO / 2023 / 055952, titled “Neurotrophic Tyrosine Receptor Kinase (NTRK) Degrading Compounds”; WO / 2023 / 039208, titled “Selected Compounds for Targeted Degradation of BRD9”; WO / 2022 / 261250, titled “Therapeutics for the Degradation of Mutant BRAF”, WO / 2023 / 283610, titled “Compounds for Targeting Degradation of IRAK4 Proteins”; WO / 2023 / 283372, titled “Compounds for Targeting Degradation of IRAK4 Proteins”; WO / 2022 / 251539, titled “EGFR Degraders to Treat Cancer Metastasis to the Brain or CNS”; WO / 2022 / 235945, titled “Compounds for Targeting Degradation of Bruton's Tyrosine Kinase”; WO / 2022 / 081928, titled “Tricyclic Heterobifunctional Compounds for Degradation of Targeted Proteins”; WO / 2022 / 081927, titled “Tricyclic Compounds to Degrade Neosubstrates for Medical Therapy”; WO / 2022 / 081925, titled “Tricyclic Ligands for Degradation of IKZF2 or IKZF4”; WO / 2022 / 032132, titled “Advantageous Therapies for Disorders Mediated by Ikaros or Aiolos”; WO / 2022 / 032026, titled “Compounds for Targeted Degradation of RET”; WO / 2021 / 255213, titled “Heterobifunctional Compounds as Degraders of BRAF”; WO / 2021 / 255212, titled “BRAF Degraders”; WO / 2021 / 178920 titled “Compounds for Targeted Degradation of BRD9”; WO / 2020 / 181232, titled “Heterocyclic Compounds for Medical Treatment”; WO / 2021 / 127561, titled “Isoindolinone And Indazole Compounds for The Degradation of EGFR”; WO / 2021 / 086785, titled “Bifunctional Compounds”; WO / 2021 / 083949, titled “Bifunctional Compounds for the Treatment of Cancer”; WO / 2020 / 210630, titled “Tricyclic Degraders of Ikaros and Aiolos”; WO / 2020 / 132561, titled “Targeted Protein Degradation”; WO / 2019 / 236483, titled “Spirocyclic Compounds”; WO2020 / 051235, titled “Compounds for the degradation of BRD9 or MTH1”; WO / 2019 / 191112, titled “Cereblon binders for the Degradation of Ikaros”; WO / 2019 / 204354, titled “Spirocyclic Compounds”; WO / 2019 / 149922, titled “ Compounds which Cause Degradation Of EGFR, For Use Against Cancer”; WO / 2019 / 121562, titled “Bifunctional Inhibitors With EGFR Having a E3 Ubiquitin Ligase Moiety”; WO / 2019 / 099868, titled “Degraders and Degrons for Targeted Protein Degradation”; WO / 2018 / 237026, titled “N / O-Linked Degrons and Degronimers for Protein Degradation”; WO / 2018 / 220149, titled “Compounds”; WO / 2018 / 115218, titled “2-Benzopyrazinyl-N- Heteroaryl-2-Phenyl-Acetamide Compounds”; WO / 2017 / 197051, titled “Amine-Linked C3- Glutarimide Degronimers for Target Protein Degradation”; WO / 2017 / 197055, titled “Heterocyclic Degronimers for Target Protein Degradation”; WO / 2017 / 197036, titled “Spirocyclic Degronimers for Target Protein Degradation”; WO / 2017 / 197046, titled “C3- Carbon Linked Glutarimide Degronimers for Target Protein Degradation”; and WO / 2017 / 197056, titled “Bromodomain Targeting Degronimers for Target Protein Degradation.” Other examples of patent applications that describe protein degrading compounds include: WO / 2019 / 195201, WO / 2020 / 078933, WO / 2020 / 264172, WO2020 / 251971, WO / 2021 / 067606, WO / 2021 / 083949, WO / 2021 / 163302, WO / 2022 / 029617, WO / 2023 / 096987, and WO / 2023 / 097031. The Switch / Sucrose Non Fermentable (SWI / SNF) is a multi-subunit complex that modulates chromatic structure through the activity of two mutually exclusive helicase / ATPase catalytic subunits: SWI / SNF-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 2 (SMARCA2, BRAHMA or BRM) and SWI / SNF-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 4 (SMARCA4 or BRG1). The core and the regulatory subunits couple ATP hydrolysis to the perturbation of histone-DNA contacts, thereby providing access points to transcription factors and cognate DNA elements that facilitate gene activation and repression. Mutations in the genes encoding the twenty canonical SWI / SNF subunits are observed in nearly 20% of all cancers with the highest frequency of mutations observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical and endometrial), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal, and renal clear cell carcinoma. Despite having a high degree of homology, and their presumed overlapping functions, SMARCA2 and SMARCA4 have been reported as having different roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is infrequent in tumor development. In fact, numerous types of cancer have been shown to be SMARCA4-related (e.g., cancers having a SMARCA4-mutation or a SMARCA4- deficiency, such as lack of expression), including, e.g., lung cancer (such as non-small cell lung cancer). SMARCA2 has been demonstrated as one of the top essential genes in SMARCA4- related or -mutant cancer cell lines. This is because SMARCA4-deficient patient populations or cells depend exclusively on SMARCA2 activity—i.e., there is a greater incorporation of SMARCA2 into the complex to compensate for the SMARCA4 deficiency. Thus, SMARCA2 may be targeted in SMARCA4-related / deficient cancers. The co-occurrence of the deficiency of the expression of two (or more) genes that leads to cell death is known as synthetic lethality. Accordingly, synthetic lethality can be leveraged in the treatment of certain SMARCA2 / SMARCA4-related cancers. There is an ongoing need for new compounds, compositions and uses for diseases that are mediated by SMARCA2 (e.g., BRAHMA or BRM). It is thus an object of the present invention to provide such compounds, compositions, and uses. SUMMARY OF THE INVENTION The present invention provides new compounds, compositions and uses for the treatment of diseases that are mediated by SMARCA2 or SMARCA4, including cancer and abnormal cellular proliferation. It has been discovered that certain compounds can provide improved efficacy by means of advantageous pharmacokinetic or physiochemical properties. In certain aspects, a compound of Formula I, Formula II, or Formula III is provided: or a pharmaceutically acceptable salt thereof, wherein: R1is –C(O)R4, –(CHR16)OC(O)R4, –C(O)NR6R7, –P(O)(OR6)(OR7), –CH2–O–P(O)(OR6)(OR7), –P(O)(OR5)(NR6R7), or –CH2–O–P(O)(OR5)(NR6R7); or R1is –CH(R20)–O–P(O)(OR6)(OR7); R20is C1-C6alkyl; in certain embodiments R1is –C(O)R4, –P(O)(OR6)(OR7), or –CH2–P(O)(OR6)(OR7); in certain embodiments R1is –CH(CH3)–O–P(O)(OR6)(OR7); R4is C1-C6alkyl, –OR15, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, or –O–CH2CH2–S–S–C1-C6alkyl; each of which is optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9, –OC(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5; R5and R6are independently hydrogen or C1-C6alkyl; R7is hydrogen or C1-C6alkyl; in certain embodiments R6and R7are hydrogen; R8is hydrogen, C1-C6alkyl, or –C(O)R10; R9is hydrogen or C1-C6alkyl; R10is C1-C6alkyl or a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; R11is C1-C6alkyl or a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; each of which is optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9and a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; R15is hydrogen or C1-C6alkyl; R16is hydrogen, methyl, ethyl, propyl or isopropyl; R2is –P(O)(OR6)(OR7), –CH2–O–P(O)(OR6)(OR7), –C(O)R12, –(CHR16)OC(O)R4, or –(CHR16)NR8R9; in certain embodiments R2is –P(O)(OR6)(OR7) or –C(O)R12; R12is C1-C6alkyl or –O–(CHR16)OC(O)R4each of which is optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9, –O–C(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5; in certain embodiments R3is –O–C1-C6alkyl, –O–C(O)R13, –C(O)OR5or a 6-membered heteroaryl or heterocycle with 1 or 2 nitrogen atoms; wherein the 6-membered heteroaryl or heterocycle with 1 or 2 nitrogen atoms is optionally substituted with one substituent selected from group consisting of –C(O)NR8R9and –C(O)OR5; in certain embodiments R3is –O–methyl, –O–C(O)R13, –C(O)OH, or a 6-membered heteroaryl or heterocycle with 1 nitrogen atom substituted with –C(O)NH2or –C(O)OH; R13is –(CHR16)NR8bR9, or C1-C6alkyl which is optionally substituted with –C(O)OR5; R8bis hydrogen, C1-C6alkyl, or –C(O)R14; and R14is C1-C6alkyl or –C1-C6alkyl–aryl, each of which is optionally substituted with one or two substituent(s) selected from the group consisting of –NR8R9and –OH. A compound of the present invention provided herein or its pharmaceutically acceptable salt and / or its pharmaceutically acceptable composition can be used to treat a disorder which is mediated by SMARCA2 or SMARCA4. In some embodiments, a method to treat a human patient with a disorder mediated by SMARCA2 or SMARCA4 is provided that includes administering an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable composition. In certain embodiments the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. Non-limiting examples of compounds of Formula I include: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula I is or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula I is a sodium salt. For example, a compound selected from:

[0002] . In certain embodiments the compound of Formula I is a potassium salt. For example, a compound selected from: . In certain embodiments the compound of Formula I is a quaternary ammonium salt. For example, a compound selected from:

[0003] . In certain embodiments the compound of the present invention is of Formula:

[0004] or a pharmaceutically acceptable salt thereof. Non-limiting examples of compounds of Formula II include: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula II is a sodium salt. For example, a compound of Formula: . In certain embodiments the compound of Formula II is a potassium salt. For example, a compound of Formula: . In certain embodiments the compound of Formula II is a quaternary ammonium salt. For example, a compound of Formula: . In certain embodiments, a compound of the present invention provides one or more, and may provide multiple, advantages over treatment of a patient in need thereof with a SMARCA2 inhibitor. For example, in certain embodiments the SMARCA2 degrading compound of the present invention can a) overcome resistance to at least one other therapy; b) prolong the kinetics of the drug effect by using a degrader instead of an inhibitor because the degrader destroys the protein, thus requiring resynthesis of the protein after the SMARCA2 degrading compound has been metabolized; c) target all functions of a protein at once rather than a specific catalytic activity or binding event; and / or d) have increased potency compared to inhibitors due to the possibility of the small molecule acting catalytically. In certain embodiments, less of a compound described herein is needed for the treatment of a SMARCA2- or SMARCA4-mediated disorder, than by mole of a SMARCA2 inhibitor alone. In certain embodiments, the compound of the present invention has less of at least one side-effect in the treatment of a SMARCA2- or SMARCA4-mediated disorder, than by mole of a SMARCA2 inhibitor alone. In certain aspects, the present invention provides a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, for use in the treatment of a SMARCA2-mediated cancer. In other aspects, the present invention provides a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, for use in the treatment of a SMARCA4-mediated cancer. In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I, Formula II, or Formula III as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The compounds of the present invention are trans / (S) chiral diastereomers which release Compound 1: . In separate different embodiments a compound that is a mixture of stereoisomers or another stereoisomer is provided. For example, in this different embodiment a compound of acceptable salt thereof, could instead be a compound of structure:

[0005] or a pharmaceutically acceptable salt thereof. Other features and advantages of the present application will be apparent from the following detailed description and claims. The present invention therefore includes at least the following features: (a) A compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt, or isotopic derivative (including a deuterated derivative) thereof; (b) Use of a compound of Formula I, Formula II, or Formula III, in an effective amount in the treatment of a patient, typically a human, with a disorder described herein; (c) A compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt, or isotopic derivative (including a deuterated derivative) thereof that is useful in the treatment of a disorder described herein; (d) Use of a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt, isotopic derivative (including a deuterated derivative) thereof, in the manufacture of a medicament for the treatment of a disorder described herein; (e) A method for manufacturing a medicament intended for the therapeutic use of treating a disorder described herein, characterized in that a compound of Formula I, Formula II, or Formula III is used in the manufacture; (f) A pharmaceutical formulation comprising an effective host-treating amount of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt or isotopic derivative, thereof with a pharmaceutically acceptable excipient; (g) A compound of Formula I, Formula II, or Formula III as a mixture of enantiomers or diastereomers (as relevant), including as a racemate; (h) A compound of Formula I, Formula II, or Formula III in enantiomerically or diastereomerically (as relevant) enriched form, including an isolated enantiomer or diastereomer (i.e., greater than 85, 90, 95, 97, or 99% pure); and (i) A process for the preparation of therapeutic products that contain an effective amount of a compound of Formula I, Formula II, or Formula III or a pharmaceutically acceptable salt or isotopic derivative thereof optionally with a pharmaceutically acceptable excipient. BRIEF DESCRIPTION OF THE FIGURES FIG.1 depicts the in vivo efficacy or antitumor effect of Compound 2 at various doses on female BALB / c nude mice bearing established SMARCA4-null A549 non-small cell lung cancer (NSCLC) xenografts. The mice were treated by oral administration (PO) with a once daily (QD) or twice daily (BID) regimen of escalating doses of Compound 2 (15 mg / kg QD, 15 mg / kg BID, 30 mg / kg QD, 30 mg / kg BID, 60 mg / kg QD, 60 mg / kg BID, and 120 mg / kg QD) or vehicle by oral gavage for twenty days. The y-axis is mean tumor volume measured in mm3± SEM and the x-axis is time measured in days. The experimental procedure is provided in Example 29. FIG.2 is a graph demonstrating the effect on body weight of Compound 2 at various doses on female BALB / c nude mice bearing established SMARCA4-null A549 NSCLC xenografts. The mice were treated with a once daily (QD) or twice daily (BID) regimen of escalating doses of Compound 2 (15 mg / kg QD, 15 mg / kg BID, 30 mg / kg QD, 30 mg / kg BID, 60 mg / kg QD, 60 mg / kg BID, and 120 mg / kg QD) or vehicle by oral gavage for twenty days. Body weight data are expressed as percent of pre-dosing body weight measured on Day 0 ± SEM. The experimental procedure is provided in Example 29. FIG.3 depicts the in vivo efficacy or antitumor effect of Compound 2 in the treatment of female BALB / c nude mice bearing established human SMARCA4-null NSCLC patient derived xenograft (PDX) LU6437 tumors over a period of time. The mice were treated by oral administration (PO) once daily (QD) or twice daily (BID) for twenty-one days with the vehicle control or for twenty-eight days with Compound 2 at the following doses: 30 mg / kg QD, 30 mg / kg BID, and 60 mg / kg BID. The y-axis is tumor volume measured in mm3and the x-axis is time measured in days. The experimental procedure is provided in Example 30. FIG.4 is a graph demonstrating the effect on body weight of Compound 2 at various doses female BALB / c nude mice bearing established human SMARCA4-null NSCLC patient derived xenograft (PDX) LU6437 tumors. The mice were treated by oral administration (PO) once daily (QD) or twice daily (BID) for twenty-one days with the vehicle control or for twenty-eight days with Compound 2 at the following doses: 30 mg / kg QD, 30 mg / kg BID, and 60 mg / kg BID. Body weight data are expressed as percent of pre-dosing body weight measured on Day 0 ± SEM. The experimental procedure is provided in Example 30. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the compounds described herein in the therapeutic treatment of cancer. I. DEFINITIONS Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. The compounds of the present invention may be in the form of a racemate, enantiomer, mixture of enantiomers, diastereomer, mixture of diastereomers, tautomer, N-oxide, isomer, as if each is specifically described unless specifically excluded by context. The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item(s). The term “or” means “and / or”. Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. The present invention includes a compound of the present invention with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine such as2H,3H,11C,13C,14C,15N,17O,18O,18F31P,32P,35S,36Cl, and125I respectively. In certain embodiments, isotopically labelled compounds can be used in metabolic studies (with, for example14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an18F labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. Isotopic substitutions, for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is 90, 95 or 99% or more enriched in an isotope at any location of interest. In certain embodiments, deuterium is 90, 95 or 99% enriched at a desired location. In certain embodiments, the substitution of a hydrogen atom for a deuterium atom can be provided in any compound of the present invention. In certain embodiments, the substitution of a hydrogen atom for a deuterium atom occurs within one or more groups selected from any of R’s or variables described herein. For example, when any of the groups are, or contain, for example through substitution, methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting embodiments, CDH2, CD2H, CD3,CH2CD3, CD2CD3, CHDCH2D, CHDCD3, CHDCHD2, OCDH2, OCD2H, or OCD3 etc.). In certain embodiments, a compound of the present invention is isotopically labeled. In certain embodiments, at least one R group independently selected from R1, R2, R5, R6, R7, R8, R8b, R9, R10, R11, R12, R13, R14, R15and R16is isotopically labeled with 1, 2, or more isotopes as allowed by valence. In certain embodiments, the isotopic label is deuterium. In certain embodiments, at least one deuterium is placed on an atom that has a bond which is broken during metabolism of the compound in vivo, or is one, two or three atoms remote form the metabolized bond (e.g., which may be referred to as an α, β or γ, or primary, secondary or tertiary isotope effect). In other embodiments, the isotopic label is13C. In other embodiments, the isotopic label is18F. In certain non-limiting embodiments, the invention includes a solvated form of a compound described herein. The term “solvate” refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules. Non- limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a compound of the invention and water. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent may be isotopically substituted, e.g., D2O, acetone-d6, DMSO-d6 (dimethyl sulfoxide). A solvate can be in a liquid or solid form. A dash (“–”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, –(C=O)NH2is attached through carbon of the carbonyl (C=O) group. “Alkyl” is a branched or straight chain saturated aliphatic hydrocarbon group. In certain non-limiting embodiments, the alkyl group contains from 1 to 6 carbon atoms or from 1 to 4 carbon atoms. In certain non-limiting embodiments, the alkyl contains from 1 to 6 carbon atoms. In certain embodiments, the alkyl is C1-C2, C1-C3, C1-C4, C1-C5, or C1-C6alkyl. The specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species. For example, the term C1-C6alkyl as used herein indicates a straight or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species and therefore each subset is considered separately disclosed. For example, the term C1-C4alkyl as used herein indicates a straight or branched alkyl group having 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The term “alkyl” also encompasses cycloalkyl or carbocyclic groups. For example, when a term is used that includes “alk” then “cycloalkyl” or “carbocyclic” can be considered part of the definition, unless unambiguously excluded by the context. For example, and without limitation, the terms alkyl, alkoxy, haloalkyl, etc., can all be considered to include the cyclic forms of alkyl, unless unambiguously excluded by context. Non-limiting examples of “cycloalkyl” include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the cycloalkyl ring. For example: group. However, group. The term “alkoxy” denotes a group of the formula -O-alkyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, and tert-butoxy. “Heteroarylalkyl” is an alkyl group as described herein substituted with a heteroaryl group as described herein. As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6–14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocycle groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. The one or more fused carbocyclyl or heterocycle groups can be 4- to 7- or 5- to 7-membered saturated or partially unsaturated carbocyclyl or heterocycle groups that optionally contain 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, sulfur, silicon and boron, to form, for example, a 3,4-methylenedioxyphenyl group. In certain embodiments, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In certain embodiments, “aryl” is a 6-carbon aromatic group fused to a heterocycle wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the aromatic ring. For example, group. However, group. In certain embodiments, “aryl” is a 6-carbon aromatic group fused to a cycloalkyl wherein the point of attachment is the aryl ring. Non-limiting examples of “aryl” include dihydro-indene and tetrahydronaphthalene wherein the point of attachment for each group is on the aromatic ring. For example, group. However, group. The term “heterocyclyl”, “heterocycle”, and “heterocyclo” includes saturated, and partially saturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. This term should not be confused with the capitalized term “Heterocyclic Moiety” that is in the present invention and separately defined. Heterocyclic rings comprise monocyclic 3, 4, 5, 6, 7, 8, 9, or 10 membered rings, as well as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 membered bicyclic ring systems (which can include bridged fused and spiro-fused bicyclic ring systems). It does not include rings containing -O-O-, -O-S- or -S-S- portions. Examples of saturated heterocyclo groups include saturated 3, 4, 5, or 6-membered heteromonocyclic groups containing 1, 2, 3, or 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms [e.g., morpholinyl]; saturated 3, 4, 5, or 6-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclo groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3- dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4- triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3- dihydro-1H-1λ’-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl, isoquinolin-1(2H)- onyl, benzo[d]oxazol-2(3H)-onyl, 1,3-dihydro-2H-benzo[d]midazol-2-onyl, benzo[d]thiazole- 2(3H)-onyl, 1,2-dihydro-3H-pyrazol-3-onyl, 2(1H)-pyridinonyl, 2-piperazinonyl, indolinyl, and dihydrothiazolyl. The term “heterocyclyl”, “heterocycle”, and “heterocyclo” groups also include moieties where heterocycle radicals are fused / condensed with aryl or heteroaryl radicals: such as unsaturated condensed heterocycle group containing 1, 2, 3, 4, or 5 nitrogen atoms, for example, indoline, isoindoline, unsaturated condensed heterocycle group containing 1 or 2 oxygen atoms and 1, 2, or 3 nitrogen atoms, unsaturated condensed heterocycle group containing 1 or 2 sulfur atoms and 1, 2, or 3 nitrogen atoms, and saturated, partially unsaturated and unsaturated condensed heterocycle group containing 1 or 2 oxygen or sulfur atoms. Additional non-limiting examples of “heterocycle” include indoline, tetrahydroquinoline, tetrahydroisoquinoline, and dihydrobenzofuran wherein the point of attachment for each group is on the heterocycle ring. For example, group. However, group. The term “heteroaryl” denotes a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) and 1, 2, 3, 4, 5, or 6, heteroatoms independently selected from O, N, and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized. Examples include, but are not limited to, unsaturated 5- to 6-membered heteromonocyclyl groups containing 1, 2, 3, or 4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- or 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- or 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 or 6- membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5- thiadiazolyl]. Additional examples include 8-, 9-, or 10-membered heteroaryl bicyclic groups such as indazolyl, indolyl, imidazo[1,5-a]pyridinyl, benzimidazolyl, 4(3H)-quinazolinonyl, quinolinyl, isoquinolinyl, isoindolyl, thienothienyl, indolizinyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzoxazolyl, benzothiazolyl, purinyl, coumarinyl, cinnolinyl, and triazolopyridinyl. As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and the maximum number of amino acids present within the protein or peptide’s sequence is typically comparable to up to that found in nature. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof. Throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and should not be construed as a limitation on the scope of the invention. The description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. II. COMPOUNDS OF THE INVENTION or a pharmaceutically acceptable salt thereof. Embodiments of Formula I In certain embodiments R1is –P(O)(OR6)(OR7). In certain embodiments R1is –CH2-P(O)(OR6)(OR7). In certain embodiments R1is –P(O)(OR5)(NR6R7). In certain embodiments R1is –CH2-P(O)(OR5)(NR6R7). In certain embodiments R1is –C(O)R4. In certain embodiments R1is –C(O)C1-C6alkyl. In certain embodiments . In certain embodiments . In certain embodiments R1is –CH(R20)–O–P(O)(OR6)(OR7). In certain embodiments R1is –CH(C1-C4alkyl)–O–P(O)(OR6)(OR7). In certain embodiments R1is –CH(Me)–O–P(O)(OR6)(OR7). In certain embodiments R20is C1-C4alkyl. In certain embodiments R20is Me. In certain embodiments R20is Et. In certain embodiments R20is propyl. As used in the embodiments below, a Cycle A, Cycle B, or Cycle C is a 4-, 5-, or 6- membered heterocycle with 1 or 2 nitrogen or oxygen atoms. .In certain embodiments .In certain embodiments Cycle A is wherein the nitrogen is attached to the carbonyl. In certain embodiments Cycle B is , . . In certain embodiments . In certain embodiments the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of the present invention is of Formula: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula I is or a pharmaceutically acceptable salt thereof. Non-limiting examples of compounds of Formula I include:

[0006] or a pharmaceutically acceptable salt thereof. Additional non-limiting examples of compounds of Formula I include: or a pharmaceutically acceptable salt thereof. . In certain embodiments the compound of Formula I is a potassium salt. For example a compound of Formula: . In certain embodiments the compound of Formula I is a quaternary ammonium salt. For example a compound of Formula:

[0007] . Embodiments of Formula II In certain embodiments R2is -P(O)(OR6)(OR7). In certain embodiments R2is –CH2–O–P(O)(OR6)(OR7). In certain embodiments R2is -C(O)R12. In certain embodiments R2is –(CHR16)OC(O)R4. In certain embodiments R2is –(CHR16)NR8R9. In certain embodiments the compound of the present invention is of Formula:

[0008] or a pharmaceutically acceptable salt thereof. Non-limiting examples of compounds of Formula II include: or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula II is a sodium salt. For example, a compound of Formula: . In certain embodiments the compound of Formula I is a potassium salt. For example, a compound of Formula: . In certain embodiments the compound of Formula II is a quaternary ammonium salt. For example, a compound of Formula: . Embodiments of Formula III In certain embodiments R3is –O–C1-C6alkyl. In certain embodiments R3is –O–C(O)R13. In certain embodiments R3is –C(O)OR5. In certain embodiments R3is a 6-membered heteroaryl or heterocycle with 1 or 2 nitrogen atoms optionally substituted with one substituent selected from group consisting of –C(O)NR8R9and –C(O)OR5. In certain embodiments the compound of the present invention is of Formula:

[0009] or a pharmaceutically acceptable salt thereof. Non-limiting examples of compounds of Formula III include:

[0010] or a pharmaceutically acceptable salt thereof. In certain embodiments the compound of Formula III is a quaternary ammonium salt. For example a compound of formula

[0011] . Embodiments of R4In certain embodiments R4is C1-C6alkyl optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9, –OC(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5. In certain embodiments R4is C1-C6alkyl. In certain embodiments R4is methyl. In certain embodiments R4is ethyl. In certain embodiments R4is propyl. In certain embodiments R4is isopropyl. In certain embodiments R4is C1-C6alkyl substituted with –NR8R9. In certain embodiments R4is C1-C6alkyl substituted with –OC(O)R11. In certain embodiments R4is C1-C6alkyl substituted with –C(O)OR5. In certain embodiments R4is a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9, –OC(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and–C(O)OR5. In certain embodiments R4is a 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms optionally substituted with a 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms. In certain embodiments R4is –O–CH2CH2–S–S–C1-C6alkyl optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9, –OC(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5. In certain embodiments R4is –O–CH2CH2–S–S–C1-C6alkyl substituted with –NR8R9. In certain embodiments R4is –OR15optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9, –OC(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5. In certain embodiments R4is –OR15. Embodiments of R5In certain embodiments R5is hydrogen. In certain embodiments R5is C1-C6alkyl. In certain embodiments R5is methyl. In certain embodiments R5is ethyl. In certain embodiments R5is propyl. Embodiments of R6In certain embodiments R6is hydrogen. In certain embodiments R6is C1-C6alkyl. In certain embodiments R6is methyl. In certain embodiments R6is ethyl. In certain embodiments R6is propyl. Embodiments of R7In certain embodiments R7is hydrogen. In certain embodiments R7is C1-C6alkyl. In certain embodiments R7is methyl. In certain embodiments R7is ethyl. In certain embodiments R7is propyl. Embodiments of R8In certain embodiments R8is hydrogen. In certain embodiments R8is C1-C6alkyl. In certain embodiments R8is methyl. In certain embodiments R8is ethyl. In certain embodiments R8is propyl. In certain embodiments R8is –C(O)R10. Embodiments of R9In certain embodiments R9is hydrogen. In certain embodiments R9is C1-C6alkyl. In certain embodiments R9is methyl. In certain embodiments R9is ethyl. In certain embodiments R9is propyl. Embodiments of R10In certain embodiments R10is C1-C6alkyl. In certain embodiments R10is methyl. In certain embodiments R10is ethyl. In certain embodiments R10is propyl. In certain embodiments R10is a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms. In certain embodiments . Embodiments of R11In certain embodiments R11is C1-C6alkyl optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9and a 4-, 5-, or 6- membered heterocycle with 1 or 2 nitrogen or oxygen atoms. In certain embodiments R11is C1-C6alkyl substituted with a 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms. In certain embodiments . In certain embodiments . Embodiments of R12In certain embodiments R12is C1-C6alkyl optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9, –O–C(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5. In certain embodiments R12is C1-C6alkyl substituted with –NR8R9. In certain embodiments R12is C1-C6alkyl substituted with –NH2. In certain embodiments . In certain embodiments R12is –O–(CHR16)OC(O)R4optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9, –O–C(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5. In certain embodiments R12is –O–(CHR16)OC(O)R4. In certain embodiments . Embodiments of R13In certain embodiments R13is –(CHR16)NR8bR9. In certain embodiments . In certain embodiments . In certain embodiments . In certain embodiments . In certain embodiments . In certain embodiments R13is C1-C6alkyl optionally substituted with –C(O)OR5. In certain embodiments . Embodiments of R8bIn certain embodiments R8bis hydrogen. In certain embodiments R8bis C1-C6alkyl. In certain embodiments R8bis methyl. In certain embodiments R8bis ethyl. In certain embodiments R8bis propyl. In certain embodiments R8bis –C(O)R14. In certain embodiments . Embodiments of R14In certain embodiments R14is C1-C6alkyl optionally substituted with one or two substituent(s) selected from the group consisting of –NR8R9and –OH. In certain embodiments R14is C1-C6alkyl–aryl optionally substituted with one or two substituent(s) selected from the group consisting of –NR8R9and –OH. In certain embodiments R14is C1-C6alkyl–aryl substituted with –OH. In certain embodiments . Embodiments of R15In certain embodiments R15is hydrogen. In certain embodiments R15is C1-C6alkyl. In certain embodiments R15is methyl. In certain embodiments R15is ethyl. In certain embodiments R15is propyl. Embodiments of R16In certain embodiments R16is hydrogen. In certain embodiments R16is methyl. In certain embodiments R16is ethyl. In certain embodiments R16is propyl. In certain embodiments R16is isopropyl. Additional Embodiments or a pharmaceutically acceptable salt thereof, wherein: R1is –C(O)R4, –(CHR16)OC(O)R4, –C(O)NR6R7, –P(O)(OR6)(OR7), –CH2–O–P(O)(OR6)(OR7), –P(O)(OR5)(NR6R7), or –CH2–O–P(O)(OR5)(NR6R7); R4is C1-C6alkyl, –OR15, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, or –O–CH2CH2–S–S–C1-C6alkyl; each of which is optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9, –OC(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5; R5and R6are independently hydrogen or C1-C6alkyl; R7is hydrogen or C1-C6alkyl; R8is hydrogen, C1-C6alkyl, or –C(O)R10; R9is hydrogen or C1-C6alkyl; R10is C1-C6alkyl or a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; R11is C1-C6alkyl or a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; each of which is optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9and a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; R15is hydrogen or C1-C6alkyl; R16is hydrogen, methyl, ethyl, propyl or isopropyl; R2is –P(O)(OR6)(OR7), –CH2–O–P(O)(OR6)(OR7), –C(O)R12, –(CHR16)OC(O)R4, or –(CHR16)NR8R9; R12is C1-C6alkyl or –O–(CHR16)OC(O)R4each of which is optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9, –O–C(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5; R3is –O–C1-C6alkyl, –O–C(O)R13, –C(O)OR5or a 6-membered heteroaryl or heterocycle with 1 or 2 nitrogen atoms; wherein the 6-membered heteroaryl or heterocycle with 1 or 2 nitrogen atoms is optionally substituted with one substituent selected from the group consisting of –C(O)NR8R9and –C(O)OR5; R13is –(CHR16)NR8bR9, or C1-C6alkyl which is optionally substituted with –C(O)OR5; R8bis hydrogen, C1-C6alkyl, or –C(O)R14; and R14is C1-C6alkyl or –C1-C6alkyl–aryl, each of which is optionally substituted with one or two substituent(s) selected from the group consisting of –NR8R9and –OH. 2. The compound of embodiment 1, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 3. The compound of embodiment 1 or embodiment 2 wherein R1is –C(O)R4, –P(O)(OR6)(OR7), or –CH2–P(O)(OR6)(OR7). 4. The compound of embodiment 1 or embodiment 2, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 5. The compound of embodiment 1 or embodiment 4, wherein R16is hydrogen. 6. The compound of embodiment 1 or embodiment 4, wherein R16is methyl. 7. The compound of embodiment 1 or embodiment 4, wherein R16is ethyl. 8. The compound of embodiment 1 or embodiment 4, wherein R16is propyl. 9. The compound of embodiment 1 or embodiment 4, wherein R16is isopropyl. 10. The compound of embodiment 1 or embodiment 2, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 11. The compound of any one of embodiments 1-10, wherein R4is C1-C6alkyl, –OR15, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, or –O–CH2CH2–S–S–C1-C6alkyl, each of which is optionally substituted with one substituent independently selected from the group consisting of –NR8R9, –OC(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5. 12. The compound of embodiment 11, wherein R4is substituted with –OC(O)R11. 13. The compound of embodiment 12, wherein R11is C1-C6alkyl optionally substituted with one substituent independently selected from group consisting of –NR8R9and a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms. 14. The compound of embodiment 12, wherein R11is or a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms optionally substituted with one substituent independently selected from group consisting of –NR8R9and a 4-, 5-, or 6- membered heterocycle with 1 or 2 nitrogen or oxygen atoms. 15. The compound of embodiment 11, wherein R4is substituted with NR8R9. 16. The compound of any one of embodiments 11-15, wherein R8is hydrogen. 17. The compound of any one of embodiments 11-15, wherein R8is C1-C6alkyl. 18. The compound of any one of embodiments 11-15, wherein R8is methyl. 19. The compound of any one of embodiments 11-15, wherein R8is –C(O)R10. 20. The compound of embodiment 19, wherein R10is C1-C6alkyl. 21. The compound of embodiment 19, wherein R10is a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms. 22. The compound of embodiment 19, wherein R10is . 23. The compound of any one of embodiments 11-22, wherein R9is hydrogen. 24. The compound of any one of embodiments 11-22, wherein R9is C1-C6alkyl. 25. The compound of any one of embodiments 11-22, wherein R9is methyl. 26. The compound of embodiment 11, wherein R4is substituted with a 4-, 5-, or 6- membered heterocycle with 1 or 2 nitrogen or oxygen atoms. 27. The compound of embodiment 11, wherein R4is substituted with –C(O)OR5. 28. The compound of embodiment 11, wherein R4is not substituted. 29. The compound of any one of embodiments 1-28, wherein R4is C1-C6alkyl. 30. The compound of any one of embodiments 1-28, wherein R4is –OR15. 31. The compound of embodiment 30, wherein R15is hydrogen or methyl. 32. The compound of any one of embodiments 1-28, wherein R4is a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms. 33. The compound of any one of embodiments 1-28, wherein R4is –O–CH2CH2–S–S–C1-C6alkyl. 34. The compound of any one of embodiments 1-10, wherein R4is , , , 35. The compound of embodiment 1 or embodiment 2 wherein R1is –P(O)(OR5)(NR6R7). 36. The compound of embodiment 1 or embodiment 2 wherein R1is –CH2–O–P(O)(OR5)(NR6R7). 37. The compound of embodiment 35 or embodiment 36, wherein R5is hydrogen. 38. The compound of embodiment 35 or embodiment 36, wherein R5is methyl. 39. The compound of embodiment 1 or embodiment 2, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 40. The compound of embodiment 1 or embodiment 2 wherein R1is –P(O)(OR6)(OR7). 41. The compound of embodiment 1 or embodiment 2 wherein R1is –CH2–O–P(O)(OR6)(OR7). 42. The compound of embodiment 1 or embodiment 2, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 43. The compound of any one of embodiments 35-42, wherein R6is hydrogen. 44. The compound of any one of embodiments 35-42, wherein R6is methyl. 45. The compound of any one of embodiments 35-44, wherein R7is hydrogen. 46. The compound of any one of embodiments 35-44, wherein R7is methyl. 47. The compound of embodiment 1, wherein the compound is or a pharmaceutically acceptable salt thereof. 48. The compound of embodiment 1, wherein the compound is: or a pharmaceutically acceptable salt thereof. 49. The compound of embodiment 1, wherein the compound is: or a pharmaceutically acceptable salt thereof. 50. The compound of embodiment 1, wherein the compound is: or a pharmaceutically acceptable salt thereof. 51. The compound of embodiment 1, wherein the compound is: or a pharmaceutically acceptable salt thereof. 52. A compound of structure: or a pharmaceutically acceptable salt thereof. 53. The compound of embodiment 1, wherein the compound is: or a pharmaceutically acceptable salt thereof. 54. The compound of embodiment 1, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 55. The compound of embodiment 1 or embodiment 54, wherein R2is –P(O)(OR6)(OR7) or –C(O)R12. 56. The compound of embodiment 1 or embodiment 54, wherein R2is –P(O)(OR6)(OR7). 57. The compound of embodiment 1 or embodiment 54, wherein R2is –CH2–O–P(O)(OR6)(OR7). 58. The compound of embodiment 54, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 59. The compound of any one of embodiments 54-58, wherein R6is hydrogen. 60. The compound of any one of embodiments 54-58, wherein R6is methyl. 61. The compound of any one of embodiments 54-60, wherein R7is hydrogen. 62. The compound of any one of embodiments 54-60, wherein R7is methyl. 63. The compound of embodiment 1 or embodiment 54, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 64. The compound of embodiment 63, wherein R12is C1-C6alkyl or –O–(CHR16)OC(O)R4each of which is optionally substituted with one substituent independently selected from the group consisting of –NR8R9, –O–C(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5. 65. The compound of embodiment 64, wherein R12is substituted with –NR8R9. 66. The compound of embodiment 1 or embodiment 54, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 67. The compound of any one of embodiments 64-66, wherein R8is hydrogen. 68. The compound of any one of embodiments 64-66, wherein R8is methyl. 69. The compound of any one of embodiments 64-68, wherein R9is hydrogen. 70. The compound of any one of embodiments 64-68, wherein R9is methyl. 71. The compound of any one of embodiments 63-65, wherein R12is –O–(CHR16)OC(O)R4. 72. The compound of embodiment 1 or embodiment 54, wherein R2is –(CHR16)OC(O)R4. 73. The compound of any one of embodiments 71-72, wherein R4is isopropyl. 74. The compound of any one of embodiments 64-73, wherein R16is hydrogen. 75. The compound of any one of embodiments 64-73, wherein R16is methyl. 76. The compound of any one of embodiments 64-73, wherein R16is ethyl. 77. The compound of any one of embodiments 64-73, wherein R16is propyl. 78. The compound of any one of embodiments 64-73, wherein R16is isopropyl. 79. The compound of any one of embodiments 63-65, wherein R12is C1-C6alkyl. 80. The compound of any one of embodiments 63-65, wherein R12is or . 81. The compound of embodiment 1, wherein the compound is: or a pharmaceutically acceptable salt thereof. 82. The compound of embodiment 1, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 83. The compound of embodiment 1 or embodiment 82, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 84. The compound of embodiment 1 or embodiment 82, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 85. The compound of embodiment 1 or embodiment 82, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 86. The compound of embodiment 1 or embodiment 82, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 87. The compound of embodiment 1 or embodiment 82, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 88. The compound of embodiment 87, wherein the compound is: . 89. The compound of embodiment 1 or embodiment 82, wherein the compound is of Formula: or a pharmaceutically acceptable salt thereof. 90. The compound of embodiment 89, wherein the compound is: or a pharmaceutically acceptable salt thereof. 91. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 90, or a pharmaceutically acceptable salt thereof, and a therapeutically acceptable excipient. 92. A method of treating a patient with a SMARCA2- or SMARCA4-mediated disorder, comprising administering an effective amount of a compound of any one of embodiments 1-90, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition. 93. The method of embodiment 92, wherein the patient is a human. 94. The method of embodiment 92 or embodiment 93, wherein the SMARCA2- or SMARCA4-mediated disorder is a cancer, tumor, or abnormal cellular proliferation. 95. The method of embodiment 94, wherein the SMARCA2- or SMARCA4-mediated disorder is a tumor. 96. The method of embodiment 95, wherein the tumor is a solid tumor. 97. The method of embodiment 94, wherein the SMARCA2- or SMARCA4-mediated disorder is an abnormal cellular proliferation. 98. The method of embodiment 94, wherein the SMARCA2- or SMARCA4-mediated disorder is a cancer. 99. The method of embodiment 98, wherein the cancer is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, 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 cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's; Burkitt’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, 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, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor. 100. The method of embodiment 98 or embodiment 99, wherein the cancer is hepatocellular cancer. 101. The method of embodiment 98 or embodiment 99, wherein the cancer is colon cancer. 102. The method of embodiment 98 or embodiment 99, wherein the cancer is breast cancer. 103. The method of embodiment 98 or embodiment 99, wherein the cancer is prostate cancer. 104. The method of embodiment 98 or embodiment 99, wherein the cancer is melanoma. 105. The method of embodiment 98 or embodiment 99, wherein the cancer is ovarian cancer. 106. The method of embodiment 98 or embodiment 99, wherein the cancer is medulloblastoma. 107. The method of embodiment 98 or embodiment 99, wherein the cancer is non-small cell lung cancer. 108. The method of embodiment 98 or embodiment 99, wherein the cancer is bladder cancer. 109. The method of embodiment 98 or embodiment 99, wherein the cancer is glioblastoma. 110. The method of any one of embodiments 92-109, wherein the patient receives an additional therapeutic agent. 111. The method of embodiment 110, wherein the additional therapeutic agent is a chemotherapeutic agent. 112. Use of a compound of any one of embodiments 1-90, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to treat a SMARCA2- or SMARCA4-mediated disorder in a patient. 113. The use of embodiment 112 wherein the patient is a human. 114. The use of embodiment 112 or embodiment 113, wherein the SMARCA2- or SMARCA4-mediated disorder is a cancer, tumor, or abnormal cellular proliferation. 115. The use of embodiment 114, wherein the SMARCA2- or SMARCA4-mediated disorder is a tumor. 116. The use of embodiment 115, wherein the tumor is a solid tumor. 117. The use of embodiment 114, wherein the SMARCA2- or SMARCA4-mediated disorder is an abnormal cellular proliferation. 118. The use of embodiment 114, wherein the SMARCA2- or SMARCA4-mediated disorder is a cancer. 119. The use of embodiment 118, wherein the cancer is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, 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 cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's; Burkitt’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, 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, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor. 120. The use of embodiment 118 or embodiment 119, wherein the cancer is hepatocellular cancer. 121. The use of embodiment 118 or embodiment 119, wherein the cancer is colon cancer. 122. The use of embodiment 118 or embodiment 119, wherein the cancer is breast cancer. 123. The use of embodiment 118 or embodiment 119, wherein the cancer is prostate cancer. 124. The use of embodiment 118 or embodiment 119, wherein the cancer is melanoma. 125. The use of embodiment 118 or embodiment 119, wherein the cancer is ovarian cancer. 126. The use of embodiment 118 or embodiment 119, wherein the cancer is medulloblastoma. 127. The use of embodiment 118 or embodiment 119, wherein the cancer is non-small cell lung cancer. 128. The use of embodiment 118 or embodiment 119, wherein the cancer is bladder cancer. 129. The use of embodiment 118 or embodiment 119, wherein the cancer is glioblastoma. 130. The use of any one of embodiments 112-129, wherein the patient receives an additional therapeutic agent. 131. The use of embodiment 130, wherein the additional therapeutic agent is a chemotherapeutic agent. 132. A compound according to any one of embodiments 1-90, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the treatment of a SMARCA2- or SMARCA4-mediated disorder in a patient. 133. The compound of embodiment 132, wherein the patient is a human. 134. The compound of embodiment 132 or embodiment 133, wherein the SMARCA2- or SMARCA4-mediated disorder is a cancer, tumor, or abnormal cellular proliferation. 135. The compound of embodiment 134, wherein the SMARCA2- or SMARCA4- mediated disorder is a tumor. 136. The compound of embodiment 135, wherein the tumor is a solid tumor. 137. The compound of embodiment 134, wherein the SMARCA2- or SMARCA4- mediated disorder is an abnormal cellular proliferation. 138. The compound of embodiment 134, wherein the SMARCA2- or SMARCA4- mediated disorder is a cancer. 139. The compound of embodiment 138, wherein the cancer is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, 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 cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's; Burkitt’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, 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, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor. 140. The compound of embodiment 138 or embodiment 139, wherein the cancer is hepatocellular cancer. 141. The compound of embodiment 138 or embodiment 139, wherein the cancer is colon cancer. 142. The compound of embodiment 138 or embodiment 139, wherein the cancer is breast cancer. 143. The compound of embodiment 138 or embodiment 139, wherein the cancer is prostate cancer. 144. The compound of embodiment 138 or embodiment 139, wherein the cancer is melanoma. 145. The compound of embodiment 138 or embodiment 139, wherein the cancer is ovarian cancer. 146. The compound of embodiment 138 or embodiment 139, wherein the cancer is medulloblastoma. 147. The compound of embodiment 138 or embodiment 139, wherein the cancer is non- small cell lung cancer. 148. The compound of embodiment 138 or embodiment 139, wherein the cancer is bladder cancer. 149. The compound of embodiment 138 or embodiment 139, wherein the cancer is glioblastoma. 150. The compound of any one of embodiments 132-149, wherein the patient receives an additional therapeutic agent. 151. The compound of embodiment 150, wherein the additional therapeutic agent is a chemotherapeutic agent. III. METHODS OF TREATMENT A compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof can be used in an effective amount to treat a patient with a SMARCA2- or SMARCA4-mediated disorder, for example a human with a SMARCA2- or SMARCA4-mediated cancer. In certain aspects, the present invention provides a compound of Formula I, II, or III described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance. In a further aspect, the present invention provides a compound of Formula I, II, or III described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of SMARCA2-mediated disorders. In a further aspect, the present invention provides a method of treating SMARCA2-mediated disorders in a subject, comprising administering an effective amount compound of Formula I, II, or III as described herein, or a pharmaceutically acceptable salt thereof, to the subject. In a further aspect, the present invention provides the use of a compound of Formula I, II, or III described herein, or a pharmaceutically acceptable salt thereof, in a method of treating SMARCA2-mediated disorders in a subject. In a further aspect, the present invention provides the use of a compound of Formula I, II, or III described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating SMARCA2-mediated disorders in a subject. In other aspects, the present invention provides a compound of Formula I, II, or III described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of SMARCA4-mediated disorders. In a further aspect, the present invention provides a method of treating SMARCA4-mediated disorders in a subject, comprising administering an effective amount of a compound of Formula I, II, or III as described herein, or a pharmaceutically acceptable salt thereof, to the subject. In a further aspect, the present invention provides the use of a compound of Formula I, II, or III described herein, or a pharmaceutically acceptable salt thereof, in a method of treating SMARCA4-mediated disorders in a subject. In a further aspect, the present invention provides the use of a compound of Formula I, II, or III described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating SMARCA4-mediated disorders in a subject. The term “SMARCA2-mediated disorder” is normally characterized by the participation of the SMARCA2 protein in the inception, or manifestation of one or more symptoms or disease markers, severity, or progression of a disorder, including SMARCA2 participation in SMARCA4-related / deficient cancers or the treatment of cancers mediated by SMARCA2. The term “SMARCA4-mediated disorder” is normally characterized by the dysregulation of SMARCA4 with concomitant participation of the paralog SMARCA2 protein in the inception, or manifestation of one or more symptoms or disease markers, severity, or progression of a SMARCA4-mediated disorder. SMARCA2 The SWItch (SWI) / Sucrose Non-Fermentable (SNF)-related, Matrix Associated, Actin-dependent Regulator of Chromatin, subfamily A, member 2 (SMARCA2) gene (Entrez Gene ID 6595) encodes the SMARCA2 protein (Q56A76). SMARCA2 is a constituent of the ATP-dependent SWI / SNF chromatin remodeling protein complex, upon which many normally chromatin-repressed genes rely to be transcriptionally activated. The SWI / SNF family of proteins at large have helicase and ATPase activities and regulate transcription of several genes through the alteration of the chromatin structure around the several genes. Genes encoding members of the SWI / SNF complexes are mutated in approximately 20% of all human tumor samples (Kadoch, C. & Crabtree, G. R. Mammalian SWI / SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics. Sci Adv. 1:e1500447(2015); Hodges, C. et al. The Many Roles of BAF (mSWI / SNF) and PBAF Complexes in Cancer. Cold Spring Harb Perspect Med.6(2016); Kadoch, C. et al. Proteomic and bioinformatic analysis of mammalian SWI / SNF complexes identifies extensive roles in human malignancy. Nat Genet. 45:592–601(2013); Masliah-Planchon, J. et al. SWI / SNF chromatin remodeling and human malignancies. Annu Rev Pathol.10:145–171(2015); Shain, A. H. & Pollack, J. R. The spectrum of SWI / SNF mutations, ubiquitous in human cancers. PLoS ONE. 8:e55119(2013)). There exist many isoforms of SMARCA2. Dysregulation of SMARCA2 is associated with the diseases Nicolaides-Baraitser Syndrome and Blepharophimosis-Impaired Intellectual Development Syndrome. Decreased levels of SMARCA2 is linked to many cancers (Guerrero-Martínez, J.A. & Reyes, J.C. High expression of SMARCA4 or SMARCA2 is frequently associated with an opposite prognosis in cancer. Sci Rep.8(1):2043(2018)), and is found to be silenced in many model cancer cell lines (Glaros, S. et al. The reversible epigenetic silencing of BRM: implications for clinical targeted therapy. Oncogene 26:7058–7066(2007)) and primary tumors (Reisman, D. N. et al. Loss of BRG1 / BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis. Cancer Res 63:560–566(2003); Karnezis, A. N. et al. Dual loss of the SWI / SNF complex ATPases SMARCA4 / BRG1 and SMARCA2 / BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type. The Journal of pathology. 238:389–400(2016)). SMARCA2 shares high protein sequence homology to the paralog SMARCA4 (Mashtalir, N. et al. Modular Organization and Assembly of SWI / SNF Family Chromatin Remodeling Complexes. Cell.175:1272–1288.e20 (2018)). SMARCA4 The SWI / SNF-related, Matrix Associated, Actin-dependent Regulator of Chromatin, subfamily A, member 4 (SMARCA4) gene (Entrez Gene ID 6597) encodes the SMARCA4 protein (P51532). SMARCA4 is also a constituent of the ATP-dependent SWI / SNF chromatin remodeling protein complex which catalyzes the transcriptional activation of many genes through chromatin restructuring. SMARCA4 can bind BRCA1 as well as regulate the expression of the oncogenic CD44 protein. SMARCA4 gene mutations cause rhabdoid tumor predisposition syndrome type 2. Elevated expression of SMARCA4 is associated with poor outcomes in many cancers including breast cancer, ovarian cancer, lung adenocarcinoma, liposarcoma, and uveal melanoma, while inversely, decreased expression of SMARCA2 is associated with good prognosis in cancers (Guerrero-Martínez, J.A. & Reyes, J.C. High expression of SMARCA4 or SMARCA2 is frequently associated with an opposite prognosis in cancer. Sci Rep. 8(1):2043(2018)). Mutation of SMARCA4 is common in ovarian small cell carcinoma of the hypercalcemic type, found in approximately 90% of cases (Jelinic, P. et al. Recurrent SMARCA4 mutations in small cell carcinoma of the ovary. Nat Genet.46:424– 426(2014)). Inactivation of SMARCA4 leads to cellular dependence on its paralog SMARCA2 (Cantley, J. et al. Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers. Nat Commun.13:6814 (2022)). SMARCA2- and / or SMARCA4-Mediated Disorders SMARCA2-mediated disorders and / or SMARCA4-mediated disorders include cancers, including, but not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, bladder urothelial carcinoma (BLCA), brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, 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 cancer, ductal breast cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing’s tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, head and neck carcinoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, kidney cancer, kidney renal clear cell carcinoma (KIRC), leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin’s and non-Hodgkin’s; Burkitt’s), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non- small cell lung cancer (NSCLC), oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, ovarian serous adenocarcinoma, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, skin cutaneous melanoma (SKCM), small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer (SCLC), stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, triple negative breast cancer (TNBC), urothelial carcinoma, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor. In some embodiments, the SMARCA2-mediated disorder is Nicolaides-Baraitser Syndrome. In some embodiments, the SMARCA2-mediated disorder is Blepharophimosis- Impaired Intellectual Development Syndrome. In some embodiments, the SMARCA4-mediated disorder is characterized by the dysregulation of SMARCA4. In some embodiments, the SMARCA4 dysregulation is a SMARCA4 mutation selected from gene amplification, deletion, rearrangement, missense, frameshift, non-frameshift, nonsense, splice, or a combination thereof. In some embodiments, the SMARCA4 mutation is a missense mutation causing an amino acid substitution at a SMARCA4 amino acid site selected from R1277, R1243, D1235, G1232, G1194, R1192, R1189, A1186, D1177, G1162, G1160, G1159, R1157, R1135, F1102, R979, R973, R966, A945, E920, P913, T910, R885, E882, E861, E821, S813, A791, K785, or a combination thereof. In some embodiments, the SMARCA4 mutation is a missense mutation causing an amino acid substitution selected from K785R, S813, E821K, E861K, E882K, R885H, T910M, P913L, E920K, A945T, R966W, R973L, R973W, R979Q, G1232S, R1135Q, R1135W, R1157Q, R1157W, G1159V, G1162C, G1162S, A1186T, R1189Q, R1192C, R1192H, G1232S, R1243W, R1277L, or a combination thereof. In certain aspects, the SMARCA2-mediated disorders and / or SMARCA4-mediated disorders is a cancer, for example a cancer selected from to hepatocellular cancer, malignancies and hyperproliferative disorders of the colon (colon cancer), lung cancer, breast cancer, prostate cancer, melanoma, and ovarian cancer. In some embodiments, the SMARCA2-mediated disorder and / or SMARCA4-mediated disorder is hepatocellular cancer. In some embodiments, the SMARCA2-mediated disorder and / or SMARCA4-mediated disorder is colon cancer. In some embodiments, the SMARCA2-mediated disorder and / or SMARCA4-mediated disorder is breast cancer. In some embodiments, the SMARCA2-mediated disorder and / or SMARCA4-mediated disorder is prostate cancer. In some embodiments, the SMARCA2-mediated disorder and / or SMARCA4-mediated disorder is melanoma. In some embodiments, the SMARCA2-mediated disorder and / or SMARCA4-mediated disorder is ovarian cancer. In some embodiments, the SMARCA2-mediated disorder and / or SMARCA4-mediated disorder is medulloblastoma. In some embodiments, the SMARCA2-mediated disorder and / or SMARCA4-mediated disorder is non-small cell lung cancer (NSCLC). In some embodiments, the SMARCA2-mediated disorder and / or SMARCA4-mediated disorder is bladder cancer. In some embodiments, the SMARCA2-mediated disorder and / or SMARCA4-mediated disorder is glioblastoma. In certain embodiments, a compound of Formula I, II or III is selective for SMARCA2 over SMARCA4. Selectivity for SMARCA2 over SMARCA4 is highly challenging to achieve in view of the homology between the two proteins, but is crucial in order to reduce or avoid toxicity associated with SMARCA4 degradation. In certain embodiments, the condition treated with a compound of the present invention is a disorder related to abnormal cellular proliferation. Abnormal cellular proliferation, notably hyperproliferation, can occur as a result of a wide variety of factors, including genetic mutation, infection, exposure to toxins, autoimmune disorders, and benign or malignant tumor induction. There are a number of skin disorders associated with cellular hyperproliferation. Psoriasis, for example, is a benign disease of human skin generally characterized by plaques covered by thickened scales. The disease is caused by increased proliferation of epidermal cells of unknown cause. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Other diseases caused by hyperproliferation of skin cells include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, melanoma, basal cell carcinoma and squamous cell carcinoma. The term “neoplasia” or “cancer” is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors. Exemplary cancers which may be treated by the present compounds either alone or in combination with at least one additional anti-cancer agent include squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitt's lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogliomas, ependymomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas; bowel cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, stomach cancer, liver cancer, colon cancer, colorectal cancer, melanoma; carcinosarcoma, Hodgkin's disease, Wilms' tumor and teratocarcinomas. Additional cancers which may be treated using compounds according to the present invention include, for example, T-lineage Acute lymphoblastic Leukemia (T-ALL), T-lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML. Additional cancers which may be treated using the disclosed compounds according to the present invention include, for example, acute granulocytic leukemia, acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), adenocarcinoma, adenosarcoma, adrenal cancer, adrenocortical carcinoma, anal cancer, anaplastic astrocytoma, angiosarcoma, appendix cancer, astrocytoma, Basal cell carcinoma, B-Cell lymphoma, bile duct cancer, bladder cancer, bone cancer, bone marrow cancer, bowel cancer, brain cancer, brain stem glioma, breast cancer, triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2-negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2-negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor-negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, carcinoid tumors, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), colon cancer, colorectal cancer, craniopharyngioma, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, hemangioendothelioma, Hodgkin lymphoma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), inflammatory breast cancer (IBC), intestinal Cancer, intrahepatic bile duct cancer, invasive / infiltrating breast cancer, Islet cell cancer, jaw cancer, Kaposi sarcoma, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, leukemia, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, mesothelioma metastatic breast cancer, metastatic melanoma metastatic squamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oat cell cancer, ocular cancer, ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T- LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Burkitts lymphoma, B-cell ALL, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, Adult T- cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; Mucosa- Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, unclassifiable, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, for example, Alpha heavy chain disease, Gamma heavy chain disease, Mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone; extraosseous plasmacytoma; primary cutaneous follicle center lymphoma, T cell / histocyte rich large B-cell lymphoma, DLBCL associated with chronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly; primary mediastinal (thymic) large B-cell lymphoma, primary cutaneous DLBCL, leg type, ALK+ large B-cell lymphoma, plasmablastic lymphoma; large B-cell lymphoma arising in HHV8-associated multicentric, Castleman disease; B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma, or B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma. In certain embodiments the cancer is an unresectable cancer. Unresectable cancers are cancers that cannot be removed (resected) by surgery. Many cancers can be either resectable or unresectable depending on the site of the tumor and the size of the tumor. In certain embodiments an unresectable cancer is treated with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In other embodiments resectable cancer is treated with a compound described herein or a pharmaceutically acceptable salt thereof wherein the treatment additionally optionally includes surgically removing the tumor. Locally advanced cancers are cancers that have grown outside of the body part where the tumor started but have not yet spread (metastasized) to other parts of the body. In certain embodiments a locally advanced cancer is treated with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. IV. COMBINATION THERAPY A compound of the present invention can be used in an effective amount alone or in combination with another therapeutic or bioactive agent to treat a host such as a human with a SMARCA2- or SMARCA4-mediated disorder. The term “bioactive agent” is used to describe an agent, other than the selected compound according to the present invention, which can be used in combination or alternation with a compound of the present invention to achieve a desired result of therapy. In certain embodiments, the compound of the present invention and the bioactive agent are administered in a manner that they are active in vivo during overlapping time periods, for example, have time-period overlapping Cmax, Tmax, AUC or other pharmacokinetic parameter. In another embodiment, the compound of the present invention and the bioactive agent are administered to a host in need thereof that do not have overlapping pharmacokinetic parameter, however, one has a therapeutic impact on the therapeutic efficacy of the other. In some aspects of this embodiment, the bioactive agent is an immune modulator, including but not limited to a checkpoint inhibitor, including as non-limiting examples, a PD- 1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, LAG-3 inhibitor, TIM-3 inhibitor, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, small molecule, peptide, nucleotide, or other inhibitor. In certain aspects, the immune modulator is an antibody, such as a monoclonal antibody. PD-1 inhibitors that blocks the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, and in turn inhibit immune suppression include, for example, nivolumab (Opdivo), pembrolizumab (Keytruda), pidilizumab, AMP-224 (AstraZeneca and MedImmune), PF- 06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company and Incyte Corporation), TSR-042 (Tesaro), and the PD-L1 / VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, and in turn inhibits immune suppression, include for example, atezolizumab (Tecentriq), durvalumab (AstraZeneca and MedImmune), KN035 (Alphamab), and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind to CTLA-4 and inhibits immune suppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884 and AGEN2041 (Agenus). LAG-3 checkpoint inhibitors, include, but are not limited to, BMS- 986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and the dual PD-1 and LAG-3 inhibitor MGD013 (MacroGenics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro). In other embodiments, an active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the female reproductive system such as breast, ovarian, endometrial, or uterine cancer, in combination or alternation with an effective amount of an estrogen inhibitor including but not limited to a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degrader), a complete estrogen receptor degrader, or another form of partial or complete estrogen antagonist or agonist. Partial anti-estrogens like raloxifene and tamoxifen retain some estrogen-like effects, including an estrogen-like stimulation of uterine growth, and also, in some cases, an estrogen- like action during breast cancer progression which actually stimulates tumor growth. In contrast, fulvestrant, a complete anti-estrogen, is free of estrogen-like action on the uterus and is effective in tamoxifen-resistant tumors. Non-limiting examples of anti-estrogen compounds are provided in WO 2014 / 19176 assigned to Astra Zeneca, WO2013 / 090921, WO 2014 / 203129, WO 2014 / 203132, and US2013 / 0178445 assigned to Olema Pharmaceuticals, and U.S. Patent Nos. 9,078,871, 8,853,423, and 8,703, 810, as well as US 2015 / 0005286, WO 2014 / 205136, and WO 2014 / 205138. Additional non-limiting examples of anti-estrogen compounds include: SERMS such as anordrin, bazedoxifene, broparestriol, chlorotrianisene, clomiphene citrate, cyclofenil, lasofoxifene, ormeloxifene, raloxifene, tamoxifen, toremifene, and fulvestratnt; aromatase inhibitors such as aminoglutethimide, testolactone, anastrozole, exemestane, fadrozole, formestane, and letrozole; and antigonadotropins such as leuprorelin, cetrorelix, allylestrenol, chloromadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, and spironolactone. Other estrogenic ligands that can be used according to the present invention are described in U.S. Patent Nos. 4,418,068; 5,478,847; 5,393,763; and 5,457,117, WO2011 / 156518, US Patent Nos. 8,455,534 and 8,299,112, U.S. Patent Nos. 9,078,871; 8,853,423; 8,703,810; US 2015 / 0005286; and WO 2014 / 205138, US2016 / 0175289, US2015 / 0258080, WO 2014 / 191726, WO 2012 / 084711; WO 2002 / 013802; WO 2002 / 004418; WO 2002 / 003992; WO 2002 / 003991; WO 2002 / 003990; WO 2002 / 003989; WO 2002 / 003988; WO 2002 / 003986; WO 2002 / 003977; WO 2002 / 003976; WO 2002 / 003975; WO 2006 / 078834; US 6821989; US 2002 / 0128276; US 6777424; US 2002 / 0016340; US 6326392; US 6756401; US 2002 / 0013327; US 6512002; US 6632834; US 2001 / 0056099; US 6583170; US 6479535; WO 1999 / 024027; US 6005102; EP 0802184; US 5998402; US 5780497, US 5880137, WO 2012 / 048058 and WO 2007 / 087684. In other embodiments, an active compounds described herein can be administered in an effective amount for the treatment of abnormal tissue of the male reproductive system such as prostate or testicular cancer, in combination or alternation with an effective amount of an androgen (such as testosterone) inhibitor including but not limited to a selective androgen receptor modulator, a selective androgen receptor degrader, a complete androgen receptor degrader, or another form of partial or complete androgen antagonist. In certain embodiments, the prostate or testicular cancer is androgen-resistant. Non-limiting examples of anti-androgen compounds are provided in WO 2011 / 156518 and US Patent Nos. 8,455,534 and 8,299,112. Additional non-limiting examples of anti- androgen compounds include: enzalutamide, apalutamide, cyproterone acetate, chlormadinone acetate, spironolactone, canrenone, drospirenone, ketoconazole, topilutamide, abiraterone acetate, and cimetidine. In certain embodiments, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include but are not limited to Crizotinib, Alectinib, ceritinib, TAE684 (NVP- TAE684), GSK1838705A, AZD3463, ASP3026, PF-06463922, entrectinib (RXDX-101), and AP26113. In certain embodiments, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), rociletinib (CO- 1686), osimertinib (Tagrisso), olmutinib (Olita), naquotinib (ASP8273), nazartinib (EGF816), PF-06747775 (Pfizer), icotinib (BPI-2009), neratinib (HKI-272; PB272); avitinib (AC0010), EAI045, tarloxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL647; EXEL- 7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006, and dacomitinib (PF-00299804; Pfizer). In certain embodiments, the bioactive agent is an HER-2 inhibitor. Examples of HER- 2 inhibitors include trastuzumab, lapatinib, ado-trastuzumab emtansine, and pertuzumab. In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include obinutuzumab, rituximab, fatumumab, ibritumomab, tositumomab, and ocrelizumab. In certain embodiments, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tasocitinib. In certain embodiments, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include venetoclax, ABT-199 (4-[4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1- en-1-yl]methyl]piperazin-1-yl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4- yl)methyl]amino]phenyl]sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide), ABT- 737 (4-[4-[[2-(4-chlorophenyl)phenyl]methyl]piperazin-1-yl]-N-[4-[[(2R)-4- (dimethylamino)-1-phenylsulfanylbutan-2-yl] amino]-3-nitrophenyl]sulfonylbenzamide) (navitoclax), ABT-263 ((R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l,l'-biphenyl]- 2-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide), GX15-070 (obatoclax mesylate, (2Z)- 2-[(5Z)-5-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-4-methoxypyrrol-2-ylidene]indole; methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4-(4,9-dioxo-4,9- dihydronaphtho[2,3-d]thiazol-2-ylamino)-phenyl ester), pogosin, ethyl 2-amino-6-bromo-4- (1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate, Nilotinib-d3, TW-37 (N-[4-[[2- (1,1-Dimethylethyl)phenyl]sulfonyl]phenyl]-2,3,4-trihydroxy-5-[[2-(1- methylethyl)phenyl]methyl]benzamide), Apogossypolone (ApoG2), HA14-1, AT101, sabutoclax, gambogic acid, or G3139 (Oblimersen). In certain embodiments, the bioactive agent is a kinase inhibitor. In certain embodiments, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a Bruton’s tyrosine kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof. Examples of PI3 kinase inhibitors include but are not limited to Wortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib, Palomid 529, ZSTK474, PWT33597, CUDC-907, and AEZS-136, duvelisib, GS-9820, BKM120, GDC-0032 (Taselisib) (2-[4-[2- (2-Isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9- yl]pyrazol-1-yl]-2-methylpropanamide), MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; or Methyl(oxo) {[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719 ((2S)-N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2- thiazolyl]-1,2-pyrrolidinedicarboxamide), GSK2126458 (2,4-Difluoro-N-{2-(methyloxy)-5- [4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide) (omipalisib), TGX-221 ((±)-7-Methyl-2-(morpholin-4-yl)-9-(l-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one), GSK2636771 (2-Methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H- benzo[d]imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R)-2-((l-(7-methyl-2- morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoic acid), TGR- 1202 / RP5264, GS-9820 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4- mohydroxypropan-1-one), GS-1101 (5-fluoro-3-phenyl-2-([S)]-1-[9H-purin-6-ylamino]- propyl)-3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N-(4-(N-(3-((3,5- dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4- methylbenzamide), BAY80-6946 (2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3- dihydroimidazo[1,2-c]quinaz), AS 252424 (5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]- meth-(Z)-ylidene]-thiazolidine-2,4-dione), CZ 24832 (5-(2-amino-8-fluoro- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide), Buparlisib (5-[2,6- Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine), GDC-0941 (2-(lH- Indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2- d]pyrimidine), GDC-0980 ((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4- morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)), SF1126 ((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17- (hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino- 4-ium)-2-oxa-7,10,13,16-tetraazaoctadecan-18-oate), PF-05212384 (N-[4-[[4- (Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-(4,6-di-4-morpholinyl-1,3,5-triazin- 2-yl)phenyl]urea) (gedatolisib), LY3023414, BEZ235 (2-Methyl-2-{4-[3-methyl-2-oxo-8- (quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile) (dactolisib), XL-765 (N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2- yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide), and GSK1059615 (5-[[4-(4- Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione), PX886 ([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9- (methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11- hexahydroindeno[4,5h]isochromen-10-yl] acetate (also known as sonolisib)), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copanlisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422), and the structure described in WO2014 / 071109. Examples of BTK inhibitors include ibrutinib (also known as PCI-32765) (Imbruvica™) (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1- yl]piperidin-1-yl]prop-2-en-1-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291 / 292 (N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4- yl)amino)phenyl)acrylamide) (Avila Therapeutics) (see US Patent Publication No 2011 / 0117073, incorporated herein in its entirety), Dasatinib ([N-(2-chloro-6-methylphenyl)- 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5- carboxamide], LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-ibromophenyl) propenamide), GDC-0834 ([R-N-(3-(6-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)- 4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide], CGI-560 4-(tert-butyl)-N-(3-(8- (phenylamino)imidazo[1,2-a]pyrazin-6-yl)phenyl)benzamide, CGI-1746 (4-(tert-butyl)-N-(2- methyl-3-(4-methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5-dihydropyrazin- 2-yl)phenyl)benzamide), CNX-774 (4-(4-((4-((3-acrylamidophenyl)amino)-5- fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide), CTA056 (7-benzyl-1-(3- (piperidin-1-yl)propyl)-2-(4-(pyridin-4-yl)phenyl)-1H-imidazo[4,5-g]quinoxalin-6(5H)-one), GDC-0834 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5- oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2- carboxamide), GDC-0837 ((R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2- yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7- tetrahydrobenzo[b]thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4-((3-(2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2- aminocyclohexyl)amino)pyrimidine-5-carboxamide hydrochloride), QL-47 (1-(1- acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one), and RN486 (6-cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl- piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin- 1-one), and other molecules capable of inhibiting BTK activity, for example those BTK inhibitors disclosed in Akinleye et ah, Journal of Hematology & Oncology, 2013, 6:59, the entirety of which is incorporated herein by reference. Syk inhibitors include, for example, Cerdulatinib (4-(cyclopropylamino)-2-((4-(4- (ethylsulfonyl)piperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide), entospletinib (6- (1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine), fostamatinib ([6- ({5-Fluoro-2-[(3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl}amino)-2,2-dimethyl-3-oxo- 2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate), fostamatinib disodium salt (sodium (6-((5-fluoro-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4- yl)amino)-2,2-dimethyl-3-oxo-2H-pyrido[3,2-b][1,4]oxazin-4(3H)-yl)methyl phosphate), BAY 61-3606 (2-(7-(3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino)- nicotinamide HCl), RO9021 (6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl- pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide), imatinib (Gleevac; 4-[(4- methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2- yl]amino}phenyl)benzamide), staurosporine, GSK143 (2-(((3R,4R)-3-aminotetrahydro-2H- pyran-4-yl)amino)-4-(p-tolylamino)pyrimidine-5-carboxamide), PP2 (1-(tert-butyl)-3-(4- chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), PRT-060318 (2-(((1R,2S)-2- aminocyclohexyl)amino)-4-(m-tolylamino)pyrimidine-5-carboxamide), PRT-062607 (4-((3- (2H-1,2,3-triazol-2-yl)phenyl)amino)-2-(((1R,2S)-2-aminocyclohexyl)amino)pyrimidine-5- carboxamide hydrochloride), R112 (3,3'-((5-fluoropyrimidine-2,4- diyl)bis(azanediyl))diphenol), R348 (3-Ethyl-4-methylpyridine), R406 (6-((5-fluoro-2- ((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)amino)-2,2-dimethyl-2H-pyrido[3,2- b][1,4]oxazin-3(4H)-one), piceatannol (3-Hydroxyresveratol), YM193306 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614- 3643 incorporated in its entirety herein), Compound D (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614- 3643 incorporated in its entirety herein), PRT060318 (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614- 3643 incorporated in its entirety herein), luteolin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), apigenin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), quercetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem. 2012, 55, 3614-3643 incorporated in its entirety herein), fisetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), myricetin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein), morin (see Singh et al. Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, J. Med. Chem.2012, 55, 3614-3643 incorporated in its entirety herein). In certain embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known, and include, for example, trametinib / GSKl120212 (N-(3-{3-Cyclopropyl-5-[(2- fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3- d]pyrimidin-1(2H-yl}phenyl)acetamide), selumetinib (6-(4-bromo-2-chloroanilino)-7-fluoro- N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide), pimasertib / AS703026 / MSC 1935369 ((S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4-iodophenyl)amino)isonicotinamide), XL-518 / GDC-0973 (l-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3- [(2S)-piperidin-2-yl]azetidin-3-ol), refametinib / BAY869766 / RDEAl 19 (N-(3,4-difluoro-2- (2-fluoro-4-iodophenylamino)-6-methoxyphenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1- sulfonamide), PD-0325901 (N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4- iodophenyl)amino]- benzamide), TAK733 ((R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2- fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione), MEK162 / ARRY438162 (5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2- hydroxyethoxy)-1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-[[3-Fluoro-2- (methylsulfamoylamino)-4-pyridyl]methyl]-4-methyl-7-pyrimidin-2-yloxychromen-2-one), WX-554, R04987655 / CH4987655 (3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)-N-(2- hydroxyethoxy)-5-((3-oxo-1,2-oxazinan-2yl)methyl)benzamide), AZD8330 (2-((2-fluoro-4- iodophenyl)amino)-N-(2 hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3- carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobimetinib, PD98059, BIX 02189, BIX 02188, binimetinib, SL-327, TAK-733, and PD318088. In certain embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, Vemurafinib (N-[3-[[5-(4-Chlorophenyl)-1H-pyrrolo[2,3-b]pyridin- 3-yl]carbonyl]-2,4-difluorophenyl]-1-propanesulfonamide), sorafenib tosylate (4-[4-[[4- chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2- carboxamide;4-methylbenzenesulfonate), AZ628 (3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(3- methyl-4-oxo-3,4-dihydroquinazolin-6-ylamino)phenyl)benzamide), NVP-BHG712 (4- methyl-3-(1-methyl-6-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-N-(3- (trifluoromethyl)phenyl)benzamide), RAF-265 (1-methyl-5-[2-[5-(trifluoromethyl)-1H- imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine), 2- Bromoaldisine (2-Bromo-6,7-dihydro-1H,5H-pyrrolo[2,3-c]azepine-4,8-dione), Raf Kinase Inhibitor IV (2-chloro-5-(2-phenyl-5-(pyridin-4-yl)-1H-imidazol-4-yl)phenol), Sorafenib N-Oxide (4-[4-[[[[4-Chloro- 3(trifluoroMethyl)phenyl]aMino]carbonyl]aMino]phenoxy]-N-Methyl- 2pyridinecarboxaMide 1-Oxide), PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265, AZ 628, SB590885, ZM336372, GW5074, TAK-632, CEP-32496, LY3009120, and GX818 (Encorafenib). In certain embodiments, the bioactive agent is an AKT inhibitor, including but not limited to, MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine, AZD5363, Honokiol, PF-04691502, and Miltefosine, a FLT-3 inhibitor, including but not limited to, P406, Dovitinib, Quizartinib (AC220), Amuvatinib (MP-470), Tandutinib (MLN518), ENMD-2076, and KW-2449, or a combination thereof. In certain embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include but are not limited to rapamycin and its analogs, everolimus (Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimus. In certain embodiments, the bioactive agent is a RAS inhibitor. Examples of RAS inhibitors include but are not limited to Reolysin and siG12D LODER. In certain embodiments, the bioactive agent is an HSP inhibitor. HSP inhibitors include but are not limited to Geldanamycin or 17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol. Additional bioactive compounds include, for example, everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, an HDAC inhibitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an IGFR-TK inhibitor, an anti- HGF antibody, a focal adhesion kinase inhibitor, a Map kinase kinase (MEK) inhibitor, a VEGF trap antibody, pemetrexed, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT- 110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX- 0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, liposomal doxorubicin, 5′-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258); 3-[5- (methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib, AG-013736, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS- 214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, paclitaxel, cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787 / ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2- hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG- filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa- 2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin- 11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa, darbepoetin alfa and mixtures thereof. In certain embodiments, the bioactive agent is selected from, but is not limited to, Imatinib mesylate (Gleevac®), Dasatinib (Sprycel®), Nilotinib (Tasigna®), Bosutinib (Bosulif®), Trastuzumab (Herceptin®), trastuzumab-DM1, Pertuzumab (PerjetaTM), Lapatinib (Tykerb®), Gefitinib (Iressa®), Erlotinib (Tarceva®), Cetuximab (Erbitux®), Panitumumab (Vectibix®), Vandetanib (Caprelsa®), Vemurafenib (Zelboraf®), Vorinostat (Zolinza®), Romidepsin (Istodax®), Bexarotene (Tagretin®), Alitretinoin (Panretin®), Tretinoin (Vesanoid®), Carfilizomib (KyprolisTM), Pralatrexate (Folotyn®), Bevacizumab (Avastin®), Ziv-aflibercept (Zaltrap®), Sorafenib (Nexavar®), Sunitinib (Sutent®), Pazopanib (Votrient®), Regorafenib (Stivarga®), or Cabozantinib (CometriqTM). In certain aspects, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic, an additional therapeutic agent, or an immunosuppressive agent. Suitable chemotherapeutic bioactive agents include, but are not limited to, a radioactive molecule, a toxin, also referred to as cytotoxin or cytotoxic agent, which includes any agent that is detrimental to the viability of cells, and liposomes or other vesicles containing chemotherapeutic compounds. General anticancer pharmaceutical agents include: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®), Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®), Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase (Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide (VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®), Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone (Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™). Examples of additional suitable chemotherapeutic agents include but are not limited to 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, adriamycin, aldesleukin, an alkylating agent, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC), an anti-mitotic agent, cis-dichlorodiamine platinum (II) (DDP) (cisplatin), diamino dichloro platinum, anthracycline, an antibiotic, an antimetabolite, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), Chlorambucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens, Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, cytochalasin B, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin (formerly actinomycin), daunirubicin HCL, daunorucbicin citrate, denileukin diftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione, Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coli L-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterified estrogens, estradiol, estramustine phosphate sodium, ethidium bromide, ethinyl estradiol, etidronate, etoposide citrororum factor, etoposide phosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids, goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea, idarubicin HCL, ifosfamide, interferon α-2b, irinotecan HCL, letrozole, leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine, lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesterone acetate, megestrol acetate, melphalan HCL, mercaptipurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate, ondansetron HCL, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL, plimycin, polifeprosan 20 with carmustine implant, porfimer sodium, procaine, procarbazine HCL, propranolol, rituximab, sargramostim, streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone, tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL, toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate. Additional therapeutic agents that can be administered in combination with a compound disclosed herein can include bevacizumab, sutinib, sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib, vandetanib, aflibercept, volociximab, etaracizumab (MEDI- 522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine, atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab, dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib, carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat, mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin, talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rilotumumab, oxaliplatin (Eloxatin), PD0332991, ribociclib (LEE011), amebaciclib (LY2835219), HDM201, fulvestrant (Faslodex), exemestane (Aromasin), PIM447, ruxolitinib (INC424), BGJ398, necitumumab, pemetrexed (Alimta), and ramucirumab (IMC-1121B). In certain embodiments, the additional therapy is a monoclonal antibody (MAb). Some MAbs stimulate an immune response that destroys cancer cells. Similar to the antibodies produced naturally by B cells, these MAbs may “coat” the cancer cell surface, triggering its destruction by the immune system. For example, bevacizumab targets vascular endothelial growth factor (VEGF), a protein secreted by tumor cells and other cells in the tumor’s microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the epidermal growth factor receptor (EGFR), and trastuzumab targets the human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. They may also trigger apoptosis and activate the immune system to destroy tumor cells. In other aspects of the present invention, the bioactive agent is an immunosuppressive agent. The immunosuppressive agent can be a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g. Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTOR inhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus (RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, a rapalog, e.g.ridaforolimus, azathioprine, campath 1H, a S1P receptor modulator, e.g. fingolimod or an analogue thereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof, e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA4lg (Abatacept), belatacept, LFA3lg,, etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®), infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®), Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab, Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate, benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin, or aspirin and ibuprofen. In certain embodiments a monotherapy or combination described herein additionally comprises administering one or more additional therapeutic agents to decrease side effects of the therapy. For example, in certain embodiments a compound described herein or a pharmaceutically acceptable salt thereof is administered concurrently, before, or after administration of an antineutropenia medication, antinausea medication, an antihistamine, and / or an antipain medication. Non-limiting examples of antineutropenia medications include growth factors for example a granulocyce colony stimulating factor (G-CSF). In certain embodiments a therapy in a table above is administered in combination with a G-CSF. G-CSF (or another active agent) can be given before, with after, or on different days than the compound of the present invention. Non-limiting examples of granulocyte colony stimulating factors include filgrastim (in the form of neupogen, zarxio, nivestym, or another form), CG-10639, and PEGF. In certain embodiments the granulocyte colony stimulating factor is pegfilgrastim. In certain embodiments the granulocyte colony stimulating factor is Neulasta. In certain embodiments the granulocyte colony stimulating factor is selected from Ristempa, Tezmota, Fulphila, Pelgraz, Udenyca, Udenyca, Pelmeg, Ziextenzo, Grasustek, Ziextenzo, Lapelga, Neutropeg, Cegfila, Nyvepria, and Stimufend. In certain embodiments the therapy described herein further comprises an antinausea medication. Non-limiting examples of antinauasea medications include aprepitant, dolasetron, granisetron, ondansetron, palonosetron, proclorperazine, promethazine, netupitant- palonosetron, rolapitant, lorazepam, metoclopramide, famotidine, dexamethasone, and ranitidine. In certain embodiments the therapy described herein further comprises an antihistamine medication. Non-limiting examples of antihistamine medications include benadryl, cetirizine, loratadine, and fexofenadine. In certain embodiments the therapy described herein further comprises an antipain medication. Non-limiting examples of antipain medications include tramadol, hydromorphone, methadone, morphine, oxycodone, hydrocodone, oxymorphone, fentanyl, and tapentadol. V. PHARMACEUTICAL COMPOSITIONS A compound described herein can be administered as a neat chemical, but is more typically administered as a pharmaceutical composition, that includes an effective amount for a host, typically a human, in need of such treatment for a disorder described herein. Accordingly, the disclosure provides pharmaceutical compositions comprising an effective amount of a compound or pharmaceutically acceptable salt together with at least one pharmaceutically acceptable excipient or carrier for any of the uses described herein. The pharmaceutical composition may contain a compound or salt as the only active agent, or, in an alternative embodiment, the compound and at least one additional active agent. In certain embodiments the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of the active compound and optionally from about 0.1 mg to about 1000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms with at least 0.1, 1, 5, 10, 25, 50, 75, 100, 200, 250, 300, 400, 500, 600, 700, or 750 mg of active compound, or its salt. A dosage form is a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, and the like. A “dosage form” can also include an implant, for example an optical implant. The pharmaceutical composition may also include a molar ratio of the active compound and an additional active agent. For example, the pharmaceutical composition may contain a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1 or from about 1.5:1 to about 4:1 of an anti-inflammatory or immunosuppressing agent. Compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implant, including ocular implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, injection, including ocular injection, intraveneous, intra-aortal, intracranial, subdermal, intraperitioneal, subcutaneous, transnasal, sublingual, or rectal or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. For ocular delivery, the compound can be administered, as desired, for example, via intravitreal, intrastromal, intracameral, sub-tenon, sub-retinal, retro-bulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral, circumcorneal, or tear duct injections, or through a mucus, mucin, or a mucosal barrier, in an immediate or controlled release fashion or via an ocular device. The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, an injection or infusion solution, a capsule, a tablet, a syrup, a transdermal patch, a subcutaneous patch, a dry powder, an inhalation formulation, in a medical device, suppository, buccal, or sublingual formulation, parenteral formulation, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose. Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidents, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils. Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention. The pharmaceutical compositions / combinations can be formulated for oral administration. These compositions can contain any amount of active compound that achieves the desired result, for example between 0.1 and 99 weight % (wt.%) of the compound and usually at least about 5 wt.% of the compound. Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the compound. Formulations suitable for rectal administration are typically presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture. Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof. Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. In certain embodiments, microneedle patches or devices are provided for delivery of drugs across or into biological tissue, particularly the skin. The microneedle patches or devices permit drug delivery at clinically relevant rates across or into skin or other tissue barriers, with minimal or no damage, pain, or irritation to the tissue. Formulations suitable for administration to the lungs can be delivered by a wide range of passive breath driven and active power driven single / -multiple dose dry powder inhalers (DPI). The devices most commonly used for respiratory delivery include nebulizers, metered- dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Selection of a suitable lung delivery device depends on parameters, such as nature of the drug and its formulation, the site of action, and pathophysiology of the lung. Pharmaceutical compositions are compositions comprising at least one active agent, and at least one other substance, such as a carrier. Pharmaceutical combinations are combinations of at least two active agents which may be combined in a single dosage form or provided together in separate dosage forms with instructions that the active agents are to be used together to treat any disorder described herein. A pharmaceutically acceptable salt is a derivative of the disclosed compound in which the parent compound is modified by making inorganic or organic, non-toxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, formic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic (TFA), HOOC-(CH2)n- COOH where n is 0-4, and the like, or using a different acid that produces the same counterion. Lists of additional suitable salts may be found, e.g., in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p.1418 (1985). VI. SYNTHETIC METHODS General Synthesis The compounds described herein can be prepared by methods known to those skilled in the art. In some non-limiting examples, the disclosed compounds can be made by the schemes provided below. Compounds of the present invention with stereocenters may be drawn without stereochemistry for convenience. One skilled in the art will recognize that pure enantiomers and diastereomers can be prepared by methods known in the art. Examples of methods to obtain optically active materials include at least the following. i) physical separation of crystals—a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization—a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions—a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis—a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis—a synthetic technique whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral auxiliaries; vi) diastereomer separations—a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (the chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct structural differences and the chiral auxiliary later removed to obtain the desired enantiomer; vii) first- and second-order asymmetric transformations—a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer. The desired enantiomer is then released from the diastereomer; viii) kinetic resolutions—this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors—a synthetic technique whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography—a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including via chiral HPLC). The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions; xi) chiral gas chromatography—a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase; xii) extraction with chiral solvents—a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent; xiii) transport across chiral membranes—a technique whereby a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through. xiv) simulated moving bed chromatography, is used in certain embodiments. A wide variety of chiral stationary phases are commercially available. Example 1A: Synthesis of 1-[1-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-4- yl]piperazin-2-one (1A-10) Step-1: To a solution of 4-iodo-1H-pyrazole 1A-1 (60 g, 309.32 mmol) in tetrahydrofuran (493.87 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil, 14.22 g, 592.66 mmol) and stirred at room temperature for 30 minutes. Then benzyl bromide (52.90 g, 309.32 mmol, 36.79 mL) was added slowly at 0 °C. The reaction mixture was stirred at room temperature for two hours. The progress of reaction was monitored by TLC. Upon completion of the reaction, the reaction mixture was poured into ice-cold water. The product was extracted with ethyl acetate, the organic layer was washed with brine solution, dried over anhydrous Na2SO4, filtered and evaporated under reduce pressure. The resulting crude product was washed with pentane (500 mL) and filtered to get 1-benzyl-4-iodo-pyrazole 1A-2 (57 g, 177.48 mmol, 57.38% yield) as white solid. LCMS (ES+): m / z 285.21 [M+2H]+. Step-2: To a solution of 1-benzyl-4-iodo-pyrazole 1A-2 (57 g, 200.64 mmol) and tert-butyl 3- oxopiperazine-1-carboxylate 1A-3 (36.16 g, 180.57 mmol) in dimethyl sulfoxide (997.50 mL) was added Cs2CO3 (196.11 g, 601.91 mmol) at room temperature. The reaction mixture was degassed with argon gas for 20 minutes and then L-Proline (23.10 g, 200.64 mmol, 16.98 mL) and CuI (19.11 g, 100.32 mmol, 3.40 mL) were added. The reaction mixture was degassed with argon for an additional 5 minutes, and it was stirred at 90 °C for 12 hours. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 500 mL), the organic layer was dried over Na2SO4, concentrated in vacuo to get the crude product, which was purified by column chromatography using Davisil silica and 50% ethyl acetate in petroleum ether as eluent to tert-butyl 4-(1-benzylpyrazol-4-yl)-3-oxo- piperazine-1-carboxylate 1A-4 (23.4 g, 65.65 mmol, 32.72% yield) as a white solid. LCMS (ES+): m / z 357.37 [M+H]+. Step-3: A stirred solution of tert-butyl 4-(1-benzylpyrazol-4-yl)-3-oxo-piperazine-1- carboxylate 1A-4 (23.4 g, 65.65 mmol) in methanol (200 mL) was degassed with argon for ten minutes and palladium, 10% on carbon, Type 487, dry (13.97 g, 131.31 mmol) and acetic acid (3.94 g, 65.65 mmol, 3.76 mL) were added at room temperature. The reaction was stirred for 20 hours at 80 °C under H2 (200 psi). The progress of reaction was monitored by TLC and LCMS. The product was filtered through a celite bed, dried over Na2SO4 and concentrated in vacuo. The resulting crude product was purified by column chromatography over silica gel (100-200 mesh) by using 70% ethyl acetate in petroleum ether as eluent to get tert-butyl 3- oxo-4-(1H-pyrazol-4-yl)piperazine-1-carboxylate 1A-5 (9.2 g, 34.55 mmol, 52.62% yield) as a white solid. LCMS (ES+): m / z 267.39 [M+H]+. Step-4: To a stirred solution of tert-butyl 3-oxo-4-(1H-pyrazol-4-yl)piperazine-1-carboxylate 1A-5 (9.2 g, 34.55 mmol) and 4-bromo-6-chloro-pyridazin-3-amine 1A-6 (7.20 g, 34.55 mmol) in N,N-dimethylformamide (100 mL) was added Cs2CO3(22.51 g, 69.10 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 12 hours. The progress of the reaction was monitored by TLC and LCMS. Upon completion of the reaction, the reaction mixture was poured in ice cooled water. The product was extracted using ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude product was purified by column chromatography over silica gel (100-200 mesh) by using 80% ethyl acetate in petroleum ether as eluent to get tert-butyl 4-[1-(3-amino- 6-chloro-pyridazin-4-yl)pyrazol-4-yl]-3-oxo-piperazine-1-carboxylate 1A-7 (9.0 g, 22.85 mmol, 66.15% yield) as a white solid. LCMS (ES+): m / z 394.31 [M+H]+. Step-5: To a solution of tert-butyl 4-[1-(3-amino-6-chloro-pyridazin-4-yl)pyrazol-4-yl]-3-oxo- piperazine-1-carboxylate 1A-7 (9.0 g, 22.85 mmol) and (2-hydroxyphenyl)boronic acid 1A-8 (3.78 g, 27.42 mmol) in 1,4-dioxane (92 mL) and water (9 mL) was added K2CO3 (7.90 g, 57.13 mmol, 3.45 mL) at room temperature. The reaction mixture was degassed with argon gas for ten minutes and tetrakis (triphenylphosphine) palladium (2.64 g, 2.29 mmol) was added. The reaction mixture was degassed with argon for an additional five minutes and stirred at 110 °C for 7 hours. Subsequently, the reaction mixture was concentrated in vacuo to get the crude product, which was purified by column chromatography using Davisil silica and 80- 100% ethyl acetate in petroleum ether as eluent to afford tert-butyl 4-[1-[3-amino-6-(2- hydroxyphenyl)pyridazin-4-yl]pyrazol-4-yl]-3-oxo-piperazine-1-carboxylate 1A-9 (6.2 g, 13.73 mmol, 60.09% yield) as a brown solid. LCMS (ES+): m / z 452.42 [M+H]+. Step-6: To a solution of tert-butyl 4-[1-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol- 4-yl]-3-oxo-piperazine-1-carboxylate 1A-9 (8.0 g, 17.72 mmol) in dichloromethane (80 mL) at 0 °C was added trifluoroacetic acid, 99% (6.06 g, 53.16 mmol, 4.10 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to get the crude product, which was triturated with diethyl ether (100 mL) and basified with saturated NaHCO3 solution. The product was extracted with 20% methanol in dichloromethane (3 × 500 mL). The combined organic layer was washed with water (200 mL) and brine solution (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to obtain 1-[1-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-4- yl]piperazin-2-one 1A-10 (5.0 g, 14.23 mmol, 80.31% yield,) as a brown solid. LCMS (ES+): m / z 352.05 [M+H]+. Example 1B: Synthesis of (3S)-3-[8-(4-oxocyclohexyl)-2,3-dihydro-1,4-benzoxazin-4- yl]piperidine-2,6-dione (1B-13)

[0012] Step-1: To a stirred solution of 2-bromo-6-nitro-phenol 1B-1 (30 g, 137.61 mmol) in methanol (400 mL) and the reaction mixture was heated at 70 °C. Then sodium dithionite (100 g, 574.36 mmol) was taken into water (360 mL) and was added slowly. The reaction mixture was stirred at the same temperature for 15 minutes. After completion of reaction, the reaction mixture was filtered through Celite. Water was then added to the filtrate, and the mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to get 2-amino-6-bromo-phenol 1B-2 (22 g, 111.60 mmol, 81% yield) as a white solid. LCMS (ES+): m / z 189.98 [M+H]+. Step-2: To a stirred solution of 2-amino-6-bromo-phenol 1B-2 (28 g, 148.92 mmol) in N,N- dimethylformamide (551.32 mL) and potassium carbonate (51.46 g, 372.30 mmol) and 1,2- dibromoethane 1B-3 (33.57 g, 178.70 mmol, 15.40 mL) was added. The reaction mixture was stirred at 100 °C overnight. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate, the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purified by normal phase flash column chromatography with 230-400 silica gel, eluted with 0-100% ethyl acetate and hexane to afford 8-bromo-3,4-dihydro-2H-1,4- benzoxazine 1B-4 (20 g, 57.14 mmol, 38% yield) as a brown oil. LCMS (ES+): m / z 215.72 [M+H]+. Step-3: To a solution of 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine 1B-4 (20 g, 93.43 mmol) and 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane 1B- 5 (24.87 g, 93.43 mmol) in dioxane (250 mL) and water (50 mL) was added potassium phosphate tribasic anhydrous (49.58 g, 233.58 mmol) at room temperature. The reaction mixture was degassed with argon gas for ten minutes and [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (6.84 g, 9.34 mmol) was added. The reaction mixture was degassed with argon for an additional five minutes and then it was stirred at 95 °C for 16 hours. After completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated in vacuo to get the crude product. The crude product was purified by column chromatography using Davisil silica and 0% to 100% ethyl acetate in petroleum ether as eluent to afford 8-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-3,4-dihydro-2H-1,4- benzoxazine 1B-6 (25 g, 90.61 mmol, 97% yield) as a brown oil. LCMS (ES+): m / z 274.89 [M+H]+. Step-4: To a stirred solution of 8-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-3,4-dihydro-2H-1,4- benzoxazine 1B-6 (15 g, 54.88 mmol) in ethyl acetate (150 mL) and tetrahydrofuran (150 mL) was added 10% palladium on carbon (2.5 g, 23.49 mmol) at room temperature. The reaction mixture was stirred in hydrogen atmosphere in a Parr Shaker reactor for 16 hours. Subsequently, the reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford 8-(1,4-dioxaspiro[4.5]decan-8- yl)-3,4-dihydro-2H-1,4-benzoxazine 1B-7 (14 g, 46.46 mmol, 85% yield) as a brown oil. LCMS (ES+): m / z 276.37 [M+H]+. Step-5: To a solution of 8-(1,4-dioxaspiro[4.5]decan-8-yl)-3,4-dihydro-2H-1,4-benzoxazine 1B-7 (5 g, 18.16 mmol) and 2,6-dibenzyloxy-3-bromo-pyridine 1B-8 (8.74 g, 23.61 mmol) in toluene (20 mL) was added sodium tert-butoxide (5.24 g, 54.48 mmol) at room temperature. The reaction mixture was degassed with nitrogen gas for ten minutes and tris(dibenzylideneacetone)dipalladium(0) (3.33 g, 3.63 mmol) and XantPhos (2.10 g, 3.63 mmol) was added to the reaction. The reaction mixture was degassed with nitrogen gas for an additional 5 minutes and stirred at 110 °C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, which was purified by normal phase column chromatography using 100-200 silica and 20% ethyl acetate in petroleum ether as eluent to afford 4-(2,6-dibenzyloxy-3-pyridyl)-8-(1,4-dioxaspiro[4.5]decan-8-yl)-2,3-dihydro-1,4- benzoxazine 1B-9 (6 g, 7.88 mmol, 43% yield) as a brown oil. LCMS (ES+): m / z 565.39 [M+H]+. Step-6: A stirred solution of 4-(2,6-dibenzyloxy-3-pyridyl)-8-(1,4-dioxaspiro[4.5]decan-8-yl)- 2,3-dihydro-1,4-benzoxazine 1B-9 (10 g, 17.71 mmol) in tetrahydrofuran (150 mL), ethyl acetate (150 mL) and ethanol (150 mL) was degassed with argon for ten minutes. 10% Palladium on carbon (9 g, 84.57 mmol) was added to the reaction mixture and it was stirred for 16 hours at room temperature under H2 pressure. Upon completion of reaction, it was filtered through Celite, and washed with tetrahydrofuran and ethyl acetate. The filtrate was evaporated under reduced pressure to give 3-[8-(1,4-dioxaspiro[4.5]decan-8-yl)-2,3-dihydro- 1,4-benzoxazin-4-yl]piperidine-2,6-dione 1B-10 (3.6 g, 8.55 mmol, 48% yield) as an off white solid. LCMS (ES+): m / z 387.58 [M+H]+. Step-7: Racemic 3-[8-(1,4-dioxaspiro[4.5]decan-8-yl)-2,3-dihydro-1,4-benzoxazin-4- yl]piperidine-2,6-dione 1B-10 (5 g, 12.94 mmol) was submitted for SFC for the separation of isomers. The fractions obtained were concentrated and lyophilized to afford (3S)-3-[8-(1,4- dioxaspiro[4.5]decan-8-yl)-2,3-dihydro-1,4-benzoxazin-4-yl]piperidine-2,6-dione 1B-11 (and (3R)-3-[8-(1,4-dioxaspiro[4.5]decan-8-yl)-2,3-dihydro-1,4-benzoxazin-4-yl]piperidine-2,6- dione 1B-12 as off white solids. 1B-11: LCMS (ES+): m / z 387.40 [M+H]+. 1B-12: LCMS (ES+): m / z 387.40 [M+H]+. Preparative SFC Conditions: Column / dimensions: CHIRALCEL-OJ-H ((30×250)mm,5µ; % CO2: 60%; % Co solvent: 40% (ACETONITRILE)); Total Flow: 100 g / min; Back Pressure: 100 bar; Temperature: 30 °C; UV: 240 nm; Solubility: ACN+THF Step-8: A stirred solution of (3S)-3-[8-(1,4-dioxaspiro[4.5]decan-8-yl)-2,3-dihydro-1,4- benzoxazin-4-yl]piperidine-2,6-dione 1B-11 (1 g, 2.59 mmol) in tetrahydrofuran (20 mL) was added 4.0 M HCl in water (4 M, 20 mL) at 0 °C and reaction mixture stirred at 28 °C for one hour. Upon completion of reaction, the reaction mixture was concentrated and diluted with water, neutralized with saturated NaHCO3 solution to form a precipitate, which was filtered, washed with cold water, and dried under vacuum to afford (3S)-3-[8-(4-oxocyclohexyl)-2,3- dihydro-1,4-benzoxazin-4-yl]piperidine-2,6-dione 1B-13 (0.8 g, 2.31 mmol, 89% yield) as an off white solid. LCMS (ES+): m / z 343.30 [M+H]+. Example 1C: Synthesis of (3S)-3-[8-[4-[4-[1-[3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl]pyrazol-4-yl]-3-oxo-piperazin-1-yl]cyclohexyl]-2,3-dihydro-1,4-benzoxazin-4- yl]piperidine-2,6-dione (Compound 1) To a stirred solution of 1-[1-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-4- yl]piperazin-2-one 1A-10 (0.25 g, 711.52 μmol), (3S)-3-[8-(4-oxocyclohexyl)-2,3-dihydro- 1,4-benzoxazin-4-yl]piperidine-2,6-dione 1B-13 (267.98 mg, 782.67 μmol), Molecular sieves, 4 Å (0.25 g, 711.52 μmol) in 1,2-dichloroethane (3 mL) and methanol (3 mL) was added acetic acid (128.18 mg, 2.13 mmol, 122.19 μL) at room temperature. The reaction mixture was stirred for 24 hours at the same temperature. Then the reaction mixture was cooled to 0 °C and SiliaBond Cyanoborohydride (CBH) (0.25 g) was added. The reaction mixture was stirred at room temperature for four hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was filtered through Buckner funnel, washed with 1,2- dichloroethane: methanol (1:1) and the filtrate was evaporated in vacuo. The crude residue was purified by Prep-HPLC, the peak-1 fraction was concentrated in vacuo to give (3S)-3-[8-[4- [4-[1-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]pyrazol-4-yl]-3-oxo-piperazin-1- yl]cyclohexyl]-2,3-dihydro-1,4-benzoxazin-4-yl]piperidine-2,6-dione Compound 1 (60.0 mg, 84.28 μmol, 11.84% yield). Prep-HPLC Purification: Column / dimensions: X-BRIDGE C18 (19×250×5um); Mobile phase A: 5mM ammonium acetate in water (aq); Mobile phase B: 100% Acetonitrile (org); Gradient (Time / %B): 0 / 20, 3 / 20, 6 / 50, 18.5 / 50, 18.51 / 100, 21 / 100, 21.1 / 20, 23 / 20; Flow rate: 18 mL / min.; Solubility: ACN+Water+THF. LCMS (ES+): m / z 678.55 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 13.4 (bs, 1H), 10.8 (s, 1H), 9.02 (s, 1H), 8.37-8.36 (d, 2H, J = 4.0 Hz), 8.06-8.04 (m, 1H), 7.75 (bs, 2H), 7.30-7.28 (m, 1H), 6.97-6.94 (m, 2H), 6.70-6.66 (m, 2H), 6.49-6.47 (m, 1H), 4.87 (dd, J = 2.7 Hz, J = 4.4 Hz, 1H), 4.17 (t, J = 4.4 Hz, 2H), 3.74 (t, J = 4.8 Hz, 2H), 3.42-3.38 (m, 2H), 3.25-2.20 (m, 2H), 2.97 (t, J = 4.8 Hz, 2H), 2.89-2.81 (m, 2H), 2.62-2.59 (m, 1H), 2.52-2.48 (m, 1H), 2.31-2.28 (m, 1H), 2.08-1.67 (m, 4H), 1.56-1.48 (m, 4H). Example 2: Synthesis of 2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol- 1-yl)pyridazin-3-yl)phenyl dihydrogen phosphate (Compound 2) and [2-[6-amino-5-[4- [4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo- piperazin-1-yl]pyrazol-1-yl]pyridazin-3-yl]phenoxy]-sodiooxy-phosphoryl]oxysodium

[0013] Step-1: A stirred solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 1 (6 g, 27.26 mmol) in tetrahydrofuran (60 mL) was cooled to 0 °C, at which point a 2 M solution of sodium bis(trimethylsilyl)amide in THF (40.90 mL) was added, then tetra benzyl diphosphate 2 (22.02 g, 40.90 mmol) was added and the resulting reaction mixture was allowed to warm to room temperature and stirred for one hour. After this time, saturated ammonium chloride solution was added to the reaction mixture, and the resulting mixture extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford a residue, which was purified by normal phase flash column chromatography (silica-gel column, Eluent: gradient from 0-30% ethyl acetate in petroleum ether) to afford dibenzyl [2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] phosphate 3 (7 g, 27% yield) as a pale-yellow liquid. LCMS (ESI): m / z 481.2 [M+H]+. Step-2: To a stirred solution of tert-butyl 4-[1-(3-amino-6-chloro-pyridazin-4-yl)pyrazol-4-yl]- 3-oxo-piperazine-1-carboxylate 4 (1.2 g, 3.05 mmol) and dibenzyl [2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl] phosphate 3 (5.85 g, 12.19 mmol) in a mixture of 1,4-dioxane (4 mL) and water (1 mL) was added K3PO4 (1.94 g, 9.14 mmol), and the resulting reaction mixture was degassed with argon for five minutes. Then XPhos Pd G3 (515.83 mg, 609.40 μmol) was added, and the resulting reaction mixture was heated to 60 °C and stirred for 16 hours. The resulting reaction mixture was concentrated under reduced pressure to afford tert- butyl 4-[1-[3-amino-6-(2-dibenzyloxyphosphoryloxyphenyl)pyridazin-4-yl]pyrazol-4-yl]-3- oxo-piperazine-1-carboxylate 5 (2 g, 10% yield) as a brown thick liquid, which was used without further purification. LCMS (ESI): m / z 712.61 [M+H]+. Step-3: A stirred solution of tert-butyl 4-[1-[3-amino-6-(2-dibenzyloxyphosphoryl- oxyphenyl)pyridazin-4-yl]pyrazol-4-yl]-3-oxo-piperazine-1-carboxylate 5 (2 g, 2.81 mmol) in dichloromethane (30 mL) was cooled to 0 °C, then a 4 M solution of HCl in 1,4-dioxane (10 mL) was added and the resulting mixture was allowed to warm to room temperature and stirred for one hour. The reaction mixture was concentrated under reduced pressure to afford crude residue, which was purified by reverse phase column chromatography [Column: Biotage C18 cartridge (80 gm) 40µm; Mobile phase A: 0.1% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile; Gradient [Time (%B)]: 0–2 min (15% B), 2–7 min (15 – 23% B), 7–17 min (23% B), 17–20 min (100% B); Flow rate: 30 mL / min] to afford [2-[6-amino-5-[4-(2- oxopiperazin-1-yl)pyrazol-1-yl]pyridazin-3-yl]phenyl] dihydrogen phosphate 6 (400 mg, 24% yield) as an off white solid. LCMS (ESI): m / z 432.25 [M+H]+. Step-4: To a stirred solution of (3S)-3-[8-(4-oxocyclohexyl)-2,3-dihydro-1,4-benzoxazin-4- yl]piperidine-2,6-dione 1B-13 (700 mg, 2.04 mmol) and [2-[6-amino-5-[4-(2-oxopiperazin-1- yl)pyrazol-1-yl]pyridazin-3-yl]phenyl] dihydrogen phosphate 6 (881.86 mg, 2.04 mmol) in dimethyl sulfoxide (7 mL) was added acetic acid (613 mg, 10.22 mmol), anhydrous sodium acetate, (670 mg, 8.18 mmol), and 4 Å molecular sieves (700 mg, 2.04 mmol), and the resulting reaction mixture was stirred at room temperature for 8 hours. At this point, MP- cyanoborohydride (1.4 g, 4.09 mmol) was added, and the resulting reaction mixture was stirred for 12 hours. Then the reaction mixture was filtered, washed with acetonitrile, and the filtrate was concentrated under reduced pressure to afford a mixture of diastereomers as a residue. The mixture of diastereomers was separated by Prep-HPLC [Column: X BRIDGE C8 (19*250) 5µm; Mobile phase A: 10mM Ammonium bicarbonate in water + 0.1% Ammonium hydroxide, Mobile phase B: Acetonitrile; Gradient (Time / %B): 0–2 min (15% B), 2–7 min (15–23% B), 7–17.1 min (23% B), 17.2 min (100% B), Flow rate: 17 mL / min]. The early eluting isomer was collected to afford cis-[2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6- dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1- yl]pyrazol-1-yl]pyridazin-3-yl]phenyl] dihydrogen phosphate (Compound 2-cis) (98 mg, 6% yield) as an off-white solid. LCMS (ESI): m / z 758.87 [M+H]+Compound 2-cis:1H NMR (400 MHz, DMSO-d6): δ 10.82 (s, 1H), 9.05 (bs, 1H), 8.50 (bs, 1H), 8.34 (s, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.47–7.36 (m, 3H), 7.20–6.95 (m, 2H), 6.68–6.66 (m, 2H), 6.48–6.45 (m, 1H), 4.91–4.86 (m, 1H), 4.17 (t, J = 4.4 Hz, 2H), 3.76 (m, 2H), 3.44– 3.38 (m, 4H), 3.18–3.16 (m, 3H), 2.84–2.80 (m, 3H), 2.57 (m, 2H), 2.29 (m, 3H), 1.94–1.87 (m, 2H), 1.79 (m, 2H), 1.52–1.39 (m, 3H) ppm. The late eluting isomer was collected to afford trans-[2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6- dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1- yl]pyrazol-1-yl]pyridazin-3-yl]phenyl] dihydrogen phosphate Compound 2 (65 mg, 4% yield) as an off white solid. LCMS (ESI): m / z 758.34 [M+H]+Compound 2:1H NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H), 9.04 (bs, 1H), 8.42 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.5–7.39 (m, 3H), 7.33–7.20 (m, 3H), 6.65–6.63 (m, 2H), 6.50–6.48 (m, 1H), 4.89–4.85 (m, 2H), 4.16 (t, J = 4.4 Hz, 2H), 3.77 (m, 2H), 3.15–3.22 (m, 3H), 3.01– 2.75 (m, 5H), 2.56 (m, 1H), 2.37 (m, 1H), 2.30–2.27 (m, 1H), 2.08–2.06 (m, 2H), 1.90–1.86 (m, 1H), 1.75–1.69 (m, 2H), 1.56–1.47 (m, 4H), 1.23 (m, 1H) ppm. Step-5: To a stirred solution of cis-[2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3- dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3- yl]phenyl] dihydrogen phosphate Compound 2-cis (60 mg, 79.18 μmol) in acetonitrile (2 mL) and water (2 mL) cooled to 0 °C was added 0.1 M aqueous sodium bicarbonate solution (1.58 mL) and the resulting reaction mixture was stirred for 10 minutes, at which point the reaction mixture was lyophilized to afford cis-[[2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]- 2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3- yl]phenoxy]-sodiooxy-phosphoryl]oxysodium Compound 3-cis (62.8 mg, 89% yield, sodium salt) as an off-white solid. LCMS (ESI): m / z 758.38 [M-2Na]+.1H NMR (400 MHz, DMSO- d6): δ 10.84 (bs, 1H), 9.38 (s, 1H), 9.18 (s, 1H), 8.39 (m, 1H), 7.80 (m, 2H), 7.52–7.23 (m, 3H), 7.04–6.90 (m, 1H), 6.69–6.65 (m, 2H), 6.46 (m, 1H), 4.91–4.83 (m, 1H), 4.16 (s, 2H), 3.69 (m, 2H), 3.22–3.19 (m, 4H), 2.9–2.82 (m, 4H), 2.56–2.50 (m, 2H), 2.28–2.23 (m, 1H), 2.07–1.66 (m, 4H), 1.52–1.38 (m, 3H), 1.23–1.05 (m, 2H) ppm. Example 3: Synthesis of [2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3- dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3- yl]phenyl] dihydrogen phosphate (Compound 2) Step-1: To a well-stirred solution of tert-butyl 4-[1-[3-amino-6-(2-hydroxyphenyl)pyridazin- 4-yl]pyrazol-4-yl]-3-oxo-piperazine-1-carboxylate 1 (40 g, 88.60 mmol) in THF (1200 mL) cooled to 0 °C was added NaH (60% dispersion in oil) (6.40 g, 266.67 mmol). The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 10 min, at which point the reaction mixture was cooled to 0 °C and dibenzyl dibenzyloxyphosphoryl phosphate 2 (81.10 g, 150.62 mmol) added. The resulting reaction was mixture was allowed to warm to room temperature and stirred for 1 hr, at which time the reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography (Stationary phase: davisil silica; Eluent: 3-5% methanol in ethyl acetate) to afford tert-butyl 4-[1-[3-amino-6-(2-dibenzyloxyphosphoryloxyphenyl)pyridazin-4- yl]pyrazol-4-yl]-3-oxo-piperazine-1-carboxylate 3 (20 g, 25 % yield) as pale yellow solid. LCMS (ES+): m / z 712.52 [M+H]+(Note: Reactions were performed in (2.5 g x 16) multiple batches). Step-2: To a well-stirred solution of tert-butyl 4-[1-[3-amino-6-(2- dibenzyloxyphosphoryloxyphenyl)pyridazin-4-yl]pyrazol-4-yl]-3-oxo-piperazine-1- carboxylate 3 (20 g, 28.10 mmol) in DCM (200 mL) cooled to 0 °C was added a 4 M solution of HCl in 1,4-dioxane (170 mL, 680 mmol). The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 16 hr, at which time the reaction mixture was concentrated under reduced pressure to afford a crude residue, which was triturated with diethyl ether (100 mL) to afford [2-[6-amino-5-[4-(2-oxopiperazin-1-yl)pyrazol-1- yl]pyridazin-3-yl]phenyl] dihydrogen phosphate 4 (11.5 g, 77 % yield, Hydrochloric acid) as an off white solid. LCMS (ES+): m / z 432.42 [M+H]+(Note: Reactions were performed in (5 g x 4) multiple batches) Step-3: To a well-stirred solution of [2-[6-amino-5-[4-(2-oxopiperazin-1-yl)pyrazol-1- yl]pyridazin-3-yl]phenyl] dihydrogen phosphate 4 (8 g, 17.10 mmol, Hydrochloric acid) in a mixture of 1,2-dichloroethane (120 mL) and methanol (120 mL) was added DIPEA (8 mL, 45.93 mmol) until the pH was adjusted to 7, then 1B-13 (5.86 g, 17.10 mmol), D-Mandelic Acid (5.20 g, 34.20 mmol), and 4 Å Molecular sieves (8 g, 1.85 mmol) were added sequentially. The resulting suspension was stirred at ambient temperature for 12 hours, at which point MP-Cyanoborohydride (9.6 g, 34.20 mmol) was added, and the resulting suspension was stirred at ambient temperature for 5 hr. After this time, the reaction mixture was filtered through a pad of celite and washed with a mixture of MeOH and DCE (1:1, 100 mL). The filtrate was concentrated under reduced pressure to afford a brownish residue, which was triturated using acetonitrile (150 mL) to afford the crude product. The crude product was purified by Prep-HPLC [Column: X BRIDGE C18 (19 x 250 mm) x 5um; Mobile Phase A: 10 mM Ammonium Bicarbonate in water, Mobile Phase B: Acetonitrile; Gradient (Time / %B): 0 – 3 min (20 % B), 3 – 7 min (20 – 27% B), 7 – 12.5 min (27% B), 12.51 min (100% B); Flow rate: 16 mL / min]. The pure fractions of the early eluting isomer were collected at -78 °C and directly lyophilized to afford [2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3- dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3- yl]phenyl] dihydrogen phosphate (Compound 2) (1.35 g, 10.12% yield) as an off-white solid. LCMS (ES+): m / z 758.38 [M+H]+1H NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H), 9.01 (bs, 1H), 8.50 (bs, 1H), 8.31 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.47 (d, J = 8 Hz, 1H), 7.37 – 7.33 (m, 3H), 7.18 (t, J = 7.2Hz, 3H), 6.70 – 6.66 (m, 2H), 6.47 – 6.45 (m, 1H), 4.90– 4.86 (m, 1H), 4.17 – 4.15 (m, 2H), 3.77 (m, 2H), 3.27 – 3.24 (m, 2H), 3.23 – 3.16 (m, 2H), 3.04 (m, 2H), 2.87 – 2.77 (m, 2H), 2.58 – 2.49 (m, 2H), 2.30 – 2.28 (m, 1H), 1.92 – 1.77 (m, 5H), 1.45– 1.36 (m, 4H) ppm.31P-NMR (162 MHz, DMSO-d6): δ -4.501 ppm. Note: Reactions were performed in multiple batches (0.2 g each x 40 batches). After completion of the reaction monitored by LCMS analysis, the reactions were combined and diluted with MeOH / DCE (1:1). The mixture was then filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The crude residue so obtained was triturated with acetonitrile (150 mL) to obtain pale yellow solid, which was further purified by Prep- HPLC purification.

[0014] Example 4: Synthesis of cis-[[2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3- dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3- yl]phenoxy]-potassiooxy-phosphoryl]oxypotassium (Compound 4) Step-1: To a stirred solution of cis-[2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3- dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3- yl]phenyl] dihydrogen phosphate Compound 2-cis (56 mg, 73.90 μmol) in water (1 mL) and acetonitrile (1 mL) cooled to 0 °C was added a 0.1 M aqueous potassium bicarbonate solution (1.48 mL) and the resulting reaction mixture was stirred for 10 minutes, at which point the reaction mixture was lyophilized to afford cis-[[2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3- piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1- yl]pyridazin-3-yl]phenoxy]-potassiooxy-phosphoryl]oxypotassium Compound 4-cis (59 mg, 88% yield, potassium salt) as an off-white solid. LCMS (ESI): m / z 758.34 [M+H-2K]+.1H NMR (400 MHz, DMSO-d6): δ 10.84 (bs, 1H), 9.38 (s, 1H), 8.93 (s, 1H), 8.39 (m, 1H), 7.83 (m, 2H), 7.52 (d, 1H), 7.28–7.22 (m, 3H), 7.06–7.02 (m, 1H), 6.68–6.61 (m, 2H), 6.46 (m, 1H), 4.74 (m, 1H), 4.16 (s, 2H), 3.70 (m, 2H), 3.22–3.19 (m, 4H), 2.90–2.74 (m, 4H), 2.43– 2.39 (m, 2H), 2.28–2.23 (m, 1H), 1.93–1.78 (m, 4H), 1.39–1.34 (m, 4H) ppm. Example 5: Synthesis of trans-[[2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]- 2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1- yl]pyridazin-3-yl]phenoxy]-sodiooxy-phosphoryl]oxysodium (Compound 3-cis) Step-1: To stirred a solution of trans-[2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]- 2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3- yl]phenyl] dihydrogen phosphate Compound 2 (14.5 mg, 19.14 μmol) in acetonitrile (0.5 mL) and water (0.5 mL) cooled to 0 °C was added a 0.1 M aqueous sodium bicarbonate solution (0.39 mL, 38.28 μmol) and the resulting reaction mixture was stirred for 10 minutes, at which point the reaction mixture was lyophilized to afford trans-[[2-[6-amino-5-[4-[4-[4-[4-[(3S)- 2,6-dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1- yl]pyrazol-1-yl]pyridazin-3-yl]phenoxy]-sodiooxy-phosphoryl]oxysodium Compound 3 (15 mg, 90% yield, sodium salt) as an off-white solid 2. LCMS (ESI): m / z 758.48 [M+H-2Na]+.1H NMR (400 MHz, DMSO-d6): δ 10.84 (bs, 1H), 9.45 (s, 1H), 9.18 (s, 1H), 8.38 (m, 1H), 7.78 (m, 2H), 7.52–7.23 (m, 3H), 6.90–6.87 (m, 1H), 6.65–6.62 (m, 2H), 6.47 (m, 1H), 4.95– 4.79 (m, 1H), 4.14 (s, 2H), 3.89-3.77 (m, 1H), 3.21–3.16 (m, 4H), 2.86–2.74 (m, 4H), 2.50– 2.48 (m, 2H), 2.27–2.24 (m, 1H), 2.08–2.06 (m, 1H), 1.95–1.75 (m, 4H), 1.52–1.36 (m, 3H), 1.23–1.05 (m, 2H) ppm. Example 6: trans-[[2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3-dihydro- 1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3- yl]phenoxy]-potassiooxy-phosphoryl]oxypotassium (Compound 4) Step-1: To stirred a solution of trans-[2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]- 2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3- yl]phenyl] dihydrogen phosphate Compound 2 (12.50 mg, 16.50 μmol) in water (0.5 mL) and acetonitrile (0.5 mL) cooled to 0 °C was added a 0.1 M aqueous potassium bicarbonate solution (0.19 mL, 13 μmol) and the resulting reaction mixture was stirred at room temperature for 10 minutes, at which point the reaction mixture was lyophilized to afford trans-[[2-[6-amino-5- [4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2- oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3-yl]phenoxy]-potassiooxy- phosphoryl]oxypotassium Compound 4 (14 mg, 93% yield, potassium salt) as an off-white solid. LCMS [ESI]: m / z 758.41 [M+H-2K]+.1H NMR (400 MHz, DMSO-d6): δ 9.51 (s, 1H), 9.04 (s, 1H), 8.40 (m, 1H), 7.83 (m, 2H), 7.80 (d, J = 7.6 Hz, 1H), 7.55 (m, 1H), 7.21 (m, 2H), 6.62–6.57 (m, 2H), 6.45 (d, J = 6.8 Hz, 1H), 4.61 (s, 1H), 4.14 (s, 2H), 3.77 (s, 2H), 3.33 (m, 2H), 3.25–3.18 (m, 2H), 2.94–2.85 (m, 3H), 2.67–2.63 (m, 1H), 2.50–2.49 (m, 2H), 2.15–2.03 (m, 3H), 1.81–1.75 (m, 1H), 1.70–1.68 (m, 2H) , 1.49–1.45 (m, 4H), 1.23 (m, 1H) ppm. Example 7: [2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3-dihydro-1,4- benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3- yl]phenoxy]sodium (Compound 5) Step-1: To stirred a solution of (3S)-3-[8-[4-[4-[1-[3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl]pyrazol-4-yl]-3-oxo-piperazin-1-yl]cyclohexyl]-2,3-dihydro-1,4-benzoxazin-4- yl]piperidine-2,6-dione Compound 1 (55 mg, 81.15 μmol) in acetonitrile (0.6 mL) and water (0.6 mL) cooled to 0 °C was added a 0.2 M aqueous sodium carbonate solution (0.40 mL) and the resulting reaction mixture was stirred for 10 minutes, at which point the reaction mixture was lyophilized to afford [2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3-dihydro- 1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3- yl]phenoxy]sodium Compound 5 (58 mg, 97 % yield, Sodium salt) as an off white solid. LCMS (ESI): m / z 678.47 [M+H-Na]+.1H NMR (400 MHz, DMSO-d6): δ 10.09 (s, 1H), 9.00 (s, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.51 (bs, 2H), 7.27 (m, 1H), 6.91 (d, J = 7.6 Hz, 2H), 6.69–6.64 (m, 2H), 6.49–6.46 (m, 1H), 4.88–4.84 (m, 1H), 4.18–4.16 (m, 2H), 3.75–3.73 (m, 2H), 3.40 (s, 2H), 3.75–3.73 (m, 2H), 2.98–2.95 (m, 2H), 2.82–2.79 (m, 2H), 2.57 (m, 2H), 2.28–2.20 (m, 1H), 2.95–2.81 (m, 5H), 1.41–1.38 (m, 4H) ppm. Example 8: 2-(6-amino-5-(4-(4-((1R,4R)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1- yl)pyridazin-3-yl)phenyl acetate (Compound 6) Step-1: To a stirred solution of Compound 1 (0.2 g, 0.295 mmol) in a mixture of N,N- dimethylformamide (1 mL) and dichloromethane (2 mL) cooled to 0 °C was added acetic acid (53.16 mg, 0.885 mmol), 4-dimethylaminopyridine (1.8 mg, 0.014 mmol), and N,N′- dicyclohexylcarbodiimide (0.121 g, 0.59 mmol). The resulting reaction mixture was allowed to warm to room temperature and stirred for three hours, after which time the reaction mixture was filtered and the filtrate concentrated under reduced pressure to afford a residue. The resulting residue was purified by prep-HPLC [Column: X BRIDGE C8 (10 x 250 mm), 5µm; Mobile phase A: 10 mM ammonium bicarbonate in water, Mobile phase B: Acetonitrile; Gradient (Time / %B): 0–3 min (35% B), 3–7 min (35–55% B), 3–12 min (35–55% B); Flow rate: 7 mL / min] to afford [2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3-dihydro- 1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3-yl]phenyl] acetate Compound 6 (75 mg, 34% yield) as an off white solid. LCMS (ES+): m / z 720.48 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.87 (s, 1H), 8.31 (s, 1H), 7.87 (s, 1H), 7.82 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.52-7.48 (m, 1H), 7.44-7.36 (m, 1H), 7.36 (s, 2H), 7.29-7.27 (m, 1H), 6.69-6.66 (m, 2H), 6.48-6.46 (m, 1H), 4.92-4.85 (m, 1H), 4.17-4.15 (m, 2H), 3.72-3.69 (m, 2H), 3.38 (s, 2H), 3.22-3.17 (m, 4H), 2.96-2.93 (m, 2H), 2.84-2.81 (m, 2H), 2.57-2.50 (m, 1H), 2.15 (s, 3H), 1.95-1.80 (m, 5H), 1.48-1.39 (m, 4H). Example 9: Synthesis of 2-(6-amino-5-(4-(4-((1R,4R)-4-(4-((S)-2,6-dioxopiperidin-3-yl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol- 1-yl)pyridazin-3-yl)phenyl [1,4'-bipiperidine]-1'-carboxylate (Compound 7) and 2-(6- amino-5-(4-(4-((1R,4R)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)pyridazin-3- yl)phenyl [1,4'-bipiperidine]-1'-carboxylate hydrochloride (Compound 8)

[0015] Step-1: A stirred solution of 1-(4-piperidyl) piperidine 1 (3 g, 17.83 mmol) in dichloromethane (50 mL) was cooled to -10 °C, then triethylamine (1.80 g, 17.83 mmol) and bis(trichloromethyl) carbonate (5.29 g, 17.83 mmol) were added, and the resulting reaction mixture was allowed to warm to room temperature and stirred for one hour. The resulting reaction mixture was diluted with dichloromethane (50 mL), washed sequentially with a saturated sodium bicarbonate solution (50 mL) and brine solution (25 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered, and the filtrate concentrated under reduced pressure to afford 4-(1-piperidyl) piperidine-1-carbonyl chloride 2 (2.5 g, 41% yield) as an off-white solid, which was used without further purification. LCMS (ESI): m / z 231.26 [M+H]+. Step-2: To a stirred solution of tert-butyl 4-[1-[3-amino-6-(2-hydroxyphenyl)pyridazin-4- yl]pyrazol-4-yl]-3-oxo-piperazine-1-carboxylate 3 (1 g, 2.21 mmol) in pyridine (5.5 mL, 66.45 mmol) cooled to 0 °C was added 4-(1-piperidyl)piperidine-1-carbonyl chloride 2 (766.60 mg, 3.32 mmol). The resulting reaction mixture was allowed to warm to room temperature and stirred for two hours, at which point the reaction mixture was concentrated under reduced pressure to afford a crude residue, which was purified by Prep HPLC [Biotage C18 cartridge (80 gm) 40µm; Mobile phase A: 0.05% Ammonium bicarbonate in water, Mobile phase B: Acetonitrile; Gradient (Time / %B): 0–2 (15% B), 2–7 (15-25% B), 7–17 (25–30% B), 17–25 (30–100% B); Flow rate: 30 mL / min] to afford tert-butyl 4-[1-[3-amino-6-[2-[4-(1- piperidyl)piperidine-1-carbonyl]oxyphenyl]pyridazin-4-yl]pyrazol-4-yl]-3-oxo-piperazine-1- carboxylate 4 (0.4 g, 20% yield) as an off-white solid. LCMS (ESI): m / z 647 [M+H]+. Step-3: To a stirred solution of tert-butyl 4-[1-[3-amino-6-[2-[4-(1-piperidyl)piperidine-1- carbonyl]oxyphenyl]pyridazin-4-yl]pyrazol-4-yl]-3-oxo-piperazine-1-carboxylate 4 (0.35 g, 542.01 μmol) in dichloromethane (2.5 mL) cooled to 0 °C was added a 4 M solution of HCl in 1,4-dioxane (0.1 mL, 2.71 mmol). The resulting reaction mixture was warmed to room temperature and stirred for two hours, at which point the reaction mixture was concentrated under reduced pressure to afford a crude residue. The residue was triturated with diethyl ether to afford [2-[6-amino-5-[4-(2-oxopiperazin-1-yl)pyrazol-1-yl]pyridazin-3-yl]phenyl] 4-(1- piperidyl)piperidine-1-carboxylate 5 (0.3 g, 72% yield, hydrochloric acid) as an off-white solid. LCMS (ESI): m / z 546.8 [M+H]+. Step-4: To a stirred solution of [2-[6-amino-5-[4-(2-oxopiperazin-1-yl)pyrazol-1-yl]pyridazin- 3-yl]phenyl] 4-(1-piperidyl)piperidine-1-carboxylate 5 (0.3 g, 515.38 μmol, hydrochloric acid salt) and (3S)-3-[8-(4-oxocyclohexyl)-2,3-dihydro-1,4-benzoxazin-4-yl]piperidine-2,6-dione 1B-13 (176.46 mg, 515.38 μmol) in dimethyl sulfoxide (7.5 mL) cooled to 0 °C was added sodium acetate (169.11 mg, 2.06 mmol, 110.67 μL), acetic acid (154.74 mg, 2.58 mmol), and 4 Å molecular sieves (0.6 g, 515.38 μmol). The resulting mixture was warmed to room temperature and stirred for 8 hours, at which point MP-cyanoborohydride (0.6 g, 1.03 mmol) was added, and the resulting reaction mixture was stirred for 16 hours. The reaction mixture was filtered and washed with acetonitrile, then the filtrate was concentrated under reduced pressure to afford a residue. The residue was purified by Prep-HPLC [Column: X-bridge C8 (10 * 250 mm), 5 µm; Mobile phase A: 10 mM ammonium bicarbonate solution in water, Mobile phase B: 0.1% ammonia in acetonitrile; Gradient (Time / %B): 0.1–3 min (30% B), 3– 7 min (30–55% B), 7–12 min (55% B), 12.1 min (100% B); Flow Rate: 7 mL / min]. The early eluting peak was collected to afford 2-(6-amino-5-(4-(4-((1R,4R)-4-(4-((S)-2,6- dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b]-[1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin- 1-yl)-1H-pyrazol-1-yl)pyridazin-3-yl)phenyl [1,4'-bipiperidine]-1'-carboxylate Compound 7 (28 mg, 6% yield), diastereomer conformation was assigned as trans. The late eluting peak was collected to afford 2-(6-amino-5-(4-(4-((1S,4R)-4-(4-((S)-2,6- dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin- 1-yl)-1H-pyrazol-1-yl)pyridazin-3-yl)phenyl [1,4'-bipiperidine]-1'-carboxylate Compound 7- cis (17 mg, 4% yield), diastereomer conformation was assigned as cis. LCMS (ESI): m / z 872.58 [M+H]+. Step-5: To a stirred solution of 2-(6-amino-5-(4-(4-((1R,4R)-4-(4-((S)-2,6-dioxopiperidin-3- yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol- 1-yl)pyridazin-3-yl)phenyl [1,4'-bipiperidine]-1'-carboxylate Compound 7 (27 mg, 0.032 mmol) in 1,4-dioxane (0.5 mL) was added a 1 N solution of HCl in 1,4-dioxane (0.05 mL), and the resulting reaction mixture was stirred at room temperature for 10 minutes, at which point the reaction mixture was lyophilized to afford [2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6- dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1- yl]pyrazol-1-yl]pyridazin-3-yl]phenyl] 4-(1-piperidyl)piperidine-1-carboxylate hydrochloride Compound 8 (29 mg, 98% yield, hydrochloric acid salt) as an off-white solid. LCMS (ESI): m / z 872.58 [M+H-HCl]+.1H NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H), 9.15 (s, 1H), 8.46 (s, 1H), 8.26 (s, 1H), 7.82 (d, J = 7.20 Hz, 1H), 7.57 (t, J = 6.4 Hz, 1H), 7.44 (t, J = 7.60 Hz, 1H), 7.32 (d, J = 8. Hz, 1H), 7.68-7.71 (m, 2H), 6.49 (d, J = 6.80 Hz, 1H), 4.95-4.85 (m, 1H), 4.40-4.25 (m, 6H), 4.10-3.9 (m, 2H), 3.50-3.40 (m, 2H), 3.40-3.10 (m, 5H), 3.0-2.75 (m, 6H), 2.5-2.55 (m, 1H), 2.3-2.2 (m, 3H), 2.1-1.6 (m, 13H), 1.6-1.3 (m, 5H), 1.23 (s, 1H). Example 10: Synthesis of 2-(6-amino-5-(4-(4-((1R,4S)-4-(4-((S)-2,6-dioxopiperidin-3-yl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol- 1-yl)pyridazin-3-yl)phenyl [1,4'-bipiperidine]-1'-carboxylate hydrochloride (Compound 8-cis) Step-1: To a stirred solution of 2-(6-amino-5-(4-(4-((1R,4S)-4-(4-((S)-2,6-dioxopiperidin-3- yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol- 1-yl)pyridazin-3-yl)phenyl [1,4'-bipiperidine]-1'-carboxylate Compound 7-cis (17 mg, 0.019 mmol) in 1,4-dioxane (0.5 mL) was added a 1 N solution of HCl in 1,4-dioxane (0.05 mL), and the resulting reaction mixture was stirred at room temperature for 10 minutes, at which point the reaction mixture was lyophilized to afford 2-(6-amino-5-(4-(4-((1R,4S)-4-(4-((S)- 2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2- oxopiperazin-1-yl)-1H-pyrazol-1-yl)pyridazin-3-yl)phenyl[1,4'-bipiperidine]-1'-carboxylate hydrochloride Compound 8-cis (19 mg, 98% yield, hydrochloric acid salt) as an off-white solid. LCMS (ESI): m / z 872.58 [M+H-HCl]+.1H NMR (400 MHz, DMSO-d6): δ 10.83 (s, 1H), 9.16 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.83 (d, J = 7.60 Hz, 1H), 7.57 (t, J = 6.40 Hz, 1H), 7.44 (t, J = 7.60 Hz, 1H), 7.32 (d, J = 8.00 Hz, 1H), 6.87 (s, 1H), 6.66 (d, J = 4.40 Hz, 2H), 4.95-4.85 (m, 1H), 4.50-4.30 (m, 2H), 4.30-4.10 (m, 5H), 4.10-3.90 (m, 2H), 3.40-3.0 (m, 8H), 3.0-2.7 (m, 5H), 2.60-2.50 (m, 1H), 2.35-2.2 (m, 3H), 2.10-1.90 (m, 4H), 1.90-1.70 (m, 7H), 1.70-1.55 (m, 3H),1.5-1.2 (m, 3H). Example 11: Synthesis of (4-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2- hydroxyphenyl)pyridazin-3-yl)phosphoramidic acid (Compound 9); (4-(4-(4-((1S,4r)-4- (4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2- oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2-oxidophenyl)pyridazin-3-yl)phosphoramidate sodium salt (Compound 10); and (4-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1- yl)-6-(2-oxidophenyl)pyridazin-3-yl)phosphoramidate potassium salt (Compound 11)

[0016] Step 1: To a stirring solution of tert-butyl 4-[1-(3-amino-6-chloro-pyridazin-4-yl)pyrazol-4- yl]-3-oxo-piperazine-1-carboxylate (1A-7, 1 equiv, ) and (2-benzyloxyphenyl)boronic acid 1 (1 equiv) in 1,4-dioxane and water was added K2CO3(2.5 equiv) at room temperature. The reaction mixture was degassed with nitrogen gas for 10 minutes and then Pd(dppf)Cl2(0.2 equiv) was added. The reaction mixture was heated to 110 °C and stirred for 16 hours, at which point the reaction mixture was filtered through a pad of celite, and the celite was washed with dichloromethane. The filtrate was concentrated in vacuo to afford the crude product, which was purified by normal phase flash chromatography (Column: silica gel, eluent: 3-4% methanol in dichloromethane) to afford tert-butyl 4-(1-(3-amino-6-(2- (benzyloxy)phenyl)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazine-1-carboxylate 2 Step 2: To a stirring solution of tert-butyl 4-(1-(3-amino-6-(2-(benzyloxy)phenyl)pyridazin-4- yl)-1H-pyrazol-4-yl)-3-oxopiperazine-1-carboxylate 2 (1 equiv) in tetrahydrofuran was added NaH (60% dispersion in oil) (1.5 equiv) at 0 °C. The resulting reaction mixture was stirred at room temperature for 5 minutes. Then tetrabenzyl pyrophosphate 3 (1.2 equiv) was added at 0 °C, the solution was warmed to room temperature and stirred for 16 hours. The resulting reaction mixture was diluted with ice-cold water and extracted with ethyl acetate to afford the crude product tert-butyl 4-(1-(6-(2-(benzyloxy)phenyl)-3- ((bis(benzyloxy)phosphoryl)amino)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazine-1- carboxylate Step 3: A solution of tert-butyl 4-(1-(6-(2-(benzyloxy)phenyl)-3- ((bis(benzyloxy)phosphoryl)amino)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazine-1- carboxylate 4 (1 equiv) in dichloromethane was cooled to 0 °C, and TFA (1 equiv) was added. The resulting reaction mixture was stirred at room temperature for 3 hours, at which point the reaction mixture was concentrated in vacuo. The resulting residue was triturated with diethyl ether to afford the crude product 5 benzyl (6-(2-(benzyloxy)phenyl)-4-(4-(2-oxopiperazin-1- yl)-1H-pyrazol-1-yl)pyridazin-3-yl)phosphoramidate which is used without purification. Step 4: To a stirring solution of benzyl (6-(2-(benzyloxy)phenyl)-4-(4-(2-oxopiperazin-1-yl)- 1H-pyrazol-1-yl)pyridazin-3-yl)phosphoramidate 5 (1 equiv) and (3S)-3-[8-(4- oxocyclohexyl)-2,3-dihydro-1,4-benzoxazin-4-yl]piperidine-2,6-dione 1B-13 (1.3 equiv) in dimethyl sulfoxide was added 4 Å molecular sieves (1 equiv) and acetic acid (5 equiv). The resulting reaction mixture was stirred at room temperature for 8 hours, then cooled to 0 °C and MP-cyanoborohydride (1.5 equiv) was added. The resulting reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The resulting reaction mixture was filtered through a Buckner funnel, washed with 1,2-dichloroethane: methanol (1:1), and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with dichloromethane and stirred for 10 minutes. Subsequently, the reaction mixture was filtered through Buckner funnel to afford benzyl hydrogen (4-(4-(4-(4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2- hydroxyphenyl)pyridazin-3-yl)phosphoramidate 6 as a mixture of diastereomers. Step 5 and Step 6: The diastereomers are separated using reverse phase preparative HPLC. The isolated diastereomers are then seperately mixed with Pd(OH)2 / C, and aqueous ammonium formate solution. The resulting mixture is put under a hydrogen atmosphere. Acetonitrile is added by syringe, and the resulting reaction mixture is heated to 50 °C for 2 hours, at which time the mixture is filtered through a pad of Celite, washed with acetonitrile, and concentrated under reduced pressure to afford a residue. The resulting residue is purified by reverse phase preparative HPLC to afford (4-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2- hydroxyphenyl)pyridazin-3-yl)phosphoramidic acid (Compound 9). Step 7: To a suspension of (4-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2- oxidophenyl)pyridazin-3-yl)phosphoramidate in acetonitrile is added sodium carbonate (3 equivalents). The resulting reaction mixture is stirred at room temperature for 6 hours, at which point the resulting reaction mixture is lyophilized to afford (4-(4-(4-((1S,4r)-4-(4-((S)-2,6- dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin- 1-yl)-1H-pyrazol-1-yl)-6-(2-oxidophenyl)pyridazin-3-yl)phosphoramidate, sodium salt (Compound 10). Step-8: To a suspension of (4-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2- oxidophenyl)pyridazin-3-yl)phosphoramidate in acetonitrile is added potassium carbonate (3 equivalents). The resulting reaction mixture is stirred at room temperature for 6 hours, at which point the resulting reaction mixture is lyophilized to afford (4-(4-(4-((1S,4r)-4-(4-((S)-2,6- dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin- 1-yl)-1H-pyrazol-1-yl)-6-(2-oxidophenyl)pyridazin-3-yl)phosphoramidate, potassium salt (Compound 11). Example 12: Synthesis of (2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol- 1-yl)pyridazin-3-yl)phenoxy)methyl dihydrogen phosphate (Compound 12), (2-(6-amino- 5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- 8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)pyridazin-3-yl)phenoxy)methyl dihydrogen phosphate, sodium salt (Compound 13), and (2-(6-amino-5-(4-(4-((1S,4r)-4- (4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2- oxopiperazin-1-yl)-1H-pyrazol-1-yl)pyridazin-3-yl)phenoxy)methyl dihydrogen phosphate, potassium salt (Compound 14) Step 1: To a stirred solution of (S)-3-(8-((1r,4S)-4-(4-(1-(3-amino-6-(2- hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazin-1-yl)cyclohexyl)-2,3- dihydro-4H-benzo[b][1,4]oxazin-4-yl)piperidine-2,6-dione in N-methylpyrrolidone is added cesium carbonate and di-tert-butyl (chloromethyl) phosphate. The resulting reaction mixture is stirred at room temperature for 16 hours, at which time ice-cold water is added to the reaction mixture, and the resulting mixture extracted using ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)pyridazin-3- yl)phenoxy)methyl di-tert-butyl phosphate. Step 2: To a stirred solution of (2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3- yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol- 1-yl)pyridazin-3-yl)phenoxy)methyl di-tert-butyl phosphate in dichloromethane is added TFA, and the resulting reaction mixture stirred at room temperature for 6 hours. At this time, the reaction mixture is triturated by the addition of diethyl ether, and the resulting suspension filtered. The solid filter cake is collected to afford (2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6- dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin- 1-yl)-1H-pyrazol-1-yl)pyridazin-3-yl)phenoxy)methyl dihydrogen phosphate (Compound 12). Step 3: To a suspension of (2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1- yl)pyridazin-3-yl)phenoxy)methyl dihydrogen phosphate (Compound 12) in acetonitrile is added sodium carbonate (2 equiv). The resulting reaction mixture is stirred at room temperature for 6 hours, at which point the mixture is lyophilized to afford (2-(6-amino-5-(4- (4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8- yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)pyridazin-3-yl)phenoxy)methyl dihydrogen phosphate, sodium salt (Compound 13). Step 4: To a suspension of (2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1- yl)pyridazin-3-yl)phenoxy)methyl dihydrogen phosphate in acetonitrile is added potassium carbonate (2 equiv). The resulting reaction mixture is stirred at room temperature for 6 hours, at which point the mixture is lyophilized to afford (2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6- dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin- 1-yl)-1H-pyrazol-1-yl)pyridazin-3-yl)phenoxy)methyl dihydrogen phosphate, potassium salt (Compound 14). Example 13: Synthesis of (2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol- 1-yl)pyridazin-3-yl)phenoxy)methyl dihydrogen phosphate (Compound 12)

[0017] Step-1: A suspension of tetra-N-butylammonium di-tert-butylphosphate 1 (20 g, 44.28 mmol) and chloroiodo methane 2 (48.41 mL, 664.21 mmol) was stirred at ambient temperature for 4 hr. After which time, the reaction mixture was concentrated under reduced pressure to afford a crude residue, which was diluted with di-ethyl ether (10 mL), forming a precipitate. The precipitate was filtered and the filtrate concentrated under reduced pressure to afford the crude product, which was purified by flash column chromatography (Stationary phase: neutral alumina; eluent: 20% ethyl acetate in pet ether) to afford di-tert-butyl (chloromethyl) phosphate 3 (4 g, 33% yield) as a yellow oil.1H-NMR (400 MHz, CDCl3): δ 5.64 (d, J = 15.2 Hz, 2H), 1.59-1.48 (m, 18H) ppm. Step-2: To a well-stirred solution of tert-butyl 4-(1-(3-amino-6-(2-hydroxyphenyl)pyridazin- 4-yl)-1H-pyrazol-4-yl)-3-oxopiperazine-1-carboxylate 4 (1A-9 in Example 1A) (1.0 g, 2.21 mmol) in NMP (15 mL) was added cesium carbonate (2.17 g, 6.64 mmol) and di-tert-butyl (chloromethyl) phosphate 3 (1.15 g, 4.43 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 5 hr, at which point the reaction was diluted with ice cold water (15 mL) and extracted using ethyl acetate (20 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford the crude product, which was triturated using di-ethyl ether (20 mL) and dried in vacuo to afford tert-butyl 4-(1-(3-amino-6-(2-(((di-tert- butoxyphosphoryl)oxy)methoxy)phenyl)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazine- 1-carboxylate 5 (1.0 g, 60% yield) as light brown solid. LC-MS (ES+): m / z 618.7 [M-tBu+H]+Step-3: To a well-stirred solution of tert-butyl 4-[1-[3-amino-6-[2-(ditert- butoxyphosphoryloxymethoxy)phenyl]pyridazin-4-yl]pyrazol-4-yl]-3-oxo-piperazine-1- carboxylate 5 (500 mg, 0.74 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (1.14 mL, 14.84 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 3 hr, at which time the reaction mixture was concentrated under reduced pressure to afford the crude product, which was triturated with di-ethyl ether (10 mL) to afford [2-[6-amino-5-[4-(2-oxopiperazin-1-yl)pyrazol-1-yl]pyridazin-3-yl]phenoxy]methyl dihydrogen phosphate 6 (400 mg, 69% yield, Trifluoroacetic acid salt) as brown solid. LC-MS (ES+): m / z 462.4 [M+H]+Step-4: To a well-stirred solution of [2-[6-amino-5-[4-(2-oxopiperazin-1-yl)pyrazol-1- yl]pyridazin-3-yl]phenoxy]methyl dihydrogen phosphate 6 (100 mg, 0.17 mmol, Trifluoroacetic acid salt), and 1B-13 (59 mg, 0.17 mmol) in DMSO (2 mL) was added acetic acid (0.05 mL, 0.86 mmol), sodium acetate (57 mg, 0.69 mmol), and 4 Å molecular sieves (100 mg) at ambient temperature. The resulting reaction mixture was heated to 40 °C and stirred for 48 hr, at which time the reaction mixture was cooled to ambient temperature and MP-Cyanoborohydride (200 mg, 0.17 mmol) was added. The resulting reaction mixture was stirred for an additional 48 hr, at which time the reaction mixture was filtered and washed with DMSO (2 mL). The filtrate was concentrated under reduced pressure using Genvac at 60 °C for 5 hours to obtain the crude product, which was purified by Prep-HPLC [Column: X- SELECT C18 (10 x 250 mm) x 5 um; Mobile phase A: 10 mM Ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Gradient (Time / %B): 0 – 2 min (15% B), 2 – 7 min (15 – 35% B) 7 – 11 min (35% B), 11.1 min (100% B); Flow rate: 8 mL / min]. The fast eluting peak was collected and lyophilized to afford [2-[6-amino-5-[4-[4-[4- [4-[(3S)-2,6-dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo- piperazin-1-yl]pyrazol-1-yl]pyridazin-3-yl]phenoxy]methyl dihydrogen phosphate (Compound 12) (13 mg, 9% yield) as an off-white solid. LC-MS (ES+): m / z 788.59 [M+H]+1H-NMR (400 MHz, DMSO-d6): δ 10.80 (s.1H), 9.37 (brs, 1H), 8.58 (brs, 1H), 8.39 (s, 1H), 7.69 (d, J = 6.4 Hz, 1H), 7.41-7.38 (m, 3H), 7.27 (d, J = 8.4 Hz, 1H), 7.07 (t, J = 7.6 Hz, 2H), 6.69-6.66 (m, 2H), 6.45 (m, 1H), 5.60-5.56 (m, 2H), 4.89-4.87 (m, 1H), 4.15 (s, 2H), 3.88 (s, 2H), 3.22-3.18 (m, 2H), 2.94-2.81 (m, 6H), 2.58-2.54 (m, 2H), 2.29-2.26 (m, 1H), 1.94-1.87 (m, 3H), 1.79-1.76 (m, 2H), 1.38-1.36 (m, 4H) ppm.31P-NMR (162 MHz, DMSO-d6): -1.705 The late eluting peak was collected and lyophilized to afford [2-[6-amino-5-[4-[4-[4- [4-[(3S)-2,6-dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo- piperazin-1-yl]pyrazol-1-yl]pyridazin-3-yl]phenoxy]methyl dihydrogen phosphate(Compound 12-cis) (7 mg, 5% yield) as an off-white solid. LC-MS (ES+): m / z 788.59 [M+H]+1H-NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H), 9.27 (brs, 1H), 8.48 (brs, 1H), 8.42 (s, 1H), 7.71-7.68 (m, 1H), 7.42-7.38 (m, 3H), 7.28 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 7.4 Hz, 2H), 6.64- 6.63 (m, 2H), 6.50-6.48 (m, 1H), 5.60-5.56 (m, 2H), 4.88-4.85 (m, 1H), 4.17-4.15 (m, 2H), 3.89 (s, 2H), 3.34-3.22 (m, 2H), 3.19-3.15 (m, 2H), 2.96 (s, 1H), 2.85-2.80 (m, 3H), 2.57-2.50 (m, 1H), 2.36-2.35 (m, 1H), 2.31-2.28 (m, 1H), 2.06-2.03 (m, 2H), 1.91-1.87 (m, 1H), 1.75- 1.69 (m, 2H), 1.56-1.45 (m, 4H) ppm.31P-NMR (162 MHz, DMSO-d6): -1.882 Example 14: Synthesis of potassium salt of (2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6- dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2- oxopiperazin-1-yl)-1H-pyrazol-1-yl)pyridazin-3-yl)phenoxy)methyl dihydrogen phosphate (Compound 14):

[0018] Step-1: To a solution of Compound 12 (50 mg, 0.063 mmol) in a mixture of acetonitrile (2 mL) and water (3 mL) cooled to 0 °C was added a 0.1 M KHCO3solution in water (0.76 mL, 0.076 mmol). The resulting suspension was lyophilised to afford [2-[6-amino-5-[4-[4-[4-[4- [(3S)-2,6-dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin- 1-yl]pyrazol-1-yl]pyridazin-3-yl]phenoxy]methyl dihydrogen phosphate (Compound 14) (45 mg, 76% yield, Potassium*2 salt) as an off white solid. LCMS (ES+): m / z 788.39 [M-2K+H]+1H-NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H), 9.60 (s, 1H), 8.72 (s, 1H), 8.41 (s, 1H), 7.68 (d, J = 6.4 Hz, 1H), 7.39-7.37 (m, 3H), 7.24 (d, J = 8.4 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.66- 6.66 (m, 2H), 6.47-6.47 (m, 1H), 5.57-5.53 (m, 2H), 4.90-4.86 (m, 1H), 4.16 (s, 2H), 3.90 (s, 2H), 3.33-3.16 (m, 4H), 2.91-2.88 (m, 2H), 2.84-2.80 (m, 2H), 2.55-2.55 (m, 2H), 2.31-2.24 (m, 1H),1.95-1.78 (m, 5H), 1.30-1.50 (m, 4H) ppm.31P-NMR (162 MHz, DMSO-d6): δ -1.570. Example 15: Synthesis of (2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol- 1-yl)pyridazin-3-yl)phenoxy)methyl dihydrogen phosphate (Compound 12)

[0019] Step-1: A suspension of tetra-N-butylammonium di-tert-butylphosphate 1 (160 g, 354.25 mmol) and chloroiodo methane 2 (387.29 mL, 5.31 mol) was stirred at ambient temperature for 4 hr. At this point, the reaction mixture was concentrated under reduced pressure to afford the crude residue, which was diluted with di-ethyl ether (500 mL), which caused a precipitate to form. The precipitate was filtered and the filtrate concentrated under reduced pressure to afford the crude product, which was purified by column chromatography (Stationary phase: neutral alumina; Eluent: 20% ethyl acetate in pet ether) to afford di-tert-butyl (chloromethyl) phosphate 3 (20 g, 21 % yield) as a yellow oil.1H-NMR (400 MHz, CDCl3): δ 5.64 (d, J = 15.2 Hz, 2H), 1.59-1.48 (m, 18H) ppm. Note: Reactions performed in 4 x 40 g batches Step-2: To a well-stirred solution of tert-butyl 4-(1-(3-amino-6-(2-hydroxyphenyl)pyridazin- 4-yl)-1H-pyrazol-4-yl)-3-oxopiperazine-1-carboxylate 4 (15 g, 33.22 mmol) in NMP (150 mL) was added cesium carbonate (32.48 g, 99.67 mmol), di-tert-butyl (chloromethyl) phosphate 3 (17.19 g, 66.45 mmol). The resulting reaction mixture was stirred at ambient temperature for 16 hr, at which time the reaction was diluted with ice cold water (500 mL) and extracted using ethyl acetate (500 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrated concentrated under reduced pressure to afford the crude product, which was triturated using di-ethyl ether (100 mL) and dried under reduced pressure to afford tert-butyl 4-(1-(3-amino-6-(2-(((di-tert- butoxyphosphoryl)oxy)methoxy)phenyl)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazine- 1-carboxylate 5 (15 g, 51 % yield) as light brown solid. LC-MS (ES+): 675.10 [M+H]+Note: Reactions performed in 3 x 5 g batches Step-3: To a well-stirred solution of tert-butyl 4-[1-[3-amino-6-[2-(ditert- butoxyphosphoryloxymethoxy)phenyl]pyridazin-4-yl]pyrazol-4-yl]-3-oxo-piperazine-1- carboxylate 5 (15 g, 22.27 mmol) in DCM (200 mL) was added TFA (34.08 mL, 445.31 mmol). The resulting reaction mixture was stirred at ambient temperature for 5 hr, at which point the reaction mixture was concentrated under reduced pressure to afford the crude product, which was triturated with di-ethyl ether (100 mL) to afford [2-[6-amino-5-[4-(2-oxopiperazin- 1-yl)pyrazol-1-yl]pyridazin-3-yl]phenoxy]methyl dihydrogen phosphate 6 (14 g, 82 % yield, Trifluoroacetic acid) as off-white solid. LC-MS (ES+): m / z 462.02 [M+H]+Note: Reactions was performed in 3 x 5 g batches Step-4: To a well-stirred solution of [2-[6-amino-5-[4-(2-oxopiperazin-1-yl)pyrazol-1- yl]pyridazin-3-yl]phenoxy]methyl dihydrogen phosphate 6 (14 g, 24.33 mmol, Trifluoroacetic acid salt), and 1B-13 (8.33 g, 24.33 mmol) in DMSO (60 mL) was added acetic acid (6.96 mL, 121.66 mmol), sodium acetate (7.98 g, 97.33 mmol), and 4 Å Molecular sieves (14 g, 24.33 mmol) and the resulting reaction mixture was heated to 40 °C and stirred for 48 hr. At this point, the reaction mixture was cooled to ambient temperature and MP-Cyanoborohydride (28 g, 24.33 mmol) was added, and the resulting reaction mixture was stirred for an additional 48 hr. At this time, the reaction mixture was filtered and washed with DMSO (100 mL). The filtrate was diluted with water (500 mL) to form a precipitate, which was filtered and triturated using acetonitrile (100 mL) to afford the crude product, which was purified by prep- HPLC [Column: X-SELECT C18 (30*150 mm) * 5um; Mobile phase A: 20 mM Ammonium bicarbonate buffer in water, Mobile phase B: Acetonitrile; Gradient (Time / %B): 0 – 2 min (25% B), 2 – 10 min (25 – 36% B), 10.01 min (100% B); Flow rate: 20 mL / min]. The pure fractions of the early eluting isomer were collected at -78 °C and lypholilized directly to afford [2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin- 8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3-yl]phenoxy]methyl dihydrogen phosphate (Compound 12) (1.03 g, 5 % yield) as off-white solid. LC-MS (ES+): m / z 788.49 (M+H)+1H-NMR (400 MHz, DMSO-d6) δ: 10.82 (s, 1H), 9.22 (brs, 1H), 8.50 (brs, 1H), 8.37 (s, 1H), 7.70-7.68 (m, 1H), 7.41-7.37 (m, 3H), 7.27 (d, J = 8.4 Hz, 1H), 7.06 (m, 2H), 6.66-6.65 (m, 2H), 6.41 (m, 1H), 5.60-5.57 (m, 2H), 4.90-4.86 (m, 1H), 4.14 (s, 2H), 3.88 (s, 2H), 3.26-3.15 (m, 4H), 3.00 (s, 2H), 2.87-2.84 (m, 1H), 2.81-2.80 (m, 1H), 2.58 (m, 2H), 2.29 (m, 1H), 1.91- 1.73 (m, 5H), 1.33-1.24 (m, 4H) ppm.31P-NMR (162 MHz, DMSO-d6): δ -2.26. Note: Reactions were performed in multiple batches (0.5 g each x 28 batches). After completion of the reaction monitored by LCMS analysis, the reactions were combined and diluted with MeOH / DCE (1:1). The mixture was then filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The crude residue so obtained was triturated with acetonitrile (150 mL) to obtain pale yellow solid, which was further purified by Prep- HPLC purification. Example 16: Synthesis of tert-butyl (S)-3-(8-((1r,4S)-4-(4-(1-(3-((tert- butoxycarbonyl)amino)-6-(2-hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-4-yl)-3- oxopiperazin-1-yl)cyclohexyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2,6- dioxopiperidine-1-carboxylate (Int-XY) To a stirred solution of (S)-3-(8-((1r,4S)-4-(4-(1-(3-amino-6-(2- hydroxyphenyl)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazin-1-yl)cyclohexyl)-2,3- dihydro-4H-benzo[b][1,4]oxazin-4-yl)piperidine-2,6-dione in tetrahydrofuran is added Cs2CO3(2 equiv), and the resulting suspension is stirred at ambient temperature for 15 minutes. Subsequently, di-tert-butyl-carbonate (3 equiv) is added slowly to the reaction mixture, then the resulting reaction mixture is heated to 60 °C and stirred for 16 hours. Upon completion of the reaction, the reaction mixture is cooled to ambient temperature, and concentrated in vacuo. The resulting residue is diluted in ethyl acetate, and then water is added. The resulting mixture is extracted with ethyl acetate 3 times, and the combined organic layer washed with water two times and brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified by reverse phase prep HPLC to afford tert-butyl (S)- 3-(8-((1r,4S)-4-(4-(1-(3-((tert-butoxycarbonyl)amino)-6-(2-hydroxyphenyl)pyridazin-4-yl)- 1H-pyrazol-4-yl)-3-oxopiperazin-1-yl)cyclohexyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4- yl)-2,6-dioxopiperidine-1-carboxylate (Int-XY). Example 17: 2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1- yl)pyridazin-3-yl)phenyl L-valinate hydrochloride salt (Compound 15-HCl)

[0020] Step 1: To a stirred solution of 2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid 1 (1 equiv) in tetrahydrofuran is added N-methylmorpholine (1.5 equiv) and isobutylchloroformate (1.2 equiv) at 0 °C, and the resulting reaction mixture is stirred for 15 minutes, at which time the reaction mixture is warmed to room temperature and stirred for 45 minutes. Then benzotriazole 2 (1 equiv) is added to the reaction mixture, and the resulting mixture is stirred for 16 hours at room temperature. Upon completion of the reaction as determined by TLC, the reaction mixture is filtered, and the filtrate concentrated under reduced pressure. The resulting residue is washed with petroleum ether, resulting in a solid precipitate, which is filtered and the filter cake is collected to afford tert-butyl N-[1-(benzotriazole-1-carbonyl)-2-methyl- propyl]carbamate 3. Step 2: To a stirred solution of Int-XY (1 equiv) in acetonitrile is added Cs2CO3 (1.5 equiv), and the resulting reaction mixture is stirred at room temperature for 2 hours. Then tert-butyl N-[1-(benzotriazole-1-carbonyl)-2-methyl-propyl]carbamate 3 (1 equiv) is added, and the resulting reaction mixture heated to 60 °C and stirred for 16 hours. At this time, the reaction mixture is cooled to ambient temperature, and concentrated in vacuo. The resulting residue is diluted with ethyl acetate and water, and extracted with ethyl acetate three times. The combined organic layers are washed with water two times and brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue. The resulting residue is purified by reverse phase prep-HPLC to afford tert-butyl (S)-3-(8-((1r,4S)- 4-(4-(1-(6-(2-(((tert-butoxycarbonyl)-L-valyl)oxy)phenyl)-3-((tert- butoxycarbonyl)amino)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazin-1-yl)cyclohexyl)- 2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2,6-dioxopiperidine-1-carboxylate 4. Step 3: To a round-bottom flask is added tert-butyl (S)-3-(8-((1r,4S)-4-(4-(1-(6-(2-(((tert- butoxycarbonyl)-L-valyl)oxy)phenyl)-3-((tert-butoxycarbonyl)amino)pyridazin-4-yl)-1H- pyrazol-4-yl)-3-oxopiperazin-1-yl)cyclohexyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)- 2,6-dioxopiperidine-1-carboxylate 4 (1 equiv) and cooled to 0 °C. Then a 4 N solution of HCl in 1,4-dioxane is added, and the resulting mixture is warmed to room temperature and stirred for 1 hour. The resulting mixture is concentrated under reduced pressure to afford 2-(6-amino- 5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8- yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)pyridazin-3-yl)phenyl L-valinate, hydrochloride salt (Compound 15-HCl). Example 18: 2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1- yl)pyridazin-3-yl)phenyl L-valinate hydrochloride salt (Compound 15-HCl) Step-1: To a well-stirred solution of (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid 1 (320.56 mg, 1.48 mmol) in a mixture of DCM (8 mL) and DMF (2 mL) cooled to 0 °C was added DMAP (108.15 mg, 0.88 mmol) and N,N′-Diisopropylcarbodiimide (0.13 mL, 0.88 mmol). The resulting reaction mixture was allowed to warm to room temperature, and stirred for 10 min, at which point Compound 1 (200 mg, 0.29 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1 hr, at which time the reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford the crude product, which was purified by prep- HPLC [Column: X BRIDGE C18 (19*250 mm) X 5µm; Mobile phase A: 10 mM Ammonium bicarbonate in water, Mobile phase B: 100% Acetonitrile; Gradient (Time / %B): 0 – 3 min (20 – 30% B), 3 – 9 min (30-72% B), 9 – 12.3 min (72% B); Flow rate: 18 mL / min] to afford [2- [6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8- yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3-yl]phenyl] (2S)-2-(tert- butoxycarbonylamino)-3-methyl-butanoate 2 (15 mg, 6% yield). LCMS (ES+): m / z 877.36 [M + H]+Step-2: To a well-stirred solution of 2 (15 mg, 0.01 mmol) in DCM (2 mL) was added 4 M HCl in 1,4-dioxane (0.1 mL) at 0 °C. The resulting reaction mixture was stirred at ambient temperature for 1 hr, at which time the reaction mixture was concentrated under reduced pressure and triturated with di-ethyl ether (2 mL) to afford [2-[6-amino-5-[4-[4-[4-[4-[(3S)- 2,6-dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1- yl]pyrazol-1-yl]pyridazin-3-yl]phenyl] (2S)-2-amino-3-methyl-butanoate (Compound 15- HCl) (7.5 mg, 48% yield, Hydrochloric acid) as off white solid. LC-MS (ES+): m / z 777.50 [M+H]+1H NMR (400 MHz, DMSO-d6) δ: 11.90 (brs, 1H), 10.83 (s, 1H), 9.02 (s, 1H), 8.52 (brs, 2H), 8.38 (s, 1H), 8.00 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.63-7.38 (m, 3H), 7.38 (d, J = 7.6 Hz, 1H), 6.72-6.69 (m, 2H), 6.47 (t, J = 8.8 Hz, 1H), 4.91-4.87 (m, 1H), 4.19-4.17 (m, 4H), 4.08-4.00 (m, 4H), 3.44-3.42 (m, 1H), 3.27-3.17 (m, 2H), 2.88-2.81 (m, 2H), 2.50 (m, 3H), 2.30-2.21 (m, 4H), 1.91-1.88 (m, 3H), 1.78-1.65 (m, 1H), 1.50-1.48 (m, 2H), 0.90-0.88 (m, 3H), 0.84-0.82 (m, 3H) ppm. Example 19: 2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1- yl)pyridazin-3-yl)phenyl 4-(dimethylamino)butanoate hydrochloride salt (Compound 16-HCl) Step 1: To an oven-dried two-necked round bottom flask is added 4-(dimethylamino)butanoic acid 1 (1 equiv) and dichloromethane and sealed with a rubber septum in both necks, one of which is vented through a mineral oil bubbler. To the resulting reaction mixture is added N,N- dimethylformamide (0.1 equiv), then oxalyl chloride (0.95 equiv) is added dropwise. The resulting reaction mixture is warmed slowly to room temperature while vigorously stirring, until the evolution of HCl gas ceases as observed by no more gas exiting the bubbler. At this time the reaction mixture is concentrated under reduced pressure, and the resulting residue diluted with acetonitrile. To this stirring solution is added Cs2CO3 (2 equiv), then a pre-mixed solution of Int-XY (1 equiv) in acetonitrile is added dropwise. Subsequently, the reaction mixture is warmed to 60 °C and stirred for 16 hours, at which time the reaction mixture is cooled to room temperature and concentrated under reduced pressure. The resulting residue is diluted with ethyl acetate and water, and extracted with ethyl acetate three times. The combined organic layers are washed with water two times and brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue. The resulting residue is purified by reverse phase prep-HPLC to afford tert-butyl (S)-3-(8-((1r,4S)- 4-(4-(1-(3-((tert-butoxycarbonyl)amino)-6-(2-((4- (dimethylamino)butanoyl)oxy)phenyl)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazin-1- yl)cyclohexyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2,6-dioxopiperidine-1-carboxylate 2. Step 2: To a round-bottom flask is added tert-butyl (S)-3-(8-((1r,4S)-4-(4-(1-(3-((tert- butoxycarbonyl)amino)-6-(2-((4-(dimethylamino)butanoyl)oxy)phenyl)pyridazin-4-yl)-1H- pyrazol-4-yl)-3-oxopiperazin-1-yl)cyclohexyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)- 2,6-dioxopiperidine-1-carboxylate 2 (1 equiv) and cooled to 0 °C. Then a 4 N solution of HCl in 1,4-dioxane is added, and the resulting mixture is warmed to room temperature and stirred for 1 hour. The resulting mixture is concentrated under reduced pressure to afford 2-(6-amino- 5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8- yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)pyridazin-3-yl)phenyl 4- (dimethylamino)butanoate, hydrochloride salt (Compound 16-HCl). Example 20: 4-(2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1- yl)pyridazin-3-yl)phenoxy)-4-oxobutanoic acid (Compound 17) Step 1: To a stirred solution of Int-XY (1 equiv) in pyridine is added succinic anhydride 1 (1.1 equiv). The resulting reaction mixture is warmed to 50 °C and stirred for 16 hours, at which point the reaction is diluted with ethyl acetate and water, and extracted with ethyl acetate three times. The combined organic layers are washed with water two times and brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue. The resulting residue is purified by reverse phase prep-HPLC to afford 4-(2-(5-(4-(4- ((1S,4r)-4-(4-((S)-1-(tert-butoxycarbonyl)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-((tert- butoxycarbonyl)amino)pyridazin-3-yl)phenoxy)-4-oxobutanoic acid 2. Step 2: To a round-bottom flask is added 4-(2-(5-(4-(4-((1S,4r)-4-(4-((S)-1-(tert- butoxycarbonyl)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8- yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-((tert- butoxycarbonyl)amino)pyridazin-3-yl)phenoxy)-4-oxobutanoic acid 2 (1 equiv) and cooled to 0 °C. Then a 4 N solution of HCl in 1,4-dioxane is added, and the resulting mixture is warmed to room temperature and stirred for 1 hour. The resulting mixture is concentrated under reduced pressure to afford 4-(2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1- yl)pyridazin-3-yl)phenoxy)-4-oxobutanoic acid (Compound 17) or alternatively an HCl salt thereof. Example 21: 2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1- yl)pyridazin-3-yl)phenyl (2-((2-aminoethyl)disulfaneyl)ethyl) carbonate hydrochloride salt (Compound 18-HCl) Step 1: To a stirred solution of tert-butyl N-[2-(2-hydroxyethyldisulfanyl)ethyl]carbamate 2 (1 equiv) in dichloromethane is added DIPEA (2 equiv). The resulting mixture is stirred for 15 minutes, then (4-nitrophenyl) chloroformate 1 (1.1 equiv) is added portion wise. The resulting reaction mixture is stirred at room temperature for 16 hours, at which point water is added and the mixture extracted with dichloromethane three times. The combined organic layers are washed with water two times and brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue. The resulting residue is purified by normal phase column chromatography to afford tert-butyl (2-((2-(((4- nitrophenoxy)carbonyl)oxy)ethyl)disulfaneyl)ethyl)carbamate 3. Step 2: To a stirred solution of Int-XY (1 equiv) and Cs2CO3 (2 equiv) in acetonitrile is added tert-butyl (2-((2-(((4-nitrophenoxy)carbonyl)oxy)ethyl)disulfaneyl)ethyl)carbamate 3 (1.1 equiv). The resulting reaction mixture is warmed to 60 °C and stirred for 16 hours, at which time the reaction mixture is cooled to room temperature and concentrated under reduced pressure. The resulting residue is diluted with ethyl acetate and water and extracted with ethyl acetate three times. The combined organic layers are washed with water two times and brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue. The resulting residue is purified by reverse phase prep-HPLC to afford tert-butyl (S)-3-(8-((1r,4S)-4-(4-(1-(3-((tert-butoxycarbonyl)amino)-6-(2-((12,12- dimethyl-10-oxo-2,11-dioxa-5,6-dithia-9-azatridecanoyl)oxy)phenyl)pyridazin-4-yl)-1H- pyrazol-4-yl)-3-oxopiperazin-1-yl)cyclohexyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)- 2,6-dioxopiperidine-1-carboxylate 4. Step 3: To a round-bottom flask is added tert-butyl (S)-3-(8-((1r,4S)-4-(4-(1-(3-((tert- butoxycarbonyl)amino)-6-(2-((12,12-dimethyl-10-oxo-2,11-dioxa-5,6-dithia-9- azatridecanoyl)oxy)phenyl)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazin-1- yl)cyclohexyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2,6-dioxopiperidine-1-carboxylate 4 (1 equiv) and cooled to 0 °C. Then a 4 N solution of HCl in 1,4-dioxane is added, and the resulting mixture is warmed to room temperature and stirred for 1 hour. The resulting mixture is concentrated under reduced pressure to afford 2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6- dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin- 1-yl)-1H-pyrazol-1-yl)pyridazin-3-yl)phenyl (2-((2-aminoethyl)disulfaneyl)ethyl) carbonate, hydrochloride salt (Compound 18-HCl). Example 22: (S)-2-(((S)-1-(2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol- 1-yl)pyridazin-3-yl)phenoxy)-3-methyl-1-oxobutan-2-yl)carbamoyl)pyrrolidin-1-ium chloride (Compound 19-HCl)

[0021] Step 1: To a stirred suspension of 1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid 1 (1 equiv) and benzyl (2S)-2-amino-3-methyl-butanoate 2 (1 equiv) in N,N-dimethylformamide is added DIPEA (3 equiv) and HATU (3 equiv) at 0 °C, and the resulting mixture is stirred for 16 hours at room temperature under a nitrogen atmosphere. The resulting reaction mixture is concentrated under reduced pressure to afford the crude product. The crude product is purified by normal phase column chromatography (Stationary phase: 100-200 mesh silica gel, eluent: 30-40% ethyl acetate in pet ether) to afford tert-butyl 2-[[(1S)-1-benzyloxycarbonyl-2-methyl- propyl]carbamoyl]pyrrolidine-1-carboxylate 3.Step 2: To an oven-dried round-bottom flask containing tert-butyl 2-[[(1S)-1- benzyloxycarbonyl-2-methyl-propyl]carbamoyl]pyrrolidine-1-carboxylate 3 (1 equiv) is added Pd / C (0.1 equiv). The resulting mixture is suspended in anhydrous THF, then hydrogen gas is bubbled through the reaction mixture for 15 minutes. Subsequently, the reaction mixture is allowed to stir for 16 hours at room temperature under a hydrogen atmosphere. Then the reaction mixture is passed through a pad of celite, and the celite bed washed with ethyl acetate three times. The filtrate is then diluted with water, and extracted with ethyl acetate three times. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a residue, which is purified by normal phase flash chromatography to afford (tert-butoxycarbonyl)-L-prolyl-L-valine 4. Step 3: To a stirred solution of (tert-butoxycarbonyl)-L-prolyl-L-valine 4 (1 equiv) in tetrahydrofuran is added N-methyl morpholine (1 equiv) and isobutyl chloroformate (1 equiv) in a dropwise manner at 0°C. The resulting reaction mixture is stirred at 0 °C for 45 minutes, then 1H-benzotriazole 5 (1 equiv) is added in one portion. The resulting reaction mixture is allowed to warm to room temperature and stirred for 16 hours. At this time, the reaction mixture is filtered, and the filtrate concentrated under reduced pressure to afford a crude product mixture, which is purified by flash normal phase column chromatography to afford tert-butyl (S)-2-(((S)-1-(1H-benzo[d][1,2,3]triazol-1-yl)-3-methyl-1-oxobutan-2- yl)carbamoyl)pyrrolidine-1-carboxylate 6. Step 4: To a stirred solution of Int-XY (1 equiv) and Cs2CO3 (2 equiv) in acetonitrile is added tert-butyl (S)-2-(((S)-1-(1H-benzo[d][1,2,3]triazol-1-yl)-3-methyl-1-oxobutan-2- yl)carbamoyl)pyrrolidine-1-carboxylate 6 (1.1 equiv). The resulting reaction mixture is warmed to 60 °C and stirred for 16 hours, at which time the reaction mixture is cooled to room temperature and concentrated under reduced pressure. The resulting residue is diluted with ethyl acetate and water, and extracted with ethyl acetate three times. The combined organic layers are washed with water two times and brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a residue. The resulting residue is purified by reverse phase prep-HPLC to afford tert-butyl (S)-3-(8-((1r,4S)-4-(4-(1- (6-(2-(((tert-butoxycarbonyl)-L-prolyl-L-valyl)oxy)phenyl)-3-((tert- butoxycarbonyl)amino)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazin-1-yl)cyclohexyl)- 2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2,6-dioxopiperidine-1-carboxylate. Step 5: To a round-bottom flask is added tert-butyl (S)-3-(8-((1r,4S)-4-(4-(1-(6-(2-(((tert- butoxycarbonyl)-L-prolyl-L-valyl)oxy)phenyl)-3-((tert-butoxycarbonyl)amino)pyridazin-4- yl)-1H-pyrazol-4-yl)-3-oxopiperazin-1-yl)cyclohexyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin- 4-yl)-2,6-dioxopiperidine-1-carboxylate (1 equiv) and cooled to 0 °C. Then a 4 N solution of HCl in 1,4-dioxane is added, and the resulting mixture is warmed to room temperature and stirred for 1 hour. The resulting mixture is concentrated under reduced pressure to afford (S)- 2-(((S)-1-(2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)pyridazin-3- yl)phenoxy)-3-methyl-1-oxobutan-2-yl)carbamoyl)pyrrolidin-1-ium chloride (Compound 19). Example 23: 2-(2-(6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1- yl)pyridazin-3-yl)phenoxy)-2-oxoethyl 2-(piperidin-1-yl)acetate hydrochloride salt (Compound 20-HCl) Step 1: To a stirred solution of Int-XY (1 equiv) in dichloromethane cooled to 0 °C is added pyridine, and the resulting mixture is stirred for 15 minutes. Then 2-chloroacetyl chloride 1 (0.95 equiv) is added dropwise, and the resulting reaction mixture is stirred at 0 °C for 6 hours, at which point the reaction mixture is concentrated under reduced pressure to afford tert-butyl (S)-3-(8-((1r,4S)-4-(4-(1-(3-((tert-butoxycarbonyl)amino)-6-(2-(2- chloroacetoxy)phenyl)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazin-1-yl)cyclohexyl)- 2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2,6-dioxopiperidine-1-carboxylate 2, which is used without purification. Step 2: To a stirred mixture of 2-(piperidin-1-yl)acetic acid 3 (2.0 equiv), K2CO3(2 equiv), and NaI (2 equiv) in N,N-dimethylformamide cooled to 0 °C, a pre-stirred mixture of tert-butyl (S)-3-(8-((1r,4S)-4-(4-(1-(3-((tert-butoxycarbonyl)amino)-6-(2-(2- chloroacetoxy)phenyl)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazin-1-yl)cyclohexyl)- 2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2,6-dioxopiperidine-1-carboxylate 2 (1.0 equiv) in N,N-dimethylformamide is added dropwise. The resulting reaction mixture is allowed to gradually warm to room temperature while vigorously stirring over 16 hours, at which point water is added to the reaction mixture, followed by a 5% aqueous LiCl solution. The resulting mixture is extracted with ethyl acetate three times, and the combined organic layer is washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure. The resulting residue is purified by reverse phase prep-HPLC to afford tert-butyl (S)- 3-(8-((1r,4S)-4-(4-(1-(3-((tert-butoxycarbonyl)amino)-6-(2-(2-(2-(piperidin-1- yl)acetoxy)acetoxy)phenyl)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazin-1- yl)cyclohexyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)-2,6-dioxopiperidine-1-carboxylate 4. Step 3: To a round-bottom flask is added tert-butyl (S)-3-(8-((1r,4S)-4-(4-(1-(3-((tert- butoxycarbonyl)amino)-6-(2-(2-(2-(piperidin-1-yl)acetoxy)acetoxy)phenyl)pyridazin-4-yl)- 1H-pyrazol-4-yl)-3-oxopiperazin-1-yl)cyclohexyl)-2,3-dihydro-4H-benzo[b][1,4]oxazin-4- yl)-2,6-dioxopiperidine-1-carboxylate 4 (1 equiv) and cooled to 0 °C. Then a 4 N solution of HCl in 1,4-dioxane is added, and the resulting mixture is warmed to room temperature and stirred for 1 hour. The resulting mixture is concentrated under reduced pressure to afford 2-(2- (6-amino-5-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)pyridazin-3- yl)phenoxy)-2-oxoethyl 2-(piperidin-1-yl)acetate hydrochloride salt (Compound 20-HCl). Example 24: 2-amino-N-(4-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2- hydroxyphenyl)pyridazin-3-yl)acetamide (Compound 21) Step 1: To a stirred solution of tert-butyl 4-[1-[3-amino-6-(2-benzyloxyphenyl)pyridazin-4- yl]pyrazol-4-yl]-3-oxo-piperazine-1-carboxylate 1 (1 equiv) in anhydrous toluene cooled to 0 °C is added a 1 M solution of trimethylaluminium (3 equiv) in toluene dropwise, and the resulting reaction mixture stirred for 10 minutes. Then methyl 2- (benzyloxycarbonylamino)acetate 2 (3 equiv) is added to reaction mixture, and the resulting reaction mixture heated to 120 °C and stirred for 16 hours. Upon completion of the reaction, the resulting reaction mixture is cooled to 0 °C and diluted by the dropwise addition of a saturated aqueous NH4Cl solution. The resulting mixture is extracted with ethyl acetate three times and the combined organic layers washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrated concentrated under reduced pressure. The resulting residue is purified by normal phase flash column chromatography on silica gel to afford tert-butyl 4-(1-(3-(2- (((benzyloxy)carbonyl)amino)acetamido)-6-(2-(benzyloxy)phenyl)pyridazin-4-yl)-1H- pyrazol-4-yl)-3-oxopiperazine-1-carboxylate 3. Step 2: To a round-bottom flask is added tert-butyl 4-(1-(3-(2- (((benzyloxy)carbonyl)amino)acetamido)-6-(2-(benzyloxy)phenyl)pyridazin-4-yl)-1H- pyrazol-4-yl)-3-oxopiperazine-1-carboxylate 3 (1 equiv) and cooled to 0 °C. Then a 4 N solution of HCl in 1,4-dioxane is added, and the resulting mixture is warmed to room temperature and stirred for 1 hour. The resulting mixture is concentrated under reduced pressure to afford benzyl (2-((6-(2-hydroxyphenyl)-4-(4-(2-oxopiperazin-1-yl)-1H-pyrazol-1- yl)pyridazin-3-yl)amino)-2-oxoethyl)carbamate hydrochloride 4. Step 3: To a stirred solution of benzyl (2-((6-(2-hydroxyphenyl)-4-(4-(2-oxopiperazin-1-yl)- 1H-pyrazol-1-yl)pyridazin-3-yl)amino)-2-oxoethyl)carbamate hydrochloride 4 (1 equiv) and (3R)-3-[8-(4-oxocyclohexyl)-2,3-dihydro-1,4-benzoxazin-4-yl]piperidine-2,6-dione 1B-13 (1.3 equiv) in dimethyl sulfoxide is added 4 Å molecular sieves (1 equiv). Then acetic acid (5 equiv) is added, and the resulting reaction mixture stirred at room temperature for 8 hours. The resulting reaction mixture is cooled to 0 °C, then MP-cyanoborohydride (2 equiv) is added portion-wise. The resulting reaction mixture is allowed to slowly warm to room temperature while vigorously stirring for over 12 hours. The resulting suspension is filtered through a Buchner funnel, and the filter cake washed with a 1:1 mixture of 1,2-dichloroethane and methanol. The filtrate is concentrated under reduced pressure, and the resulting residue diluted with dichloromethane and stirred for 10 minutes. The resulting suspension is filtered through a Buchner funnel, and the filter cake collected to afford benzyl (S)-(2-((4-(4-(4-(4-(4-(2,6- dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin- 1-yl)-1H-pyrazol-1-yl)-6-(2-hydroxyphenyl)pyridazin-3-yl)amino)-2-oxoethyl)carbamate 5. Step 4: To an oven-dried round-bottom flask is containing benzyl (S)-(2-((4-(4-(4-(4-(4-(2,6- dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin- 1-yl)-1H-pyrazol-1-yl)-6-(2-hydroxyphenyl)pyridazin-3-yl)amino)-2-oxoethyl)carbamate 5 (1 equiv) is added Pd / C (0.1 equiv). The resulting mixture is suspended in anhydrous tetrahydrofuran, then hydrogen gas is bubbled through the reaction mixture for 15 minutes. Subsequently, the reaction mixture is allowed to stir for 16 hours at room temperature under a hydrogen atmosphere. Then the reaction mixture is passed through a pad of celite, and the celite bed washed with ethyl acetate three times. The filtrate is then diluted with water and extracted with ethyl acetate three times. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a residue, which is purified by reverse phase prep-HPLC to afford (S)-2-amino-N-(4-(4-(4-(4- (4-(2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2- oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2-hydroxyphenyl)pyridazin-3-yl)acetamide 6. Step 5: The mixture of diastereomers of (S)-2-amino-N-(4-(4-(4-(4-(4-(2,6-dioxopiperidin-3- yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol- 1-yl)-6-(2-hydroxyphenyl)pyridazin-3-yl)acetamide 6 is purified by SFC chromatography. The early eluting peak is collected and lyophilized to afford 2-amino-N-(4-(4-(4-((1S,4r)-4-(4- ((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2- oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2-hydroxyphenyl)pyridazin-3-yl)acetamide. The late eluting isomer is collected and lyophilized to afford 2-amino-N-(4-(4-(4-((1R,4s)-4- (4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2- oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2-hydroxyphenyl)pyridazin-3-yl)acetamide (Compound 21). Example 25: 2-amino-N-(4-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2- hydroxyphenyl)pyridazin-3-yl)acetamide hydrochloride (Compound 21-HCl) Step-1: To a well-stirred solution of 2-(tert-butoxycarbonylamino)acetic acid 1 (5 g, 28.54 mmol) and 1H-benzotriazole 2 (5.10 g, 42.81 mmol) in DCM (80 mL) cooled to 0°C was added DCC (11.78 g, 57.08 mmol). The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 16 hr, at which time the reaction mixture was filtered and the filtrated concentrated under reduced pressure to afford the crude product, which was triturated with dichloromethane / pet-ether (1:1) to afford tert-butyl N-[2-(benzotriazol-1-yl)-2- oxo-ethyl]carbamate 3 (7 g, 80% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ: 8.29-8.26 (m, 1H), 8.15-8.13 (m, 1H), 7.78 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 5.30-5.28 (m, 1H), 4.81 (d, J = 6 Hz, 2H), 1.43 (s, 9H) ppm. Step-2: A mixture of Compound 1 (200 mg, 0.295 mmol) and tert-butyl N-[2-(benzotriazol- 1-yl)-2-oxo-ethyl]carbamate 3 (693 mg, 2.51 mmol) was suspended in DMF (2 mL), warmed to 130 °C, and stirred for 16 hr. After this time, the reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by prep-HPLC [Column: X- SELECT C18 (19*150 mm) X 5um; Mobile phase A: 10 mM Ammonium Bicarbonate in water + 0.1% NH3, Mobile phase B: Acetonitrile; Gradient (Time / %B): 0 – 3 min (30% B), 3 – 7 (30-55% B), 7 – 12 min (55% B), 12.1 min (100% B); Flow rate: 18 mL / min] followed by achiral-SFC purification [Column: DCPAK P4VP (30 X 250 mm) X 5µ; Isocratic mobile phase: 60 % CO2, 40% of 0.1% DEA in Methanol; Flow rate: 100 mL / min; Back Pressure: 100 bar; Temperature: 30 °C; UV detection: 220 nm] to afford tert-butyl N-[2-[[4-[4-[4-[4-[4- [(3S)-2,6-dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin- 1-yl]pyrazol-1-yl]-6-(2-hydroxyphenyl)pyridazin-3-yl]amino]-2-oxo-ethyl]carbamate 4 (37 mg, 15% yield) as an off white solid. LC-MS (ES+): m / z 835.77 [M+H]+1H NMR (400 MHz, DMSO-d6) δ: 12.14 (brs, 1H), 11.37 (brs, 1H), 10.83 (brs, 1H), 8.85 (brs, 1H), 8.60 (s, 1H), 8.35 (s, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.60 Hz, 1H), 7.20 (brs, 1H), 7.05-7.0 (m, 2H), 6.70-6.66 (m, 2H), 6.49-6.47 (m, 1H), 4.90-4.86 (m, 1H), 4.18- 4.16 (m, 2H), 3.83-3.81 (m, 2H), 3.73 (m, 2H), 3.38-3.37 (m, 2H), 3.19-3.16 (m, 2H), 2.95 (m, 2H), 2.84-2.81 (m, 2H), 2.50 (m, 2H), 2.33-2.29 (m, 1H), 2.10 (m, 1H), 1.95-1.81 (m, 5H), 1.39-1.23 (m, 12H) ppm. Step-3: To a well-stirred solution of tert-butyl N-[2-[[4-[4-[4-[4-[4-[(3S)-2,6-dioxo-3- piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]- 6-(2-hydroxyphenyl)pyridazin-3-yl]amino]-2-oxo-ethyl]carbamate 4 (30 mg, 0.035 mmol) in DCM (2 mL) cooled to 0 °C was added a 4.0 M HCl solution in 1,4-dioxane (0.2 mL, 0.8 mmol). The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 1 hr, at which time the reaction mixture was concentrated under reduced pressure, triturated with diethyl ether (3 mL), and lyophilized to afford 2-amino-N-[4-[4-[4-[4-[4-[(3S)-2,6-dioxo- 3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1- yl]-6-(2-hydroxyphenyl)pyridazin-3-yl]acetamide hydrochloride (Compound 21-HCl) (19.5 mg, 65% yield, Hydrochloric acid salt) as an off white solid. LC-MS (ES+): m / z 735.49 [M+H]+1H NMR (400 MHz, DMSO-d6) δ: 11.51 (brs, 1H), 11.47 (s, 1H), 10.83 (s, 1H), 8.91 (m, 1H), 8.63 (s, 1H), 8.35 (m, 1H), 8.16 (s, 2H), 8.05 (d, J = 7.2 Hz, 1H), 7.41 (t, J = 7.20 Hz, 1H), 7.07-7.01 (m, 2H), 6.68 (m, 2H), 6.47 (t, J = 4 Hz, 1H), 4.91-4.87 (m, 1H), 4.24-4.18 (m, 4H), 4.0-3.99 (m, 3H), 3.57 (m, 1H), 3.24-3.17 (m, 3H), 2.88-2.80 (m, 3H), 2.55 (m, 2H), 2.36- 2.27 (m, 3H), 2.10 (s, 1H), 1.90-1.89 (m, 5H), 1.50 (m, 2H) ppm. Example 26: 1-(((4-(4-(4-((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2- hydroxyphenyl)pyridazin-3-yl)carbamoyl)oxy)ethyl isobutyrate (Compound 22)

[0022] Step 1: To a stirred solution of 4-nitrophenol 2 (1 equiv) in dichloromethane cooled to -10 °C is added pyridine (1.2 equiv) and 2-chloropropanoyl chloride 1 (1.2 equiv). The resulting reaction mixture is allowed to warm to room temperature and stirred for 1 hour. The resulting reaction mixture is diluted with dichloromethane, then washed sequentially with sodium bicarbonate and brine solution. The combined organic layers are dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford (4-nitrophenyl) 2- chloropropanoate 3. Step 2: To a stirred solution of (4-nitrophenyl) 2-chloropropanoate 3 (1 equiv) in 2- methylpropanoic acid 4 (2 equiv) is added silver oxide (1 equiv) and the resulting reaction mixture is heated to 90 °C and stirred for 4 hours. The resulting reaction mixture is diluted with dichloromethane, then washed sequentially with sodium bicarbonate and brine solution. The combined organic layers are dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford [1-methyl-2-(4-nitrophenoxy)-2-oxo-ethyl] 2- methylpropanoate 5. Step 3: In an oven-dried microwave vial equipped with a magnetic stir bar is added tert-butyl 4-(1-(3-amino-6-(2-(benzyloxy)phenyl)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazine-1- carboxylate 6 (1 equiv), [1-methyl-2-(4-nitrophenoxy)-2-oxo-ethyl] 2-methylpropanoate 5 (1.2 equiv), and DIPEA (2 equiv). The resulting mixture is dissolved in N,N- dimethylformamide, and the microwave vial is sealed with a crimp-top cap. The resulting reaction mixture is subjected to microwave heating at 120 °C under vigorous stirring for 1 hour, and the resulting reaction mixture is concentrated under reduced pressure to provide a residue, which is purified by flash normal phase column chromatography to afford tert-butyl 4-(1-(6-(2-(benzyloxy)phenyl)-3-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)pyridazin-4- yl)-1H-pyrazol-4-yl)-3-oxopiperazine-1-carboxylate 7. Step 4: To an oven-dried round-bottom flask is containing tert-butyl 4-(1-(6-(2- (benzyloxy)phenyl)-3-(((1-(isobutyryloxy)ethoxy)carbonyl)amino)pyridazin-4-yl)-1H- pyrazol-4-yl)-3-oxopiperazine-1-carboxylate 7 (1 equiv) is added Pd / C (0.1 equiv). The resulting mixture is suspended in anhydrous tetrahydrofuran, then hydrogen gas is bubbled through the reaction mixture for 15 minutes. Subsequently, the reaction mixture is allowed to stir for 16 hours at room temperature under a hydrogen atmosphere. Then the reaction mixture is passed through a pad of celite, and the celite bed washed with ethyl acetate three times. The filtrate is then diluted with water and extracted with ethyl acetate three times. The combined organic layers are washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a residue, which is purified by normal phase flash chromatography to afford tert-butyl 4-(1-(6-(2-hydroxyphenyl)-3-(((1- (isobutyryloxy)ethoxy)carbonyl)amino)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazine-1- carboxylate. Step 5: To a round-bottom flask is added tert-butyl 4-(1-(6-(2-hydroxyphenyl)-3-(((1- (isobutyryloxy)ethoxy)carbonyl)amino)pyridazin-4-yl)-1H-pyrazol-4-yl)-3-oxopiperazine-1- carboxylate (1 equiv) and cooled to 0 °C. Then a 4 N solution of HCl in 1,4-dioxane is added, and the resulting mixture is warmed to room temperature and stirred for 1 hour. The resulting mixture is concentrated under reduced pressure to afford benzyl (2-((6-(2-hydroxyphenyl)-4- (4-(2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)pyridazin-3-yl)amino)-2-oxoethyl)carbamate hydrochloride 8. Step 6: To a stirred solution of benzyl (2-((6-(2-hydroxyphenyl)-4-(4-(2-oxopiperazin-1-yl)- 1H-pyrazol-1-yl)pyridazin-3-yl)amino)-2-oxoethyl)carbamate hydrochloride 8 (1 equiv) and (3R)-3-[8-(4-oxocyclohexyl)-2,3-dihydro-1,4-benzoxazin-4-yl]piperidine-2,6-dione 1B-13 (1.3 equiv) in dimethyl sulfoxide is added 4 Å molecular sieves (1 equiv). Then acetic acid (5 equiv) is added, and the resulting reaction mixture stirred at room temperature for 8 hours. The resulting reaction mixture is cooled to 0 °C, then MP-cyanoborohydride (2 equiv) is added portion-wise. The resulting reaction mixture is allowed to slowly warm to room temperature while vigorously stirring for over 12 hours. The resulting suspension is filtered through a Buchner funnel, and the filter cake washed with a 1:1 mixture of 1,2-dichloroethane and methanol. The filtrate is concentrated under reduced pressure, and the resulting residue diluted with dichloromethane and stirred for 10 minutes. The resulting suspension is filtered through a Buchner funnel, and the filter cake collected to afford 1-(((4-(4-(4-(4-(4-((S)-2,6- dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin- 1-yl)-1H-pyrazol-1-yl)-6-(2-hydroxyphenyl)pyridazin-3-yl)carbamoyl)oxy)ethyl isobutyrate 9. Step 7: The mixture of diastereomers of 1-(((4-(4-(4-(4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6- (2-hydroxyphenyl)pyridazin-3-yl)carbamoyl)oxy)ethyl isobutyrate 9 is purified by SFC chromatography. The early eluting peak is collected and lyophilized to afford 1-(((4-(4-(4- ((1S,4r)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8- yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2-hydroxyphenyl)pyridazin-3- yl)carbamoyl)oxy)ethyl isobutyrate. The late eluting isomer is collected and lyophilized to afford 1-(((4-(4-(4-((1R,4s)-4-(4-((S)-2,6-dioxopiperidin-3-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-8-yl)cyclohexyl)-2-oxopiperazin-1-yl)-1H-pyrazol-1-yl)-6-(2- hydroxyphenyl)pyridazin-3-yl)carbamoyl)oxy)ethyl isobutyrate (Compound 22). Example 27: Synthesis of [2-[6-amino-5-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3- dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]pyridazin-3- yl]phenyl] dihydrogen phosphate (Compound 2) Step 1: A 1 L three-necked round bottomed flask was equipped with a magnetic stirbar and an internal thermometer. 200 mL of THF was added, followed by Compound 1 (10 g, 14.39 mmol, 1 equiv.) and bis(1,1-dimethylethyl) N,N-diethylphosphoramidite (7.89 g, 31.65 mmol, 2.2 equiv.) at 25 °C. The resulting reaction mixture was stirred at 25 °C as measured by internal thermometer for 10 min, at which point the reaction mixture was cooled to an internal temperature of 0 – 5 °C. Then 5-benzylthio-1H-tetrazole (8.30 g, 43.16 mmol, 3 equiv.) was added at 0 – 5 °C, and the resulting reaction mixture was stirred at the same temperature for 2.5 h. After this time a solution of iodine (7.30 g, 28.77 mmol, 5.80 mL, 2 equiv.) in a mixture of water (37 mL) and THF (75 mL) was added dropwise to the reaction mixture at 0 – 5 °C. The resulting reaction mixture was allowed to warm to an internal temperature of 25 °C and stirred for 12 h, at which point the reaction was monitored by LCMS. The reaction mixture was then cooled to an internal temperature of 0 – 5 °C and diluted with water (1 L) and a saturated aqueous solution of sodium sulfite (30 mL). The resulting reaction mixture was stirred at the same temperature for 1 h, at which time the resulting suspension was filtered. The filter cake was washed with water (57 mL, 3X) and then dried in vacuo to provide a crude mixture of Compound 23 (14.9 g, crude, 58% purity, 23% of BTT) as a light brown solid.10 g of the crude solid was purified by preparative HPLC (column: Kromasil Eternity XT 250 x 80mm x 10um; mobile phase A: H2O modified with 10mM NH4HCO3, mobile phase B: ACN; gradient:15%-40% B over 20.0 min). The collected fractions of pure material were dewatered using a TELEDYNE ISCO CombiFlashRf150 (column: 330g YMC-Triart PrepC18-S20 μm; 120 Å.; eluent MeCN then MeOH) to provide 3 fractions of pure product. The first fraction was eluted in 2.5 L MeCN, and was concentrated in vacuo (35°C) to afford Compound 23 (975 mg, 1.16 mmol, 97.1% purity) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 10.84 (s, 1H), 9.04 (br s, 1H), 8.49 (br s, 1H), 8.16 (br d, J = 7.2 Hz, 1H), 7.86 (br d, J = 7.4 Hz, 1H), 7.50 (br d, J = 8.2 Hz, 1H), 7.37 - 7.37 (m, 1H), 7.44 - 7.31 (m, 3H), 7.18 (br t, J = 7.2 Hz, 1H), 6.74 - 6.65 (m, 2H), 6.48 (br dd, J = 3.4, 5.4 Hz, 1H), 4.90 (br dd, J = 4.6, 12.6 Hz, 1H), 4.18 (br s, 2H), 3.87 (br s, 2H), 3.30 - 3.15 (m, 4H), 2.95 - 2.66 (m, 4H), 2.58 (br d, J = 16.4 Hz, 2H), 2.38 - 2.24 (m, 1H), 2.08 - 1.97 (m, 2H), 1.94 - 1.75 (m, 3H), 1.45 (br d, J = 5.8 Hz, 4H), 1.31 (s, 9H). The second fraction was eluted in 2.5 L MeCN, and was concentrated in vacuo (35°C) to afford Compound 23 (2.6 g, 3.04 mmol, 95.3% purity) as a white solid.1H NMR (400 MHz, DMSO-d6) δ = 10.83 (s, 1H), 8.96 (s, 1H), 8.36 (s, 1H), 8.02 (br s, 1H), 7.88 (br d, J = 7.4 Hz, 1H), 7.56 - 7.36 (m, 4H), 7.31 - 7.20 (m, 1H), 6.78 - 6.65 (m, 2H), 6.48 (br dd, J = 2.8, 5.8 Hz, 1H), 4.90 (br dd, J = 4.4, 12.6 Hz, 1H), 4.18 (br t, J = 3.8 Hz, 2H), 3.95 (br s, 2H), 3.30 - 3.11 (m, 4H), 3.02 - 2.73 (m, 4H), 2.64 - 2.51 (m, 2H), 2.38 - 2.24 (m, 1H), 2.18 - 2.08 (m, 2H), 1.87 (br dd, J = 6.2, 19.4 Hz, 3H), 1.63 - 1.39 (m, 4H), 1.33 (s, 9H). The final fraction was eluted in 200 mL of MeOH, and was concentrated in vacuo (35°C) to afford Compound 23 (490 mg, 578.00 μmol, 96% purity) as a light yellow solid.1H NMR (400 MHz, DMSO-d6) δ = 10.84 (s, 1H), 8.95 (s, 1H), 8.36 (s, 1H), 8.00 (br s, 1H), 7.89 (br d, J = 7.4 Hz, 1H), 7.53 - 7.35 (m, 4H), 7.32 - 7.20 (m, 1H), 6.74 - 6.65 (m, 2H), 6.48 (br dd, J = 3.0, 5.6 Hz, 1H), 4.90 (br dd, J = 4.6, 12.8 Hz, 1H), 4.18 (br t, J = 4.0 Hz, 2H), 3.96 (br s, 2H), 3.34 - 3.12 (m, 4H), 2.98 - 2.73 (m, 4H), 2.65 - 2.51 (m, 2H), 2.39 - 2.24 (m, 1H), 2.11 (br d, J = 1.4 Hz, 2H), 1.95 - 1.77 (m, 3H), 1.62 - 1.38 (m, 4H), 1.33 (s, 9H). Step 2: A 5 mL round bottom flask was equipped with a magnetic stirbar. Then MeCN (0.5 mL) was added, followed by Compound 23 (100 mg, 116.73 μmol, 1 equiv.) at 25 °C. To this well-stirred mixture was added a 2 N solution of HCl in 1,4-dioxane (466.92 μL, 8 eq.) at 25 °C, and the resulting reaction mixture was stirred for 1 h, at which time the reaction was monitored by LCMS. The reaction mixture was then concentrated in vacuo to afford Compound 2 (80 mg, crude, 95% purity) as an off-white solid. LCMS: RT: 0.402 min, m / z: 758.6 [M+1]+1H NMR (400 MHz, DMSO-d6) δ = 12.84 - 11.70 (m, 1H), 10.82 (s, 1H), 9.08 (s, 1H), 8.77 - 8.51 (m, 1H), 8.48 (d, J = 2.0 Hz, 2H), 7.73 (d, J = 7.4 Hz, 1H), 7.63 - 7.54 (m, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 6.69 (d, J = 4.6 Hz, 2H), 6.47 (t, J = 4.6 Hz, 1H), 4.90 (br dd, J = 4.6, 12.8 Hz, 1H), 4.18 (br t, J = 4.2 Hz, 3H), 4.09 - 3.94 (m, 2H), 3.83 - 3.54 (m, 1H), 3.74 - 3.51 (m, 1H), 3.51 - 3.39 (m, 1H), 3.30 - 3.12 (m, 2H), 2.94 - 2.80 (m, 2H), 2.64 - 2.51 (m, 2H), 2.37 - 2.22 (m, 3H), 1.97 - 1.84 (m, 3H), 1.80 - 1.66 (m, 2H), 1.57 - 1.41 (m, 2H).

[0023] Example 28: Synthesis of (2S)-2-amino-N-[4-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3- dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]-6-(2- hydroxyphenyl)pyridazin-3-yl]-3-methyl-butanamide hydrochloride (Compound 24- HCl) Step-1: To a well-stirred solution of (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid 1 (2 g, 9.21 mmol) in THF (30 mL) cooled to 0 °C was added N-methylmorpholine (1.52 mL, 13.81 mmol) and isobutylchloroformate (1.44 mL, 11.05 mmol). The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 30 min, at which time 1H- benzotriazole 2 (1.10 g, 9.21 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 16 hr, at which time the reaction mixture was filtered, and the filtrate concentrated under reduced pressure to afford the crude product. The crude product was triturated using pet-ether (20 mL) and dried in vacuo to afford tert-butyl N-[(1S)-1- (benzotriazole-1-carbonyl)-2-methyl-propyl]carbamate 3 (1.4 g, 43 % yield) as an off white solid.1H NMR (400 MHz, CDCl3) δ: 8.29 (d, J = 8 Hz, 1H), 8.14 (d, J = 8Hz, 1H), 7.67 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.6Hz, 1H), 5.66 (bs, 1H), 5.30 (m, 1H), 2.47 (m, 1H), 1.45 (s, 9H), 1.17 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H) ppm. Step-2: A solution of Compound 1 (0.1 g, 0.147 mmol) and tert-butyl N-[(1S)-1- (benzotriazole-1-carbonyl)-2-methyl-propyl]carbamate 3 (70 mg, 0.221 mmol) in DMF (2 mL) was heated to 130 °C and stirred for 16 hr. At this time, the reaction mixture was concentrated under reduced pressure to afford the crude product, and the crude product was purified by prep-HPLC [Column: X-SELECT C18 (10 x 250 mm) X 5µm; Mobile phase A: 10 mM Ammonium bicarbonate and NH4OH in water; Mobile Phase B: Acetonitrile; Gradient (Time / %B): 0 – 3 min (40% B), 3 – 7 min (30 – 70 % B), 7 – 10 min (70% B); Flow rate: 7 mL / min] to afford tert-butyl N-[(1S)-1-[[4-[4-[4-[4-[4-[(3S)-2,6-dioxo-3-piperidyl]-2,3- dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]-6-(2- hydroxyphenyl)pyridazin-3-yl]carbamoyl]-2-methyl-propyl]carbamate 4 (17 mg, 13% yield) as an off white solid. LC-MS (ES+): m / z 877.91 [M+H]+Step-3: To a well-stirred solution of tert-butyl N-[(1S)-1-[[4-[4-[4-[4-[4-[(3S)-2,6-dioxo-3- piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1-yl]pyrazol-1-yl]- 6-(2-hydroxyphenyl)pyridazin-3-yl]carbamoyl]-2-methyl-propyl]carbamate 4 (17 mg, 0.019 mmol) in DCM (2 mL) cooled to 0 °C was added 4.0 M HCl solution in 1,4-dioxane (0.2 mL, 0.8 mmol). The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 1 hr, at which time the reaction mixture was concentrated under reduced pressure and triturated with diethyl ether (3 mL) to afford (2S)-2-amino-N-[4-[4-[4-[4-[4-[(3S)-2,6- dioxo-3-piperidyl]-2,3-dihydro-1,4-benzoxazin-8-yl]cyclohexyl]-2-oxo-piperazin-1- yl]pyrazol-1-yl]-6-(2-hydroxyphenyl)pyridazin-3-yl]-3-methyl-butanamide (Compound 24- HCl) (12.3 mg, 73% yield, Hydrochloric acid salt) as an off white solid. LC-MS (ES+): m / z 777.46 [M+H]+1H NMR (400 MHz, DMSO-d6) δ: 11.67 (s, 1H), 11.51 (s, 1H), 10.83 (brs, 1H), 8.88 (s, 1H), 8.59 (s, 1H), 8.26 (s, 1H), 8.17 (s, 2H), 8.05 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 7.20 Hz, 1H), 7.11-6.98 (m, 2H), 6.68 (m, 2H), 6.47 (t, J = 4 Hz, 1H), 4.91-4.87 (m, 1H), 4.23-4.18 (m, 3H), 4.03-3.94 (m, 3H), 3.50 (m, 2H), 3.24-3.17 (m, 3H), 2.88-2.81 (m, 2H), 2.59 - 2.55 (m, 1H), 2.30-2.21 (m, 3H), 1.90-1.89 (m, 3H), 1.86-1.72 (m, 2H), 1.48-1.37 (m, 3H), 1.23 (s, 1H), 1.09-1.08 (m, 3H), 0.9-0.8 (m, 3H) ppm. Table 1. Non-limiting examples of compounds of the present invention

[0024] Example 29: Anti-Tumor Activity in SMARCA4-Mutant A549 Non-Small Cell Lung Cancer Xenograft Model To evaluate the in vivo efficacy effect of Compound 2 in the human SMARCA4- mutant non-small cell lung cancer (NSCLC) tumor setting, female BALB / c nude mice bearing A549 tumor xenografts (WuXI AppTech, Shaghai, China) were treated by oral administration (PO) with a once daily (QD) or twice daily regimen of escalating doses of Compound 2 (15 mg / kg QD, 15 mg / kg BID, 30 mg / kg QD, 30 mg / kg BID, 60 mg / kg QD, 60 mg / kg BID, and 120 mg / kg QD) or vehicle for twenty days. The A549 tumor cells (Catalog no. CCL-185, ATCC, Manassas, Virginia, USA) were maintained in F-12K medium (Catalog no. 21127022, Thermo Fisher Scientific, Waltham, MA, USA) supplemented with 10% fetal bovine serum medium (Catalog no. 26140079, Thermo Fisher Scientific, Waltham, MA, USA) and 1% Penicillin-Streptomycin medium (Thermo Fisher Scientific, Waltham, MA, USA) at 37 °C in an atmosphere of 5% CO2 in air. The tumor cells were routinely sub-cultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. Six- to eight-week old female BALB / c nude mice (Zhejiang Vital River Laboratory Animal Co., LTD., Zhejiang Sheng, China) were inoculated subcutaneously at the right flank with A549 cells (5 x 106) in 0.1 mL of PBS supplemented with Matrigel (PBS:Matrigel = 1:1) for tumor development. Treatments were started when the average tumor volume reached 123 mm3. The number of mice in the vehicle group and each treatment group was six. Prior to the onset of drug treatment (T0), mice were measured for tumor size in two dimensions using a caliper, and the tumor volume (mm3) was calculated using formula V = 0.5 a × b2 where a and b are the long and short diameters of the tumor in mm, respectively. Mice were randomized into different treatment groups based on the tumor volume. Mouse body weight was also measured on T0. Compound 2 was formulated in 10% DMSO + 30% Solutol + 60% (23% SBE-β-CD in ddH2O), which was also used as the vehicle control. Tumor size and body weight were measured twice weekly in the same fashion as was done on T0. The study end point was Day 20. Statistical analysis was performed using an unpaired two-tailed t-test analysis on Day 20 tumor volumes. Data are expressed as mean tumor volume ± SEM and percent of pre-dosing body weight measured on Day 0 (T0) ± SEM. TGI was calculated for each group using Day 20 tumor volume measurements using the formula: TGI (%) = [1-(Ti-T0) / (Ci-C0)] ×100; where Ti is the average tumor volume of a treatment group on a given day, T0 is the average tumor volume of the treatment group on the day of treatment start, Ciis the average tumor volume of the vehicle control group on the same day as Ti, and C0 is the average tumor volume of the vehicle group on the day of treatment start. TGI and t-test analyses were performed on Day 20, the last day all animals were on study. The resulting data are shown in Figures 1 and 2 and Table 2. Table 2. Tumor Growth Inhibition (TGI) of A549 xenograft tumors with Compound 2 treatment. Compound 2 was well tolerated in this study. The 60 mg / kg BID group was the only Compound 2-treated group with a negative mean bodyweight change greater than 1% with a maximum mean body weight loss of 5.7% on Day 20 (Figure 2). Compound 2 was efficacious in the A549 xenograft model with dose-dependent efficacy observed (Table 2). Tumor growth inhibition (TGI) was 72% (P < 0.0001) and 60% (P=0.0001) for doses 60 mg / kg BID and 120 mg / kg BID, respectively. Example 30: Anti-Tumor Activity in the SMARCA4-Null NSCLC Patient Derived Xenograft Model LU6437 To evaluate the in vivo efficacy effect of Compound 2 in the human SMARCA4- mutant NSCLC tumor setting, BALB / c nude female mice bearing NSCLC patient-derived tumor xenografts (Crown Bioscience, Beijing, China) were treated with a once daily (QD) or twice daily (BID) regimen of escalating doses of Compound 2 (30 mg / kg QD, 30 mg / kg BID, and 60 mg / kg BID) or vehicle via oral gavage for twenty-one days (vehicle) or twenty-eight days (Compound 2 treatment). Human NSCLC patient derived xenograft tumor model LU6437 tumor fragments were harvested from stock mice and used for inoculation of study mice. Six- to nine-week old female BALB / c nude mice (GemPharmatech Co., Ltd, Nanjing, China) were inoculated subcutaneously at the right flank with LU6437 tumor fragments (2-3 mm in diameter) for tumor development. Treatments were started when the average tumor volume reached 120 mm3. The number of mice in the vehicle group and each treatment group was six. Prior to the onset of drug treatment (T0), mice were measured for tumor size in two dimensions using a caliper, and the tumor volume (mm3) was calculated using formula V = (L x W x W) / 2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L). Mice were randomized into the different treatment groups when the mean tumor size reached approximately 100 mm3. Randomization was performed based on “Matched distribution” method (Study DirectorTMsoftware, version 3.1.399.19). The date of randomization was denoted as Day 0. Mouse body weight was also measured on T0. Compound 2 was formulated in 10% DMSO + 30% Solutol + 60% (23% SBE-β-CD in ddH2O), which was also used as the vehicle control. Tumor size and body weight were measured twice weekly in the same fashion as was done on T0. The study end point was Day 28, but vehicle-treated mice were euthanized on Day 21. Statistical analysis was performed using an unpaired two-tailed t-test analysis on Day 21 tumor volumes. Data are expressed as mean tumor volume ± SEM and percent of pre-dosing body weight measured on Day 0 (T0) ± SEM. TGI was calculated for each group using Day 21 tumor volume measurements using the formula: TGI (%) = [1-(Ti-T0) / (Ci-C0)] ×100; where Ti is the average tumor volume of a treatment group on a given day, T0is the average tumor volume of the treatment group on the day of treatment start, Ciis the average tumor volume of the vehicle control group on the same day as Ti, and C0 is the average tumor volume of the vehicle group on the day of treatment start. TGI and t-test analyses were performed on Day 21, the last day vehicle group animals were on study. The resulting data are shown in Figures 3 and 4 and Table 3. Table 3. Tumor Growth Inhibition (TGI) of NSCLC PDX LU6437 tumors with Compound 2 treatment Compound 2 was well tolerated in this study (Figure 4). Compound 2 was efficacious in this NSCLC PDX model with significant efficacy observed at all doses. Tumor growth inhibition (TGI) was 71% (P < 0.0001), 75% (P < 0.0001), and 70% (P < 0.0001) for doses 30 mg / kg QD, 30 mg / kg BID, and 60 mg / kg BID, respectively. Example 31: Pharmacokinetics in Rodents The pharmacokinetics(PK) profile in plasma of Compound 2 and Compound 12 of the present invention and Compound 1 were determined in male CD1 mice or Sprague Dawley (SD) rats following single dose oral administration (PO) at 10 mg / kg for all three compounds in both mice and rats, 30 mg / kg and 100 mg / kg for Compound 2 and Compound 12 in mice, and 30 mg / kg, 100 mg / kg, and 300 mg / kg for Compound 2 in rats. This study was performed under non-GLP conditions, and unless otherwise stated, all analytical reagents were standard laboratory reagent grade. Normal healthy animals certified by the attending veterinarian were selected and acclimatized for a minimum of three days prior to initiation of study. Animals are identified with body markings. Animals were housed in cages with clean bedding, and maintained and monitored for good health in accordance with test facility standard operating procedures and at the discretion of the laboratory animal veterinarian. Certified rodent diet was provided, and water was made available ad libitum. Periodic analysis of the water was performed, and the results archived. Environmental controls for the animal room were set to maintain a temperature of 22 to 25 °C, humidity of 40-70% relative humidity and a 12-hour light / 12-hour dark cycle. Animals were fasted 10-12 hours prior to dosing, and fed 2 hours post dose. Formulations used in these PK experiments were as follows: (a) for Compound 1 in both mice and rats, 10% DMSO / 30% solutol / 60% (23% sulfobutylether-^-cyclodextrin) (SBECD, Captisol®, CyDex Pharmaceuticals, Inc., San Diego, CA), in water; (b) for Compound 2, the formulation used in mice at all doses tested was 10% DMSO / 30% solutol, / 60% (23% SBECD), and the formulation used in rats at all doses tested was d-α- tocopheryl polyethylene glycol 1000 succinate (VETPGS) (10%v / v) + 25%w / v (2- hydroxypropyl)-ß-cyclodextrin (HP-β-CD) in 50mM pH 6.8 phosphate buffer 90%v / v), final pH 5.41; and (c) for Compound 12 the formulation used in mice at all doses tested was VETPGS:25%HP-β-CD in 50mM pH6.8 phosphate buffer (1 / 9,v / v), final pH ~7, and the formulation used in rats was.10% DMSO / 30% solutol, / 60% (23% SBECD) The formulations were kept for sonification for twenty minutes with intermittent stirring. Formulations were freshly prepared on the day of dosing and stored at room temperature until used. All animals were weighed prior to drug administration, and the standard weight of the CD1 mice used was 30 grams and of SD rat was 300 grams. The animals were dosed orally (PO) using a gastric gavage needle, with 3 animals in each dose group. The dosing volume was 5 mL / kg body weight, and the animals were in fasted stated during the study. Using aseptic techniques, whole blood was collected from the saphenous vein (serial sampling) of each animal for plasma isolation at pre-dose (0.00 hours), and 0.25, 0.50, 1, 2, 4, 6, 8, and 24 hour timepoints . The back of the hind leg is shaved until the saphenous vein is visible. The animal was restrained, hind limb immobilized, and slight pressure was applied gently above the knee joint. The vein was punctured using a 20 G needle and the required (~30 µL) volume of blood was collected in pre-labeled pre-chilled tubes. After blood collection from each animal, the time of collection was documented in the sample collection sheet. The anti-coagulant solution used was 6% (v / v) Sodium citrate (200 mM, pH 4.79). After collection of blood samples at each time point, the blood samples was stored on ice, prior to centrifugation. Blood samples were centrifuged within half an hour of collection to separate plasma. Centrifugation was conducted at 2500 x g for 15 minutes at 4 °C. For sample preparation, 5 µl of each plasma sample was precipitated with 150 µl of acetonitrile containing internal standard (Telmisartan, 50 ng / mL). Samples were vortexed at 1000 rpm and centrifuged for 10 minutes at 4000 rpm.120 µl of supernatant was transferred to 96-well plate and analyzed using LC-MS / MS. For sample dilution, 2 µl of sample was diluted with 18 µl of blank plasma. After vortexing, 5 µl was aliquoted from the sample and regular processing procedures continued. A 10X dilution factor was applied to diluted samples while processing. Samples were analyzed by Sciex ExionLC AD (AB Sciex LLC, Framingham, MA) high- pressure liquid chromatography (HPLC) system followed by tandem mass spectroscopy analysis (MS / MS) with SCIEX Triple Quad™ 6500 (AB Sciex LLC, Framingham, MA). The samples were resolved on a Kinetex®(Phenomenex, Inc., Torrance, CA) 5 µm C18 100Å, 50*4.6 mm column. 10 mM ammonium acetate and 0.1% formic acid in Milli-Q®water (EMD Millipore, Burlington, MA) was used as an aqueous (A) mobile phase and acetonitrile as an organic (B) mobile phase. The flow rate was set at 0.8 mL / min. The LC gradient program included initial conditions of 80% A, with switch to 20% A at 0.8 min., and hold until 2.5 min before returning to initial conditions of 80% A at 2.1 min. with a hold until 3.0 min at 80% A. A positive electrospray ionization (ESI) method was used for detecting the analytes and internal standard by mass spectroscopy. The MRM conditions for Compound 2 and Compound 12 were Q1 m / z of 758.3, Q3 m / z 432.0, declustering potential (DP) 200 V, collision energy (CE) 57 eV, and Collision Cell Exit Potential (CXP) 12. The MRM conditions for Compound 1 were Q1 m / z 678.5, Q3 m / z 390.2, DP 200 V and CE of 46 eV, and Collision Cell Exit Potential (CXP) 12. Other MS / MS conditions included Collision Gas (CAD) medium, Curtain Gas (CUR) 45, Ion spray voltage (V) 5500, Temperature (TEM) 550, GS150, and GS2 55. Pharmacokinetic parameters were calculated for individual animals by non- compartmental model with Phoenix software version 8.1. The pharmacokinetic parameters calculated include: Cmax, which is maximum concentration; tmax, which is time until maximum concentration; ; thalf, which is half-life; tlast, which is time until last measurable time; MRTlast, which is mean residence time until last measurable time; AUClast, which is area under the curve until last measurable time; AUCinf, which is area under the curve until infinity; and F is fraction absorbed (bioavailability). The results are shown in Tables 4-6 below. Table 4. PK Parameters Following 10 mg / kg Dosing in Male CD-1 Mice and SD Rats “--” means not calculated. Table 5. PK Parameters Following 30 mg / kg & 100 mg / kg Dosing in Male CD-1 Mice “--” means not calculated. Table 6. PK Parameters Following 30 mg / kg, 100 mg / kg & 300 mg / kg Dosing in Male SD Rats Example 32: SMARCA2 HiBiT and SMARCA4 HiBiT degradation assay (cellular) To generate A549 and HT1080 cell lines stably expressing SMARCA2 HiBiT or SMARCA4 HiBiT for the quantitative cellular degradation of the target protein degradation mediated by the compounds of the invention, HiBiT was appendant to the gene sequence of the targeted proteins, SMARCA2 in A549 SMARCA4-deficient parental cell line or SMARCA2 or SMARCA4, in HT1080 SMARCA4 wild-type parental cell line using CRISPR- mediate HiBiT tagging technology, as described by Promega. RNA complexes were assembled and delivered by electroporation into cells, as previously described. Specifically, 16 ng (100 pmol) Cas9 and 10.8 ng of sgRNA were incubated for 10-15 minutes at room temperature. Cells were resuspended in 20 L of SF 4D- nucleofector solution (Amaxa SF cell line4D Nucleofector X kit (Lonza, #V4XC-2032). RNA complex and 16.6 pmol of DNA oligo were electroporated into cells using FF-113 program (Amaxa 4D Nucleofector). Following electroporation, cells were incubated at room temperature for 5 minutes and then transferred to a six-well plate for culturing. At 24−48 h postelectroporation, cells were analyzed for insertion with Nano-Glo® HiBiT Lytic Detection System. Nano-Glo®HiBiT Lytic Detection System was used to assess luminescence for each guide RNA tested (ACS Chem. Biol.2018, 13, 467−474). Unedited cells were used as negative control for background. Following successful detection of the HiBiT luminescence signal in the pool, the pool of cells was subjected for single cell sorting (SH800S Cell Sorter, Sony Biotechnology). Only clones that gave the highest HiBiT luminescence signal were further expanded in cell culture and were used in the SMARCA2 HiBiT and SMARCA4 HiBiT degradation assay (cellular). SMARCA2 HiBiT and SMARCA4 HiBiT HT1080 (referred to here as HT1080.1 and HT1080.2, respectively) and SMARCA2 HiBiT A549 (referred to here as A549.5) cell lines were generated in house as described herein. The HT1080 parental cell line, as well as SMARCA2 HiBiT HT1080 and SMARCA4 HiBiT HT1080 cell lines were routinely cultured up to passage 25 in the following medium: Earle`s MEM (Gibco, #41090) with Earle’s salts containing 10% serum (Thermo Fisher, 10437036) and 5 mM L-glutamine (Corning, # 10- 010-CV). A549 SMARCA2 HiBiT cells were grown in DMEM (Thermo Fisher, #21063045) with 10% FBS also only up to passage 25. Assay plates used were Corning®384-well Flat Clear Bottom White Polystyrene TC-treated Microplates (Corning, #3765). Cells for lysed in Nano-Glo® HiBiT Lytic Reagent, Nano-Glo®HiBiT Lytic Detection System, Promega, (#N3050). To conduct the SMARCA2 HiBiT and SMARCA4 HiBiT degradation assays, a day before compound treatment, cells were seeded onto 384- well plates in medium. A549.5 cells were seeded at 4000 cells per well in RPMI no phenol red (Thermo Fisher, #11835030) with 10% FBS. HT1080.1 or HT1080.2 cells were seeded in Earle’s MEM with no phenol red and Earle’s salts and 10% FBS. HT1080 cells were seeded at a density of 2500 cells for HiBiT- tagged SMARCA2 (HT1080.1) and 5000 cells for HiBiT-tagged SMARCA4 (HT1080.2). The following day, Compound 1 was added to the 384-well plate from a top concentration of 10 μΜ with 11 points, half log titration in duplicates. Additionally, the negative control cells were treated with vehicle alone. The plates were incubated at 37 °C with 5% CO2 for duration of the assay (6 hours). After the desired incubation time, cells were lysed by addition of Nano-Glo®HiBiT Lytic Reagent (prepared according to the manufacture recommendations and added to the cells in ratio 1:1, v / v). Microplates were incubated for ten minutes at room temperature. Finally, the luminescence signal was acquired on an Envision Multimode Plate Reader (Perkin Elmer, #2104-0010). Quantification of luminescence responses measured in the presence of compound were normalized to a high signal / no degradation control (untreated cells + lytic detection reagent) and a low signal / full degradation control (untreated cells, no lytic detection reagent). Data were analyzed with a 4-parameter logistic fit to generate sigmoidal dose-response curves that minimized the root mean squared error between observed and calculated values. The DC50 is the concentration of compound at which exactly 50% of the total cellular SMARCA2 or SMARCA4 has been degraded. The Emax, or maximum effect of each compound, represents the amount of residual protein remaining in the cell following compound treatment. As used in Tables 7-9 below, IP refers to the inflection point. Table 7. HiBiT-Degradation (A549.5 SMARCA2, 6 hours) Table 8. HiBiT-Degradation (HT1080.1 SMARCA2, 6 hours) Table 9. HiBiT-Degradation (HT1080.2 SMARCA4, 6 hours) All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teaching of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the invention as defined in the appended claims. Additionally, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the present application.

Claims

CLAIMS We claim:or a pharmaceutically acceptable salt thereof, wherein: R1is –C(O)R4, –(CHR16)OC(O)R4, –C(O)NR6R7, –P(O)(OR6)(OR7), –CH2–O–P(O)(OR6)(OR7), –P(O)(OR5)(NR6R7), or –CH2–O–P(O)(OR5)(NR6R7); or R1is –CH(R20)–O–P(O)(OR6)(OR7); R20is C1-C6alkyl; R4is C1-C6alkyl, –OR15, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, or –O–CH2CH2–S–S–C1-C6alkyl; each of which is optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9,–OC(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and – C(O)OR5; R5and R6are independently hydrogen or C1-C6alkyl; R7is hydrogen or C1-C6alkyl; R8is hydrogen, C1-C6alkyl, or –C(O)R10; R9is hydrogen or C1-C6alkyl; R10is C1-C6alkyl or a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; R11is C1-C6alkyl or a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; each of which is optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9and a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms; R15is hydrogen or C1-C6alkyl; R16is hydrogen, methyl, ethyl, propyl or isopropyl; R2is –P(O)(OR6)(OR7), –CH2–O–P(O)(OR6)(OR7), –C(O)R12, –(CHR16)OC(O)R4, or –(CHR16)NR8R9; R12is C1-C6alkyl or –O–(CHR16)OC(O)R4each of which is optionally substituted with one or two substituent(s) independently selected from the group consisting of –NR8R9, –O–C(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5; R3is –O–C1-C6alkyl, –O–C(O)R13, –C(O)OR5or a 6-membered heteroaryl or heterocycle with 1 or 2 nitrogen atoms; wherein the 6-membered heteroaryl or heterocycle with 1 or 2 nitrogen atoms is optionally substituted with one substituent selected from the group consisting of –C(O)NR8R9and –C(O)OR5; R13is –(CHR16)NR8bR9, or C1-C6alkyl which is optionally substituted with –C(O)OR5; R8bis hydrogen, C1-C6alkyl, or –C(O)R14; and R14is C1-C6alkyl or –C1-C6alkyl–aryl, each of which is optionally substituted with one or two substituent(s) selected from the group consisting of –NR8R9and –OH.

2. The compound of claim 1, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or claim 2 wherein R1is –C(O)R4, –P(O)(OR6)(OR7), or –CH2–O–P(O)(OR6)(OR7).

4. The compound of claim 1 or claim 2, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 or claim 4, wherein R16is hydrogen.

6. The compound of claim 1 or claim 4, wherein R16is methyl.

7. The compound of claim 1 or claim 4, wherein R16is ethyl.

8. The compound of claim 1 or claim 4, wherein R16is propyl.

9. The compound of claim 1 or claim 4, wherein R16is isopropyl.

10. The compound of claim 1 or claim 2, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 1-10, wherein R4is C1-C6alkyl, –OR15, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, or –O–CH2CH2–S–S–C1-C6alkyl, each of which is optionally substituted with one substituent independently selected from the group consisting of –NR8R9, –OC(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5.

12. The compound of claim 11, wherein R4is substituted with –OC(O)R11.

13. The compound of claim 12, wherein R11is C1-C6alkyl optionally substituted with one substituent independently selected from group consisting of –NR8R9and a 4-, 5-, or 6- membered heterocycle with 1 or 2 nitrogen or oxygen atoms.

14. The compound of claim 12, wherein R11is or a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms optionally substituted with one substituent independently selected from group consisting of –NR8R9and a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms.

15. The compound of claim 11, wherein R4is substituted with NR8R9.

16. The compound of any one of claims 11-15, wherein R8is hydrogen.

17. The compound of any one of claims 11-15, wherein R8is C1-C6alkyl.

18. The compound of any one of claims 11-15, wherein R8is methyl.

19. The compound of any one of claims 11-15, wherein R8is –C(O)R10.

20. The compound of claim 19, wherein R10is C1-C6alkyl.

21. The compound of claim 19, wherein R10is a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms.

22. The compound of claim 19, wherein R10is .

23. The compound of any one of claims 11-22, wherein R9is hydrogen.

24. The compound of any one of claims 11-22, wherein R9is C1-C6alkyl.

25. The compound of any one of claims 11-22, wherein R9is methyl.

26. The compound of claim 11, wherein R4is substituted with a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms.

27. The compound of claim 11, wherein R4is substituted with –C(O)OR5.

28. The compound of claim 11, wherein R4is not substituted.

29. The compound of any one of claims 1-28, wherein R4is C1-C6alkyl.

30. The compound of any one of claims 1-28, wherein R4is –OR15.

31. The compound of claim 30, wherein R15is hydrogen or methyl.

32. The compound of any one of claims 1-28, wherein R4is a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms.

33. The compound of any one of claims 1-28, wherein R4is –O–CH2CH2–S–S–C1-C6alkyl.

35. The compound of claim 1 or claim 2 wherein R1is –P(O)(OR5)(NR6R7).

36. The compound of claim 1 or claim 2 wherein R1is –CH2–O–P(O)(OR5)(NR6R7).

37. The compound of claim 35 or claim 36, wherein R5is hydrogen.

38. The compound of claim 35 or claim 36, wherein R5is methyl.

39. The compound of claim 1 or claim 2, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

40. The compound of claim 1 or claim 2 wherein R1is –P(O)(OR6)(OR7).

41. The compound of claim 1 or claim 2 wherein R1is –CH2–O–P(O)(OR6)(OR7).

42. The compound of claim 1 or claim 2, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

43. The compound of any one of claims 35-42, wherein R6is hydrogen.

44. The compound of any one of claims 35-42, wherein R6is methyl.

45. The compound of any one of claims 35-44, wherein R7is hydrogen.

46. The compound of any one of claims 35-44, wherein R7is methyl.

47. The compound of claim 1, wherein the compound isor a pharmaceutically acceptable salt thereof.

48. The compound of claim 1, wherein the compound is:or a pharmaceutically acceptable salt thereof.

49. The compound of claim 1, wherein the compound is:or a pharmaceutically acceptable salt thereof.

50. The compound of claim 1, wherein the compound is:or a pharmaceutically acceptable salt thereof.

51. The compound of claim 1, wherein the compound is:or a pharmaceutically acceptable salt thereof.

52. A compound of structure:or a pharmaceutically acceptable salt thereof.

53. The compound of claim 1, wherein the compound is:or a pharmaceutically acceptable salt thereof.

54. The compound of claim 1, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

55. The compound of claim 1 or claim 54, wherein R2is –C(O)R12.

56. The compound of claim 1 or claim 54, wherein R2is –P(O)(OR6)(OR7).

57. The compound of claim 1 or claim 54, wherein R2is –CH2–O–P(O)(OR6)(OR7).

58. The compound of claim 54, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

59. The compound of any one of claims 54-58, wherein R6is hydrogen.

60. The compound of any one of claims 54-58, wherein R6is methyl.

61. The compound of any one of claims 54-60, wherein R7is hydrogen.

62. The compound of any one of claims 54-60, wherein R7is methyl.

63. The compound of claim 1 or claim 54, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

64. The compound of claim 63, wherein R12is C1-C6alkyl or –O–(CHR16)OC(O)R4each of which is optionally substituted with one substituent independently selected from the group consisting of –NR8R9, –O–C(O)R11, a 4-, 5-, or 6-membered heterocycle with 1 or 2 nitrogen or oxygen atoms, and –C(O)OR5.

65. The compound of claim 64, wherein R12is substituted with –NR8R9.

66. The compound of claim 1 or claim 54, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

67. The compound of any one of claims 64-66, wherein R8is hydrogen.

68. The compound of any one of claims 64-66, wherein R8is methyl.

69. The compound of any one of claims 64-68, wherein R9is hydrogen.

70. The compound of any one of claims 64-68, wherein R9is methyl.

71. The compound of any one of claims 63-65, wherein R12is –O–(CHR16)OC(O)R4.

72. The compound of claim 1 or claim 54, wherein R2is –(CHR16)OC(O)R4.

73. The compound of any one of claims 71-72, wherein R4is isopropyl.

74. The compound of any one of claims 64-73, wherein R16is hydrogen.

75. The compound of any one of claims 64-73, wherein R16is methyl.

76. The compound of any one of claims 64-73, wherein R16is ethyl.

77. The compound of any one of claims 64-73, wherein R16is propyl.

78. The compound of any one of claims 64-73, wherein R16is isopropyl.

79. The compound of any one of claims 63-65, wherein R12is C1-C6alkyl.

80. The compound of any one of claims 63-65, wherein R12is or.

81. The compound of claim 1, wherein the compound is:or a pharmaceutically acceptable salt thereof.

82. The compound of claim 1, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

83. The compound of claim 1 or claim 82, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

84. The compound of claim 1 or claim 82, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

85. The compound of claim 1 or claim 82, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

86. The compound of claim 1 or claim 82, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

87. The compound of claim 1 or claim 82, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

88. The compound of claim 87, wherein the compound is:.

89. The compound of claim 1 or claim 82, wherein the compound is of Formula:or a pharmaceutically acceptable salt thereof.

90. The compound of claim 89, wherein the compound is:or a pharmaceutically acceptable salt thereof.

91. A pharmaceutical composition comprising a compound of any one of claims 1 to 90, or a pharmaceutically acceptable salt thereof, and a therapeutically acceptable excipient.

92. A method of treating a patient with a SMARCA2- or SMARCA4-mediated disorder, comprising administering an effective amount of a compound of any one of claims 1-90, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition.

93. The method of claim 92, wherein the patient is a human.

94. The method of claim 92 or claim 93, wherein the SMARCA2- or SMARCA4-mediated disorder is a cancer, tumor, or abnormal cellular proliferation.

95. The method of claim 94, wherein the SMARCA2- or SMARCA4-mediated disorder is a tumor.

96. The method of claim 95, wherein the tumor is a solid tumor.

97. The method of claim 94, wherein the SMARCA2- or SMARCA4-mediated disorder is an abnormal cellular proliferation.

98. The method of claim 94, wherein the SMARCA2- or SMARCA4-mediated disorder is a cancer.

99. The method of claim 98, wherein the cancer is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, 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, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma,skin cancer, small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

100. The method of claim 98 or claim 99, wherein the cancer is hepatocellular cancer.

101. The method of claim 98 or claim 99, wherein the cancer is colon cancer.

102. The method of claim 98 or claim 99, wherein the cancer is breast cancer.

103. The method of claim 98 or claim 99, wherein the cancer is prostate cancer.

104. The method of claim 98 or claim 99, wherein the cancer is melanoma.

105. The method of claim 98 or claim 99, wherein the cancer is ovarian cancer.

106. The method of claim 98 or claim 99, wherein the cancer is medulloblastoma.

107. The method of claim 98 or claim 99, wherein the cancer is non-small cell lung cancer.

108. The method of claim 98 or claim 99, wherein the cancer is bladder cancer.

109. The method of claim 98 or claim 99, wherein the cancer is glioblastoma.

110. The method of any one of claims 92-109, wherein the patient receives an additional therapeutic agent.

111. The method of claim 110, wherein the additional therapeutic agent is a chemotherapeutic agent.

112. Use of a compound of any one of claims 1-90, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament to treat a SMARCA2- or SMARCA4- mediated disorder in a patient.

113. The use of claim 112 wherein the patient is a human.

114. The use of claim 112 or claim 113, wherein the SMARCA2- or SMARCA4- mediated disorder is a cancer, tumor, or abnormal cellular proliferation.

115. The use of claim 114, wherein the SMARCA2- or SMARCA4-mediated disorder is a tumor.

116. The use of claim 115, wherein the tumor is a solid tumor.

117. The use of claim 114, wherein the SMARCA2- or SMARCA4-mediated disorder is an abnormal cellular proliferation.

118. The use of claim 114, wherein the SMARCA2- or SMARCA4-mediated disorder is a cancer.

119. The use of claim 118, wherein the cancer is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocyticleukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, 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, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

120. The use of claim 118 or claim 119, wherein the cancer is hepatocellular cancer.

121. The use of claim 118 or claim 119, wherein the cancer is colon cancer.

122. The use of claim 118 or claim 119, wherein the cancer is breast cancer.

123. The use of claim 118 or claim 119, wherein the cancer is prostate cancer.

124. The use of claim 118 or claim 119, wherein the cancer is melanoma.

125. The use of claim 118 or claim 119, wherein the cancer is ovarian cancer.

126. The use of claim 118 or claim 119, wherein the cancer is medulloblastoma.

127. The use of claim 118 or claim 119, wherein the cancer is non-small cell lung cancer.

128. The use of claim 118 or claim 119, wherein the cancer is bladder cancer.

129. The use of claim 118 or claim 119, wherein the cancer is glioblastoma.

130. The use of any one of claims 112-129, wherein the patient receives an additional therapeutic agent.

131. The use of claim 130, wherein the additional therapeutic agent is a chemotherapeutic agent.

132. A compound according to any one of claims 1-90, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition, for use in the treatment of a SMARCA2- or SMARCA4-mediated disorder in a patient.

133. The compound of claim 132, wherein the patient is a human.

134. The compound of claim 132 or claim 133, wherein the SMARCA2- or SMARCA4- mediated disorder is a cancer, tumor, or abnormal cellular proliferation.

135. The compound of claim 134, wherein the SMARCA2- or SMARCA4-mediated disorder is a tumor.

136. The compound of claim 135, wherein the tumor is a solid tumor.

137. The compound of claim 134, wherein the SMARCA2- or SMARCA4-mediated disorder is an abnormal cellular proliferation.

138. The compound of claim 134, wherein the SMARCA2- or SMARCA4-mediated disorder is a cancer.

139. The compound of claim 138, wherein the cancer is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, liver cancer, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, 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, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, malignant rhabdoid tumor (MRT), rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor.

140. The compound of claim 138 or claim 139, wherein the cancer is hepatocellular cancer.

141. The compound of claim 138 or claim 139, wherein the cancer is colon cancer.

142. The compound of claim 138 or claim 139, wherein the cancer is breast cancer.

143. The compound of claim 138 or claim 139, wherein the cancer is prostate cancer.

144. The compound of claim 138 or claim 139, wherein the cancer is melanoma.

145. The compound of claim 138 or claim 139, wherein the cancer is ovarian cancer.

146. The compound of claim 138 or claim 139, wherein the cancer is medulloblastoma.

147. The compound of claim 138 or claim 139, wherein the cancer is non-small cell lung cancer.

148. The compound of claim 138 or claim 139, wherein the cancer is bladder cancer.

149. The compound of claim 138 or claim 139, wherein the cancer is glioblastoma.

150. The compound of any one of claims 132-149, wherein the patient receives an additional therapeutic agent.

151. The compound of claim 150, wherein the additional therapeutic agent is a chemotherapeutic agent.

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